AU8550701A - Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents - Google Patents

Description

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ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Bayer Aktiengesellschaft D-51368 Leverkusen Germany Bayer Corporation 100 Bayer Road Pittsburgh Pennsylvania 15205 United States of America Address for Service: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Substituted pyridines and biphenyls as antihypercholesterinemic, anti-hyperlipoproteinemic and antihyperglycemic agents Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me:- WO 98/04528 PCT/US97/13248 0 SUBSTITUTED PYRIDINES AND BTPHENYLS AS ANTI-HYPERCHOLESTERINEMIC

ANTI-

HYPERLIPOPROTETNEMIC AND ANTI-HYPERGLYCEMIC

AGENTS

Field This application relates to substituted biaryl compounds which inhibit cholesterol ester transfer proteins (CETPs), stimulate reverse cholesterol transport, and inhibit the action of glucagon.

Background The present invention concerns certain substituted pyridines, processes for the production thereof, and the use thereof in pharmaceutical products. It also concerns certain substituted biphenyls, processes for their production, pharmaceutical compositions containing them, and methods for their use.

7-(polysubstituted pyridyl) hept-6-enoates for the treatment of arteriosclerosis, lipoproteinemia, and hyperlipoproteinemia are known from US 169 857. In addition, the production of 7 4 -aryl-3-pyridyl)-3,5-dihydroxy-hept-6enoate is described in EP 325 130.

Glucagon is a peptide hormone whose main function is to increase hepatic glucose production. Insulin, on the other hand,, functions to decrease glucose production. Together, these two hormones are necessary for maintaining a correct level of glucose in the blood.

Diabetes is a complex disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is also associated with elevated glucagon levels. The heterogeneous nature of the disease requires different strategies to address the different abnormalities in metabolism found in affected individuals.

In the diabetic state (all forms of Type I and Type II), hyperglycemia often is associated with elevated glucagon levels. Accordingly, a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.

Glucagon receptor antagonists, materials which block the action of endogenous glucagon, are known to have many and varied applications. Among these applications are the following: 1 W, "7 WO 98/04528 PCT/US97/13248 0 1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonist can be used either alone or in combination with any other therapies to treat hyperglycemia.

2. Treatment of impaired glucose tolerance (IGT).

3. Treatment of insulin resistance syndromes including those due to obesity, polycystic ovarian syndrome, "Syndrome drugs and hormones, endocrinopathies and genetic syndromes.

4. To decrease free fatty acid levels and treat conditions associated with elevated free fatty acids levels such as insulin resistance, obesity, all or part of Syndrome X, Type I and II diabetes, hyperlipidemias and elevated hepatic glucose output associated with insulin resistance, Type I and Type II diabetes, obesity, and Syndrome X. To treat conditions associated with genetic defects in insulin action due to alterations in insulin receptor structure and function or alterations in post receptor signal transduction. To treat diabetes associated with anti-insulin antibodies, drug induced diabetes, diabetes associated with endocrinopathies and diabetes associated with genetic syndromes.

6. To treat gestational diabetes mellitus.

7. To treat autoimmune and non autoimmune causes of Type I diabetes including those due to known genetic defects of the beta cell, pancreatic diseases, drug or toxin induced beta cell dysfunction, endocrinopathies, infectious causes, malnutrition associated and idiopathic Type I diabetes.

8. To prevent and treat diabetic ketoacidosis and decrease hepatic ketone body production 9. To treat hyperglycemia of exercise in diabetes.

To reduce fasting and postprandial glucose.

11. Treatment of insulin resistance in liver, muscle, and fat.

12. Treatment of conditions of hyperlipidemia.

13. To treat glucagonomas and all other conditions associated with elevated glucagon levels.

14. To treat conditions of increased futile cycling of glucose in the liver.

To increase insulin secretion.

16. To decrease glucose toxicity.

2 WO 98/04528 PCTIUS97/13248 0 17. To decrease the renal prostaglandin response to protein and amino acids.

18. To decrease elevated GFR and albumin clearance due to diabetes or proteins or amino acids.

19. To decrease renal albumin clearance and excretion.

20. To treat acute pancreatitis.

21. To treat cardiovascular disease including causes of increased cardiac contractility.

22. To treat cardiac hypertrophy and its consequences.

23. As a diagnostic agent and as a diagnostic agent to identify patients having a defect in the glucagon receptor.

24. Treatment of gastrointestinal disorders, treatment of decreased gut motility.

As a therapy to increase gastric acid secretions.

26. To reverse intestinal hypomobility due to glucagon administration.

27. To reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of Type I and Type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions.

28. To treat any of the above conditions or diseases in post-operative or operative period.

29. To decrease satiety and increase energy intake.

Glucagon receptor antagonists of the prior art, such as those described in W09518153-A and references cited therein, are predominantly peptide analogues of glucagon. They are susceptible to the actions of endogenous proteases, may precipitate antibody' production and immune reactions and can be difficult and expensive to manufacture. Such peptides are usually unsuitable for oral delivery.

One non-peptide glucagon receptor antagonist has been reported (Collins, et al; BioMed. Chem Lett. 1992,2, 915-918). This quinoxaline derivative, CP-99,711, was shown to inhibit glucagon binding and glucagon action in rat liver membrane at micromolar concentrations.

It would be desirable to have inhibitors of CETP which possess valuable pharmacological properties that are superior to those of the state of the art.

Certain of the substituted pyridine compounds of the invention are highly effective 3 iri~ WO 98/04528 PCT/US97/13248 0 inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. They cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.

It would also be desirable to have readily prepared non-peptidic glucagon receptor antagonists which are metabolically more stable than peptidic antagonists of the prior art, and which afford good activity and bioavailability. Certain of the substituted pyridine compounds as well as the substituted biphenyls of the invention are highly effective inhibitors of the glucagon receptor. Accordingly, these compounds may be used to treat glucagon-mediated conditions such as those listed above.

Summary The present invention concerns substituted biaryl compounds which fall within the three general formulae and (IC) shown below. The definitions of these general formulae are given broadly in the following text. In the subsequent detailed description sections, each of these broad general formulae is discussed in more detail in terms of its preferred and most preferred molecular constituents, procedures for making, examples of particular materials made, testing procedures, and results obtained.

It should be noted that in the text below, and in the subsequent detailed description sections, the definitions of the various constituent and substituent groups apply only to the particular subset of the compounds of the invention then under consideration. The same symbols may have different definitions in connection with the other subsets of compounds.

The present invention concerns substituted pyridines of the general formula

(IA),

A

T

D

(IA)

L N E in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, 4 WO 98/04528 PCTIUS97/13248 0 acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula

-NR

1

R

2 wherein

R

1 and R 2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stand for cycloalkyl with 3 to 8 carbon atoms, or E has the above-mentioned meaning and L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or RM branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR 3

R

4 wherein

R

3 and R 4 are identical or different and have the meaning given above for R1 and R 2 or E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or t WO 98/04528 PCT/US97/13248 0 stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula

-NR

5

R

6 wherein

R

5 and R 6 are identical or different and have the meaning given above for

R

1 and R 2 and L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, T stands for a radical of the formula

R

9 R7-X--

R

8

V

or wherein

R

7 and R8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heterocyclic atoms from the series S, N and/or 0, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula

-NR

1 1

R

12 wherein 6 I 14 -1 .1-111, 15 "I Ir WO 98/04528 PCTIUS9713248

R

1 1 and R 1 2 are identical or different and have the meaning given above for R 1 and R 2 X denotes a straight or branched alkyl chain or alkenyl chain with 2 to carbon atoms each, which are optionally substituted up to 2 times by hydroxy,

R

9 denotes hydrogen, and

R

1 0 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula -NR 1 3

R

1 4 wherein

R

13 and R 1 4 are identical or different and have the meaning given above for R 1 and R 2

R

9 and R 10 form a carbonyl group together with the carbon atom, and the salts thereof.

The present invention also concerns substituted pyridines of general formula

(IB)

R'-E-V-1

,CH

2

OH

(IB)

in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by. halogen, hydroxy, 7 r XI E--~II-~i~-i~i~iiilTC~r*~LI?^~:li-~~C~ri C WO 98/04528 PCT/US97/13248 0 trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula

-NR

2

R

3 and/or

-WR

4 wherein

R

2 and R 3 are the same or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, W denotes an oxygen or sulfur atom,

R

4 denotes aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by (7 halogen, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR 5 wherein

R

5 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl,

R

1 stands for cycloalkyl with 3 to 6 carbon atoms, or stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzocondensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 carbon atoms from the series S, N, and/or 0, 8 4C~il.

WO 98/04528 PCT/US97/13248 0 in which the heterocycles, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member heterocyclic compound with up to 3 heterocyclic atoms from the series S, N, and/or 0, and/or are substituted by a group of the formula -OR 6

-SR

7 -SO2R 8 or -NR9R10, wherein

R

6

R

7 and R 8 are identical or different and denote aryl with 6 to 10 carbon atoms, which in turn is substituted up to 2 times in an identical manner or differently by phenyl or halogen or by straight-chain or branched alkyl with up to 4 carbon atoms,

R

9 and R 10 are identical or different and have the above-indicated meaning of R 2 and R 3 L and T are identical or different and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heterocyclic atoms from the series S, N and/or O, with binding in the case of a nitrogen atom also being possible via this atom, with the heterocycles optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by 9 T-7 WO 98/04528 PCTIUS97/'13248 0 straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, and the salts thereof.

This invention also relates to compounds having glucagon receptor antagonistic activity and the general formula (IC) shown below.

Ar R3 Rib

(IC)

In general formula IC, the groups X, Rla, Rib, R 2

R

3 and Ar have the following meanings: X represents N or CR 8 R8represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (CI-C10)-alkyl, substituted (CI-C1O)-alkyl, (C1-C6)-alkoxy, (C3-C7)- cycloalkyl, phenyl-(Cl-C3)-alkoxy, (C1-C6)-alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or -NR4R5. The substituents on the substituted phenyl or subsitued lky R8groups are from 1 to *3 of, for example, hydroxy, fluoro, (Ci- C6)-alkoxy, (C3-C7)-cycloalkyl, phenyl, phenyl-(Cl-C3)-alkoxy, (Cl-C6)alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or The groups

R

4 and R 5 are independently hydrogen, MC-C6)-alkyl, (C3-C6)alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl(Cl-C 6 )-alkl phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(CI-C 6 ).alkyl, or substituted naphthyl-(Cl-C6)alkyl. The substitutents on the substituted phenyl or substituted naphthyl

R

4 and

R

5 groups are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (Cl-C 4 alkyl, or (C1-C4)-alkoxy groups.

R

4 and R 5 may be joined together to form -(CH2)rA(CH2)s- wherein the subscripts r and s are independently 1 to 3 and A is CHR6, NRO, 0, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-C6)-alkyl, piperidin-1.yl, phenyl, or phenyl-(C1-C6)-alkyl.

IRaand Rib are independently trifluoromethyl, (C1-Clo)-alkyl, substituted (Cl-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-Clo)-alkynyl, WO 98/04528 WO 9804528PCTIUS97/13248 o substituted (C2-Cl0)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (Ci -C6)alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, -and substituted alkynyl R 1 a and Rib groups are independently from 1 to 3 of, for example, -OR 4

-C(O)R

4 -C02R 4

-C(O)NR

4

R

5

-NR

4

R

5 or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (CI-C4)-alkyl, or (Ci-C4)-alkoxy groups.

R

2 is (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 )-alkenyl, substituted

(C

2 -Cl 0 )-alkenyl,

(C

2 -Clo)-alkynyl, substituted (C2-Cl 0 )-alkynyl,

(C

3

C

6 )-cycloalkyl-(Cl-C 6 )-alkyl, or substituted (C3-C 6 )-cycloalkyl-(Cl-C 6 )-alkyl. The substitutents; on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are indepenidently from 1 to 3 of halogen, phenyl, substituted phenyl, i,3-dioxolan-2-yl,

-C(O)NR

4

R

5 or -S(O)mR 7 wherein m is 0, 1, or 2. The substitu ents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (Cl-C 4 )-alkyl, or (Ci-C4)-alkoxy.

R

7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(Ci-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Ci-C6)alkyl, substituted pyridyl-(Ci-C6).alkyl, naphthyl, substituted naphthyl, naohthyl- (Ci-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The 'substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano, or hydroxy.

R

2 and Rib. may be joined to form an alkylene bridge containing from 3 to carbon atoms, between the ring carbon atoms to which R 2 and Rilb are attached.

R

3 is hydroxy, trifluoroacetyl, (Cl-C 6 )-alkanoyl, substituted (C 1

-C

6 -alkyl, or substituted (C 3

-C

6 )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R 3 groups are from 1 to 3 hydroxy ortiloomethyl groups.

Ar is an optionally substituted aromatic or heteroaromatic ring. Examples of possible Ar groups are: phenyls, naphthyls, pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The option-al substitutents on the group Ar are independently 1 to 3 of, for example, halogen, (Cl-C 6 )-alkyl, substituted (Cl-C 6 alkyl, (C 2

-C

6 )-alkenyl, substituted (C2-C 6 )-alkenyl, (C 2

-C

6 )-alkynyl, substituted (C2-C 6 )-alkynyl, (C 3

-C

7 )-cydoalkyl, cyano, nitro, trifluoromethyl, -OR 4

-C(O)R

4

OC(O)R

4 -C02R 4

-NR

4

R

5

-C(O)NR

4 R5, or -S(O)mR 7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR 4

R

5 phenyl, or 11 WO 98/04528 PCT/US97/13248 0 substituted phenyl in which the phenyl group may bear, for example, one or more halogen,

(C

1

-C

4 alkyl, or (C1-C4) alkoxy groups.

Pharmaceutically acceptable salts of these materials are within the scope of the invention.

The invention also relates to a pharmaceutical product containing the substituted pyridines according to general formula (IA) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the inhibition of cholesterol ester transfer proteins, and to the use of the claimed substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of cholesterol ester transfer protein inhibitors.

The invention further relates to a pharmaceutical product containing the substituted pyridines 3 -heteroalkyl-aryl-substituted pyridines according to general formula (IB) and, if appropriate, a pharmacologically tolerable formulation adjuvant. It further relates to such pharmaceutical product for the treatment of hyperlipoproteinemia, and to the use of the claimed substituted pyridines for the production of pharmaceutical products, and to use of the claimed substituted pyridines for the production of pharmaceutical products for the treatment of hyperlipoproteinemia.

The invention also relates to a pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound having glucagon receptor antagonistic activity and a structure within general structural formula

IC,

plus a pharmaceutically acceptable carrier.

The invention further relates to a method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound having glucagon receptor antagonistic activity and a structure within general structural formula

IC.

WO 98/04528 PCT/US97/13248 0 Detailed description with reference to compounds of general formula (IA) The substituted pyridines according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.

Within the context of the present invention, physiologically safe salts are preferred. Physiologically safe salts of the compounds according to the invention can be salts of substances according to the invention with mineral acids, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly preferred.

Physiologically safe salts can also be metallic or ammonium salts of the .compounds according to the invention that possess a free carboxyl group: For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenyl-ethylamine are particularly preferred.

The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not behave like an image and mirror image (diastereomers). The invention concerns both enantiomers or diastereomers or the ihixtures thereof. These mixtures of enantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.

Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 7-member, preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or 0. Indolyl, isoquinolyl, quinolyl, benzothiazolyl, benzo[b]thiophene, benzo[b]furanyl, benzoxazolyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl, or piperidyl are cited as examples. Quinolyl, pyridyl, indolyl, benzothiazolyl, or benzoxazolyl are preferred.

WO 98/04528 PCTIUS9713248 0 Compounds of the general formula (IA) are preferred, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula

-NR

1

R

2 wherein

R

1 and R 2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned'meaning and L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR 3

R

4 WO 98/04528 PCT/US97/13248 0 wherein

R

3 and R 4 are identical or different and have the meaning given above for

R

1 and R 2 or E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR 5

R

6 wherein

R

5 and R 6 are identical or different and have the meaning given above for

R

1 and R 2 and L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula

R

9 Rio

'R

7 -X

R

or wherein

R

7 and R 8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoro-methoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or WO 98/04528 PCT/US97/13248 0 branched alkyl, alkoxy, or alkoxycarbonyl with up to 5 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn by substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, and/or the rings are optionally substituted by a group of the formula -NR11R12, wherein

R

1 1 and R 1 2 are identical or different and have the meaning given above for R 1 and R 2 X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 8 -4 carbon atoms each, which are optionally substituted up to 2 times by hydroxy,

R

9 denotes hydrogen, and

R

1 0 denotes hydrogen, fluorine, chlorine,.bromine, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 4 carbon atoms, or a radical of the formula NR13R14, wherein

R

13 and R 1 4 are identical or different and have the meaning given above for R 1 and R 2 or 0

R

9 and R 1 0 form a carbonyl group together with the carbon atom, and the salts thereof.

16 W- 41FMI, 1 9A 01 or, IIUIT 1 1 IIKAP-W r 4 -I I I F, A WO 98/04528 PCT/US97/13248 0 Compounds of the general formula (IA) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, S 25 trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, or E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, and WO 98/04528 PCT/US97/13248 0 L in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula

R

9

R

10 R-X- or R wherein

R

7 and R 8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote phenyl, pyridyl, quinolyl, indolyl, naphthyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 2 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, X denotes a straight or branched alkyl chain with 2 to 6 carbon atoms each, which are optionally substituted up to 2 times by hydroxy,

R

9 denotes hydrogen, and

R

10 denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms, or

R

9 and R 10 form a carbonyl group together with the carbon atom, and the salts thereof.

18 77M.- 7.gr-77 WO 98/04528 PCT/US97/13248 Compounds according to the invention of the general formula (IA) are most preferred, in which A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl.

Furthermore, a process for the production of compounds according to the invention of the general formula (IA) has been discovered, characterized by the fact that compounds of the general formula (II) or (III)

R

1 in which A, E, L, and T have the above-mentioned meanings, and

R

1 3 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, or, in the case of compounds of the general formula (III), direct reductions are carried out, optionally via several steps.

The compounds according to the invention can be explained, for example, by means of the following reattion diagram: WO 98/04528 PCTIUS97/13248

OHC

6 T F Gdg\nard reactionI

COOCH

3

DAST

LiA\IH4 WO 98/04528 WO 9804528PCT1US97/13248

OHO

CH

3 0 000OC 2

H

C -Oi 'C000 2

H

DIBAL-H\

CH

3 0 -Suitable solvents are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimnethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, o r cyclohexane, or petroleum fractions, or halocarboris, such as dichloromethane, trichioromethane, tetrachioromethane, dichioroethylene, or trichioroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethyiphosphoric triamide, aceton itrile, acetone, or nitromethane. It is likewise possible to use mixtures of said solvents. Dichioromethane is preferred.

WO 98/04528 PCTIUS97/13248 0 Suitable organometallic reagents are systems such as Mg/bromobenzene trifluoride and p-trifluoromethylphenyllithium. The Mg/bromobenzene trifluoride system is preferred.

The reductions and derivatizations are carried out according to the abovementioned methods.

In general, the reductions are carried out in ethers, such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons, such as benzene, hexane, or toluene. Toluene and tetrahydrofuran are preferred.

Suitable reductants are complex metal hydrides, such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride, dimethoxymethylaluminate sodium salt, or sodiumbis-( 2 -methoxyethoxy)-dihydroaluminate (Red-Al). Diisobutyl-aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.

The reductant is generally added in a quantity ranging from 4 moles to moles, preferably from 4 moles to 5 moles, relative to 1 mole of the compound to be reduced.

The reduction generally takes place within a temperature range of -78*C to preferably from -78°C to 0°C, and most preferably at -78°C, depending on the choice of both the reductant and the solvent.

The reduction generally takes place at normal pressure, but it is also possible to.work at increased or reduced pressure.

However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides, such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl borohydride, or lithium aluminum hydride. More particularly preferably, the reduction is carried out using sodium borohydride in the presence of triethylborane.

WO 98/04528 PCT/US97/13248 0 The reaction can also take place via hydrogenation. The hydrogenation takes place according to the customary methods using hydrogen in the presence of noble metal catalysts, such as Pd/C, Pt/C, or Raney nickel in one of the abovementioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20'C to +100'C, preferably from 0°C to +50°C, at normal pressure or elevated pressure.

As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig reactions/Grignard reactions, and amidation/sulfoamidation.

The customary strong basic compounds can be used as auxiliary agents.

Among these are, preferably, organolithium compounds, such as n-butyllithium, sec-butyllithium, tert-butyllithium, or phenyllithium, or amides, such as lithium diisopropylamide, sodium amide, or potassium amide, or -lithium hexamethylsilylamide, or alkali hydrides, such as sodium hydride or potassium hydride. Particularly preferably, n-butyllithium, or sodium hydride are used.

Furthermore, the customary inorganic bases are suitable bases. Among these are, preferably, alkali hydroxides or alkaline earth hydroxides, such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali carbonates, such as sodium carbonate, potassium carbonate, or sodium hydrogen carbonate. Particularly preferably, sodium hydroxide:or potassium hydroxide are used.

Alcohols, such as methanol, ethanol, propanol, butanol, or tert-butanol, are also suitable solvents for the individual reaction steps. Tert-butanol is preferred.

It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.

The halogenation generally takes place in one of the above-mentioned chlorinated hydrocarbons, whereby methylene chloride is preferred.

Diethylamino sulfur trifluoride (DAST) or SOC1 2 for example, are suitable halogenation agents.

23 a x Z~k$-kr-t i t r* WO 98/04528 PCT/US97/13248 0 The halogenation generally takes place within a temperature range of -78°C to +50'C, preferably from -78C to 0°C, and most preferably at -78°C, depending on the choice of both the halogenation agent and the solvent.

The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.

The customary reagents are suitable as Wittig reagents. 3-Trifluoromethylbenzyl triphenylphosphonium bromide is preferred.

One of the above-mentioned bases are generally suitable as bases, preferably Li-bis-(triethylbutyl)amide.

The base is introduced in a quantity ranging from 0.1 mole to 5 moles, preferably from 0.5 mole to 2 moles, relative to 1 mole of the starting compound.

The reaction using Wittig reagents is generally carried out within a temperature range of O0C to 150 0 C, preferably at 25 0 C to In general, the Wittig reactions are carried out at normal pressure.

However, it is also possible to carry out the process at reduced pressure or high pressure within a range from 0.5 to 5 bar).

Compounds of the general formula (II) in the case wherein L is other than alkoxy/cyclooxy are known or can be produced by processing compounds of the general formula (IV) A

.R

16 2 C C0 2

R

R162'b c 2 R 17

(IV)

L" N E

H

in which 6** A, E, and L' have the above-mentioned meanings,

R

1 6 and R 1 7 are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, 24 WO 98/04528 PCT/US97/13248 0 in inert solvents with oxidants, and selectively reducing the alkoxycarbonyl function (CO 2

R

17 to the hydroxy function in a second step.

Suitable solvents for the oxidation are ethers, such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylol, hexane, or cyclohexane, or petroleum fractions, or halocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is likewise possible to use a mixture of said solvents. Dichloromethane is preferred.

Suitable oxidants are, for example, 2 3 -dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2 3 -dichloro-5,6-dicyanobenzoquinone (DDQ) is preferred.

The oxidant is introduced in a quantity ranging from 1 mole to 10 moles, preferably from 2 moles to 5 moles, relative to 1 mole of the compound of the general formula (IV).

The oxidation generally takes place within a temperature range of -50°C to HI +100°C, preferably from 0°C to room temperature.

The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increasedor reduced pressure.

1, 4 -Dihydropyridine-3,5-dicarboxylic acid esters of the general formula (IV) are known and can be produced according to known methods.

The reaction is generally carried out at normal pressure. However, it is also possible to carry out the process at reduced pressure or high pressure within a range of 0.5 to 5 bar).

WO 98/04528 PCT/US97/13248 Compounds of the general formula (II) in the case wherein L is alkoxy/cyclooxy are known and can be produced by first oxidizing compounds of the general formula (V) .C0 2 R19 in which A and E have the above-mentioned meanings and

R

1 8 and R 1 9 have the meaning given above for R 1 6 and R 1 7 and are identical to or different from these, with ceric(IV) ammonium nitrate into compounds of the general formula

(VI)

ri ne u-,

(VI)

in which A, E, R 18 and R 19 have the above-mentioned meanings, then, by reaction with alkylation agents of the general formula

(VII)

(VI)

in which stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, WO 98/04528 PCT/US97/13248 0 and Y stands for halogen, preferably for bromine or iodine, in inert solvents and in the presence of a base, converting them into compounds of the general formula (VIII)

A

R'

8 0C C0 2

R'

1 9 S|(VIm)

R

2 0 0 N E in which A, E, R 1 8

R

1 9 and R 2 0 have the above-mentioned meanings, and finally, as described above, carrying out a selective reduction with diisobutylaluminum hydride of the alkoxycarbonyl group -CO2R 1 8 to the hydroxymethylene function, followed by an oxidation to the corresponding aldehyde, likewise as described above, preferably with PCC.

The individual reaction steps each take place in one of the above-mentioned solvents and/or bases; preferably, the oxidation is carried out with ceric(IV) ammonium nitrate in acetonitrile, the alkylation is carried out with dimethyl formamide and sodium hydride, and the reduction is carried out in toluene within a temperature range of -30°C to 100°C, at normal pressure, and, if.applicable, under a protective gas atmosphere.

Compounds of the general formulas and (VII) are known in and of themselves or can be produced according to the customary methods.

Compounds of the general formulas (VI) and (VIII) are known in part or are.

novel and can therefore be produced according to the above-mentioned process.

Compounds of the general formula (III) are novel and are produced by converting compounds of the general formula (IX) WO 98/04528 PCT/US97/13248

A

T

CO

2

R

2 1 S (IX) 0 L N E in which A, E, L, and T have the above-mentioned meanings and

R

21 denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms, first by reduction of the alkoxycarbonyl function, into compounds of the general

C

formula (la)

A

T (Ia) .L N E in which A, E, L, and T have the above-mentioned meanings, and in a second step, oxidizing the hydroxymethyl function into the aldehyde according to the above-mentioned conditions, preferably with pyridinium chlorochromate

(PCC).

The individual reaction steps are generally carried out within a temperature range of -10°C to +160°C, preferably 0°C to +100"C, and at normal pressure.

Compounds of the general formula (IX) are produced analogously to the methods described above for the production of compounds of the general formula

(II).

Compounds of the general formula (la) are also novel and can be produced as described above.

28 k -zj-~bi ~x*rrs R f F- WO 98/04528 PCT/US97/13248 0 Compounds of the general formulas (IA) and (Ia) according to the invention have an unforeseeable pharmacological spectrum of action.

Compounds of the general formulas (IA) and (Ia) according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. The active compounds according to the invention cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.

The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (adiposis), and diabetes mellitus.

Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistat, AI-3688, testatin, pradimicin-Q, and salbostatin.

The combination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of the general formula (IA) according to the invention is preferred.

The pharmacological action of the substances according to the invention was determined in the following test: CETP Inhibition Test 1. Obtaining CETP CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and is used for testing. In so doing, human plasma is adjusted with NaBr to a density of 1.21 g per ml and is centrifuged for 18 h at 50,000 rpm at 4"C. The bottom fraction (d 1.21 g/ml) is applied to a Sephadex® Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCI/0.001 m TrisHCI, pH 7.4, and then eluted with dist. water. The CETPactive fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose® (Pharmacia) column. They were then eluted with a WO 98/04528 PCT/US97/13248 0 linear gradient (0-1 M NaC1). The pooled CETP fractions were dialyzed against mM TrisHC1, pH 7.4, and were then further purified by chromatography over a Mono Q® column (Pharmacia).

2. Obtaining Radioactively Tagged HDL ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4'C for 18 h at 50,000 rpm in the Ty 65 rotor. The upper phase was used to obtain cold LDL. The lower phase was dialyzed against 3x4 1 of PDB buffer (10 mM Tris/HC1, pH 7.4, 0.15 mM NaC1, 1 mM EDTA, 0.02% NaN 3 20 gl 3H cholesterol (Du Pont NET-725; 1 -pC/gl dissolved in ethanol) was subsequently added per 10 ml of dialysis residue volume and incubated for 72 h at 37C under

N

2 The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20°C. The upper phase was obtained and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of 1.26. Every 4 ml of this solution was covered in centrifuge tubes (SW rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20 0 C in the SW 40 rotor. The intermediate layer between the densities 1.063 and 1.21 that contained the tagged HDL was dialyzed against 3x100 volumes of PDB buffer at 4°C.

The dialysis residue contained radioactively tagged 3 H-CE-HDL, which was adjusted to approx. 5x10 6 cpm per ml and used for the test.

3. Conducting the Test In order to test the CETP activity, the transfer of 3 H cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins was measured.

The reaction was ended by adding Streptavidin-SPA® beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.

In the test batch, 10 pl HDL- 3 H cholesterol ester 50,000 cpm) was incubated for 18 h at 370C with 10 pt biotin-LDL (Amersham) in 50 mM HEPES 0.15 m NaCI 0.1% bovine serum albumin 0.05% NaN 3 pH 7.4, with 10 gl CETP (1 mg/ml) and 3 il solution of the substance to be tested (dissolved in 10% DMSO WO 98/04528 PCT/US97/13248 0 1% BSA). Then 200 pl of the SPA-Streptavidin bead solution (Amersham TRKQ 7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 L1 buffer, 10 pl CETP at 4°C, and 10 1l CETP at 37°C served as controls.

The transferred activity in the control batches with CETP at 37'C was assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as an IC 5 0 value.

CETP inhibitory activity of the following compounds: Example No. IC 5 0

(M)

7 0.6 24 Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.80 mg/kg atropine, 0.80 mg/kg Ketavet® s.c., later 50 mg/kg Nembutal The jugular vein was then exposed and cannilated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H 2 0, ad 100 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals up to 24 hours after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 pl). Coagulation was completed by incubating at 4°C overnight, then the blood was centrifuged for minutes at 6000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was diluted in a suitable manner with physiological saline solution.

100 pl serum dilution was mixed with 100 pl test substance in 96-hole perforated plates and incubated 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 nM (SLT-Spectra). The triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.

c WO 98/04528 PCT/US97/13248 0 The determination of the HDL cholesterol content was carried out after precipitation of the lipoproteins containing Apo B by means of a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.

In attempting to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orally to Syrian golden hamsters from the company's own breeding via a pharyngeal tube. The control animals received identical volumes of solvent without any test substance. Feed was then withheld from the animals and blood was drawn at different intervals up to 24 hours after administration of the substance via puncture of the retroorbital venous plexus. It was further processed as described above.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this connection, the therapeutically active compound should be present in each case in a concentration of about 0.5% to 90% by weight, in amounts that are sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used, if appropriate, as auxiliary solvents.

The administration takes place in a customary manner, preferably orally or parenterally, in particular, perlingually or intravenously.

In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.

In general, it has proved advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight, to attain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

WO 98/04528 PCT/US97/13248 0 In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of administration route, individual behavior toward the medication, the type of formulation thereof, and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the minimum amount previously mentioned, whereas in other cases the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses over the day.

Starting Compounds Example I Diethyl 4-(4-fluorophenyl)-6-isopropyl-(H)-pyrid-2-one-3,5-dicarboxylate

F

HsC 2 00C COOC 2

H

0 N

H

149 g (0.395 mmol) of diethyl 3, 4 -dihydro-4-(4-fluorophenyl)-6-isopropyl- (1H)-pyrid-2-one-3,5-dicarboxylate is dissolved in 800 ml of acetonitrile, mixed with 475 g (0.867 mol) of ceric(IV) ammonium nitrate dissolved in 500 ml of H 2 0, and subsequently stirred for 3 h. The aqueous phase is extracted two times with ethyl acetate. The combined ethyl acetate phases are washed with salt water, dried, and concentrated. The residue is mixed with isopropanol immediately thereafter, whereby crystallization is started by cooling with ice. The product is drawn off by suction and dried in a high vacuum.

Yield: 58.8 g (39.6% of theory) Rf 0.5 (toluene ethyl acetate 1:1) WO 98/04528 PCT/US97/13248 0 Example II Diethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3,5-dicarboxylate

H

5

C

2 000

H

3 C00 1.72 mg (42.9 mmol; 1.61 eq.) of sodium hydride (60% dispersion in mineral oil) is added to 10 g (26.6 mmol) of the compound from Example I dissolved in 40 g of DMF, and the mixture is suspended in 30 ml at -20°C. Afterwards, the suspension is heated to +30°C, 3.3 ml (53.2 mmol; 2 eq.) of methyl iodide is added, and it is heated for 2.5 hours to 80°C 100°C. The reaction solution is mixed with 500 ml ethyl acetate and 300 ml H 2 0, and the aqueous layer is separated off and extracted one time with ethyl acetate. The combined ethyl acetate phases are washed with water and saline solution, dried, and concentrated. The crude product is dissolved in 20 ml of toluene and chromatographed over 200 ml of silica gel 60 using toluene as the eluant.

Yield: 10 g (96.4% of theory) Rf 0.28 (toluene) Example III Ethyl 4-( 4 -fluorophenyl)-6-isopropyl-2-methoxy-3-hydroxymethyl-pyridine-5carboxylate cr a o r .rr q

OOUO~

O

.COOC

2

H

H

3

C

WO 98/04528 PCTIUS97/13248 0 500 mg (1.284 mmol) of the compound from Example II in 40 g of toluene p.a. is mixed under argon at -78°C with 3.21 ml (3.852 mmol) of diisobutylaluminum hydride (DIBAL-H, 1.2 molar in toluene). The mixture is stirred 30 min at -78'C, and the batch is allowed to stand overnight at -30°C in the refrigerator. It is further cooled to -70°C, 20% potassium sodium tartrate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is dried with Na 2

SO

4 and concentrated.

Yield: 287 mg (64.5% of theory) Rf 0.41 (toluene ethyl acetate 9:1) Example IV Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-formyl-pyridine-5-carboxylate

F

OHC

COOC

2

H

H

3 CO N 21.3 g (0.0988 mol, 3.8 eq.) of pyridinium chlorochromate (PCC) is added to a solution of 9.07 g (0.026 mol) of the compound from Example Il in 400 ml CH 2 C12 in the presence of neutral A 2 0 3 (10.07 g 0.0988 mol), and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH 2 Cl 2 then the filtrate is concentrated in a vacuum and chromatographed on silica gel 60 (500 ml) using toluene ethyl acetate Yield: 8.88 g (98.4% of theory) Rf 0.62 (toluene ethyl acetate 9:1) WO 98/04528 PCT/US97/13248 0 Example V Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3-[2-(benzoxazol-2-yl)-l-hydroxy-

F

N-N OH 0 1 COOC 2

H

CH3O N 400 mg (3 mmol) of 2 -methylbenzoxazole dissolved in 5 g THF p.a. is cooled under argon to -78°C. 1.83 ml (3 mmol) of n-butyllithium (1.6 molar in hexane) is added to this, and the mixture is stirred for 120 min at -78°C. 1.036 g (3 mmol) of the compound from Example IV is then added by drops at -78"C; the mixture is stirred for 10 min at -78*C and overnight until it reaches room temperature. After adding 50 ml of water, it is extracted by shaking with 100 ml of ethyl acetate. The aqueous phase is separated off, washed two times with saline solution, dried over Na 2

SO

4 and concentrated. The residue is chromatographed on 60 ml of silica gel using toluene and toluene ethyl acetate The concentrated fractions are dried in a high vacuum.

Yield: 4 50 mg (31.4% of theory) Rf 0.22 (toluene ethyl acetate 9:1) Example VI 2 0 r Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-ethoxy [2(benzoxazol-2-yl)-ethenyl]-

F

0- COOC 2

H

CH

3 0' WO 98/04528 PCT/US97/13248 0 100 mg (0.209 mmol) of the compound from Example V is boiled in 10 g toluene p.a. under argon in the presence of 25 mg (0.131 mmol) of ptoluenesulfonic acid hydrate for 6 h under reflux, and afterwards the mixture is stirred at room temperature overnight. The reaction solution is then applied to a column filled with 40 ml of silica gel and consecutively eluted with toluene and toluene ethyl acetate The desired fractions are concentrated and dried in a high vacuum.

Yield: 91 mg (94.6% of theory) Rf 0.59 (toluene ethyl acetate 9:1) Example VII Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)pyridie-3,5-dicarboxylate

F

H

5

C

2 00C

COOC

2 Hs I I

H

528 g (2 mol) of 4 -carboxymethyl-5-(4-fluorophenyl)-2-methyl-pent-4en-3-one and 350 g (2 mol) of 90% ethyl 3 -amino-4-methyl-pent-2-enoate are stirred in 1800 ml ethanediol overnight at a bath temperature of 200°C. The mixture is cooled slowly and poured into a large glass beaker at approx. 80°C. After further cooling to 0°C, the solution is drawn off by suction from the precipitated sediment, then the sediment is washed well with ice cold ethanol and dried in a desiccator.

The ethanol solution is concentrated, and the residue together with the ethanediol mother liquor is extracted four times with 1.5 1 ether each time. The combined ether phases are washed three times each with 500 ml of 10% hydrochloric acid and once each with 500 ml of saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and allowed to stand overnight at room temperature. The solution is drawn off by suction from the precipitated sediment, subsequently washed with ice cold ethanol, and dried in a desiccator. The ethanol solution and the ether mother liquor are concentrated together in a vacuum to a 37 WO 98/04528 PCT/US97/13248 0 volume of approx. 21, allowed to stand overnight again, and drawn off by suction from the precipitated sediment.

Total yield: 556.9 g (69.1% of theory) 1 H-NMR (CDC1 3 8= 1.1 1.3 18H); 4.05 4.25 6H); 5.0 1H); 6.13 1H); 6.88 20H); 7.2 2H) ppm.

Example VIII Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate

F

H

5

C

2 00C COOC2H

N

171.7 g (0.757 mol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone is added to a solution of 304.8 g (0.757 mol) of the compound from Example VII in 2 1 of dichloromethane, and the mixture is stirred overnight at room temperature. The mixture is drawn off by suction over diatomaceous earth and subsequently washed well with dichloromethane. After concentration of the dichloromethane phase to a volume of approx. 800 ml, it is chromatographed on a column (2 kg of silica gel 230 mesh) with dichloromethane.

Yield: 222 g (73.4% of theory) 1 H-NMR (CDC13): 0.98 6H); 1.41 12H); 3.1 2H); 4.11 4H); 7.04 2H); 7.25 2H) ppm.

38 WO 98/04528 PCT/US97/13248 0 Example IX Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-hydroxymethylpyridine-5-carboxylate

F

HO

CO

O C 2

H

N

T

257 ml (0.9 mol) of a 3.5 molar solution of sodium-bis-(2-methoxyethoxy)dihydroaluminate is steadily added by drops under nitrogen to a solution of 120 g (0.3 mol) of the compound from Example VIII in 800 ml of dried tetrahydrofuran at room temperature, and the mixture is subsequently stirred for h. After cooling to 0°C, 500 ml of water is carefully added by drops, the phases are separated, and the aqueous phase is extracted three times with 250 ml ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is mixed with petroleum ether, drawn off by suction, and dried in a desiccator.

Yield: 69.1 g (64.2% of theory) 1H-NMR (CDC1 3 8 0.95 3H); 1.31 12H); 3.05 1H); 3.48 1H); 3.95 2H); 4.93 2H); 7.05 7.31 4H) ppm.

Example X Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-formyl-pyridine-5-carboxylate WO 98/04528 PCT/US97/13248 0 14.18 g (0.139 mol) of neutral A1 2 0 3 and 29.96 g (0.13 mol) of pyridinium chlorochromate (PCC) are added to a solution of 25.0 g (0.0695 mol) of the compound from Example IX in 500 ml CH 2 C1 2 and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH 2 C1 2 and the filtrate is concentrated in a vacuum, whereby the product precipitates out.

Yield: 20 g (80.48% of theory) 1 H-NMR (DMSO-d 6 8 0.92 3H); 1.39 (dd, 6H); 3.02 3.13 1H); 3.75 3.86 1H); 3.95 4.05 2H); 7.32 4H); 9.8 1H) ppm.

Example XI Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)hydroxymethyl]-

F

HO It 10.0 g (27.98 mmol) of aldehyde from Example X is cooled to -70°C in 100 g THF p.a. under argon, 33.6 ml (33.58 mmol, 1.2 eq.) of p-fluorophenyl magnesium bromide solution is added by drops at -70'C, and the mixture is then stirred for another 2 h at -70°C. The reaction solution is mixed with 200 ml of cone. NH 4 C1 solution, the cooling bath is removed, and the solution is adjusted with 1 molar HC1, pH 6. After extraction with 400 ml of CH 2

CI

2 and drying over Na 2

SO

4 the organic phase is concentrated in a vacuum and the rigid foam is crystallized using n-heptane.

Yield: 8.97 g (70.7% of theory) Rf 0.18 (toluene) L ri^^ S .A

A

f l .~ifW w, !i wii.s, "fs>p r X WO 98/04528 WO 9804528PCTIUS97/ 13248 o Example XII Ethyl 2 6 -diisopropyl-4-(4-fluorophenyl)-3-[(4-fluorophenyl)-chloromethyl].

.COOC

2

H

907 mg (2 mmol) of the compound from Example XI is dissolved in 20 g of

CH

2 C1 2 p.a. and cooled under argon at -40 0 C, and 0.44 ml (6 mmol) SOC1 2 are added. The solution is stirred for 1.5 h fr 'om -40*C to -5*C and afterwards agitated in 50 ml of ethyl acetate 40 ml of NaHCO 3 solution. The organic phase is separated off, dried over Na 2

SO

4 concentrated in a vacuum, and chromatographed on diatomaceous earth using toluene.

Yield: 899 mg (95% of theory) Rf 0.79 (toluene) Example XIII 3-Ethyl 5-methyl 3 4 -dihydro-4-(4-fluorophenyl)&6p-fluorophenyl(H)pyrid2- WO 98/04528 PCT/US97/13248 0 30.69 g (115.3 mmol) of ethyl l-carboethoxy-2-(4-fluorophenyl)-propenate, 22.5 g (115.3 mmol) of methyl 3 -amino- 3 -(4-fluorophenyl)-acrylate, 115 mg of sodium methylate, and 0.6 ml of ethanol are stirred for 48 h at a bath temperature of 140°C. The reaction mixture is absorbed in ethyl acetate, washed three times with water, dried over Na 2

SO

4 and concentrated in a vacuum.

Yield: 43.2 g (90.2% of theory) Rf 0.26 (toluene ethyl acetate 9:1) Example XIV 3-Ethyl 5-methyl 4 4 -fluorophenyl)-6-p-fluorophenyl-(1H)-pyrid-2-one-3,5dicarboxylate

H

5

C

2 00 r Analogously to Example I, 1.00 g (0.2407 mol) of the compound from Example XIII is stirred with 277 g (0.506 mol) of ceric(IV) ammonium nitrate in 600 ml of acetonitrile and 600 ml of water for 3 h at room temperature. After extraction with ethyl acetate, the residue is crystallized from isopropanol.

Yield: 28.59 g (28.7% of theory) Rf 0.16 (toluene ethyl acetate 8:2) r r s~-7.

WO 98/04528 WO 9804528PCI US97/13248 0 Example XV 3-Ethyl 5-methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3,5-.

dicarboxylate

H

5 0 2 00 -COOCH 3 Following the instructions in Example HI, 5.0 g (0.0121 mol) of the mixture from Example XIV in 20 ml of DMF is reacted in the presence of 0.783 g- (0.0196 mol) of 60% NaH with 3.61 g (0.0242 mol) of cyclopentyl bromide.: After chromatography on silica gel using toluene, 5.14 g (88.3% of theory) is obtained.

Rf =0.34 (toluene) Example XVI Methyl 4-4furpey)6(-loohnl--ylpnoy3hdoyehl

F

HO0

COOCH

3

F

Analogously to Example 111, 3.719 g (7.72 mmol) of the compound from Example XV in 150 g of toluene is stirred with 11.58 ml (11.58 mmol) of DIBAL-H 43 WO 98/04528 PCT/US97/13248 0 (1.0 molar) for 2.5 h at -78C. The compound is chromatographed on silica gel first with toluene and then with toluene ethyl acetate Yield: 1.648 g (48.5% of theory) Rf 0.45 (toluene ethyl acetate 9:1) Example XVII Methyl 4-(4-fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-formyl-pyridine-5carboxylate

F

.COOCH

3 Following the instructions in Example IV, 1.636 g (3.72 mmol) of the compound from Example XVI in 150 ml of CH 2 C12 is stirred with 0.759 g (7.44 mmol) of A1 2 0 3 (neutral) and 1.604 g (7.44 mmol) of PCC for 1.5 h. The crude product is purified by chromatography on silica gel using toluene.

Yield: 1.484 g (91.2% of theory) Rf 0.59 (toluene ethyl acetate 9:1) oiar Example XVIII Methyl 4-(4-uorophenyl)-6-(4flur phenyl)-2-cyc WO 98/04528 PCT/US97/13248

F

HO

COOCH3

F

0 53.4 mg (2.2 mmol) of magnesium shavings is heated to reflux in 10 ml of THF p.a. under argon. 313 mg (1.51 mmol) of 2-bromonaphthalene dissolved in ml of THF is added to this and the solution is boiled 75 min to reflux in the presence of iodine crystals Grignard reagent). 220 mg (0.503 mmol) of the compound from Example XVII is dissolved in 5 ml of THF p.a. and cooled under argon to and the Grignard reagent is sprayed in. The batch is subsequently stirred for one hour without cooling. The reaction solution is distributed in ethyl acetate ammonium chloride solution, and the organic phase is separated off, washed with NaCl solution, dried, and concentrated. Chromatography is then carried out on silica gel using toluene.

Yield: 261 mg (91.9% of theory) Rf 0.57 (toluene ethyl acetate 9:1) Example XIX Methyl 4-( 4 -fluorophenyl)-6-(4-fluorophenyl)-2-cyclopentoxy-3-[(naphthyl-2)-

F

COOCH3

F

WO 98/04528 PCT/US97/13248 0 0.08 mmol (0.602 mmol) of diethylamino sulfur trifluoride (DAST) is added to a solution of 227 mg (0.401 mmol) of the compound from Example XVIII in 10 g of CH 2 C1 2 at -40°C under argon, the cooling bath is removed, and the solution is stirred for 20 min. The reaction solution is subsequently distributed in ethyl acetate NaHCO 3 solution, and the organic layer is dried with Na 2

SO

4 and concentrated in a vacuum. The crude product is chromatographed on silica gel using toluene.

Yield: 224 mg (98.6% of theory) Rf 0.67 (toluene) Production Examples Example 1 2,6-Diisopropyl-3-p-fluorobenzyl-4-p-fluorophenyl-5-hydroxymethyl-pyridine

F

F OH

I

5.7 g (150 mmol) of LiAlH4 are suspended in 200 ml of THF, heated to 80°C, and mixed by drops with a solution of 23.7 g of the compound from Example XII in 150 ml of THF. After being stirred for 5 h, the mixture is cooled, carefully neutralized with 20% Na-K-tartrate solution, and extracted three times with ethyl acetate, and the organic phase is dried, concentrated, and chromatographed over silica gel 60 (toluene).

Yield: 13.6 g (69% of theory) Rf 0.59 (toluene ethyl acetate 9/1) 46 WO 98/04528 WO 9804528PCT/US97/13248 The compounds listed in Table 1(A) are produced in analogy to the instructions in Example 1: Table 1(A): Ex. G Rf Solvent No. 2 OH 0.60 toluene/

CH

3 ethyl acetate 9:1 3 OH- 0.74 toluene/

OH

3 ethyl acetate 9:1 4 OH 0.75 toluene!

OH

3 ethyl acetate 9:1 WO 98/04528 PCT/US97/13248 0 Example 4 4 -fluorophenyl)-6-(4fluorophenyl)..2cycopentoxy3[(naphthyl12)- Analogously to the instructions of Example 1, 182 mg (0.32 1 mmol) .oPf the compound from Example XIX in 10 ml of THF p.a. is boiled with 18.3 mg (0.1481 mmol) of LiAII-I 4 for 1 h under reflux. The compound is purified by chromatography on silica gel first with toluene and then with toluene /ethyl acetate Yield: 86 mg (49.7% of theory) Rf 0.47 0* WO 98/04528 WO 9804528PCT1US97/13248 The compounds listed in Table 2(B) are produced in analogy to the instructions of Example Table 2(B): Ex. E R22 Z 1 1Z 2 L Rf No. (solvent) 6 cYcl-C6Hfl H p-F H CH(CH 3 2 0.59 toluene/ ethyl acetate 7 CH(CH 3 2

NH

2 p-F /H CH(CH 3 2 0.60 toluene/ ethyl acetate 1:1 8 CH(CH 3 2 SH p-F H CH(CH 3 2 0. 31 toluene/ ethyl acetate 9:1 9 CH(CH 3 2 Cl p-CF 3 /H CH(CH 3 2 0.54 tolune w/ ethyl acetate 9.1 1 .0 CH(CH 3 2 H 3,4-F 2

CH(CH

3 2 0.26 toluene.

1 4--H 4 F p-CF 3 /H -C 3 0.48 toluene/ ethyl acetate 9:1 WO 98/04528 PCT/US97/13248 0 Table contd.

Ex.

No.

12

R

2 2 Z1/Z 2 L Rf (solvent)

CH(CH

3 2 0.21

CH(CH

3 2 F p-F H 13 4-F-C6H 4 F p-CF 3 H (cyclo-C7H 13

)O

toluene 0.28 petroleum ether ethyl acetate 5:1 Example 14 2 -Isopropyl-6-methoxy-4-(4-fluorophenyl)-5-[ 2 -(benzoxazol-2-yl)ethyl]-3hydroxymethylpyridine

I

CH

3 0' 69 mg (0.15 miol) of the compound from Example VI is dissolved in 5 g of toluene and mixed With 0.6 ml DIBAL-H (1.0 molar in toluene). The mixture is then stirred without a cooling bath for 4 h to +15°C. 30 ml of ethyl acetate and 15 ml of a potassium sodium tartrate solution is added, and the solution is stirred for min. The aqueous layer is separated off, and the organic phase is dried, concentrated, and chromatographed. After chromatography on 20 ml of silica gel using toluene ethyl acetate 19 mg (30.2% of theory) is obtained.

Rf= 0.28 (toluene ethyl acetate 9:1) o.

kfl' oooo ~ruii o v u u oi :t U*-1~vS-voU UU.4U U 0'- WO 98/04528 PCT/US97/13248 0 Detailed description with reference to compounds of general formula (IB) The compounds according to the invention can also occur in the form of the salts thereof. In general, salts with organic or inorganic bases or acids are mentioned here.

Within the context of the present invention, physiologically safe salts are preferred. Physiologically safe salts from the compounds according to the invention can be salts of substances according to the invention with mineral acds, carboxylic acids, or sulfonic acids. Salts with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, or benzoic acid are particularly preferred.

Physiologically safe salts can also be metallic or ammonium salts of the compounds according to the invention that possess a free carboxyl group. For example, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, that are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine, or 2-phenylethylamine are particularly preferred.

The compounds according to the invention can exist in stereoisomeric forms, which either behave like an image and mirror image (enantiomers) or do not behave like an image and mirror image (diastereomers). The invention concerns both enantiomers or diastereomers or the mixtures thereof. These mixtures of Senantiomers and diastereomers can be separated in the known manner into stereoisomerically homogeneous components.

Within the context of the invention, the heterocyclic compound, which is optionally benzo-condensed, stands in general for a saturated or unsaturated, 5- to 7-member, and preferably 5- to 6-member, heterocyclic compound that can contain up to 3 heteroatoms from the series S, N, and/or 0. Tetrazolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrinyl, benzothiazolyl, phenoxathinzyl, benzoxazolyl, tetrahydropyrimidyl, pyrazolopyrimidyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl are cited as examples. Quinolyl, furyl, pyridyl, tetrahydropyrimidyl, 51 0 WO 98/04528 PCT/US97/13248 0 indolyl, benzothiazolyl, benzoxazolyl, pyrinyl, and pyrazolopyrimidyl are preferred.

This also includes 5- to 7-member saturated heterocyclic compounds bound via N, which can also contain up to 2 oxygen, sulfur, and/or nitrogen atoms as heteroatoms, such as piperidyl, morpholinyl, or piperazine or pyrrolidinyl.

Piperidyl and pyrrolidinyl are particularly preferred.

Compounds of general formula (IB) are preferred, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula

-NR

2

R

3 and/or by a group of the formula

-W-R

4 wherein

R

2 and R 3 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, W denotes an oxygen or sulfur atom,

R

4 denotes phenyl or benzyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 6 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula

-NR

5 52 WO 98/04528 PCT/US97/13248 0 wherein

R

5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl,

R

1 stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrimidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, tetrahydropyrimidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N function in the case of nitrogen-containing rings, being optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or by a group of the formula -OR 6

-SR

7 or -SO2R 8 wherein

R

6

R

7 and R 8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or by straight-chain or branched alkyl with up to 4 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 7 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, or phenyl, which in turn can be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or 53 TTTT A7 A WO 98/04528 PCT/US97/13248 0 L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or for naphthyl, phenyl, pyridyl, or furyl, which optionally can be substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, and the salts thereof.

Compounds of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromnethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 4 carbon atoms each or by benzyloxy, which in turn can be substituted by fluorine or chlorine. D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula -NR 5 wherein

R

5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms,

R

1 stands for cyclopropyl, cyclopentyl, or cyclohexyl, or tetrahydropyrinidyl stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, 54 er, WO 98/04528 PCTIUS97/13248 0 morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -OR 6

-SR

7 or -S0 2

R

8 wherein

R

6

R

7 and R 8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, Sor L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, and the salts thereof.

WO 98/04528 PCT/US97/13248 The compounds according to the invention of general formula (IB) are particularly preferred, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, methoxy, methyl, or by fluorine- or chlorine-substituted benzyloxy.

Moreover, a process for the production of compounds according to the invention of general formula (IB) has been discovered, characterized in that in the case of V O compounds of general formula (II)

HO-D.

i in which

I

r r o o o A, D, L, and T have the indicated meaning, and stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula -CH2-O-Si(CH 3 2

C(CH

3 3 Cj~. are reacted with compounds of general formula (ml)

R

1 -E-Z (m) in which

R

1 and E have the indicated meaning and WO 98/04528 PCT/US97/13248 0 Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group

R

11 or compounds of general formula (II) are first converted by reactions with compounds of general formula (IV)

O

II

R'

1 C

(IV)

O

in which

R

1 2 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V)

A

R'I2 O'

SL(V)

L N T in which A, D, L, T, R 1 1 ,and R 12 have the indicated meaning, and these are then reacted with compounds of general formula (VI)

R

1 -E-V-H

(VI)

in which

R

1 E, and V have the indicated meaning, and reductive separation is carried out, WO 98/04528 PCT/US97/13248 0 and optionally, the groups listed under substituents A, L, T, and R 1 are introduced or varied according to customary methods.

The processes according to the invention can be explained, for example, by means of the following reaction diagrams:

F

HO '-C0 2

C

2

H

5

F

3 C

F

N Br

F

3 C C0 2

C

2

H

F

N

r0 N oil

F

3 C OH

F

F

3 C N 0 0- Si F

N'

Si WO 98/04528 WO 9804528PCT/US97/13248

[B]N

F

F

HO NC0 2

C

2

H

5

H

3

CO

2 SO NCO 2

C

2

H

NN

F

N 0 NCO 2

C

2 H1

FI

IN 0 jN OH N N -blocking F HCI/methanol N 0 0- Si

N

N 0 0

F

H

3 C- S-0 N o- Si N 0 N

H

3 C-S0 2

C

F

HO N 0- Si

N

59 WO 98/04528 PCTfUS97/13248

-I

N a"

OH

Suitable solvents for this process are inert organic solvents which do not change under the reaction conditions. These include* ethers such as diethyl ether or tetrahydrofuran, halocarbons such as dichioromethane, trichloromethane, tetrachloromethane, l, 2 -dichloroethane, trichioroethane, tetrachioroethane, l, 2 -dichloroethane, or tric hioroethylene, hydrocarbons such as -benzene, xylene, toluene, .hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformnamide, acetone, acetonitrile, or hexamethylphosphoric triamide. It is WO 98/04528 PCT/US97/13248 0 also possible to use mixtures of the solvents. Dichloromethane, tetrahydrofuran, toluene, or dimethylformamide are particularly preferred.

In general, as auxiliary agents for the process according to the invention, inorganic or organic bases may be used. These preferably include alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth hydroxides such as barium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate, alkaline earth carbonates such as calcium carbonate, or alkali or alkaline earth alcoholates such as sodium or potassium ethanolate, sodium or potassium methanolate, or potassium tert-butylate, or organic amines (trialkyl(C1-C 6 )amines) such as triethylamine, or heterocyclic compounds such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1, 8 -diazabicyclo[5.4.0]undec-7-ene

(DBU),

pyridine, diaminopyridine, methylpiperidine, or morpholine. It is also possible to use alkali metals such as sodium and hydrides thereof such as sodium hydride as bases. Sodium and potassium carbonate and triethylamine are preferred.

As bases, the usual strongly basic compounds can be used for the individual steps. These preferably include lithium organic compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithiumhexamethylsilyl amide, or alkali hydrides such as, sodium hydride or potassium hydride. N-butyl lithium or sodium hydride should preferably be used.

The bases are used in a mixture of 1 mole to 5 moles, and preferably 1 mole to 3 moles, relative to 1 mole of the compound of general formula (II).

In general, the reaction is carried out in a temperature range of 0OC to 150C, and preferably from +20"C to +110 C.

The reaction can be carried out at normal, increased, or reduced pressure (for example, 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.

As derivatizations, the following types of reactions are cited as examples: oxidations, reductive separation, reductions, hydrogenations, halogenation, Wittig/Grignard reactions, and amidation/sulfoamidation.

WO 98/04528 PCT/US97/13248 0 Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use mixtures of said solvents. Dichloromethane is preferred.

Suitable organometallic reagents are Grignard systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyl lithium. The Mg/bromobenzotrifluoride system is preferred.

The reductions and derivatizations are carried out according to the above-mentioned methods.

In general, the reductions are carried out in ethers such as dioxane, tetrahydrofuran, or diethyl ether, or in hydrocarbons such as benzene, hexane, or toluene. Toluene and tetrahydrofuran are preferred.

Suitable reductants are complex metal hydrides such as lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutyl aluminum hydride, dimethoxymethyl aluminate sodium salt, or sodium-bis(2-methoxyethoxy) dihydroaluminate (Red-Al). Diisobutyl aluminum hydride and dimethoxymethylaluminate sodium salt are preferred.

The reductant is generally added in the amount of 4 moles to 10 moles, and preferably from 4 moles to 5 moles, relative to 1 mole of the compound to be reduced.

The reduction generally takes place within a temperature range of -78°C to preferably from -78C to OC, and particularly preferably at -78C, depending on the choice of both the reductant and the solvent.

The reduction generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.

.~ri4ii' ~;5~ii~s~ej nir I v WO 98/04528 PCT/US97/13248 0 However, the reductions can also be carried out with reductants that are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this regard is reduction using metal hydrides.or complex metal hydrides in inert solvents, if appropriate, in the presence of a trialkyl borane. Preferably, the reduction is carried out using complex metal hydrides such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, or lithium aluminum hydride. More preferably, the reaction is carried out using sodium borohydride in the presence of triethyl borane.

The hydrogenation takes place according to the customary methods using hydrogen in the presence of noble metal catalysts such as Pd/C, Pt/C, or Raney nickel in one of the above-mentioned solvents, preferably in alcohols such as methanol, ethanol, or propanol, within a temperature range of -20°C to +100°C, preferably from 0°C to 50°C, at normal pressure or elevated pressure.

As derivatizations, the following types of reactions are cited by way of examples: oxidations, reductions, hydrogenations, halogenation, Wittig/Grignard reactions, and amidation/sulfoamidation.

The customary strongly basic compounds can be used as bases for the individual steps. These preferably include organolithium compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, or phenyl lithium, or amides such as lithium diisopropylamide, sodium amide, or potassium amide, or lithium hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride. n-butyl lithium or sodium hydride are particularly preferred.

Furthermore, the customary inorganic bases are suitable bases. These preferably include alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali carbonates such as sodium carbonate, potassium carbonate, or sodium hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly preferred.

Alcohols such as methanol, ethanol, propanol, or tert-butanol are also suitable solvents for the individual reaction steps. Tert butanol is preferred.

It may possibly be necessary to carry out several reaction steps under a protective gas atmosphere.

WO 98/04528 PCT/US97/13248 0 The halogenations generally take place in one of the above-mentioned chlorinated hydrocarbons, with methylene chloride being preferred.

Diethylamino sulfur trifluoride (DAST) or SOC 2 for example, are suitable halogenation agents.

The halogenation generally takes place within a temperature range of -78C to +50"C, preferably from -78C to 0°C, and particularly preferably at -78°C, depending on the choice of both the halogenation agent and the solvent.

The halogenation generally takes place at normal pressure, but it is also possible to work at increased or reduced pressure.

The customary reagents are suitable as Wittig reagents. 3-Trifluoromethylbenzyltriphenylphosphonium bromide is preferred.

In general, one of the above-mentioned bases is suitable as a base, preferably Li-bis-(triethylbutyl)amide.

The base is used in an amount of 0.1 moles to 5 moles, preferably 0.5 moles to 2 moles, in relation to 1 mole of the parent compound. The reaction with Wittigreagents is generally carried out in a temperature range of 0OC to 150C, preferably at 25"C to The Wittig reactions are generally carried out at normal pressure. However, i it is also possible to carry out the process at reduced or high pressure within a range of 0.5 to 5 bar).

The compounds of general formula (II) are known in part or new and can then be produced from the corresponding dihydropyridines of general formula

(VII)

A

R'

3 2 C CO 2

R'

4 1 1 vn) L I

(VII)

L N T

H

64 WO 98/04528 PCT/US97/13248 0 in which A, L, and T have the above-indicated meaning, and

R

13 and R 14 are identical or different and denote straight-chain or branched alkyl with up to 4 carbon atoms, through oxidation into the corresponding pyridines and finally depending on the substituents a reduction according to conventional methods can be carried out.

Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, or glycol dimethyl ether; or hydrocarbons such as benzene, toluene, xylene, hexane, or cyclohexane, or petroleum fractions, or halocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, or trichloroethylene, or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, or nitromethane. It is also possible to use a mixture of said solvents. Dichloromethane is preferred.

Suitable oxidants are, for example, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide, and manganese dioxide. For the above-mentioned step, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is preferred.

The oxidant is introduced in an amount of 1 mole to 10 moles, preferably 2 moles to 5 moles, relative to 1 mole of the compound of general formula (VII).

The oxidation generally takes place within a temperature range of -50°C to +100'C, preferably from 0°C to room temperature.

The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at increased or reduced pressure.

The dihydropyridines of general formula (VII) are known per se or can be produced by customary methods.

WO 98/04528 PCT/US97/13248 0 The compounds of general formulas (III), and (VI) are known per se or can be produced by customary methods.

The compounds of general formula are new or can be manufactured as described above.

The 3 -heteroalkyl-aryl-substituted pyridines according to the invention possess valuable pharmacological properties that are superior to those of the state of the art; in particular, they are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. The active compounds according to the invention cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.

The invention additionally concerns the combination of compounds according to the invention with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (adiposis), and diabetes mellitus.

Within the context of the invention, glucosidase and/or amylase inhibitors are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, testratin, pradimicin-Q, and salbostatin. The combination of acarbose, miglitol, emiglitate, or voglibose and one of the above-mentioned compounds of general formula (IB) according to the invention is preferred.

CETP Inhibition Test 1. Obtaining

CETP

CETP was obtained in partially purified form from human plasma by differential centrifugation and column chromatography and was used for testing. In so doing, human plasma was adjusted with NaBr to a density of 1.21 g/ml and was centrifuged for 18 h at 50,000 rpm at 4°C. The bottom fraction (d>1.21 g/ml) was applied to a Sephadex® Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl/0.001 m Tris HCI, pH 7.4, and then eluted with dist. water. The CETP-active fractions were pooled, dialyzed against 50 mM Na acetate, pH 4.5, and applied to a CM-Sepharose® WO 98/04528 PCT/US97/13248 0 (Pharmacia) column. They were then eluted with a linear gradient (0-1 M NaCI). The pooled CETP fractions were dialyzed against 10 mM Tris HC1, pH 7.4, and were then further purified by chromatography over a Mono Q® column (Pharmacia).

2. Obtaining radioactively-labeled HDL ml of fresh human EDTA plasma was adjusted with NaBr to a density of 1.12 and centrifuged at 4°C for 18 h at 50,000 rpm in the Ty rotor. The upper phase was.used to obtain cold LDL. The lower phase was dialyzed against 3 x 4 1 PDB buffer (10 mM Tris/HC1, pH 7.4, 0.15 mM NaC1, 1 mM EDTA, 0.02% NaN 3 20 pl of 3H cholesterol (Du Pont NET-725; 1 -gC/pl dissolved in ethanol) was subsequently added per 10 ml of dialysis residue volume and incubated for 72,h at 37°C under N 2 The sediment was then adjusted with NaBr to a density of 1.21 and centrifuged in the Ty 65 rotor for 18 h at 50,000 rpm at 20°C. The upper phase was obtained, and the lipoprotein fractions were purified by gradient centrifugation. In so doing, the isolated, tagged lipoprotein fraction was adjusted with NaBr to a density of l:26. Every 4 ml of this solution was covered, in centrifuge tubes (SW 40 'rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml of a solution with a density of 1.063 (density solutions from PDB buffer and NaBr) and then centrifuged for 24 h at 38,000 rpm and 20°C in the SW .40 rotor. The intermediate layer between the density of 1.063 and 1.21 that contained the labeled HDL was dialyzed against 3 x 100 volumes of PDB buffer at 4'C.

The dialysis residue contained radioactively-labeled 3

H-CE-HDL,

which was adjusted to approx. 5 x 106 cmp per ml and used for the test.

3. Conducting the test In order to test the CETP activity, the transfer of 3 H cholesterol ester from human HD lipoproteins ito biotinylated LD lipoproteins was measured.

The reaction was ended by adding Streptavidin-SPA® beads (Amersham), and the transferred radioactivity was determined directly in the liquid scintillation counter.

In the test batch, 10 gl of HDL- 3 H cholesterol ester (-50,000 cpm) was incubated for 18 h at 37°C with 10 l of biotin-LDL (Amersham) in 50 mM HEPES 0.15 m NaCI 0.1% bovine serum albumin 0.05% NaN 3 pH 7.4, with 10 pl of CETP (1 mg/ml) and 3 gl solution of the substance to be tested 67 WO 98/04528 PCT/US97/13248 0 (dissolved in 10% DMSO 1% BSA). Then, 200 gl of the SPA-Streptavidin bead solution (Amersham TRKQ 7005) was added, and the mixture was further incubated for 1 h under agitation and subsequently measured in the scintillation counter. Corresponding incubations with 10 pl buffer, 10 l CETP at 4'C, and 10 il CETP at 37C served as controls.

The transferred activity in the control batches with CETP at 37°C was assessed as 100% transfer. The substance concentration in which this transfer was reduced by half was indicated as the IC 5 0 value.

Syrian golden hamsters from the company's own breeding were anesthetized after fasting for 24 h (0.88 mg/kg atropine, 0.80 mg/kg Ketavet® s.c., 50 mg/kg Nembutal The jugular vein was then exposed and cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g glycerin, 100 ml H20, ad 100 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals received the same volume of solvent without any test substance. The vein was then ligated and the wound closed up. At different intervals-up to 24 h after administration of the test substance blood was drawn from the animals by puncture of the retroorbital venous plexus (approx. 250 tl). Coagulation was completed by incubating at 4°C overnight, and the blood was then centrifuged for 10 minutes at 6,000 g. The cholesterol and triglyceride content in the serum obtained in this manner was determined using modified commercially-available enzyme tests (cholesterol enzymatic 14366 Merck, triglyceride 14364 Merck). The serum was diluted in a suitable manner with physiological saline solution. 100 Pl serum dilution was mixed with 100 pl of test substance in 96-well plates and incubated for 10 minutes at room temperature. The optical density was then determined with an automatic plate reader at a wavelength of 492 nm (SLT-Spectra). The triglyceride/cholesterol concentration contained in the samples was determined using a parallel-measured standard curve.

The determination of the HDL cholesterol content was carried out after precipitation of the lipoproteins containing Apo B by means of a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.

In attempting to determine oral efficacy, the test substance, which was dissolved in DMSO and suspended in 0.5% methylcellulose, was administered orally to Syrian golden hamsters from the company's own breeding via a pharyngeal WO 98/04528 PCT/US97/13248 0 tube. The control animals received identical volumes of solvent without any test substance. Feed was then withheld from the animals, and blood was drawn at different intervals--up to 24 h after administration of the substance-via puncture of the retroorbital venous plexus. Further processing was carried out as described above.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, nontoxic, pharmaceutically-suitable excipients or solvents. In this connection, the therapeutically-active compound should be present in each case in a concentration of about 0.5% to 90% by weight, in amounts that are sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, with it being possible, for example, in the case of the use of water as a diluent, to use organic solvents, if appropriate, as auxiliary solvents.

Administration takes place in a customary manner, preferably orally or parenterally, in particular, perlingually or intravenously.

In the case of parenteral use, solutions of the active compound can be employed using suitable liquid excipients.

In general, it has proved to be advantageous in intravenous administration to administer amounts of about.0.001 to 1 mg/kg, preferably about 0.01 to mg/kg of body weight, to obtain effective results, and in oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of administration route, individual response to the medication, the type of formulation thereof, and the time or interval at which administration takes place. Thus in some cases, it may be sufficient to manage with less than the minimum amount previously mentioned, whereas in other cases, the upper limit mentioned must be exceeded. If larger amounts are administered, it may be advisable to divide these into several individual doses:over the day.

69 WO 98/04528 PCT/US97/13248 0 I. Mobile solvents for thin-layer chromatography

A

1 PE 98: EE 2

A

2 PE 95: EE

A

3 PE9 :EE1

A

4 PE85: EE

A

5 PE8 :EE2

A

6 PE 75; EE

A

7 PE7 :EE3

A

8 PE 65:EE35 Ag PE6 :EE4

A

10 PE 55: EE All PEl :.EE

A

12 Toluene/ethyl acetate 1/1

A

13 Toluene/ethyl acetate 8/2

A

14 Acetonitrile/water 9/1 PE petroleum ether; EE ethyl acetate Example I 1,4-Dihydro-2-cyclopentyl-6-ethyl-4-(4- dicarboxylic acid- 3

F

H

3 COOC

COOC

2

H

N

II

6.2 g (50 mmol) of 4 -fluorobenzalcehyde, 8.5 g (50 mmol) of 3-aminocyclopentylprop2-ene-carb o xylic methylester, and 7.2 g (50 mmol) of 4 -methylacetoacetic ethylester are heated for 18 hours to 130*C while stirring. After cooling to room temperature, chromatography is carried out over silica gel ttt~2 fl~ ,Yt. YS WO 98/04528 WO 9804528PCTIUS97113248 o (200 g of silica gel, 230-400 mesh; d 3.5 cm, mobile solvent ethyl acetate/ petroleum ether 1 9).

Yield: 2.8 g (14% of theory) Rf (ethyl acetate petroleum ether 2: 8) 0.31 Example 11 2-ylpny--ty--4furpey~yiie35dcroyi acid-3-methylester-

F

H

3 COOC N COOC 2

H

2.8 -g (6.98. mmol) of* l,4-dihydr6-2-cyclopentyl-6-ethyl-4-(4-fluoro.

acid-3-methylesteri-5-ethylesier is dissolved in 100 ml of .absol., mnethylene ,chloride, and after addition ;of 1.6 g (6.98 mmol) of 2 ,3-dichloro-5,6-dicyano- p-benzoquinone (DIDQ), the mixture is stirred for 1 hour at room temperature. After this, it is drawn off by suction over diatomaceous earth and concentrated in a vacuum. The residue is: chromnatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate petroleum ether 5:95).

Yield: 2.1 g (75.4% of theory) Rf (ethyl acetate petroleum ether 1:9) 0.56 1 H-NMR (CDCl 3 8 0.95 311); 1.32 311); 1.6 2.1 (in, 8H); 2.83 211); 3.14 (in, 1H); 3.53 3H); 4.02 2H);'7.0-7.3 (in, 4H) ppm.

Example III and Example IV 2-ylpny--ty--4furpey)3hdoyehlyiie5 carboxylic acid ethylester (Example II) and 2 -Cyclopentyl-6-thyl-4-(4-fluorophenyl)-5-hydroxymethypyridine.3 carboxylic acid methylester (ExampleIV 7 1 WO 98/04528 PCT/US97/13248 0 F

F

HO CO H 5 H 3 COOC

OH

N

N

(III)

V)

Under argon, 2.1 g (5.26 mmol) of 2 -cyclopentyl-6-ethyl-4-(4acid- 3 -methylester5-ethylester is dissolved in 50 ml of absol. toluene. 26.6 ml of diisobutyl aluminum hydride (1 M solution in toluene) is added dropwise to this solution at -60°C. After this, the mixture is stirred for 15 minutes at -60"C, and the reaction solution is then cooled at -30°C for 18 h. After heating to 0°C, 50 ml of water is added, and the resulting sediment is drawn off by suction and washed 4 times with 50 ml of ethyl acetate. The aqueous phase is washed with 100 ml of ethyl acetate, and the combined organic phases are shaken out with 150 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, d 3.5 cm, mobile solvent ethyl acetate petroleum ether 15:85).

Yield (Example 0.263 g (13.5% of theory) Rf (ethyl acetate petroleum ether 2:8) 0.42 1 H-NMR (CDC13): 0.95 3H); 1.28 3H); 1.6-2.1. 8H); 2.76 4H); 3.55 1H); 3.97 4H); 4.48 2H); 7.0-7.3 4H) ppm. Yield (Example IV): 0.907 g (48.3% of theory) Rf (ethyl acetate petroleum ether 2:8) 0.32 1 H-NMR (CDC1 3 5 1.32 3H); 1.6-2.1 8H); 2.97 3H); 3.06 1H); i" 3.45 3H); 4.45 2H) ppm.

The compounds shown in Table I(B) are produced analogously to the instructions for Examples

I-IV:

72 ^aa^ ^w 'r .a C OS C Table I(B) R 17 CO0R 2 0 Ex. R 15 R6R 17

R

18

R

19

R

20 T L Rf (solvent) V H H F H H C2H5 CH(CH 3 )2 C14(CH 3 2 0.51 VI H H F H H C2H5 CH(CH3)2 CH3 0.28

(AS)

VII H H F H H C83 CH3 CH3 0.33 (A7) VII H H F H H C2H5 CH(CH 3 )2 cYclO-C3H5 0.41 Ix H H F. H' H C2H5 cyclo-C3H5 cyclo-C 3 H5 0.44 X H H H H H C2H5 CH(CH3)2 CH(GH3)2 0.41 1_

(AS)

Ex. R 1 5

R

1 6

R

1 7

R

1 8

R

19

R

2 0 T L Rf X1 H H F 'H H C2H5 CH(CH 3 2 cYclO-C4H 7 0.45 H H F H H 'C2H5 CH(CH 3 2 cyclo-C5H 9 0.46 Xmi H H F H H CR3 cyclo-CSH 9

CH(CH

3 2 0.41 Xlv H

CR

3 F H H C2H5 CH(CH 3 2

CH(CH

3 2 0.26 (A3) xv CR3 H F H H C 2

H

5

CH(CH

3 2

CH-(CH

3 2 0.48 XVI H H F H H C2H5 CH(CH 3 2 sec-C4H9 0.58 XVII H H F H H CH 3 sec-C 4

H

9

CH(CH

3 2 0.53

-(AS)

XVII H H F H H C2H5 CH(CH 3 2

CH(OCH

3 2 0.45 -I

(AS)

XIX H H F H H C2H5 CH2CH 3

CH(CH

3 2 0.49

(AS)

XX H H F H H C2H5 CH(CH 3 2 CH2CH 3 i0.44

(AS)

*0 C 4 0 0 0 0 C. C 0 0 C S o *0 C C. C 4 C 0* C 0

S

C C C C C C

-I

0* Ex. R5R 16

R

17

R

18 R1 9

R

20 T L Rf (solvent) XXI H H OH H' H C2H5 CH-(CH 3 2

CH(CH

3 2 0.21 -(A7) XXII H H CH3 H H C2H5 CH(CH 3 2

CH(CH

3 2 0.25 _(A3) H H F H H CH3 CH3 cyclo-C3H5 0.43 XXIV H H F H H CH3 cyclo-C3H5 CH 3 0.36 (A7) XXV H H F H H C2H5 thiophen-2-yl CH(CH 3 2 XXVI H H F H H C'2H5 C6H5 CH(CH 3 2 0.42

-(AM)

XXVII H H F H H C2H5 CH(CH3)2 4-F-C6H4 0.49

_(AS)

XXVIII H H F H H CH3. 4-F-C 6

H-

4

CH(CH

3 2 0.34 XXIX H H F H H C2HS furan-2-yl CH(CH3)2 0.36 I

(A)

XXX H H F H H C2H5 CH(CH 3 )2 C6HSCH2CHCH 3 0.42

N

*Ex.

R

1 5 ji

R

17

R

1 8

R

1 9

R

2 0 T L Rf XXXI H H F H H 'C2H51 CH(CH 3 2 (solvent)0.4

_(AS)

XXXII H H F H H C2HS5

CH(CH

3 2 C6HSCHCH 3 0.45 XXXIII H H H H H C2H5S

CI-(CH

3 2 CYClO-C3H5 0.37

(AS)

XXXIV H H F H .1H C2H5

CH(CH

3 2 n-C 3H7 0.24 A3) XIXXV H H F H H C 2H,5 CH(CH 3 2 n-C4H 9 0.27 XXXVI H H F H H C2H5 CH(CH 3 2 (A3)H 2 2 XXXVII H- H F H H CH 3 4-CH3O-C 6

H

4 CH(CH 3 2 0.52 (7) XXXV9Iu H H F H H. C2H5 2-F-C6H 4

CH(CH

3 2 0.34

(AS)

XXXIX H H F H H C2H5 pyrrolidin-1-yl

CH(CH

3 2 0.35 XL H H- F H H C 2

H

5 piperidin-I-yI

CH(CH

3 2 0.47 C C.

V

a Ex. R1 1. R 17

R

18

R

19

R

20 T L Rf (solvent) XLI H H F H H C2H5 cYClO-C6Hll CH(CH3)2 0.53 XUII H H F H H C2H5 pyridin-4-yI CH(CH 3 2 0.38 XLffl H H4 F H H C2H5 pyridin-3.yl GH(CH 3 )2 0.44 XLIV H H F H H C2H5 3-CH3O-C6H4 CH(CH3)2 0.30 XLV H H F H H C2H5 4-N02-C6H4 CH(CH3)2 0.38

(AS)

XLVI H H F H H C2H5 CH(CH3)2 C6F5 0.22

(AM)

XLVII H H F H H C2H5 2-CH 3

-C

6

H

4

CH(CH

3 2 04

(AS)

XLVIII H H F H H C2H5 4-CI-C 6

H

4

CH(CH

3 2 0.21 _(A3) XLIX H H H H H C2H5 CH(CH3)2 4-F-C6H4 0.37 (A3) L H H H H H CR3 4-.F-C6H4 CH(CH3) 2 0.2 (M3) Ex. R5R6R 17

R

18

R

19

R

20 T L Rf -(solvent) u C6H 5

CH

2 O H H H H C2H 5

CH(CH

3 2 4-F-C6H- 4 0.27 LI C6H 5

CH

2 O H H -H H CH 3 4-F-C 6

H

4 CHCH) 01 LM 2-F-C6H 4

CH

2 O H H H. H C2H5 CH(CH 3 2 CH(CH 3 2 0.23 uIv 4-F-C 6

H

4

CH

2 O H H H H C 2 H 5

CH(CH

3 2 CH(CH 3 2 0.21 -(A4) LVI H4-C-C 6

H

4

CH

2 H H H C2H 5

CH(CH

3 2 CH(CH 3 2 0.12 LVii H H H H H CH 3 4-F-C6H 4 CH 3 0.21 -(A7) LVII H H F H H C2H 5 3-C1-C 6

H-

4 CH(CH 3 2 0.4

(AM)

LIX H H F H H CH 3

CH(CH

3 2 4-F-C6H 4

CH

2 0.19 -(M3) LX H- H F H H &13 4-F-C6CH

CH(CH

3 2 0.28 -I (A4) C C C C C C C CCC CC C C C C*C C C C C C C C C* C C C C xl Ex. R5R6R 17

R

18

R

19

R

20 T L Rf (solvent) LXI H H F H H CH 3

CH(CH

3 2 4-F-C6H 4

CH

2 0.23 (A4) LXII H H OCH 3 H' H CE! 3 4-F-C 6

H-

4

CH(CH

3 2 0.18 LXIII H H Cl H H CH3 4-F-C6H 4

CH(CH

3 2 0.16 (A3) LXIV H Cl H H H' CE! 3 4-F-C6H 4

CH(CH

3 2 0.28 _(A3) LXV H H F H H CR3 4-F-C 6 E14 CH(C 2

H

5 2 0.32 LXVI H Cl Cl H H CH3 4-F-C6H4 CH(CH 3 2 0.29 (M4) LXVII H CF 3 H H H CE! 3 4-F-C 6

H

4

CH(CH

3 2 0.44 LXVIII H CH 3 H H H CR3. .4-F-C 6 H4j CH(CH 3 2 0.34 _(A5) LXIX H H CH 3 H H CR3 4-F-C 6 14 CH(CH 3 )2 0.31 LXX H Cl H Cl H CE! 3 4-F-C 6

H

4

CH(CH-

3 2 0.22 1 Ex.

R

1 Ex.

R15

R

16

R

17

R

18

T

I

L

L

I I I Rf (solvent) 0.22

LXXI

H

H H CI1 3 4-F-C 6

H

4 CH(CH 3 2 LXXIl H OCH 3 H H H ICH 3 4-F-C 6

H

4 CI(I) 0.25) LXM OCH3 HH H H CH 3 4-F-C 6

H

4 CH(CH 3 2 0.2 LXXIV Cl Cl H H H CH 3 4-F-C 6

H

4 CH(CH 3 2 0.14 (A4) LXXV H

CF

3 Cl H H CR 3 4-F-C6H 4 1

CH(CH

3 2 0.21 (A4) LAkA V I t-F3

CH-

3 4-F- LXXVII H cl CF3 H H CH 3 4-- LXXVII H H F H U CH 3 4-F-( LXXIX H H F H H CH 3 4-F-C :6F4 6H4 6H4 :6H 4

CH(CH

3 2 0.24 (A4)

CH(CH

3 2 0.23 (M3) cyclo-C 5 H9 0.39 CYCIO-C3H, 5 0.28

(AS)

CH(CH

3 2 02

LXXX

H

H H CH- 3 4-F-C 6

H

4 I (4 C, C~ 4 a C-C C 0 t C C 0 CC C 0 Ex. RISR1 R 17

R

18

R

9

R

20 T L Rf (solvent) LXXXI H H CF3 H* H CH3 4-F-C 6

H

4

CH(CH

3 2 0.39 LXXXII H H F H H CH3 4-F-C 6

H

4 4-F-C 6

H

4 0.3 LXXXIII H H F H Hi CH3 CYClo-C3H5 cyclo-C3H-I 0.3 -(A5) LXXXIV Cl Cl H H H CH3 4-F-C 6

H

4 4-F-C6H 4 0.36 (A7) LXXXV H CF3 F H H CH 3

CH(CH

3 2 CH(CH3)2 0.41 LXXXVI H CF 3 F H H CH 3 4-F-C6-L1 4-F-C6H4L 0.25 LXXXVII CR3 H H H H CR3 4-F-C6H 4 CH(CH3)2 0.32 LXXXVIII Cl H H H, H CH 3

CH(CH

3 2

CH(CH

3 2 0.21

(AS)

LXXXIX Cl H H H H CR3 4-F-C6H4 CH(CH 3 )2 0.13

_(AS)

XC Cl H H H H CH 3 4-F-C 6

H

4 4-F-C 6

H-

4 0.35 Ex. R 15 XCI Cl XCII Cl XcII H XCJV H XCV H XCVI H XCV1I H XCVm H XCDX H c H H1

H

H

H

H

H

H

H

H

R

17 Cl Cl

F

F

F

F

F

F

F

F

R

18

R

19

IR

20 T L Rf (solvent) H H CHI 4-F-C 6

F

4

CH(CH

3 2 0.23 H H C.H3 4-F-C 6

H

4 4-F-C 6

H

4 0.31 H H CH3 3-CF3-C 6 Hi 4

CH(CH

3 2 0.31

_(AS)

H H CH3 3-CH 3

-C

6

H

4

CH(CH

3 2 0.31 H H CH 3 4-CH3-C 6

H

4

CH(CH

3 2 0.27

-(AS)

H H CH3 2-CI-C6H 4

CH(CH

3 2 0.27 H H CH 3 4-.CH3O-C 6

H

4

CH(CH

3 2 0.22 H H CH 3 2-CH 3

O-C

6 1-1 4

CH(CH

3 2 0.43 (A H H &13 3-CH3O-C6H4

CH(CH

3 2 0.25 H -2 H C 6 H (A 5 H H 2

H

5 ycl-C 6

H

1 4F-C 6 -1 4 0.45 00 0* 0 Ex. R 15

R

16

R

17

R

18

R

19

R

20 T L Rf (solvent) al H H F H* H CF! 3 4-F-C6H 4 cYclo-C6H11 0.33 Cii H H F H; H C2HS 4-CI.-C 6 H-4 cyclo-C5H9 0.22 _(A4) 011l H H F H H CH3 3-CF3-C6H4 CYCIO-C5H9 0.29 CIV H H F H H CH3 4-F-C 6

H

4 CYClO-C4H-7 0.2 CV H H F H H C2H 5 cYc/o-C7Hl 3 4-F-C 6

H

4 0.4 CVI H H F H H CF! 3 4-F-C 6

H

4 cyclo-C7H 13 0.3

(AS)

CVII H H F H H C2H5 furan-2-yl 4-F-C 6

H

4 0.32 (A6) CVIII H H F H H CH3 4-FC6H 4 furan-2-yl 0.21 _(A6) CD( H H F H H CF! 3 4-F-C 6

H

4 (cyclo-C5H9)CH 2 0.11 (A4) CX H H F H H C2HS5 (cyclo-C6Hll)CH 2 4-F-C 6

H

4 0.31 I_

I

Ex.

R15

IR

18 Rf I (slent) CXI H HF H H CH 3 4-F-C6H 4 (CYCIO-C6Hll)CH 2 0.21 CXII H H F H H C2H5

CF

3 4-F-C 6

H

4 0.26 CliiI H H F H H CH 3 cyclo-C5H 9 4-CF 3

-C

6

H-

4 0.30 (A4) CXIv H H F H H C2H5 4-CF 3

-C

6

H

4 cyclo-C 5

H

9 0.19 (A4) CXV H H F H H C2H5 I-naphthyl CyClo-C5H 9 0.21 (A4) CXVI H H F H H CH 3 cyclo-CSH 9 3,5-.(CF3)2-CAH 3 0.25 (M 3) CXVII H H F H H C 2

H

5 2-naphthyl

CYCIO-C

5

H

9 0.23 C(VfflI H H F H H 0-13 3-CH3-C 6

H

4 CYCIO-C5H 9 0.32 CXIx H H F H H CH3 2-CF3-C 6

H

4 cyClO-C5H 9 0.2 -a -CXX H H F H H CH3 CYCIO-C5H 9 2-CF3-C6H4 0.17 -(A5) Ut 0 000 0 0 C C U 0 0 0 0 U 0 0 0 0 C. 6 0 0 0 0 0 0 0 Ex. RIS R 16

R

17

R

18

R

19

R

20 T L Rf (solvent) CXXI H H F H -H C2H5 4-F-C6H4CH2 cyclo-C5H9 0.4 CXXII H H F H; H CH 3 cyclo-C.5H9 4-F-C 6

H

4

CH

2 0.32 CXXIIi H H F H H C2HUS 4-F-C6Hi4CH2 4-F-C6H4 0.28 CXXIV H H F H H CH3 cClO-C5H9 2,4-F2-C 6

H

3 0.32

_(AS)

CXXV H H F H H C2H5 3,4-F2-C6F-LCH2 CYClO-C5H 9 0.23 _(A4) CXXVI H H F H H CH3 cYclo-C5Hq cyclo-C5H 9 0.34 (A4) CXXVII H H F H H C 2

H

5 4-F-C 6

H-

4

CH

2 4-F-C 6

H

4

CH

2 0.4 0CXVII H H F H H C2H5 3-CF3-C6H 4 (CH2) 2 cyclo-C5H 9 0.36 MXIX H H F H H CHI cyclo-C,5H9 3-CF3-C6H 4

(CH

2 2 0.34 CXXX H H F H. H- C2H5 3-CF 3

-C

6

H

4

CH

2 3-CF3-C 6

H

4

(CH

2 2 0.35 Ex. 1 R 15 R 16R17 R18 R19 R201 T L Rf (solvent) CXx H F H H 2

H,

5 C2H 5 cyclo-C 5

H

9 04 CxXI HF H CH 3 CYCIO-C5H 9 C 2

H

5 0.32 CXXXIII H H F H H C2H 5 C2H5 C2H5 0.22 (A7) CXXXIV H H F H H C2H 5 3-CF3-C6H 4

CH

2 cyclo-C5H 9 CXXXV H H F H H CH3 cyclo-C5H 9 4-F-C6H- 4

CH

2 CXXXVI H H F H H C2H 5 (CYClO-C5H9)(CH 2 2 (cyclo-C,5H 9

)(CH

2 2 LAAX VII C2H5 (CYCIO'-CSH9)(CH 2 2 4-F-C 6

H

4 t. I. I cxxxviii

H

.H C.! 3 4-F-C 6

H

4 (cycIO-C5H 9 (Cl- 2 2

I

I

C

WO 98/04528 PCT/US97/13248 0 Example CXXXIX 2 -Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3-trifluoromethylbenzyloxyacid ethylester

F

F

3 C

COOC

2

H

N

186 mg (0.5 mmol) of 2 -cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-hydroxyacid ethylester dissolved in 5 ml of absol. dimethyl formamide is added dropwise at 0°C while stirring to a suspension of 18 mg mmol) of sodium hydride in 5 ml of dimethyl formamide and subsequently stirred for 30 minutes. After this, 143 ng (0.6 mmol) of trifluoromethylbenzylbromide dissolved in 3 ml of dimethyl formamide is added, and the mixture is stirred for 18 h at room temperature. After addition of 25 ml of water, the mixture is extracted twice with 50 ml of ethyl acetate each time, arid the combined ethyl acetate phases are shaken out with 10 ml of saturated sodium chloride solution, dried with sodium sulfate, and concentrated in a vacuum. The residue is chromatographed over silica gel (100 g of silica gel, 230-400 mesh, diameter 3.5 cm, mobile solvent ethyl acetate petroleum ether 1:9).

Yield: 0.246 g (93.1% of theory) Rf value (ethyl acetate petroleum ether 1:9) 0.35 1H-NMR (CDCl 3 8 0.95 3H); 1.32 3H); 1.6-2.1 8H);'2.78 4H); 3.44 1H); 3.95 4H); 4.28 2H); 4.42 2H); 7.0-7.6 8H) ppm.

WO 98/04528 PCTIUS97/13248 0 Example

CXL

2 6 -Diisopropy4(4fluoropheny)pyriine35dicarbxli acid diethylester

F

C

2

H

5 00C

COOC

2 H1 3.8 g (16.4 mmol) of 2,-ihoo56dcaopbnounn is added to a solution of 6.6 g (16.4 mmol) of 1 4 -dihydro-2,6-.diisopropyl-4- 4 -fluorophenyl)pyridine..35dicarboxylic acid diethylester in 200 ml of analysis grade methylene chloride, and the mixture is then stirred for 1 h at -room temperature. After this, it is drawn off by suction over diatomaceous earth, and the methylene chloride phase is extracted 3 times with 100 ml of water each time and dried on magnesium sulfate. After. concentrating in a vacuum, the resi due is chromatographed on a columnn (100 g of silica gel, 70-230 mesh, diameter 3.5 cm, with ethyl acetate /petroleum ether 1:9).

Yield: -5.8 g (87.9% of theory).

1 1--NMR (CDCl 3 5 0.98 611);,1.41 12H); 3.1 (in, 2H); 4.11 4H); 7.04 (in, 7.25 (in, 2H) ppm.

Examvle

CXLI)

2 6Diorpl4(-loohnl--yrxmty-yiie35croyi acid ethylester.

F

HH

2 C

COOCH-

N O 88 WO 98/04528 PCT/US97/13248 0 Under nitrogen, 21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis(2methoxyethoxy)dihydroaluminate in toluene is added to a solution of 9.2 g (23 mmol) of the compound from Example CXL in 100 ml of dried tetrahydrofuran at to and the mixture is stirred for 5 h at room temperature. After cooling to 0°C, 100 ml of water is carefully added dropwise, and extraction is carried out 3 times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is chromatographed on a column (200 g of silica gel, 70-230 mesh, diameter 4.5 cm, with ethyl acetate petroleum ether 3:7).

Yield: 7.2 g (87.2% of theory) 1 H-NMR (CDCI 3 8 0.95 3H); 1.31 12H); 3.05 1H); 3.48 1H); 3.95 2H); 4.93 2H); 7.05-7.31 4H) ppm.

Example CXLII 5-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3-carboxylic acid ethylester

F

CH

3

(H

3

C

3 C- Si- H 2 C COOC 2

H

CH

3

N

2.1 g (13.8 mmol) of tert-Butyldimethylsilyl chloride, 1.8 g (27.5 mmol) of imidazole, and 0.05 g of 4-dimethyl-aminopyridine are added to a solution of 4.5 g (12.5 mmol) of the compound from Example CXLI in 50 ml of dimethyl formamide at room temperature. The mixture is stirred overnight at room temperature, 200 ml of water is added; and the mixture is adjusted to a pH of 3 with 1 N hydrochloric acid. The mixture is extracted 3 times with 100 ml of ether each time, and the combined organic phases are washed once with saturated sodium chloride solution, -dried over magnesium sulfate, and concentrated in a vacuum. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, diameter 4 cm, with ethyl acetate petroleum ether 1:9).

89 WO 98/04528 -PCTIUS97/13248 0 Yield: 4.2 g (73.7% of theory) Rf 0.75 (AM) Example

CXLIII

3 -(tert-Butyldimethylsiyloxymethyl) 2 6 diisorpl 4 -(flurpeyhydroxymethylpyridine

F

CH

3

(H

3

C)

3 C- Si- 0- H 2

C

C6 3 jOH N.'9 Under argon, 76.0 ml (0.266 mmol; 3.6 eq.) of a 3.5 molar solution of sodium bi(mtoytoydhdolmnt (Red-Al) in toluene is slowly added to a solution of 35.0 g (0.0738 mmol) of the compound from Example CXLIII in 500 ml of analysis-grade TI-F at room temperature, and stirring is then carried out for 3 h.

The reaction solution is mixed under ice cooling with 50 ml of a 20% potassim sodium tartrate solution and extracted with 200 ml of ethyl acetate. The organic phase is washed once with a saturated NaCl solution, dried over Na 2

SO

4 and concentrated in a vacuum. The residue is chromatographed over silica gel 60 with toluene ethyl acetate Yield: 30.2 g (94.7% of theory).

Rf =0.71 (toluene /ethyl acetate 8:2) Example

CXLIV

3 -(tertBu tyldimethiylxmehyl)ymethy bpl) 2 4 methylsulfonyloxymetliylpyridine U WO 98/04528 WO 9804528PCTIUS97/13248

F

0 0- Si

H

3 C-S-0-HA 2

C

N

0 16.94 g (39.24 mmol) of 3-(tert-butyldimethylsilyloxymethyl)- 2 6 -diisopropyl- 4 -(4-fluorophenyl)-5-hydroxymethylpyridine is dissolved in 220 g of analysis grade CH 2

CI

2 cooled to -60*C, and mixed dropwise with 11.0 ml (78.48 mmol; 2 eq.) of triethylamine and 6.1 ml (78.48 mmol; 2 eq.) of methanesulfonyl chloride under nitrogen while stirring. Stirring is carried out for 1 h at -60*C to and for 30 minutes at 0*C. After this, the reaction solution is washed with cold NaHCO 3 solution, dried over Na 2

SO

4 concentrated, dried for 60 min. in a high vacuum, and then stored at Yield: 19.8 g (99% of theory) Rf 0.77 (toluene /ethyl acetate 8:2) Example CXLV 3 (trtButyldimeffylsilyloxymethyl)2,6.diisopropyl(4fluorophenyl)' (1.

methylimidazole..2-thiomethyl)pyridire

F

N

H

3

C

N

1.0 g (1.96 mmol) of 3 -(tert-butyldimethysilyloxymethyl).2,6.diisopropyl-4- 4 -fluorophenyl)--methylsulfonyloxymethylpyridine -is placed in 15 ml of analysis-grade DMF. 0.256 g (2.25 minol; 1.15 eq.) of 2-mercapto-1-methylimidazole and 0.41 ml (2.35 mmol; 1.2 eq.) of N,N-diisopropylamine are added, and the WO 98/04528 PCTIUS97/13248 0 mixture is stirred overnight at 60*C. After this, 80 ml of ethyl acetate is added, and the mixture is then successively washed with saturated NaHCO 3 solution, 1 N

H

2 S0 4 and saturated NaCI solution. The organic phase is dried over Na 2

SO

4 filtered, and concentrated.

Yield: 0.93 g (89.8% of theory) Rf 0.35 (toluene ethyl acetate 8:2) Example CXLVI 3-(tert-Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-

F

H

'N

H

V- M-f

N

g (3.92 mmol) of 3 -(tert-butyldimethylsilyloxymethyl)-2,6-diisopropyl-4- (4-fluorophenyl)-5-methylsulfonyloxymethylpyridine is reacted in 20 ml of analysis grade DMF under nitrogen with 0.674 g (5.1 mmol; 1.3 eq.) of 5-aminoindole and 0.82 ml (4.71 mmol) of N,N-diisopropylethylamine analogously to the instructions of Example

CXLII.

Yield: 2.05 g (95.8% of theory) Rf 0.75 (toluene ethyl acetate 8:2) Production Examples Example 1 2-Cyclopentyl-6-ethyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-(3-trifluoromethylbenzyloxymethyl)pyridine :ii- WO 98/04528 PCT/US97/13248

F

3 C 0 N OH 0 A suspension of 30 mg (0.8 mmol) of lithium aluminum hydride in 10 ml of absol. tetrahydrofuran is heated under argon. After this, 212 mg (0.4 mmol) of 2-cyclopentyl-6-ethyl-4-(4-uorophenyl)-3-(3trifluoromethylbenzyloxymethyl)pyridine-5-carboxylic acid ethylester dissolved in 10 ml of absolute tetrahydrofuran is added. Next, the mixture is refluxed for 1 h. After cooling to room temperature, ml of a 10% potassium hydroxide solution is added. The resulting sediment is drawn off by suction and boiled off several times with 10 ml of diethyl ether. The combined mother liquors are dried with sodium sulfate, concentrated in a vacuum, and chromatographed over silica gel (mobile solvent ethyl acetate petroleum ether 2:8).

Yield: 149 mg (76.5% of theory) Rf value (ethyl acetate petroleum ether 2:8) 0.08 1 H-NMR (CDC1 3 8 1.32 3H); 1.6-2.1 8H); 2.95 4H); 3.41 1H); 4.16 2H); 4.38 2H); 7.0-7.6 8H) ppm.

Example 2 2,6-Diisopropyl-4-(4-fluorophenyl)-5-(1-methylmidazole-2-thiomethyl)-3hydroxymethylpyridine

F

N S OH

H

3 C

N

N

93 WO 98/04528 PCT/US97/13248 U 10 ml of 3 N hydrochloric acid is added to 0.5 g (0.947 mmol) of the compound from Example CXLII dissolved in 10 ml of methanol, and the mixture is stirred for 3 h at room temperature. The mixture is concentrated in a vacuum, covered with a layer of ethyl acetate, and adjusted to a pH of 8.0 with a saturated NaHCO 3 solution, and the organic phase is separated off. The aqueous phase is again extracted with ethyl acetate, and the combined organic phases are washed with salt water, dried over Na 2

SO

4 and concentrated.

Yield: 230 mg (58.7% of theory) Rf 0.76 (toluene ethyl acetate 1:1) .e

I)

a .v a I o i a WO 98/04528 WO 9804528PCT/tJS97/13248 The compounds listed in Tables 1(B) through 5(B) are produced analogously to the procedures of Examples 1 and 2: Table 1(B):

'OH

Example No. RIRf (solvents)

N-

3'N 0.56 (A12)

CH

3

N-N

4 N 0.42 (A13)

N

CH

3

NN

0.12 (A13) 6 0.62 (A13) 7 CN 0.42 (A14) WO 98/04528 PCTIUS97/13248 Example No. R1Rf (solvents) 8 0.54 (A13)

I

N

0.59 (A13) 12 13 14

NH

NH

H_

N-N

N

jN.

F

3

C

CNr 0.54 (A12) 0.5 (A12) 0.68 (A13) 0.71 (A13) 0.23 (A12) bwl w WO 98/04528 WO 9804528PCTIUS97/13248 0 Example 2,6-Diisopropyl-4-(4-fluorophenyl)- 5-(indolyl-5-aminomethyl)-3-hydroxy.

methylpyridine

F

H

N

N- OH

N

Analogously to Example 2, 2.3 g (4.21 mmol) of the compound from ExamplE CXLIII is desilylated in methanol in the presence of 3 N hydrochloric acid.

Yield: 720 mg (39.6% of theory) Rf =0.48 (A13) The compounds listed in Table 2(B) are synthesized according to, these instructions' WO 98/04528 0 Table 2(B): PCTIUS97II 3248

N

H

Example No.

16 17 18 19 21

R

1

H

3

CO

CH

2 MeO 2

C

NCH

3 Rf (solvents) 0.46 (A13) 0.33 (A13) 0.86 (A13) 0.48 (A13) 0.35 (A13) 0.39 (A13) WO 98/04528 0 Table 3(B) PCTIUS97/13248 R' E-O'

OH

Ex. R 17 Rl-E T L Rf (solvent) 22 F 4-F-C6JH

CH(CH

3 2

CH(CH

3 2 0.43

(AM)

23 F 4-CF 3

-C

6

W

1

GH(CH

3 2

CH(CH

3 2 0.40

(AM)

24 F 3-CF3-C6H 4

CH(CH

3 2

CH(CH

3 2 0.47

(AM)

F 2-CF3-C 6

H

4

CH(CH

3 2 CH(CH3) 2 0.41

(AM)

26 F 4-F-C6H 4

(CH

2 2

CH(CH-

3 2

CH(CH

3 2 0.17

(MS)

27 1H 12-CF3-C6H 4

(CH

2 2

CH(CHA)

2

CH(CH

3 )1 2 0.38

(AS)

28 1F 12-F-C6H4(CH 2 2

CH(CH

3 2

CH(CH

3 2 0.16 (M3) 29 F 4-CF3-C6NH~C~c 3

CH(CH

3 2

CH(CH

3 2 0.17 (A3) F 3-CF3-C6H 4 1(CH- 2 2

CH(CH

3 2

CH(CH

3 2 0.49 31 F 3-CF3-C61-MCCH 3 CH(CH3) 2

CH(CH

3 2 0.47

(AS)

32 F 0 NCH 2

CH

2

CH(CH

3 2

CH(CH-

3 2 02 (All) 33 F (4-pyridyl)CH 2

CH(CH

3 2

CH(CH

3 2 0.16 (A9) 99 WO 98/04528 Ex. RI 34 F

F

36 F 37 F 38 F 39 F

F

41 F 42 F 43 F 44 F

F

46 F 47. F 48 F 49 F

H

17 Rl-E (3-pyridyl)CH2 (2-pyridyl)CH 2 4-Ph-C 6

H

4 3-Ph-C 6

H

4 2-Ph-C6H4 4-.F-C6H 4

(CH

2 3

N

N N- C 6

H

4 (1-naphthyl)CH- 2 2-naPhthYL(Q-1 2 2 1-naphthyl(CH 2 2 C6HS 4-F-C61i4 4-CF3-C 6

H

4 3-CF3-C6]HA 2-CF3-C6H4 4 -F-C6H4(CH2) 2 2-CF 3

-C

6

TH

4

(CI-

2 2 PCTIUS97/13248

T

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2

CH(CH

3 2 CH(CHk) 4-F-C 6 4 4-F-C6H 4-F-C6HA 4-&C- 4-F-C 6

H

4-F-C 6

H

4 L Rf (solvent)

CH(CH

3 2 0.20 (A9)

CH(CH

3 2 0.38 CH(CH3)2

CH(CH

3 2 0.24 (A4)

CH(CH

3 2 0.27 CH(CH32 0A4)

CH(CH

3 2 0.26 (A9)

CH(CH-

3 2 0.14 (A3)

CH(CH

3 2 0.13

CH(CH-

3 2 0.14 (A3)

CH(CH

3 2 (A3)

CH(CH

3 2 0.15 (A3)

CH(CH

3 2 0.4

-(AS)

CH(CH

3 2 0.42

CH(CH

3 2 0.40

(AS)

CH(CH

3 2 0.45

(AS)Q

CM-(CH

3 2 0.41 100 WO 98/04528 PTU9134 PCTIUS97113248 Ex. R 1 7

R

1 -E T L Rf 51 F 2-F-C6H 4

(CH

2 2 4-F-C6H4 CH(GH 3 2 0.14 (M3) 52 F 4-CF3-C6H4CHCH 3 4-F-C6H4 CH(CH 3 2 0.11 53 F 3-CF3-C6H 4

(CH

2 2 4-F-C6H 4

CH(CH

3 2 0.43

(AS)

54 F 3-CF3-C6H 4

CHCH

3 4-F-C 6

H

4

CH(CH

3 2 0.42 F 0 NCH 2

CH

2 4-F-C6NH CH(CH 3 2 0.48 (A9) 56 F (2-pyridyl)CH2 4-F-C6H 4

CH(CH

3 2 0.20 (A9) 57 F (3-pyridyl)CH2 4-F-C6H 4

CH(CH

3 2 0.19 (A9) 58 F 4-F-C 6

H-L(CH

2 3 4-F-C 6

H

4

CH(CH

3 2 0.33

(AS)

59 F (4-pyridyl)CH 2 4-F-C 6

H

4

CH(CH

3 2 0.25 (All) F 2-Ph-C 6

H

4 4-F-C 6

H

4

CH(CH

3 2 0.38 61 F 3-Ph-C 6

H

4 4-F-C 6 4

CH(CH

3 2 0.32 62 F 4-Ph-C 6 H4 4-F-C 6

H

4

CH(CH

3 2 0.33

(AS)

63 F 2.-naphthyi(CH 2 4-F-C 6 FkL CH(CH 3 2 0.33

(AS)

64 F 1-naphthyl(CH 2 4-F-C 6

H

4

CH(CH

3 2 0.32

(AS)

F 2-naPhthYl(CH 2 2 4-FP-C 6 11 4

CH-(CH

3 2 0.34

(AS)

66 F 1-ntaphthyl(CH- 2 2 4-F-C 6

H

4

CH(CH-

3 2 0.34 (A3) 67 F 4-CF3O-C 6

H-

4

CH

2 4-F--C 6

H

4

CH(CH

3 2 0.31

(AS)

101 WO 98/04528 Ex. R 1 l 68 F 69 F

F

71 F 72 F 73 F 74 F

F

76 F 77 F 78 F Rl-E 3-CF3O-C 6

H

4

CH

2 3-CF3-C6H 4

(CH

2 3 L-FOC1kH 4-CF3O-C 6

H

4

CH

2 3-CF3-C 6

H

4

CH

2 4-F-C6H 4 0(CH 2 2 3-CF 3

-C

6

H-

4 4-CF3-C 6

H

4 3-C F3-c6H 4

(CH

2 2 3-CF3O-C61ULCH 2 3-CF3-C6HACH 2 PCTIUS97/13248

T

4-F-C 6 H4 4-F-C6H 4 4-F-C 6

H-

4 4-F-C 6

H-

4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6

H

4 3-CF3-C 6 11 4 4-F-C 6

H

4

L

CH(CH

3 2

CH(CH

3 2 CYCIO-C5H 9 cyclo-C5H 9 cyclo-C5H 9 cyclo-C 5

H

9 cycLo-C 5

H

9 cyclo-C5H 9 cyclo-C 5

H

9 cyclo-.C 5

H

9 4-F-C6H 4 Rf -(solvent) 0.34

(AS)

0.16 0.35

(AS)

0.33

(AS)

0.28 (A4) 0.67 0.46

(AS)

0.42

(AS)

0.4-2

(AS)

0.33

(AS)

0.20 (A7) e- 102 WO 98/04528 0 Table 4(B) PCTIUS97/13248 R'-E-O OH Ex. R 1 -E T L Rf (solvent) 79 2-CN-C6 4

CH

2

CH(CH

3 2

CH(CH

3 2 0.16 (M3) 3-CN-C 6

H

4

CH

2

CH(CH-

3 2

CH(CI-

3 2 0.10 I_ (AM) 81 14-CN-C6HCH 2

CH(CH

3 2 CH(C11 3 2 0.10

(AM)

82 14-F-C6H4CH 2 cyci o-C 315 CH(CH 3 2 0.46 _(A5) 83 4-F-C614 4

CH

2 C2H5 CH(CH 3 2 0.36 84 C6HSCH 2

C

2 H5 CH(CH 3 2 0.36 4-F-C6H 4

CH

2

CH(CH

3 2 pyrrolidin-1-yl 0.10 (M3) 86 3-CF3-C6H 4

CH

2

CH(CH

3 2 cyclo-C 6

H

11 0.15 (M3) 87 4-F-C 6

H

4

CH

2

CH(CH

3 2 cYdJo-C 6 Hjj 0.15 88 -F-C6H 4

CH

2

CH(CH

3 2 2-CH3-C 6

H

4 0.12 89 4-F-C 6

H

4

CH

2 CH(C-1 3 2 4-C1-C 6

H-

4 0.19 4-F-C 6

H

4 C14 2 4-F- CH(CH 3 2 0.11 4

(CH,

2 (M3) 91 3-CF3-C 6

H

4

CCH

2 4-F-C 6

H-

4

CF

3 0.24 I_ (AS) 103 wo 98/04528 Ex. Rl-E T L Rf (solvent) 92 4-F-'C6H 4

CH

2 4-F-C 6

H-

4 CF 3 0.25 A r) PCTIUS97/13248 93 94 3-CF3-C6H 4

CH

2 4-CF3-C6H 4

CH

2 2,4-F2-C 6

H

3 2,4-F2-C 6

H

3 cyclo-C 5

H

9 cyclo-C 5 1- 9 0.18 (A4) 0.22 (A4) 104 Table R 1

~OH

Ex. RIS R 16

R

17

R

18

R

19 RLT L Rf H H F H H C6H5CH-2 CH(CH3)2 CH(Ci1 3 2 0.41 (A3) 96 H H F H H 4-F-C6H 4

CH

2

CH(CH

3 2

CH(CH-

3 2 0.20 (A3) 97 H H F H H 3-F-C6H 4 CH2 CH(CH 3 2

CH(CH

3 2 0.17 _(M3) 98 H H F H H 2-F-C6H4CH2 CH(CH 3 )2 CH(CH 3 2 0.21 (A3) 99 H H F H H 44(enzothiazol-2-yl)-C6H 4

CH

2 CH(CH3)2 CH(CH 3 2 0.09 (A3) H H F H H 4-CF3O-C6FkCH 2

CH(CH

3 2

CH(CH

3 2 0.25 (A3) Ex. RIS R 16

R

7 1R 18

IR

19

RI-E

F

SH 2-naphth9 i-CH- 2 T I T

L

CH-(CH

3 2 CH(CH 3 2

CH(CH

3 2 CH(CH 3 2

CH-(CH

3 2 CH(CH 3 2

H

H

4-[(4-tolyl)S(D:J-C6H4CH2 Rf (solvent) 0.20 (M3) 0.13 (A4) 0.23 I T t I i i

I

4 CI-C6H 4

CH

2 1 1 f I f 104j H H 1 F H IHJ 4-CH3O-C 6

H

4

CH

2 3-CH3O-C 6

F

4

CH

2 I I I1 106 1H H F H I H 3,4-F2-c6H 3

CH

2 107 H. H F H H 2,4-F2-CtH 3

CH

2 108 H H F H H 2-CH3-C6H-LCH 2 109 H H F H H 3-CH3-C 6

H

4

CH

2 CH(CH)2 C(CH3(A0.1

CH(CH

3 2 CH(CfH 3 2 0.17 (A3)

CH(CH

3 2 CH(CH- 3 2 0.27

CH(CH

3 2 CH(CH3) 2 0.15 (A3)

CH(CH

3 2 CH(CH 3 2 0.25 (A3)

CH(CH

3 2 CH(CH 3 2 0.30

CH(CH

3 2

CH(CH

3 2 0.61

(AS)

110 4-CH3-C6H 4

CH

2 0~ P 0 C C 00 C.

0* 0 o P 0 Ex. RIS R 16

R

17

R

18

R

19 Rl-E' T L Rf (solvent) ill H H F H H 4-F-C6H 4

CHCH

3

CH(CH

3 2

CH(CH

3 2 0.21 112 H H F H H 2,6-(CH3)2-4-(t-C4H9)-C 6

H

2

CH

2

CH(CH

3 2

CH(CH

3 2 0.25 113 H H F H -H 4-(i-C3H7)-6H4CH 2 CH(CH3) 2

CH(CH

3 2 0.22 (A3) 114 H H F H H 2,4,6+(-C3H7)3-C6H2CH 2

CH(CH-

3 2

CH-(CH

3 2 0.36 (M3) 115 H H F H H 3-(C6H-50)-5..CH 3

-C

6

H

3

CH

2

CH(CH

3 2

CH(OH

3 2 0.25 1 1 1 11 1(A3) 1161 H IH F IH IH I2,4-C12-q6H3CH 2

CH(CH

3 2

CH(CH

3 2 0.24 (_A3) 1117 H H F H H- 3-CF3-4-CI-C 6

H

3

CH

2

CH(CH

3 2

CH(CH

3 2 0.19 (M3) 118 H H F H H 3-CF3-C6H 4

CH

2

CH(CH

3 2

CH(CH

3 2 0.13 (M3) 119 H H F H H C6H5CH 2 CH(CH 3 2 CH3 0.11 (M3) 120 H H F H H 4-F-C61{ 4

CH

2 CH(CH 3 2

CH

3 0.29 I I I Ex. R 1 5

R

1 6

R

1 7

R

1 8 121 H H F H 122 H HF

H

123 H H F H 124 H H F H RlR 1 -E T L Rf (solvent) H

-F-C

6 1 4

CH

2 CH(CH 3 2 CH 3 0.13 H C6H5CH 2 CH 3 cYClo-C3H 5 0.14 (A3) H C6H5CH 2 CH(CH 3 2 CH(CH 3 2 0.53 H 4-F-C6H 4

CH

2 CH(CH- 3 2 CH(CH 3 2 0.47 125 F H IH C6H5CH 2 CH(CHJ 3 2 cyclo2 CoIi 9

(_AS)

0.57

(AS)

126J IH F HJ 'H C6H5CH2- 127 128

H

H-

HI F H 4-F-C6H4CH 2 121H 130 H F

F

H

H

7H 3-F-C6H-LCH 2 H 2-F-C6FkCH 2 H 44(enzothiazol-2-yl)-C 6

H

4

CH

2 ZC(C3 2CH(CH 3 2 0.23

(AM)

C6H5

CH-(CH

3 2 0.43

C

6

H

5 CH(CH 3 2 0.13 (M3) C6H5

CH(CH

3 2 0.16

(AM)

C6H- 5 =CH(CH 3 2 0.33

(AM)

~-cc o u ee 4 U C C C C

C

C ~C 4 S S

C

cc o Ex. R 15

R

16

R

17 Rl 8

R

19

R

1 -E T L Rf (solvent) 131 H H F H H 2-naphthyl-CH2 C6H,5 CH(CH 3 )2 0.31 (A4) 132 H H F H H 4-CF3O-C 6

H

4

CH

2

C

6 H5 CH(CH 3 2 0.31 (A4) 133 H H F H 14 4-[(4-tolyl)S02]-C6H4CH2 C6H5 CH(CH3)2 0.15 134 H H F H H 4-F-C6H4CH2 CH(CH 3 2 4-F-C 6

H

4 0.46

(M)

135 H H F H H 4-F-C6H 4 CH2 4-F-C 6 11 4

GH(CH

3 2 0.57 136 H H F H H 4-C1-C6H 4 CH2 4-F-C 6 H4 CH(CH 3 2 0.21 137 H H F H H 4-(i-C3H7)-C6FUCH 2 4-F-C 6

H

4

CH(CH

3 2 0.20 (A3) r138 H H F H H 3-(2-F-C 6

H

4 0)-C 6

H

3

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.44 1 939 H H F H H 3-(4-F-C6H4O)-C6H 3

CH

2 4-F-C6H 4

CH(CH

3 2 0.41 140 H H F H H 3,4-F2-C6H 3

CH

2 4-F-C 6

H

4 CH(CH3)2 0.17 _(M3) Ex. R 1 5

R

1 6

R

1 7 RIS R 19 Rl-E T L Rf (solvent) 14. H. H F H H 2AFC6H 3

CH

2 4-FC 6

H

4

CH(CH

3 2 0.18 (A3) 142 H H F H H 2-CH3-C6H.

4

CH

2 4-F-C 6

H-

4

CH(CH

3 2 0.09 (A2) 143 H H F H 113-CH3-C6H 4

CH

2 4-F-C6H 4

CH(CH

3 2 0.22 (A3) 144 H H F H H 4-CH3-C6H 4

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.23 (A3) 145 H H F H H 4-CF3-C 6 Hi 4

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.12 (M3) 146 H H F H H 4-F-C6H4CHCH 3 4-F-C6H 4

CH(GH

3 2 0.28 (A3) 147 H H F H H 2,4-C12-C6H 3

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.23 (M3) 3-CF3-4-Cl-C6H 3

CH

2 4-F-C 6

H

4 CH(CH 3 2 0.16 H.49jH H F H H3,-CF3-C6H 4

CH

2 4-F-Cl-Li(C3) 04 150 2-Cl-4-CF3-C6H 3

CH

2 4-F-C 6

H

4 CH(CH 3 2 0.35 (A4) J L I I b* S S S* Ex. R 15

R

16

R

17

R

18 0 9 Rl-E T L Rf 151 H H F H H 3-{4-(C6HS)-C6H4OIC 6

H

4

CH

2 4-F-C6H 4

CH(CH

3 2 0.19

(AS)

152 H H F H H 2-F-C 6 H-4CH 2 4-F-C6H 4

CH(CH

3 2 0.42 153 H H F H H 3-F-C6H-LCH 2 4-F-C 6

H

4

CH(CH

3 2 0.46 154 H H F H H 3-(C6H50)-59-CH 3

-C

6

H

3

CH

2 4-F-C6H 4

CH(CH

3 2 0.46

CH

2 155 H H F H H 0 4-F-C 6

H-

4

CH(CH

3 2 0.42 C(S 156 H H F H H. 3,5-(CF3)2-C6H 3

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.28

(AS)

157 H H p H H 4-F-C6H4CH2 2-F-C6H 4

CH(CH

3 2 0.36

(AS)

158 H H F H H 4-FC6H 4

CH

2 pyrrolidin-1..yl

CH(CH

3 2 0.14 (M3) 159 H H F H H 3-CF3-C 6

H

4

CH

2

CYCIO-C

6

H

11

CH(CH

3 2 0.58

(AS)

I I I *I I Ex.I R 15 Rl-E

L

1 t i 1 1 Rf (solvent) 0.53

H

H 4-F-C 6

H

4

CH

2 CYCIO-C6H11

CH(CH

3 2 161 H H F H H 4-F-C6H 4

CH

2 2-CH 3

-C

6 F-L CH(CH 3 2 0.15 (M3) 162 H H F H H 3-CH3-C6H 4

CH

2 4-CI-C6H4

CH(CH

3 2 0.19 163 H H F H H 4-F- C6F 4

CH

2 4-CI-C6H 4

CH(CH

3 2 0.28 164 H H F H H 3,4-F2-C6H3CH2 4-CI-C6H 4 CH(C H 3 2 0.18 (3) 1651 H IH F H H 4-F-C6H 4

CH

2 4-Cl-C6H 4

CH(CH

3 2 0.20 (A3) 166 H H F H H 4-CI-C 6

H

4

CH

2 4-CI-C-6HA

CH(CH

3 2 0.25 (M3) 2-CH3-C 6

H-

4 CH4 2 4-CI-C 6

H

4 t I t I I I I 4-CH3-C6H4CH 2 4-Cl-C6H4

CH(CH

3 2 0.49

CH(CH

3 2 0.51

CH(CH

3 2 0.29 (A4)Q ~1 I' t I I* I

H

H 3-CF3-C6H 4 CH1 2 4-C1-C 6

H

4 C. C~ 14 Ex. RIS R 16

R

17

R

1 8 R 19 Rl-E T L Rf 170 H H F H H 2,4-C1 2

-C

6

H

3 CH2 4-CI-C6H4 CH(Cl1 3 2 0.19 171 H H F H H 4-F-C 6

H-LCH

2 CH(CH3)2 4-F-C 6 H4 0.36 172 H H F H -H 4- F-C6H-LCH2 4-F-C6H4 CH(CH3)2 0.42 173 H H F H H 3-CF 3

-C

6

H

4 CH2 4-F-C 6 H4L CH(CH 3 2 0.30 (A4) 174 H H F H H 3,4-F2-C6H3CH 2 4.-F-C6H4 CH(CH3)2 0.09 (A3) 175 H H F H H 2,4-F 2 -C6H3CH 4-F- .C6H4 GH(CH3)2 0.13 176 H H F H H 2,4-C12-C6H3CHl 4-F-C6F-4 CH(CH 3 2 0.13 1 (M3) (Continued) Ex. R5R 16

R

17

R

18

R

19 Rl-E T L Rf (solvent) 177 C 6

H

5

CH

2 O H F H H 4-F-C6H4CH 2

CH(CH

3 2 4-F-C 6

H

4 0.08 (A3) 178 C6H5CH 2 O H F H H 4-F-C 6

H-LCH

2 4-F-C 6

H

4

CH(CH

3 2 0.11

(AM)

179 2-F-C61-LCH 2 O H F H H 4-F-.C6H 4

CH

2

CH(CH

3 2

CH(CH

3 2 0.11 (M3) 180 4-F-C6H 4

CH

2 O H F H H 4-F-C"HCH 2

CH(CH

3 2

CH(CH

3 2 0.17 (3) 181 4-CI-.C6H4CH 2 O H F H H 4-F-C6H 4

CH

2

CH(CH

3 2

CH(CH

3 2 0.11 (M3) 182 H 2-F-C6H4CH 2 O F H H 4-F-C6H 4

CH

2

CH(CH

3 2

CH(CH

3 2 0.17 1 I(M3) '.0 9 a t a a 'IT) 4* a a a a a a a a a a a. a a a a a a

S.

JOC

Table (Continued)

-A

-U,

Ex. RIS R 16

R

17

R

18

R

19 RI-E T L -Rf (solvent) 183 H H F H H 4-F-C 6

H

4

CH

2 4-F-C 6

H

4

CH

3 0.10 184 H H F H H1 3,4-F2-C6H3CHi 2 4-F-C 6

H

4

CH

3 0.31 (A7) 185 H H F H H 3-CF3-C6H4CH2 4-F-C 6

H

4 CH3 0.28 (A7) 186 H H F H H 3,4-F2-C6H 3

CH

2 3-Cl-C6H4 CH(CH 3 2 0.73 187 H H F H H 4-F-C6H 4

ICH

2 3-Cl-C6H4 CH(CH 3 )2 0.62 188 H H F H H 4-F-C6H 4 C H 2

CH(CH

3 2 4-F-C 6

H

4

(CH

2 2 0.31

(AM)

189 H H F H H 3,4-F2-C6H 3

CH-

2

CH(CH

3 2 4-F-C6H4(CH 2 2 0.37

(AM)

190 H H F H H 4-F-C 6

H

4

CH

2 4-F-C6H 4

CH

2

CH(CH

3 2 0.22 191 H H F H H 4-F-C 6

H

4

CH

2

CH(CH

3 2 4-F-C6H 4

CH

2 0.19 Ex. R 1 5

R

1 6

R

1 7

R

1 8

R

1 9

R

1 -E T L Rf0 00 (solvent) 192 H H19 3 H H4FC6-IH 6 H

HC

3 2 04 193 H H OCH3 H IH 4-FC6H 4

CH

2 4-F-C6H.

4

CH(CH

3 2 0.65 0

(AS)

194 H H Cl H H

-F-C"HCH

2 4-F-C6 H 4 CH(CH 3 2 0.09 (A3) 195 H Cl H H H -CF-C6 4

CH

2 4-.F-C 6

H

4 CH(CH 3 2 0.15 A3) 196 H Cl H H H

-F-C

6

H

4

CH

2 4-F-C 6

H

4 CH(CH 3 2 0.29 (A3) 197 H Hl F H H 3-CF-C6H 4

CH

2 4-F-C6H 4 C(2S 2 02 198 H H F H H -F-C6H 4

CH

2 4-F-C6H 4 CH(C 2

H

5 2 0.56

(MS)

1991 H CH CF H H

-CF-C

6

H

4

CH

2 4-F-C 6

H

4 CH(C2H) 2 0.59 21 H CH 3 H H H 4-F-C6H 4

CH

2 4-F-C 6

H

4 CH(CH 3 2 0.519 H 0CF H H H 4- 6H C 20 *0-C H C H 0.4 H 0H H0 H H 4- -60H 4 -C H 0H 0.51 Ex. R 15

R

16

R

17

R

18

R

19 Rl-E T L Rf (solvent) 202 H CH3 H H H 3-CF 3

-C

6

H

4

CH

2 4-F-C 6 H4i CMH(C- 3 2 0.08 (A3) 203 H H CH3 H H 4-F-C6H 4

CH

2 4-F-C6H4 CH(CH 3 2 0.55 204 H Cl H Cl 14 4-F-C~fkCH2 4-F-C6H 4 CH(CH3)2 0.37 205 H OCH 3 H H H 4-F-C6H 4

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.37 206 OCH 3 H H H H 4-F-C 6

F

4

CH

2 4-F-C 6

H

4

CH(CH

3 2 0.32

(AS)

207 Cl Cl H H H 4-F-C6HICH 2 4-F-C6H 4 CHRCH3)2 0.19

(AS)

208 H CF3 Cl H H 4-F-C6HFiCH2 4-F-C6H 4 CH(CH3) 2 0.43

(AS)

209 H CF 3 F H H A-F-C 6 H-LjH 2 4-F-C6H 4

CH(CH

3 2 04

(AS)

210 H' Cl CF 3 H H .4-FC6HCH 2 4-F-C 6 Fk1 CH(CH 3 2 0.54

(AS)

211 H H F H H 4-F-C6H-4CtH 2 4-F-C6H 4 cyclo-C5H9 0.31 I I I *I I 1 Ex. RIS

R

17

I

1 R18 Rl-E 212 H IH 3,5-4CF3)2-iZ6H 3

CH

2 213 H H F. H H 3-CF3-C 6

H

4

CH

2 214 H- H F H H 2,4-C12-C6H3CH 2 215 H H F H H 3-CF3-4C-C 6

IH

3

CH

2 216 H 217 I*1 218 H 219* H 220 H 221 H t t

H

H

H

H

H

F H F H F H F H

CF

3 H F

HN

H

H

H

H

H.

4-F-C6H 4

CH

2 3-CF3-C6H 4

CH

2 2,4-C12-C 6

H

3

CH

2 4-F-C6H 4

CH

2 4-F-C6H 4

CH

2 4-F-C6H 4

CH

2 T L Rf (solvent) 4-F-C6H 4 cyclo-C5H 9 0.37 4-F-C 6

H.

4 cYclO-C5Hq 0.23 (M4) 4-F-C 6

H

4 cYclO-C.

5

H

9 0.49

(AS)

r 4-F-C6

H

4 cyclo-C5H9 0.47 4-F-C 6

H

4 CYCIO-C3H 5 03 4-F-C6H 4 cYcIO-C3H 5 0.14 (A4) 4-F-C 6

H

4 CYClO-C 3

H

5 0.49 4-F-C 6

F

4 CH(CH 3 2 0.38 ~C0 c 0* 0~ S Q. 10 5* C S S Ex. R 15

R

16

R

17

R

18

R

19

R

1 -E T L Rf (solvent) 222 H H F H H 4-F-C6H4CH2 4-F-C6H4 4-F-C 6 H4 0.24 223 CI Cl H H. H 4-F-C 6 1{ 1

CH

2 4-F-C6H4 CH(CH 3 )2 0.42 224 CI H H H H 4-F-C6H4CH2 CH(CH 3 )2 CH(CH3)2 0.33

_(AM)

225 Cl H H H H 4-F-C 6

H

4 CH2 4-F-C6H4 4-F-C 6 H4 0.18 226 Cl H Cl H H 4-F-C 6 1{4CH2 4-F-C611 4

CH(CH

3 2 0.50 227 CI H Cl H H .47F-C 6

H

4

CH

2 4-F-C 6

H

4 4-F-C6H4 0.34

_(AM)

228 H H F H H3-CF 3

-C

6

H

4 CH2 3-CF 3

-C

6

H

4

CH(CH

3 2 0.46

_(AS)

229 H H F H H 4-F-C6H 4

CH

2 3-CF3-C 6

H

4

CH(CH

3 )2 0.47

(AS)

230 H H F H H 4-F-C6H4CH2 3-CH3-C6H4 CH(CH 3 )2 0.25 21 H H F, H H 3-CF3-C6H4CH2 3-CH3-C 6 H4 CH(CH 3 2 0.22 (A4) Ex.- 232 R

R

16 H H

R

18

R

19

R

1 -E T

L

H H 4-]F-C 6

H

4 CHi 2 4-.CH3-C 6

H-

4

CH(CH

3 2 H 3-CF3-C6H 4

CH

2 4-CH 3

-C

6

H

4

C(H)

H H 3-CF3-C6H 4

CH

2 2-Cl-CAHA CHITCH-N- Rf (solvent) 0.32 (A4) 0.25

(A)

233 1 H I H IT 234 H 23.1 H 1 F H H 4-F-C6H 4

CH

2 31L0.20 2-CI-C6H 4 CH(CH 3 2 0.21 4-_CH3O-C6H4

CH(CH

3 2 02 [236 H fH ~F H !Ht .F-64H H H H F H H 239 1H) HI FH 4-F-C6H4CH 2 4-CH3O-C 6

H

4

CH(CH

3 2 0.27 3-CF3-C6H 4

CH

2 2-CH3O-C 6 -L

CH(CH

3 2 0.18 .4-FC6HCH22-C30-CH4 H(C3)2(A5) 4-F-6H4C 2 2-H3OC 6

H

4

CH(C

3 2 0.21

(AS)

3-CF3-C6H 4

CH

2 3-CH3O-C 6

H-

4

CH(CH

3 2 0.14 (A4) 4-F-C 6

H

4

CH

2 3-CH3O-C 6

H-

4

CH(CH

3 2 0.15 (A4) Un 113IT- H(Hj 241

H

I

LA

H VIY

H

cc. O.OC~jt2 Ex. RIS R 16

R

17

R

18

R

19 Rl-E T L Rf 242 H H F H H 3-CF3-C 6 1- 4

CH

2 cYclo-C6Hll 4-F-C 6

H

4 0.40

LA)

243 H H F H H 4-F-C 6

H

4

CH

2 CYCIO-C6H11 4-F-C 6

H

4 0.45 244 H H F H H 3-CF3-C6H4CH2 4-F-C6H4 cyclo-C6H11 0.37 245 H H F H H 4-F-C 6

H

4

CH

2 4-F-C 6

H

4 cyclo-C6Hjj 0.43 246 H H F H H 3-CF 3 -4-CI.C 6

H

3

CH

2 4-F-C 6

H

4 CYClo-C6H11 0.29 .247 H H F H H 2,4-C12-C6H3CH2 4-F-C6H4 CYCIO-C6H11 0.35 _(AS5) 248 H H F H H 3-CF 3

-C

6

H

4

CH

2 4-Cl-C6H4 cyclo-C5H 9 0.56 249 H H F H H 3-CF 3

-C

6 F4LCH 2 3-CF 3

-C

6

H

4 cyclo-CSH 9 0.44

(AS)

250 H H F H H 4-F-C6H4CH 2 3-CF3-C6H 4 cyclo-C 5

;H

9 0.41 251 H H F H H 3-CF 3

-C

6

H

4

CH

2 4-F-C 6 11 4 cYClO-C4H7 0.36 Ex. IR 15

I

1

R

17

IR

18

IR

19 RI-E T L IRf 00 ~(solvent) a 252 H H F H H 4-F-C 6 H4 4

CH

2 4-F-C 6 H CYCIO-C 4

H

7 0.38 00 (A 253 H H F H H 3-CF 3

-C

6

H-

4

CH

2 cyclo-C7Hl 3 4-F-C 6

H

4 0.35

(AS)

254 H H F H H 4-F-C6F 4

CH

2 cyci o-C 7H713 4-F-C6H 4 0.33 255 H H F H H 3-CF3-C 6

H

4

CH

2 4-F-C 6

F

4 cYclO-C7HI 3 0.39 256 H H F H H 4-F-C6H 4

CH

2 4-F-C 6

H

4 ccl- 7 13 04 H H F H

F&HC

2 furan-2-yl 4-F-C6H 4 0.13 258 H H F H H 3-CF3-C6H 4

CH

2 4-FC 6

H

4 furan-2.yl 0.18

(AS)

259 H H F H H 4-F-C6H 4

CH

2 4-F-C 6

H

4 (cyclo-C5H 9

)CH

2 0.25

(AS)

260 H H F H H 3-CF3-C6H 4

CH

2 4-F-C 6 Fk1 (coC 5 9 )i 0.2 261 H H 3,-(C3)2- 6

H

3

H

2 -F-6H 4 (cyclo-C5H 9

)CH

2 0.23

(AS)

2 6 1 H H 3 5 F 3 C 1 1 3 H 2 4 F C H 4 C c I C H 9 C .20 .2 A Rl Cgo Ex, R 15

R

16

R

17

R

18

RI

9 Rl-E T L Rf 262 H H F H H 3-CF3-C6H4CH2 4-F-C 6

H-

4 (cyclo-C6Hll)CH 2 0.24 263 H H F H H 4-F-C6H4CH2 4-F-C6H 4 (cYclO-C 6 Hll)CH 2 0.25 264 H H F .1 H 3-.CF3-C6H4CH2 4-CF3-C6H 4 cyclo-C5H9 0.40 265 H H F H H 4-CF3-C6FkCH2 4.-CF3-C 6 H4L cyclo-C5H 9 0.30 266 H H. F H H 3-CF 3

-C

6

H

4 CH2 1-naph thyl cyclo-C5H 9 0.24 267 H H F H H 4-CF3-C6H4CH2 1-naphthyl cyclo-C5H9 0.14 268 H H F H H 3-CF3-C6H 4 CH2 2-naphthyl cyclo.-C5H9 0.32 269 H H F H H 4-CF3-C 6 H4CH 2 2-naphthyl cyclo-C5H9 0.23 270, H H F H 14 3-CF3-C6Ii4CH2 3-CH3-C6H 4 cyclo-C5H 9 0.22 271 H H F H H, 4-CF 3

-C

6

H-LCH

2 3-CH 3

-C

6

F

4 CYCIO-C5H 9 0.21 _(M4) Ex. R 15

R

16

R

17 IRIB R 19 RI-E

T

L jRf I -iI -(solvent) 272 H H F H H4-CF3-C6H4CH 2 2-CF 3

-C

6

H

4 CYCIO-C5H9 0.13 273 H H F H H 3-CF3-C6H 4

CH

2 2-CF 3

-C

6

H

4 cyl- 9018 274 H H. F H H 3-CF3-C6H 4

CH

2 4-F-C6H 4

CH

2 cyclo-C.

5

H

9 0.24 275 H H F H H 4-CF3-C6H 4

CH

2 4-F-C6H 4

CH

2 cyclo-C5H9 0.26

(AS)

276 H H F H H 3-CF3-C 6

H

4

CH

2 3,4-F2-C 6

H

3 CYClo-C 5

H

9 0.29 1 1 1 (A4) 2771 H. H F H H 4-CF3-C6H4CH 2 3,4-F2-C6H 3 cYclO-C5H9 0.30 (A4) 278 H H F H H 3-CF3-C6H 4

CH

2 cyclo-C5H 9 cyclo-C5H 9 0.23 (M3) 279 H H F H H 4-CF3-C6F 4

CH

2 cyclo-C 5

H

9 cyclo-C 5

H

9 0.27 (A3) 280 H H F H H 3-CF3-C6H 4

CH

2 3-CF3-C 6 1- 4

(CH

2 2 CYCIO-C5H 9 0.35

(AS)

281 H H F H H 4-.CF3-C6H 4

CH

2 3-CF3-C6H 4

(CH

2 2 cyclo,-C5H 9 0.33 *fl t* Ex. IR 15

R

16

R

17

R

18

R

19 Rl-E T L Rf (solvent) 282 H H F H H 3-CF3-C6H 4

CH

2 3-CF3-C61-L(CIH 2 2 .3-CF3-C6H- 4

(CH

2 2 0.20 (A7) 283 H H F H H 4-CF3-C 6

H

4

CH

2 3-CF3-C 6 1- 4

(CH

2 2 3-CF3-C6H- 4

(CH

2 2 0.20 (A7) 24 H H F H H 3-CF3-C6H4CH 2 C2H5 ciyclo-C5H 9 0.36 (A6) WO 98/04528 PCT/US97/13248 0 Detailed description with reference to compounds of general formula (IC) In the above structural formula (IC) the following terms have the indicated meanings: The term alkyl means alkyl groups which are straight chain or branched and have the designated number of carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, and isohexyl.

The term cycloalkyl means an alkyl group which is in the form of a ring and contains the designated number of carbon atoms. Examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

The term alkoxy means a group in which the alkyl portion is straight or branched and has the designated number of carbon atoms. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, and isohexoxy.

The term alkanoyl means groups of formula -C(O)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include: acetyl, propionyl and butanoyl.

The term alkanoyloxy means groups of formula -OC(O)-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include

-OC(O)CH

3 -OC(O)C2H5, and -OC(O)C3H7.

The term alkoxycarbonyl means groups of formula -C(O)O-alkyl in which the alkyl group has the designated number of carbon atoms. Examples include

-C(O)OCH

3 -C(O)OC2H5, and -C(O)OC3H 7 The term cycloalkyl-alkyl means groups in which ar alkyl group bears a cycloalkyl substituent, and the cycloalkyl and alkyl portions each contain the designated number of carbon atoms. Examples include -C2H4-C5H9.

The term phenyl-alkyl means groups in which an alkyl group bears a phenyl substituent, and the alkyl portion contains the designated number of carbon atoms Examples include -C2H4-C6H5.

The term naphthyl-alkyl means groups in which an alkyl group bears a naphthyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -C2H4-C10H 7 The term pyridyl-alkyl means groups in which an alkyl group bears a pyridyl substituent, and the alkyl portion contains the designated number of carbon atoms. Examples include -C2H4-pyridyl.

WO 98/04528 PCT/US97/13248 0 The term alkenyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon double bond.

Examples include: ethenyl, propen-1-yl, propen-2-yl and penten-1-yl.

The term alkynyl means straight chain or branched groups having the designated number of carbon atoms and containing a carbon-carbon triple bond.

Examples include ethynyl, propyn-1-yl and butyn-1-yl.

The term halogen means the halogen atoms fluorine, chlorine, bromine and iodine.

The term "substituted" is defined implicitly by the exemplary substituents disclosed for the various substituted groups in the above discussion of general formula These lists of exemplary substituents are not intended to be considered as limiting; those skilled in the art will recognize that other similar substituents can also be employed.

C Certain of the above defined terms may occur more than once in the formulae employed herein, and upon such occurrence each term shall be defined independently of the other.

Preferred and most preferred groups constituting the compounds of general formula (IC) are as follows: X preferably represents CR 8 When X is CR 8

R

8 is preferably hydrogen, halogen, trifluoromethyl or (Cialkyl. R 8 is; most preferably hydrogen.

R

1a and Rib preferably are independently trifluoromethyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C3- C7)-cycloalkyl, or (C3-C7)-cycloalkenyl.

R

la and Rlb most preferably are independently (C1-C6)-alkyl or (C2-C6)-alkenyl.

R

2 is preferably

(C

1

-C

10 )-alkyl, substituted

(C

1

-C

1 0 )-alkyl, (C 2

-C

10 )-alkenyl or substituted (C 2

-C

10 )-alkenyl. The substituents on the substituted alkyl and substituted alkenyl R 2 groups preferably are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR 4 R5, or -S(O)mR 7 wherein m is 0, 1, or 2. Most preferably, the substituents are halogen or -S(O)mR 7 wherein m=0.

The groups R 4 and R 5 are preferably independently hydrogen, (C1-C6) alkyl, (C3-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1- C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl.

R

4 and R 5 are most preferably independently hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1-C6)-alkyl.

WO 98/04528 PCT[US97/13248 0 When R 4 and R 5 are joined together to form -(CH2)rA(CH2)s-, in this linkage it is preferable that the subscripts r and s are independently 1 to 3, and A is CHR6, NR6, O, or S(O)n wherein n is 0, 1, or 2, and R 6 is hydrogen, (C1-C6) alkyl, phenyl, or phenyl (C1-C6) alkyl.

R

7 is preferably (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)alkyl, substituted phenyl-(C1-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1- C6)-alkyl, or substituted pyridyl-(C1-C6)-alkyl.

R

7 is most preferably (C1-C6)alkyl, phenyl, substituted phenyl, phenyl (C1-C6)-alkyl or substituted phenyl (C1- C6)-alkyl. The substituents on the substituted

R

7 groups are preferably 1-3 of halogen, trifluoromethyl, or (C1-C6) alkyl.

When R 2 and Rib are joined to form an alkylene bridge, this bridge preferably contains 3 or 4 carbon atoms.

R

3 is preferably

(C

1

-C

6 alkanoyl, substituted

(C

1

-C

6 )-alkyl, or substituted

(C

3

-C

6 )-alkenyl, wherein the substitutents are preferably from 1 to 3 hydroxyl groups. Most preferably,

R

3 is substituted

(C

1

-C

6 )-alkyl or substituted (C3-C6)alkenyl where the substitutents are from 1 to 2 hydroxyl groups.....

Preferences for the aromatic and heteroaromatic groups Ar of structural formula (IC) are presented below. Compounds of general formula (IC) are further classified into four subsets represented by structural formulae 1A, 1B, 1C, and 1D, which relate respectively to 4-heteroaryl-substituted pyridines, 4-aryl-substituted pyridines, heteroaryl-substituted benzenes, and aryl-substituted benzenes. The 4-heteroaryl pyridine compounds included within formula (IC) have the formula 1A SR Rib Rla N R1 b 1A wherein

R

l a and Rib are independently trifluoromethyl, (C1-C10)-alkyl, substituted (C1-C10)-alkyl, (C2-C10)-alkenyl, substituted (C2-C10)-alkenyl, (C2-C10)-alkynyl, substituted (C2-C10)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (C1-C6)alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R l a and Rib groups are independently from 1 to 3 of, for WO 98/04528 WO 9804528PCT/US97/13248 o example, -OR 4

-C(O)R

4 -C02R 4

-C(O)NR

4

R

5

-NR

4

R

5 or phenyl which is ojptio nally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (C1-C4)-alkoxy groups.

The groups R 4 and R 5 are independently hydrogen, (C-C6)-alkyl, (C3-C6)alkenyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalky1- (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted naphthyl-(C'1-C 6 alkyl. The substitutents on the substituted phenyl or substituted naphthyl R 4 and are 1 to 3 of, for example, halogen, cyano, trifluoromethyl, (Cl-C 4 alkyl, or (C1-C4)-alkoxy groups.

R

4 and R 5 may be joined together to form -(CH2)rA(CH2)s- whe rein the subscripts r and s are independently 1 to 3 and A is CHR6, NR6, 0, or S(O)n in whidch n is 0, 1, or 2; and R6 is hydrogen, (Cl-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl.

R2is (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 lkyl, (C 2 -Clo)-alkenyl, substituted

(C

2 -Cl 0 )-alkenyl,

(C

2 -Cl 0 )-alkynyl, substituted

(C

2 -Clo)-alkynYl,

(C

3 C6)-cycloalkyl-(Cl-C 6 )~al orsbtttd(3C)cycloaky-(Cl-C 6 lkyl. The suibstitutents on the substituted. alkyl, substitutedc alkenyl, substituted .alkyniyl, and subtiutd ycoakyl R rup r independently from I to 3 of halogen,, phenyl, substituted phenyl. 1,3-dioxolan-2'yl1

-CON

4

R

5 hri is 0, 1, or 2. The subsituents on the substituted phenyl' R 2 substituent group are from 1 to 3 of, for example, halogen, (Cl-C 4 )-alkyl, or'(Cl-C4)-alkoxy.

R

7 is (Cl-C6)-alkyl,. phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted p-henyl-(C1-C6)-alkyl; pyridyl, substituted pyridyl, pyfdyl-(C alkyl, substituted pyridyl-(Cl-C6)*-alkyl, naphthyl, substituted naphthl naphthyl- (C1-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. 'The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from 1 to 5 of, for -example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (C1-C6)-alkoxy, itro, cyano, or hydroxy.

R

2 and Rib may be joined to form an alkylene bridge containing from 3 to carbon Atoms, between the ring carbon atoms to which R 2 and Rib are attached.

R

3 is hydroxy, trifluoroacetyl,- (Cl-C 6 )-alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted

(C

3

-C

6 )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R 3 groups from 1 to 3 hydroxy or trifluoromethyl groups.

Ar' is an optionally substituted heteroaroniatic ring. Examples 'of possible Ar'groups are pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The WO 98/04528 PCT/US97/13248 0 optional substitutents on the group Ar' are independently 1 to 3 of, for example, halogen,

(C

1

-C

6 )-alkyl, substituted

(C-C

6 )-alkyl, (C 2

-C

6 )-alkenyl, substituted

(C

2

C

6 )-alkenyl, (C2-C 6 )-alkynyl, substituted

(C

2

-C

6 )-alkynyl, (C3-C 7 )-cycloalkyl, cyano, nitro, trifluoromethyl,

-OR

4

-C(O)R

4

-OC(O)R

4 -C02R 4

-NR

4

R

5

-C(O)NR

4

R

5 or -S(O)mR7. The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar' are from 1 to 3 of, for example, halogen, hydroxy,

-NR

4

R

5 phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen,

(C

1

-C

4 alkyl, or (C 1 C4) alkoxy groups.

Pharmaceutically acceptable salts of these materials are within the scope of the invention.

In formula 1A, the preferred and most preferred groups

R

1 a, Rlb, R 2

R

3 as well as the additional groups

R

4

R

5

R

6 and R 7 embedded thierein, and the various substituent groups thereon, are as defined in connection with general formula

(IC)

above.

In formula 1A, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are.preferably independently from 1 to 3 of, for example, halogen,

(C

1

-C

6 )-alkyl,

(C

2

-C

6 )-alkenyl,

(C

2

-C

6 )-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR 4 or -OC(O)R 4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl. (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C 1

-C

4 alkyl. Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are, most preferably independently from 1 to 3 of, for example, halogen,

(C

1

-C

6 )-4lkyl, (C 2

-C

6 )-alkenyl,

-OR

4 or -OC(O)R 4 where R 4 is hydrogen or (C1-C6) alkyl.

r The 4 -aryl-substituted formula 1B pyridines included within formula (IC) have the Rib wherein WO 98104528 WO 9804528PCTfUS97/13248 0 Ria and Rib are independently trifluoromethyl, (Cl-Clo)-alkyl, substituted (Cl-Cio)-alkyl, (C-ClO)-alkenyl, substituted (C2-ClO)-alkenyl, (C-Clo)-alkynyl, substituted (C2-C1o)-alkynyl, (C3-C7)-cycloalkyl,.(C3-C7)-cycloalkenyl, or (Cl-C6)alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl Ria and Rib groups are independently from 1 to 3 of, for example, -OR 4

-C(O)R

4 -C02R 4

-C(O)NR

4

R

5

-NR

4

R

5 or phenyl which is optionally substituted with from 1 to 3 halogen, (Ci-C4)-alkyl, or (Cl-C4)-alkoxy groups.

The groups R 4 and R 5 are independently hydrogen, (C1-C6)-alkyl, (C3-C6)alkenyl, (C3-C7)cycloalkyl, (C3-C7)-cycloalkyl-(Cl-C 6 )-alkyl, phenyl,, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl,. or substituted naphthyl-(Cl-C6)alkyl. The substitutents on the substituted phenyl or substituted naphthyl R 4 and

R

5 groups are*1 to 3 of, for example,.halogen, cyano, trifluoromethyl, (Cl-C 4 alkyl, or (Cl-C4)-alko xy groups.

R

4 and R 5 may be joined together to form -(CH2)rA(CH2)s- wherei n the subscripts r and s are independently 1 to 3 and A is; CHR6, NR6, 0, orSO n which n is 0, 1, or 2; and R6 is hydrogen, (q21-C6)-alkyl,. pieridin-1-yl, phenyl, or phenyI-(C1-C6)-alkyl.

R

2 'is (Cl-Cl 0 )-alkyl, substituted .(Cl-Cl 0 )-alkyl, (C 2 -Cl 0 ).-alkenyl, substituted (C 2 -Clo)-alkeni (C 2

-C

1 0 )-alyyl .subtitedC.- 1 )alyl,(-

C

6 )-cycloalkyl-(C 1

-C

6 )-alkyi, or substituted. (C 3

-C

6 )-cycloalky ,-(Cl-C 6 )-ailkyl.. The substitutents on the substituted alkyl, substituted alkenyl,, substituted alkynyl, and substituted cycloalkyl RI- groups are independently from,i to 3 9f halogen, phenyl, *substituted phenyl, 1,3 dioxolan-2-yl, -C(O)NR 4

R

5 or -S(O)mR 7 wherein m is 0, 1, or 2. The siibstituents on the substituted phenyl k 2 substituent grou r rm1t 3-of,. for:iexample,:-halogen, (Cl-C 4 )-alkyl, or (Ci-C4)--alkoxy.

R

7 is (C-C6)-alkyl, phenyl, substituted "phenyl, phenyl-(Cl-C6)i-alkyl, substituted phenyl-(Cl-C6)-alkyl, -pyridyl, substituted pynidyl'- pyridyl-(Cl-C6)alkyl, substituted pyridyl-(Cl-C)"alkyl, naphthyl, substituted naphthyl, naphthyl- (Cl-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are from' 1 to 5 of, for example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C6)-alkoxy, nitro, cyano, or hydroxy.

R

2 and Rib may be joined to form an alkylene bridge containing from 3 to carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached.

WO 98/04528 PCT/US9713248 0

R

3 is hydroxy, trifluoroacetyl, (C1-C 6 )-alkanoyl, substituted

(C

1

-C

6 )-alkyl, or substituted (C3-C 6 )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl

R

3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.

Ar" is an optionally substituted aromatic ring. Examples of possible Ar" groups are phenyls and naphthyls. The optional substitutents on the group Ar" are independently 1 to 3 of, for example, halogen,

(C

1

-C

6 )-alkyl, substituted (Cl-C6)alkyl, (C 2

-C

6 )-alkenyl, substituted (C2-C 6 )-alkenyl, (C2-C 6 )-alkynyl, substituted

(C

2

-C

6 )-alkynyl,

(C

3

-C

7 )-cycloalkyl, cyano, nitro, trifluoromethyl,

-OR

4

-C(O)R

4

-OC(O)R

4 -C02R 4

-NR

4

R

5

-C(O)NR

4

R

5 or -S(O)mR 7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar" are from 1 to 3 of, for example, halogen, hydroxy,

-NR

4

R

5 phenyl, or substituted phenyl in which the phenyl group may bear, for example, one or more halogen,

(C

1

-C

4 alkyl, or (C1-C4) alkoxy groups.

Pharmaceutically acceptable salts of these materials are within the scope of the invention.

In formula iB, the preferred and most preferred groups la, Rib, R 2

R

3 as well as the additional groups R 4

R

5

R

6 and R 7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula

(IC)

above.

In formula 1B, aromatic ring Ar" pre'ferably is a phenyl ring wherein the optional substitiitents are preferably independently from 1 to 3 of, for example, halogen,

(C

1

-C

6 )-alkyl,

(C-C

6 )-alkenyl, (C2-C6)-alkyriyl, (C3-C7)-cycloalkyl, cyano, -OR 4 br -OC(O)R 4 where

R

4 is hydrogen, (Cl-C 6 alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl sUbstitutents are from 1 to 3 of hailogen or (C 1

-C

4 alkyl. Most preferably, the optional substituitents are from 1 to 3 of, for example, halogen,

(C

1

-C

6 )-alkyl, (C2-C6)-alkenyl,

-OR

4 or

-OC(O)R

4 where

R

4 is hydrogen or (C1-C6) alkyl.

132 i' V~7~ ~;tiij"" i- i~:i WO 98/04528 WO 9804528PCTIUS97113248 0 The heteroaryl-substituted benzenes included within formula (IC) have the formula 1C Ae wherein

R

8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Ci-Cio)-alkyl, substituted (Cl-Clo)-alkyl, (C1-C6)-alkoxy, (C3-C7)cycloalkyl, phenyl-(Cl-C3)-alkoxy, (Cl-C6)-alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or -NR 4 R5. The substituents on the substituted phenyl "or C) substituted alkyl R5 groups are from 1 to 3 of, for example; hydroxy, fluoro, (Cl- C6)-alkoxy, (C3-C7)-cycloalkyl,, phenyl, Phenyl-(C1-C3)-alkoxy, (Cl-C6)alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or The groups R 4 and R 5 are independently hydrogen, (Cl-C6)-alkyl, (C3-C6)aleyl C3C)cycloalkyl, (C3-C7)-cycloalkyl(i6ly, phnl ustituted phenyl, phenyl-(Cl-C6)7alkyl, substituted. phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted naphthyl-(C1 al .kyl. The substitutents on the substituted phentyl or substituted naphthyl R 4 and are 1 to 3 of, for example, halogen, cyano, trifluoromethyl,

.C)

alkyl, or (Cl-C4)-alkoxy groups.,

R

4 and R 5 may be joined together to form {-CH2)rA(CH2)s- wherein the subscripts r and. s ,are independently;i1 to 3 and 'A is CHR6, NR 6 0, or S(O)n in which nis 0, 1, or.2; and R6 is hydrogenj, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or* phenYl-(C1-C6)-alkyl..

ad Ribare independently, trifluoro'methyl, (Ci-Cio)-alkyl, subsiue (C1-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-Clo)-alkenyl, (C2-Clo)-alkynyl, substituted. (C2-Cio)-alkynyl,(C327)cycloalkyl, (C3-C7.)-cycloalkehyl, or (C1-C6)alkanoyl. The substituents on the substituted alkyl, substituted 'alkiiiyl, and substituted alkynyl Rla and Rib groups are independently from 1 to. 3 of, for example, -OR 4

-C(O)R

4 -C02R 4

-C(O)NR

4

R

5

-NR

4

R

5 or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Cl-C4)-alkyl, or (Cl-C4)7alkoxy groups.

R

2 is (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl,' 2 -Cl 0 )-alkenyl, substituted

(C

2 -Cl 0 )-alkenyl, (C2-Cl 0 )-alkynyi, substituted

(C

2 -Cl 0 )-alkynyl,

(C

3 C6)cycoalyl~c 1 .c 6 alkyl, or substituted (C3-C 6 )-CYClOaly-C- 6 -alkyl. The 133 WO 98/04528 PCTIUS97/13248 0 substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl

R

2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl,

-C(O)NR

4

R

5 or -S(O)mR 7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen,

(C

1

-C

4 )-alkyl, or (C1-C4)-alkoxy.

R

7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl substituted phenyl-(C1-C 6 )-alkyl, pyridyl, substituted pyridyl, pyridyl-(C1-C 6 alkyl, substituted pyridyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl- (C1-C6)-alkyl, or substituted naphthyl-(C1-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl

R

7 groups are from 1 to 5 of, for example, halogen, trifluoromethyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, cyano, or hydroxy.

R

2 and Rib may be joined to form an alkylene bridge containing from 3 to carbon atoms, between the ring carbon atoms to which R 2 and R1b are attached.

R

3 is hydroxy, trifluoroacetyl, (C1-C 6 )-alkanoyl, substituted

(C

1

-C

6 )-alkyl, or substituted (C3-C 6 )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R3 groups are from 1 to 3 hydroxy or trifluoromethyl groups. Ar' is an optionally substituted heteroaromatic ring. Examples of possible Ar' groups are: pyridyls, firanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls. The optional substitutents on the group Ar' are independently 1 to 3 of, for example halogen,

(C

1

-C

6 )-alkyl, substituted

(C

1

-C

6 )-alkyl, (C 2

-C

6 )-alkenyl, substituted

(C

2

C

6 )-alkenyl, (C2-C 6 )-alkynyl, substituted

(C

2

-C

6 )-alkynyl,

(C

3

-C

7 )-cycloalkyl, cyano, nitro,: trifluoromethyl,

-OR

4

-C(O)R

4

-OC(O)R

4 -C2R 4

-NR

4

R

5

-C(O)NR

4 R5, or -S(O)mR 7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar' ae from 1 to 3 of, for example, halogen, hydroxy,

-NR

4

R

5 phenyl, or substituted phenyl in which the pheyl group may bear, for example, one or more halogen,

(C

1

-C

4 )-alkyl, or (Cl- C4)-alkoxy groups.

Pharmaceutically acceptable salts of these materials are within the scope of the invention.

In formula 1C, the preferred and most preferred groups Rla, Rib, R 2

R

3 and R 8 as well as the additional groups R 4

R

5

R

6 and R 7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.

In formula 1C, heteroaromatic ring Ar' is preferably selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and WO 98/04S28 PTU9(34 PCT/US97113248 o thiazolyls, and the optional substitutents on the group Ar' are preferably independently from 1 to 3 of, for example, halogen, (Cl-C 6 )-alkyl, (C2-C 6 )-alkenyl,

(C

2

-C

6 )-alkynyl, (C 3

-C

7 )-cycloalkyl, cyano, -OR 4 or -OC(O)R 4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl (Cl-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C 1

-C

4 alkyl.

Heteroaromatic ring Ar' is most preferably selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents thereon are most preferably independently from 1 to 3 of, for example, halogen, (Cl-C 6 alkyl, (C 2

C

6 alkenyl, -OR 4 or -OC(O)R 4 where R 4 is hydrogen or (Cl-C6) alkyl.

The aryl-substituted benzenes included within formula (IC) have the formula 1D Ae'

R

3

R

1D wherein

R

8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cl-Cio)-alkyl, substituted (Cl-Cio)-alkyl, (Cl-C6)-alkoxy, ,(C3-C7)cycoalyl phny-(C1-C )'-alkoxy, (C;1-C6)-alkanoyloxy, (Cl-C6)-alkoxycarbo*nyl, carboxy, formyl, or -NR 4 R5. The substituents on the substituted. phenyl or substituted alkyl R 8 groups are from 1 to 3 of, for example, hydroxy, fluoro, (Cl- C6)-alkoxY, (C3-C7)cycloalkyl, phenyl, phenyl-(Ci -C3)-alkoxy, (C1-C6)alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or The groups R 4 and R 5 are independently hydrogen, (C1-C6)-alkyl, (C3-C6)alkenyl, (C'-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Cl-C-6).alkyl, ,pheniyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C1-C6)-alkyl, or substituted *naphthyl-(C1-C6)alkyl. The substitutents on the substituted phenyl or substituted naphthyl R 4 and

R

5 groups are 1 to 13 of, for example, halogen, cyano,'trifluoromethyl, (Cl-C 4 alkyl, or (C1-C4)-alkoxy groups.

R

4 and R 5 may be joined together to form -(CH2)rA(CH2)s- wherein -the subscripts r and s are independently 1, to 3 and A. is CHR6,. NO6, 0, or S(O)n in which n is 0, 1, or 2; and R6 is hydrogen, (Cl-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(ClpC6)-alkyl.

135 WO 98/04528 PTU9/34 PCTIUS97/13248 0 Ria and Rib are independently trifluoromethyl, (Cl-Cio)-alkyl, substituted (Cl-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-C10)-alkenyl, (C2-Clo)-alkynyl, substituted (C2-Clo)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkenyl, or (Cl-C6)alkanoyl. The substituents on the substituted alkyl, substituted alkenyl, and substituted alkynyl R 1 a and Rib groups are independently from 1 to 3 of, for example, -OR 4

-C(O)R

4 -C02R 4

-C(O)NR

4

R

5

-NR

4

R

5 or phenyl which is optionally substituted with from 1 to 3 of, for example, halogen, (Ci-C4)-alkyl, or (Ci-C4)-alkoxy groups.

R2is (Cl-C 1 0 )-alkyl, suibstituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 )-alkenyl, substituted

(C

2 -Cl 0 )-alkenyl,

(C

2 -Clo)-alkynyl, substituted (C2-Cl 0 )-alkynyl,

(C

3

C

6 )-cycloalkyl-(Cl-C 6 )-alkyl, or substituted (C3-C 6 )-cycloalkyl-(Cl-C 6 )-alkyl. .The substitutents on the substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, i,3-dioxolan-2-yl,

-C(O)NR

4 RS5, or -S(O)mR 7 wherein m is 0, 1, or 2. The substituents on the substituted phenyl R 2 substituent group are from 1 to 3 of, for example, halogen, (Cl-C 4 )-alkyl, or (C1-C4)-alkoxy.

R

7 is (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)alkyl, substituted pyridyl-(C-C6)-.alkyl, naphthyl, substituted naphthyl, naphthyl- (Cl-C6)-alkyl, or 'substituted naphthyl-(CI-C6)-alkyl. The substitutents on the substituted phenyl, substituted pyridyl or substituted naphthyl R 7 groups are, from 1 to 5 of, for example, halogen, trifluoromethyl, (Cl-C6)-alkyl, (Cl-C6)-aikoxy, nitro, cyano, or hydroxy.

R

2 and Rib may be joined to formn an alkylene bridge containing from 3 to. carbon atoms, between the ring carbon atoms between the ring carbon atoms to which R 2 and Rib are attached.

R

3 is hydroxy trifluoroacetyl, (Cl-C 6 )-Alkanoyl, substituted (Cl-C 6 )-alkyl, or' substituted

(C

3

-C

6 )-alkenyl. The substitutents on the substituted alkyl and substituted alkenyl R 3 groups are from 1 to 3 hydroxy or trifluoromethyl groups.

Ar" is'an optionally substituted aromatic ring. Examples of. possible Ar" groups are phenyls and naphthyls. The optional substitutents on the group Ar are independently 1 to 3 of, for example, halogen, (Cl-C 6 )-alkyl, substituted (Cl-C 6 alkyl, (C 2

-C

6 )-alkenyl, substituted

(C

2

-C

6 )-alkehyl, (C 2

-C

6 )-alkynyl, substituted (C2-C 6 )-alkynyl, (C 3

-C

7 )-cycloalkyl, cyano, nitro, trifluoromethyl,

-OR

4

-C(O)R

4

-OC(O)R

4 -C02R 4

,.-NR

4 RS5, -C(O)NR 4

R

5 or -S(O)mR 7 The substitutents on the substituted alkyl, substituted alkenyl, and substituted alkynyl substituent groups on Ar are from 1 to 3 of, for example, halogen, hydroxy, -NR 4

R

5 phenyl.- or 136 1' z 11 4t- 1 WO 98/04528 PCT/US97/13248 0 substituted phenyl in which the phenyl group may bear, for example, one or more halogen, (C 1

-C

4 )-alkyl, or (C1-C4)-alkoxy groups.

Pharmaceutically acceptable salts of these materials are within the scope of the invention.

In formula 1D, the preferred and most preferred groups R la Rlb, R 2

R

3 and R 8 as well as the additional groups R 4

R

5

R

6 and R 7 embedded therein, and the various substituent groups thereon, are as defined in connection with general formula (IC) above.

In formula 1D, aromatic ring Ar" preferably is a phenyl ring wherein the optional substitutents are preferably from 1 to 3 of, for example, halogen, (C 1

-C

6 alkyl, (C 2

-C

6 )-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, cyano, -OR 4 or

-OC(O)R

4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl where the phenyl substitutents are from 1 to 3 of halogen or (C 1

-C

4 alkyl. Most preferably, the substitutents are from 1 to 3 of, for example, halogen, (C 1

-C

6 )-alkyl, (C 2

-C

6 )-alkenyl, -OR 4 or -OC(O)R 4 where R 4 is hydrogen or (C1-C6) alkyl' Basic compounds of the invention are generally isolated in the form of their pharmaceutically acceptable acid addition salts derived using inorganic or organic acids. Examples of such materials are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, and malonic acids.

Compounds of the invention which contain an acidic functionality such as a carboxyl group can be isolated in the .form of pharmaceutically acceptable addition salts derived using inorganic or organic bases. The salt forming ion derived from such bases can be a metal ion such as sodium, potassium, lithium, calcium, magnesium, etc., or an ion of an organic base, such as an ammonium or substituted ammonium ion derived from an amine. Examples of suitable amines for this purpose include ammonia, arylalkylamines such as dibenzylamine and N,Ndibenzylethylenediamine, lower alkylamines such as methylamine, t-butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benzathine, or salts derived from amino acids such as arginine or lysine.

The present invention also encompasses pharmaceutically acceptable "prodrugs" of the compounds of formula (IC) which form such derivatives. These 137 WO 98/04528 PCT/US97/13248 0 are typically acylated derivatives of alcohol-containing compounds of the invention, though other types of prodrugs are known. Preparation of such derivatives is within the skill of the art.

The inhibitors of the present invention are contemplated for use in veterinary and human applications. For such applications, the active agent(s) are employed in pharmaceutical compositions which comprise the active ingredient(s) plus a pharmaceutically acceptable carrier which contains one or more diluents, fillers, binders, or other excipients, depending on the administration mode and dosage form contemplated. Examples of such agents include carriers such as sucrose, lactose, or starch; lubricating agents such as magnesium stearate; adjuvants, such as wetting agents; excipients such as cocoa butter or suppository wax; emulsifying and suspending agents, and sweetening, flavoring and perfuming agents and buffering agents. The pharmaceutical compositions of the invention may also include one or more known antidiabetic agents in addition to a compound of structural formula Examples of such antidiabetic agents are: a-glucosidase inhibitors such as acarbose or voglibose, insulin sensitizers such as bromocriptine, thiazolidinediones such as troglitazone, insulin secretagogues such as glimepride, sulfonylureas such as glyburide, GLP-1 and its derivatives such as insulinotropin, amylin and its derivatives such as AC-137, calcitonin, insulin and its derivatives such as HOE-901, biguanides such as metformin, aldose reductase inhibitors such as tolrestat, 33 agonists such as BTA-243, and hypocholesterolemics such as lovastatin.

The method of treating glucagon-mediated conditions by administering a glucagon receptor antagonist of the present invention nay be practiced in mammals, including humans, which exhibit such conditions. A typical application is treatment of diabetes.

The compounds of this invention can be administered by oral, parenteral intramuscular, intraperitoneal, intravenous or subcutaneous injection or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms T :Y~~-1-:11~1-lr1l_1 i jln;l\Llllli- it;Jin6 lu-ir Iri~";;~55;l;~~jlPfi~~xli irr WO 98/04528 PCT/US97/13248 0 may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings such as the OROS-CT/OsmetTM and PULSINCAPTM systems from ALZA and Scherer Drug Delivery Systems.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.

Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils,, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Alternatively intramuscular, intraarticular or subcutaneous depot injection with or without encapsulation of the drug into degradable microspheres comprising poly(DLlactide-co-glycolide) may be used to obtain prolonged sustained drug release. For improved convenience of the dosage form it may be possible to use an i.p.

implanted reservoir and septum such as the Percuseal system available from Pharmacia. Improved convenience and patient compliance may also be achieved by the use of either injector pens the NovoPen or Q-pen) or needle-free jet injectors from Bioject, Mediject or Becton Dickinson). Prolonged:zero-order or other precisely controlled release such as pulsatile release can also be achieved as needed using implantable pumps with delivery of the drug through a cannula into the synovial spaces. Examples include the subcutaneously implanted osmotic pumps available from ALZA, such as the ALZET osmotic pump.

SCompositions for nasalor sublingual administration are also prepared with standard excipients well known in the art.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.

The compounds of this invention can be manufactured into the above listed formulations by the addition of various therapeutically inert, inorganic or organic carriers well known to those skilled in the art. Examples of these include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, water, saccharose, alcohols, glycerin and the like. The formulations may be sterilized by, for example, filtration through a 139 WO 98/04528 PCT/US97/13248 0 bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Various preservatives, emulsifiers, dispersants, flavorants, wetting agents, antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like are also added, as required to assist in the stabilization of the formulation or to assist in increasing bioavailability of the active ingredient(s) or to yield a formulation of acceptable flavor or odor in the case of oral dosing.

The amount of the pharmaceutical composition to be employed will depend on the recipient and the condition being treated. The requisite amount may be determined without undue experimentation by protocols known to those skilled in the art. Alternatively, the requisite amount may be calculated, based on a determination of the amount of target receptor which must be inhibited to treat the condition. An effective amount of active ingredient is generally in the range 0.0001 mg/kg to 100 mg/kg of body weight.

The treatment method of the invention is not limited to administration of the above-described pharmaceutical composition. Rather, this treatment regimen may be employed in combination with conventional treatments of diabetes (both Type I and Type II) or of other conditions which are sometimes found in diabetic subjects.

Thus, for example, treatment may be administered in conjunction with diet restrictions and exercise; insulin, or other drugs used to treat ketoacidosis; (c) any drug used for the treatment of hyperlipidemia, such as lovastatin, or cardiovascular disease, such as enalapril; drugs used to treat diabetic complications, such as epalrestat and drugs that lower body weight, such as dexfenfluramine.

The glucagon receptor antagonists of the invention are useful not only for treatment of the pathophysiological conditions discussed above, but are also useful in other applications such as a diagnostic agent. For example, these compounds can be administered to humans in vivo in the fasting state as a diagnostic tool to directly determine whether the glucagon receptor is functional. Serum samples taken before and after such administration can be assayed for glucose levels; comparison of the amounts of blood glucose in each of these samples would be a means for directly determining the ability of the patient's glucagon receptor to WO 98/04528 PCTIUS97113248 0 modulate hepatic glucose output. Alternatively, compounds of the present invention may be useful for finding new glucagon antagonists. For example, a binding assay employing a radiolabeled derivative (such as 3 H) of a compound of formula (IC) would be useful in identifying new compounds that competitively bind to the glucagon receptor. Such an assay is useful in identifying structurally novel antagonists that may offer advantages in ease of chemical modification, selectivity and oral bioavailability.

WO 98/04528 PCT/US97/13248 0 The compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. Each such asymmetric center will produce two optical isomers. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. For example, for certain compounds of Formula (IC) wherein Ar is taken as substituted phenyl, there exist additional isomers due to restricted rotation about the central aryl-aryl bond, depending on the substitution pattern.

0 0 G G R3 R2 3\ R 2 Rla Rib Ra X R lb It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of compounds of Formula (IC) wherein

R

3 is taken as 1hydroxyethyl, it has been found that the isomer in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.

OH Ar HRa X R1b C H 3 o,, Ic 142 3 WO 98/04528 WO 9804528PCTIUS9 7113248 Representative examples of the nomenclature employed herein are given below: 2 6 -DimethyI-3-hydroxymethyl-4-(3..bromophenyl)..5-isobutylpyridine Br 3,5-Di-t-butyl-2-(phenylthio)methyl..& hydroxymethyl-3',5'-dichloro-1,1 '-biphenyl Ci) The compounds of. general formula (IC) of the present invention are prepared, as indicated in the following reaction Schemes.

The phenylpyridine compounds of formula (IC) N) are prepared from a common intermediate 6 using the 'well-known Hantzsch pyridine synthesis, as shown in Scheme 1 (Stout, D. Myers, A. I. Chern. Rev. 19 82,'223).

WO 98/04528 PCT/US97/13248 0 SCHEME 1 0 R1b. CO2Et 0 AcO-NH 4 cyclohexane NH2 R b E C0 Ria CO2Et R Na COgEt 3

-H

2 0 Ar- CHO 1 2 4 Ar EtO 2 C rCO 2 Et DDQ CH 2

C

2 EtO2C COEt Rla I N -Rlb Rla'N" Rib H R R b

RN

6 The ketoester 1, (commercially available or prepared according to the procedure of Deslongchamps, Synth. Comm., 1976, 6, 169) is treated with an ammonium salt such as ammonium acetate, in an inert solvent such as cyclohexane capable of forming an azeotrope with water, to give the enamine 2. Compound 2 is then treated with the ketoester 3, which may or may not be identical to the ketoester 1, and an aromatic aldehyde, in a polar solvent such as ethanol, to produce the dihydropyridine 5. Certain substituents on aldehyde 4 may need to be protected during the Hantzsch pyridine synthesis. A description of suitable protecting groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991. Oxidation of is achieved by any of several known methods. For example, treatment of 5 with 2,3-dichioro-5,6-dicynobenzoquinone (DDQ) in a solvent such as methylene chloride (CH2C1 2 or with ceric ammonium nitrate (CAN) in a mixture of solvents such as aqueous acetone, affords the intermediate 6. Separation of unwanted side products and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (Still, Khan, Mitra, A. J. Org. Chem., 1978,43,2923) An alternative Hantzsch pyridine synthesis of the intermediate 6, where R la and Rib of formula (IC) are identical, can be accomplished following the procedure of Chucholowski Patent 4,950,675), Scheme 2. By heating two equivalents of ketoester 1 with ammonium hydroxide and the aldehyde 4 in a polar solvent such as methanol, the dihydropyridine 5 is obtained directly. Compound 5 is oxidized to pyridine 6, according to the procedure described in Scheme 1.

144 y t, WO 98/04528 PCT/US97/13248 SCHEME 2 Ar- CHO Ar Ar 2 COEt EtO2C j CO 2 Et DDQ CHAC 2 EtO2C CO 2 Et RlaH CO2Et 4 1

NH

4 OH/MeOH RAla N Ra Rla' N RIa 1 H In Scheme 3, another alternative Hantzsch pyridine synthesis of intermediate 6 is described. Ketoester 1 is condensed with aldehyde 4 by treatment with catalysts such as acetic acid and piperidine without solvent to afford intermediate 7.

Treatment of 7 with ketoester 3 in the presence of a base such as sodium methoxyde, in a polar solvent such as methanol produces the diketone 8.

Cyclization of 8 is achieved by treatment with an ammonium salt such as ammonium acetate in a polar solvent such as acetic acid to afford the previously described dihydropyridine 5 (Scheme which is oxidized to the pyridine 6 according to the procedure as indicated in Scheme 1.

SCHEME 3 ArCHO 0' 4 a)K,,CO2Et Ar

EO

2

C

AcOH la 0 O .Ar Rb ~R CO 2 Et

CO

2 Et N NaOMe O R 1 a MeOH

Z

)2Et DDQ CHCI 2

E

tC D 2 The synthesis of aryl pyridine derivatives of formula (IC) wherein R 2 is alkyl and R 3 is hydroxymethyl (Ha) is described in Scheme 4.

WO 98/04528 PCTIUS97/13248 0 SCHEME 4 Ar Ar EtOgC

CO

2 Et Red-AI THF EtO 2 C OH PCC CH 2

CI

2 Ria N' Rlb Rb N Rb 6 9 Ar Ph 3 Ar EtO2C CHO a EtO 2 C 1)LAH/THF Ra /N--Rlb THF Ra- N Rib 2) H 2 Pd/C 12 Ar Ar HO R 2 HO R 2 IIa Rla N- Rib Rla -N Rlb IIa Ib Chemical reducing agents such as sodium bis( 2 -methoxyethoxy)aluminum hydride (Red-Al) in an inert solvent, such as tetrahydrofuran (THF) or diethyl ether (Et20), can result in a monoreduction of the pyridinediester 6 to give the alcohol 9.

Oxidants such as pyridinium chlorochromate (PCC), in a solvent such as CH2C12, convert compound 9 to the aldehyde 10. Wittig reaction with compound 10 and an ylide a in an inert solvent such as THF or Et20, affords olefin 12 obtained usually, but not always, as a mixture of E and Z isomers The reagent 11a is prepared from an alkyl triphenyl phosphonium salt, wherein the alkyl group may contain a heteroatom, and a suitable base such as butyllithium or sodium amide, according to known methods (Maercker, A. in Organic Reactions, Vol. 14, Ed.; Wiley, New York, 1965, Chapter Olefin 12 is successively treated with a reducing agent such as lithium aluminum hydride (LAH), in an inert solvent such as THF or and hydrogen in the presence of a metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol, to afford compounds of formula IIa. In some of these compounds,

R

2 may contain substituents such as alcohol, acetate, ester, carboxylic acid, and amide. These products can be obtained directly by the procedures of Scheme 4, with or without the use of appropriate protecting groups, or by additional steps familiar to those skilled in the art. For example, a primary alcohol can be converted to a carboxylic acid by standard methods of oxidation, WO 98/04528 PCTIUS97/13248 0 such as those described by Eisenbraun (Eisenbraun, E. J. Org. Syn. Coll., 1973, 310).

If the Wittig reaction is performed with methoxymethyl triphenylphosphonium as ylide (lib), followed by treatment with an acid such as hydrochloric acid, the homologous aldehyde 13 is obtained. This can undergo another Wittig reaction to afford olefin 14, (Scheme This known procedure (Wittg, Walter, Kruck, Chem. Ber. 1962, 2514) allows one to synthesize extended alkyl chain (R 2 analogs of formula Ia, which may not be directly prepared by usual Wittig reaction due to limited availability of the requisite alkyl triphenylphosphonium salt.

Oxidation of the compounds of formula IIa by the method described in Scheme 4 affords intermediates that can be converted to homologues of compounds of formula Ia, containing the -CH2-CH2- linkage between the pyridine nucleus and the hydroxy group (IIb).

Ar OMe Ar R r C 1) Ph 3 Et Ph3P--- EtOC. A CHO EtPHa C 11b CHO 11a Ria" N Rlb 2) HCI Ra N Rib .13 Ar Ar EtO 2 C R 1) LAH/THF H R a N Rlb 2) H 2 Pd/C. Ra Rb :14 IIa Synthesis of aryl pyridine derivatives of formula wherein R 2 is alkyl containing a heteroatom such as sulfur and R 3 is hydroxymethyl (Ila and IIb), is outlined in Scheme 6. Alcohol 9 is converted to an alkyl halide 15 by treatment with a suitable reagent such as dibromotriphenylphosphorane in an inert solvent.

Treatment of 15 with a thiol and a base such as N-methyl morpholine in an inert solvent produces intermediate 16. The sulfur atom of compounds 16 can be oxidized (n 1 or 2) by any of several known methods. For example, it can be accomplished by treatment of 16 wherein n=0, with an oxidant such as mchloroperbenzoic acid in a solvent such as CH2C12. Chemical reducing agents such 147 WO 98/04528 PCT/US97/13248 0 as lithium aluminum hydride (LAH) in an inert solvent such as tetrahydrofuran or diethyl ether, can reduce the ester 16 to a compound of formula IIIa. Intermediate can also react with alcohols following the methods outlined in Scheme 6, to afford compounds of formula Iic.

SCHEME 6 Ar Ar EtO2C OH Ph 3 P *Br 2 EtO2CBr

R

7

SH/CH

2 C12 Ria IN- R1b CH 2

CI

2 R1a IN R 1 b N-Me-morpholine 9 Ar Ar EtO 2 Ci s(0)n-R 7 LAHTHF HO Nk S(O)n-R 7 R Nla -Rb Rlia N Rlb 16 Ilia Ar Ar HO S(O)n-R 7 HO bO-.R4 Ra N- Rlb Ra N b Rb IIIb Ic* The synthesis of aryl pyridine derivatives of formula (IC) wherein R 2 is alkyl containing a heteroatom such as nitrogen and R 3 is hydroxymethyl (IVa), is outlined in Scheme 7. Treatment of 15 with a primary or secondary amine in an inert solvent results in the intermediate 17. Chemical reducing agents such as lithium aluminum hydride in an inert solvent, such as tetrahydrofuran or diethyl ether, can reduce ester 17 to a compound of formula IVa. Reduction of aldehyde 13 by the method outlined in Scheme 4 affords an intermediate that can be converted to homologues of compounds of formula ma and IVa, containing the -CH2-CH2linkage between the pyridine nucleus and the sulfur or nitrogen substituent (IIb and IVb).

148 WO 98/04528 PCT/US97/13248 0 SCHEME 7 Ar Ar Et 2 C Br

R

4

R

5 NH Et2C N R4 LAH/THF Ria N R1b CH 2 C12 R Ia N R R 17 Ar Ar R 4 HORNR HO N/ N HoNR RiH N Rib 5 Ria N Rlb IVa IVb Synthesis of aryl pyridine derivatives of formula (IC) wherein R 2 is alkyl and

R

3 is 1-hydroxyethyl is outlined in Scheme 8. Oxidants such as pyridinium chlorochromate (PCC), are used to convert compounds of formula II to the aldehyde 18. Treatment of 18 with an organometallic reagent such as methyl magnesium bromide or methyl lithium in an inert solvent such as THF or affords racemic compounds of formula Va. Chiral 1-hydroxyethyl aryl pyridine derivatives of formula Vb are obtained by resolution of the racemates Va by classical methods. For example, resolution can be achieved by formation of diastereomeric adducts of the racemic compounds with optically active reagents such as a-methoxy-a-(trifluoromethyl)phenylacetic acid (Dale, Dull, D.L.; Mosher, H.S. J. Org. Chem. 1969,34, 2543). Altematively, separation of enantiomers is achieved by HPLC on chiral solid phase. Determination of absolute stereochemistry can be achieved in a number of ways familiar to those skilled in the art, including X-ray analysis of a suitable crystalline derivative, such as a Mosher ester.

SCHEME 8 Ar Ar

HO

2 PCC/ CH 2 C OHCb R2

CH

3 MgBr/THF RI' N R1b Ra N R1 b II 1 OH Ar CH3a j Ri N R 1 b Va 149 n: s i- WO 98/04528 PCT/US97/13248 0 An alternative synthesis of aryl pyridine derivatives of formula Vb is achieved by treating aldehyde 18 with the anion of methyl toluylsulfoxide 19 to give a diastereomeric mixture of alcohols 20 as shown in Scheme 9 (Blase, F. Le H. Tet. Lett. 1995, 36, 4559). The diastereomers are separated by flash chromatography and treated separately with Raney nickel and hydrogen in ethanol to provide pure enantiomers enantiomeric excess, of the compounds of formula Vb. Alternatively, the chromatographic step is avoided by a two step sequence consisting of oxidation of the mixture 20 with manganese dioxide in an inert solvent, followed by reduction of the ketone with a chemical reductant such as LAH, to provide the enantiomerically pure alcohol 21. Treatment of 21 with Raney nickel and hydrogen in a polar solvent provides pure enantiomer e.e.) of the compounds of formula Vb.

SCHEME 9 0 Ar CH20L OH Ar 2 2 R Ri b THF a* 'Rb 18 1) Separate Sdiastereomers 2) H 2 Raney Ni 1) MnO2CH24 OH Ar

H

2) LAHR.F

R

2

H

2 H A R 2 2) LAHT F, Raney Ni H3 R 'N"Rib R IR N Rlb 1 Vb A preferred alternative enantioselective synthesis of aryl pyridine derivatives of formula Vb is shown in Scheme 10. Treatment of the racemic mixture of compounds of formula Va with an oxidant such as pyridinium chlorochromate (PCC), gives the ketone 22. Reduction of 22 with a complex of LAH and Nmethylephedrine (Kawasaki, Susuki, Terashima, S. Chem. Lett. 1984, 239) in an inert solvent, provides the alcohol of formula Vb with an enantiomeric excess of WO 98/04528 PCT/US97/13248 0 SCHEME OH Ar 0 Ar

R

2 PCC/CH2C R 2 N-Me-ephednrne-LAH CH 3

CH

3 ether. -78C R'a N R 1 b R1a N Rlb Va2 OH Ar 3 R 2 CH3 RI ,lb Vb The synthesis of aryl pyridine derivatives of formula (IC) wherein R 2 is alkyl and R 3 is 1,2-dihydroxyalkyl is described in Scheme 11. A methyl triphenylphosphonium salt is treated with a suitable base such as butyllithium in an inert solvent and reacted with intermediate 18 to afford olefin 23. Treatment of compound 23 with a suitable oxidant such as osmium tetroxide in a polar solvent such as pyridine gives the compounds of formula VI.

SCHEME 11 Ar Ar OHC R 2 Ph 3 P=CHR R R2 Ria .N R1b THF Ria N'RIb 23 F w Ar os0 4 pyridine HO a R1b

VI

The synthesis of aryl pyridine derivatives of formula (IC) wherein R 2 and

R

1 b are taken together to form an alkylene bridge and R 3 is hydroxymethyl (VIIa), is described in Scheme 12. The ketoester 1, is treated with an aromatic aldehyde and catalysts such acetic acid and piperidine, in ethanol, to afford the a,Punsaturated ketoester 24. Treatment of 24 with the cyclic ketone 25 and a base such as lithium bis(trimethylsilyl)amide in an inert solvent such as THF affords an intermediate which is treated with ammonium acetate and copper acetate in acetic 151 ^s^^Vaiy Fi^^t^ ,4 4-N' WO 98/04528 PCT/US97/13248 0 acid to give the pyridine 26. Chemical reducing agents reduce the ester 26 to analogs of formula VIIa. It may be appreciated that these analogs can be used as intermediates to generate new derivatives of formula (IC) wherein R 2 and Rib are taken together and R 3 is 1-hydroxyethyl (VIIb) according to the procedures described in Scheme 8.

SCHEME 12 0 Ar-CHO Rla CO2Et -4 AcOH, piperidine Ar C0 2 Et 0 Rla 0 1) Rlb R2 a LiHMDS/THF 2) NH 4 0Ac, AcOH Ar EtO 2 Cs R2

N^R"

LAHITHF HO R2' Rla R 1 b) R2 R'b The synthesis of the aryl pyridine derivative Ia wherein Rib is CH20H is described in Scheme 13. Alcohol 27 (aryl pyridine IIa in which Rib is CH3) is treated with a trialkylsilyl chloride, such as tert-butyldiphenylsilyl chloride, and a base to'yield silyl ether 28. Treatment of 28 with meta-chloroperbenzoic acid in an inert solvent, such as chloroform, provides the N-oxide 29. The N-oxide is treated with acetic anhydride to afford pyridine acetate 30. Treatment of 30 with aqueous methanol in the presence of potassium carbonate, yields alcohol 31. The silyl ether is cleaved with tetrabutylammonium fluoride in THF to provide aryl pyridine derivative 32.

WO 98/04528 WO 9804528PCT/US97/13248 SCHEME 13 Ar

HO"

Ria N CH 3 27 Ar

TBDPSO

Y+ N CH 3 0- Ar TBDPSCI

BPOR

Imidazole Ra N' OH 3 mCPBA

AC

2 0O

TBDI

H

2 0/MeOH

K

2 C0 3 Ar TBDPSO'

R

Rla

OH

TBAF

31 32 The synthesis of aryl pyridine derivatives Xa wherein Rib is -CH2NR 4

R

5 is described in Scheme. 14. Oxidation of alcohol 31 as, described! in Schei~ 4 -yields aldehyde 33. Treatment of the aldehyde with an amine in thie presene 'of a: Lewis acid, such as zinc chloride, and a reducing agent, such as sodium -cyanoborohydride, provides the amine 34. Deprotection -of the alcohol as described in Scheme 13 affords aryl pyridine derivative Xa.

SCHEME 14 Ar

TBDPSO

Ala N OH Ar _TBDPSO R RlaI N CHO

HNR

4

R

ZnCI 2 NaCNBH 3 Ar Ar R 2 TBDPSO '-.TBAFH R2

NR

4

R

5 laN 4 Ria NR

N

34 Xa An alternative synthesis of amine 34 is shown in Scheme 15. Treatment of pyridine N-oxide 29 with phosphorus oxychloride and a base, such as triethylamine, in CH2Cl2, yields chloromethylpyridine 3. The chloride is treated WO 98/04528 PCT/US97/13248 0 with an amine providing amine 3-4.

SCHEME Ar Ar JIDPS POC1 3

TBDPSO

Et 3 N, 0H 2 Ci 2 l 6- OH 3 Rt N CH 2

CI

0- 29 Ar HNR 4

R

TBDPSO

RN

Rla N NR 4

R

.34 The synthesis of aryl pyridine derivatives Xb wherein Rib is -CH=CHR is described in Scheme 16. Alcohol 31 is converted to the corresponding bromide as described in Scheme 6. Treatment of 36 with sodium phosphite in benzene yields phosphonate 37. The phosphonate is treated with a base,. such as sodium hydride, and subsequently with. an aldehyde affording olefin 38. Deprotection of the alcohol as described affords aryl pyridine Xb..

SCHEME 16 Ar Ar 22PS Br 2 PPh 3 RRPS 22 NaPO(OEt) 2 lal OH la Ra N R N Ar Ar *0 rBDF~SO 0 TB)NaH

TBAF

.1 p 2)ROHO TDP a

R

1 I N >OEt) 2 Rt N

R

Ar HO2 A a

N

Xb An alternative synthesis of olefin 38 is shown in Scheme 17. Aldehyde 33 is 154 WO 98/04528 PCT/US97/13248 0 treated with an ylide as described in Scheme 4 to yield olefin 38.

SCHEME 17 Ar TBDPSO R 2 R a N CHO R PPh 3 The synthesis of aryl pyridine derivative Xc wherein Rib is -CH2CH2R is described in Scheme 18. Hydrogenation of olefin Xb as described in Scheme 4 yields the alkane Xc.

SCHEME 18

HO:)Y

2 R N R The synthesis of aryl pyridine derivative Xd wherein Rib is -CH(OH)R is described in Scheme 19. Treatment of aldehyde 33 with a Grignard reagent in an inert solvent, such as THF, yields alcohol 39. Deprotection of the alcohol as described affords aryl pyridine derivative Xd.

SCHEME 19 Ar TBDPSO 'I R 2 Ria N CHO 33 Ar RMgBr TBDPSO R2 Sla N'

R

OH

TBAF

Xd The synthesis of aryl pyridine derivatives Xe wherein Rib is -COR is 155 WO 98/04528 WO 98/04528 PCT/US97/13248 0 described in Scheme 20. Oxidation of alcohol 39 as described in Scheme 4 yields ketone 40. Deprotection of the alcohol as described affords the aryl pyridine derivative Xe.

SCHEME Ar TBDPSO

R

R

R

1 a N

OH

39 Ar PCC TBDPSO R 2 Ra N R 0

TBAF

The synthesis of aryl pyridine derivatives Xf wherein Rib is -C(OH)RR' is described in Scheme 21. Grignard addition to ketone 40 as described in Scheme 19 yields alcohol 41. Deprotection of the alcohol as described affords the aryl pyridine derivative Xf.

SCHEME 21 Ar

TBDPSO'-A

R 2 aR R 1

N

0 R'MgBr IlL Ar

TBDPSO

R

TBAF

R I N R' HO R 41 o 33^ o r ,uo oo The synthesis of aryl pyridine derivatives Xg wherein Rib is -C(OR 4 )RR' is described in Scheme 22. Treatment of alcohol 41 with a base, such as sodium hydride, and an alkylating agent in THF, yields ether 42. Deprotection of the 156 it WO 98/04528 PCT/US97/13248 0 alcohol as described affords the aryl pyridine derivative Xg.

SCHEME 22 Ar Ar R

R

TBDPSO 2

R

4 X TBDPSO R

TBAF

Ra N R' NaH Ria R' HO R R40 R 41 42 Ar

R

4 0 R Xg The biphenyl analogs described in formula (IC) (X C-R 8 wherein R 8 is are prepared by the methods described by Fey, et al. US Patent 5,138,090. The key step of the synthesis is the coupling of an arylpalladium dimer with an aryl Grignard reagent (Scheme 23).

SCHEME 23 2) H*

RO

O dNPh 1) ArMgBr.5 T Rlalb

R

A specific example of this method is shown in Scheme 24. Treatment of diol 43 (prepared according to the procedure of Fey, et al. US Patent 5,138,090) with (2methoxy)ethoxymethyl chloride and diisopropylethylamine in CH2Cl2 solvent gives MEM ether 44. Oxidation of the remaining alcohol of 44 as described in Scheme 4 provides aldehyde 45. Treatment of the aldehyde with aniline in the presence of a catalytic amount of p-toluenesulfonic acid (pTSA) and molecular sieves in toluene solvent gives imine 46. The imine is converted to the palladium dimer 47 upon treatment with palladium acetate in acetic acid solvent. Treatment of 47 with triphefiylphosphine, then with 4 -fluorophenylmagnesium bromide 157 S~4~tW WO 98/04528 PCT/US97/13248 0 (prepared from l-bromo-4-fluorobenzene and magnesium metal), and finally with aqueous hydrochloric acid in benzene solvent yields biphenyl 48. The aldehyde moiety of biphenyl 48 is converted to a pentyl group by the methods described in Scheme 4. MEM ether 50 is treated with trimethylsilyl chloride and sodium iodide in acetonitrile solvent, and subsequently with sodium acetate in DMF solvent to provide acetate 51. Saponification of the acetate using potassium hydroxide in methanol solvent provides alcohol 52. Hydroxymethyl biphenyl 52 is transformed to racemic hydroxyethyl biphenyl 54 as described in Scheme 8.

SCHEME 24 HO N OH MEMCI MEMO N OH iPr 2 NEt P 43 44 MEMO~CHO NPh MM PhNH 2 MEMO Pd(OAc) 2 pTSA HOAc l 46

F

MEMO-Pd-NPh 1) F MgBr 47 48 F

F

BuPPh 3 Br

H

2 MEMO Pd/C MEMO C 41 158 7 2K WO 98/04528 PCT/US97/13248 1) TMSCI/Nal 2) NaOAc

KOH

PCC

MeLi An alternative synthesis of biphenyls of formula (IC) is the coupling of a suitably, functionalized benzene derivative 57 (where X can be trifluoromethanesulfonate, methoxy, bromide, or iodide) with an arylmetal reagent ArMYn (where M may be B, Sn, or Mg, and Y is a ligand).

SSCHEME x

R

3 N n2 X1 Rla Rib ArMYn M B, Sn, Mg Ar R

R

Ria. Rlb 57 X OTf, OMe, Br, I i 10 An example of such a biaryl coupling is the Suzuki reaction (Miyaura, N., Yanagi, Suzuki, A. Synth. Comm. 1981, 11,513-519; Oh-e, Miyaura, Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208) in which a benzene derivative 58 (in which X can be trifluoromethanesulfonate, bromide, or iodide) is coupled with an arylboronic acid (Scheme 26).

WO 98/04528 PCT/US97/13248 0 SCHEME 26 x Ar

R

3

AR

2 ArB(OH) 2 R 2 Rla Rib Rla Rib 58 X OTf, Br,I

I

The requisite arylboronic acid 60 may be prepared by sequential reaction of an aryl halide 59 (X Br or I) with magnesium metal, a boronic ester, and hydrochloric acid.

SCHEME 27 ArX 1)Mg X Br, I ArB(OH) 2 r 2) B(OR)3 0 3) HCI A specific example of the use of the Suzuki reaction to synthesize a biphenyl analog is depicted in Scheme 28. Phenol 61 is treated sequentially with sodium hydride and allyl bromide in dimethylformamide solvent to afford allyl ether 62. Claisen rearrangement of the ether provides phenol 63. The phenol is treated with trifluoromethanesulfonic anhydride (triflic anhydride) and pyridine in CH2C1 2 solvent to give triflate 64. Treatment with 4-fluorophenylboronic acid, tetrakistriphenylphosphine palladium potassium phosphate (tribasic), and potassium bromide in 1,4-dioxane solvent affords biphenyl 65. Catalytic hydrogenation as described in Scheme 4, and reduction of the ketone with lithium aluminum hydride in THF solvent provides the desired biphenyl analog 67.

SCHEME 28 0 O aH01O i OH- 1 N a H 61 62 6 61 62 63 160 WO 98/04528 PCT/US97/13248 Pyr B(OH)2 Pd(PPh) 3

K

3 P0 4 /KBr LAH OH

OH

H

2 Pd/C

C

An alternative synthesis of biphenyls of type I uses a cycloaromatization of a ketodiester 68 with a diketone in the presence of a catalytic amount of sodium methoxide in methanol solvent to give a phenol 69. The phenol is then coupled with an arylboronic acid as described in Scheme 28 to afford biphenyl diester The diester is then transformed as described in Schemes 4, 8, and 10 to give the analog with the desired R 2 and R 3 groups.

0 SCHEME 29 1 M0 0 0 0 MeO) AOM A" Rb O OH 0 MeO' _OMe R la Rlb 1) 2) ArB(OH) 2 Pd(PPh 3 4

K

3 PO4/KBr An alternative method of transforming phenol 69 to biphenyl 70 is shown in Scheme 30. Treatment of the phenol with dimethylsulfate and a base such as potassium carbonate yields the methyl ether 71. The ether is treated with an aryl Grignard reagent to afford biphenyl -ru~u4 i;n Y;rKk~br~' E~E~l~df~iri~_pS ~i~S~i~S~~~S3rl iilECti l~r~irg~S~y4 a~14 -~ix~i~~R~ncr~RZ, ifl;P WO 98/04528 PCT/US97/13248 SCHEME Me 2

SO

4

K

2 C0 3 69 71 0 Ar 0 ArMgBr, MeO kJOMe The diester 70 can be further transformed by an alternative method shown in Scheme 31, to give the analogs with the desired R 2 and R 3 groups. Chemical reducing agents such as sodium bis-( 2 -methoxyethoxy)-aluminum hydride (Red- Al), can result in a mono reduction of the diester 70 to give the alcohol 72. Alcohol 72 can be attached to a polymeric support such as Wang resin, by treatment with a base such as sodium hydride in DMF, to give the intermediate 73. The ester group of intermediate 73 can be transformed to an alkyl halide in a two step process; 73 is treated with a reducing agent such as LAH, then Phosphorous tribromide to afford compound 74. The alkyl halide 74 is treated with an alkyl thiol and a base such as Nmethyl morpholine, then by TFA to cleave the ether linkage with the polymeric resin, to afford the alcohol 75.

SCHEME 31 Ar Ar Cl ,KjO

Z

MeO OMe Red-AI/THF MeOOH Ria R ib RVa Rib

SR

l a R70 ete 0l *e ^S3^? 0 Ar Me O& 1) LAH/THF Ria Rb 2) PBr 3 Ar Br Rlab 74

(Z

1) R 7

SH/CH

2 C1 2 N-Me-morpholine 2) TFA/CH 2

CI

2 7 Ar R S-

OH

Ria Rib Z Polystyrene r WO 98/04528 PCT/US97/13248 0 It will be appreciated that synthesis of some compounds of formula (IC) may require use of protecting groups at various stages of the procedures. These are removed in subsequent steps. For example, the removal of O-benzyl ether protecting groups is carried out by treatment with hydrogen in the presence of a metal catalyst, such as palladium on carbon, in a polar solvent such as ethanol. The removal of silyl ether protecting groups is carried out by treatment with fluoride salts, such as tetrabutylamonium fluoride in a solvent such as THF. Conditions required to remove other protecting groups which may be present can be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.

The order of carrying out the steps of the foregoing reaction schemes is not always significant, and it is within the skill of the art to vary the order of reactions Sto facilitate the reaction or to avoid unwanted reaction products.

The following examples are provided for the purpose of further illustration only and are not intended to limit the disclosed invention.

EXAMPLE 1

F

HO

N

2, 6 -Diisopropvl-3-hydroxvmethvl-4-(4-fluorophenvl)-5-pentylpridine Step A: 3 -Amino-4-methyl-2-pentenoic acid, ethyl ester To 100 g (0.63 mol) of ethyl isobutyryl acetate was added ammonium acetate (68.2 g, 0.89 mol), cyclohexane (230 mL) and isopropanol (74 mL). The mixture was heated at reflux under argon atmosphere with a Dean-Stark trap. After 2 hours, a second portion of ammonium acetate (14.6 g, 0.19 mol) was added to the reaction.

The reaction was heated at. reflux for 12 hours and then allowed to cool to room 163 WO 98/04528 PCT/US97/13248 0 temperature. A total of -30 mL of water was collected in the Dean-Stark trap. An ice bath was used to cool the reaction to 10 0 C and then ammonium hydroxide (63 mL) was added dropwise. The organic layer .was separated, dried with sodium sulfate, filtered, and concentrated to yield a yellow oil. The crude product (90.9 g, 0.58 mol, 92%) was taken directly to the next step without any further purification.

Step B: Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)-35pyridinedicarboxylate To ethyl 3 -amino-4-methylpent-2-enoate (Step A) (90 g, 57 mmol) was added ethyl isobutyryl acetate (90g, 57 mmol) and 4 -fluorobenzaldehyde (61.4 mL, 0.57 mmol). The mixture was heated under argon at 130 0 C for 26 hours (Precaution: Check the reflux condenser after a few hours as excess ammonium acetate will clog the condenser). The reaction was allowed to cool to room temperature and left to crystallize for 4 days. The solid was collected by filtration with vacuum (46.9 g, 116 mmol, 20%) and taken directly to the next step without further purification.

tep C: Diethyl 26-diisopropl-4-(4fluorophenl)-3,5-pridinedicarboxyla To the intermediate obtained in Step B (33 g, 82 mmol) in dichloromethane (400 ml) was added 2 3 -dichloro-5,6-dicyanobenzoquinone (DDQ, 20.5 g, 90 mmol) under argon and the mixture was stirred for 2 hours. The stirring was stopped to allow the precipitate to settle. The precipitate was filtered, washed with dichloromethane (3 x 30 mL), and discarded. The filtrate was concentrated to afford a brown solid, which was subjected to flash chromatography (6/4 mixture of dichloromethane/hexanes) resulting in a pure white solid (25.8 g, 64.3 mmol, 78%).

1 H NMR (300 MHz, CDC13): 6 7.28 2 7.06 2 4.03 1 7.0 Hz, 4 H), 3 .11.(septet, J 6.6 Hz, 2 1.32 J= 6.5 Hz, 12 0.979 3.3 Hz, 6 FAB- MS: calculated for. (C23H28N04F) 401, found 402 Anal. calc for C23H28NO 4 F: C, 68.64; H, 7.24; N, 3.48; F, 4.72. Found: C, 69.12; H, 6.98; N, 3.42; F, 4.96. mp 72-74 0 C. Rf=0.4 (10% ethyl acetate/hexane).

tep D: Ethyl 2 6 -diisopropvl-4-(4-fluorophenyl)-5-hydroxmethl-3pyridinecarboxylate To a solution of the intermediate obtained in Step C (23.4 g, 58.3 mmol) in anhydrous tetrahydrofuran (300 mL) stirred under argon at 0°C was added a solution of 3.4M of sodium bis( 2 -methoxyethoxy)aluminum hydride in toluene (Red-Al) (61 mL, 204 mmol, 65 wt% in toluene) via syringe over 20 min. The reaction mixture was allowed to stir at room temperature for 7 hr, then cooled 164 WO 98/04528 PCT/US97/13248 0 again to 0°C and carefully quenched by the dropwise addition of water. The solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography (300 g silica) via step gradient. Elution with 5% diethyl ether/hexane afforded 6.6 g (16.4 mmol, 28%) of recovered starting material and elution with 40% diethyl yielded the desired product as a yellow waxy solid (14 g, 39 mmol, 1 H NMR (300 MHz, CDC13): 8 7.27 2 7.10 2 4.46 J 5.2 Hz, 2 3.98 J 7 Hz, 2 3.48 (sept, J 6.6 Hz, 1 3.05 (sept, J 6.6 Hz, 1 1.32 J 6.6 Hz, 12 0.97 J 7 Hz, 3 FAB-MS: calculated for (C21H26FN0 3 359, found 360 Rf 0.2 (20% ethyl acetate/hexane).

Step E: 5-Carboethoxy-26-diisopropyl-4-(4-fluorophenyl)-3pyridinecarboxaldehvde To a solution of the intermediate obtained in Step D (13 g, 36 mmol) in dichloromethane (1 L) was added Brockman I neutral alumina (7.4 g, 72 mmol).

The suspension was stirred at room temperature and treated with pyridinium chlqrochromate (PCC) (16 g, 72 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hex (1 L), filtered through a pad of silica, the pad washed with diethyl ether (500 mL) and the combined eluent concentrated to afford a viscous oil which slowly solidified (12.8 g, 35.9 mmol, Rf 0.31 (10% ethyl acetate/hexane). 1H NMR (300 MHz, CDC13): 9.85 1 H),.7.27 2 7.13 2 4.04 J 7 Hz, 2 3.88 (sept, J 6.6 Hz, 1 3.12 (sept, J 6.6 Hz, 1 1.33 J= 6.6 Hz, 12 1.00 J 7Hz, 3 EI-MS calcd for (C21H24FN0 3 357, found 358 Anal. Calcd for C21H24FN03: C, 70.57; H, 6.77;-N, 3.92. Found: C, 70.62; H, 6.78; N, 3.84.

Step: Ethyl 2 6 -diisopropyl-4-(4-fluorophenyl)-5-(1-pentenl)-3pyridinecarboxylate Butyltriphernylphosphoiium bromide (2.7 g, 6.76 mmol) was suspended in anhydrous THF (75 mL) under argon and stirred at -78 0 C. A 1.6 M solution of nbutyllithium in hexanes (4.2 mL, 6.76 mmol) was added dropwise. The reaction mixture was allowed to come to 0°C and was stirred at that temperature for 1.5 hr.

The resulting brightly colored solution was cooled again to -78°C and treated dropwise with a solution of the intermediate obtained in Step E (2 g, 5.60 mmol) in THF (20 mL). The reaction mixture was allowed to stir at 0°C for 1 hr, then quenched by the addition of water (5 mL). The THF was removed in vacuo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated. Flash 165 WO 98/04528 PCT/US97/13248 0 chromatography through silica diethyl ether/hexane) affords a viscous oil (2 g, mmol, 90%) (E,Z mixture). 1 H NMR (300 MHz, CDC13): 8 7.14 2 7.02 (m, 2 6.10 (dt, J 1.8,11.4 Hz, 0.4 6.04 (dt, J 1.5, 16.2 Hz, 0.6 5.48 (dt, J 7, 11.4 Hz, 0.4 5.33 (dt, J 7, 16.2 Hz, 0.6 4.00 J 7 Hz, 0.8 3.98 J 7 Hz, 1.2 3.39 (sept, J 6.6 Hz, 0.6 3.27 (sept, J 6.6 Hz, 0.4 3.06 1 H), 1.95 (dq, J 1.5, 7 Hz, 1 1.26 13 1.19 2 0.97 J 7 HZ, 3 0.77 J 7 Hz, 1.2 0.76 J 7 Hz, 1.8 EI-MS calculated for (C25H32FN0 2 397, found 397 Rf 0.5 (10% ethyl acetate/hexane).

Step G: 2,6-Diisopropyl-3-hydroxvmethyl-4-(4-fluorophenyl)-5pentenyl)pyridine The intermediate obtained in Step F (2 g, 5.03 mmol) was dissolved in anhydrous THF (100 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, 10 mmol). The reaction mixturewas stirred at reflux for 1 hr, cooled to room temperature and quenched by the addition of 0.38 mL H20, 0.38 mL 20% aqueous NaOH and 1.1 mL The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by chromatography through silica ethyl acetate/hexane) to afford the product as a white foam (1.42 g, 4 .0.mmol, Rf 0.2 (109% ethyl acetate/hexane).

Step H: 2 ,6-Diisopropvl-3-hydroxvmethyl-4-(4-fluorophenyl)-5pentylpyridine The intermediate obtained in Step G was dissolved in absolute ethanol mL) under argon, treated with 10% palladium on carbon (140 mg, 0.1 eq), then stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (1.4 g, 3.9 mmol, 1 H NMR (300 MHz, CDC13): 6 7.15 4 H), 4.33 J 4.4 Hz, 2 3.41 (sept, J 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.26 2 1.33 (dJ 6.6 Hz,6 1.30 J 6.6 Hz, 6 1.27 2 1.13 0.79 J 6.6 Hz, 3 FAB-MS; calculated for (C23H32FNO) 357, found 358 Anal. calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.46; H, 8.95; N, 3.78. Rf=0.3 (20% ethyl acetate/hexane). mp 100-101°C.

fV-II. -r WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 2

HO

2 6 -Dimethyl- 3 -hydroxymethyl4-henyl5(2mehl..1propenyl)..pyridine The title compound was prepared from ethyl acetoacetate, benzaldehyde and isopropyl triphenyiphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDCl13)::8- 7.34 (in, 3 7.10 (in, 2 5.70 1 4.42 2 2.69 3 2.43 3 1.60 3 1.35 3 H).

EL-MS calculated for (C18H21N0) 267, found 267 mp 48-50*C. Rf 0.3 ethyl acetate/ hexane).

EXAMPLE 3 The title compound was prepared from ethyl acetoacetate, benzaldehyde and butyl triphenyiphosphoniuni bromide accordinfg to, the procedures described in Example 1, Steps A-G. The product- was obtained as a mixture 3:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDC13): 8 7;37 (in, 7.12 (mn, 2 H), 5.94 (in, 1 5.40 (in, 1 4.41 (bs, 2 2.71 2.68 (2s, 3 2.57 2A6 (2s, 3 H), 1.91 1.69 (2q, J 7 Hz, 2 1.52 (bs, 1 1.19 (in, 2 0.77 (in, 3 EI-MS: calculated for (C19H23N0) 281, found 281. Rf 0.4 (90% ethyl acetate/hexane).

t WO 98/04528 PCT/US97/13248 0 EXAMPLE 4 2 6 -Dimethvl- 3 The title compound was prepared from 2 ,6-dimethyl-3-hydroxymethy..4-.

phenyl-5-(1-pentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. 1 H NMR (300 MIHz, CDCI 3 8 7.42 (in; 3 7.15 (in, 2 4.33 2 2.65 3 2.56 3 2.27 (i,2 1.29 (in, 2 1.11 (in, 4 0.76 (t, 7 Hz, 3 EI-MS: calculated for (C19H25N0) 283, found 283 Anal.

calculated for C19H25N0: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.39; H, 8 85; N, 4.85. mp 99-100*C. Rf =0.3 (90% ethyl acetate /hexane).

HO

rN £.AJ-Liethl-3-hdonmvlarx pmethv..4..phy.5..{2..nvl)yidin The title compound was prepared from ethyl propionylacetate, beazaldehyde and isopropyl triphenyiphosphoniurn iodide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 Mffz, CDCl3): 5 7.34 (in, 3 7.11 (mn, 2 5.76 1 H), 4.44 J=5.5 Hz, 2 3.01 J= 7.4 Hz, 2 2.75 J 7.4 Hz, 2 1.58 3 1.35 (mn, 7 1.21 J 7.4 Hz, 3 FAB-MS: calculated for (C20H25N0) 295, found 296 Anal. Calcd for C20H25N0: C, 81.31; H, 8.53; N, 4.74. Found: C, 81.03; H, 8.55; N, 4.65. mp 103-104*C. Rf 0.4 (50% ethyl acetate/hexane).

168 S -C §tAs-s WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAMPLE 6 2, 6 -Diethvl-3-hydroxvmethyl-4-phenyl-5-(l-pentenyl)pyridine The title compound was prepared from ethyl propionylacetate, benzaldehyde and butyl triphenyiphosphoniumn bromide according to the procedures described in Example 1, Steps A-C. The product was obtained as a mixture 6:4 trans:cs isomers. 1 H NM (300 MHz, CDCl3): 8 7.36 (in, 3 7.14 (in, 2 6.00 (in, 1 5.37 (in, 1 4.42 (mn, 2 2.90 (mn, 4 1.89 1.67 2 q, j 7 Hz, 2 1.25 (in, 9 0.76 (in, 3 FAB-MS: calculated for (C21H27N0) 309, found 310 Anal. Calcd for C21H27N0: 81.51; H, 8.79; N, 4.53. Found: C, 81.95; H, 8.90; N, 4.45. mp 74-76*C. Rf =0;5 (50% ethyl acetate/hexane) EXAMPLE 7 The title compound was prepared from 2,6-diet hyl-3-hydroxymethyl-4phenyl-5-(1-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. 1 H NMR (300 MI-z, CDC13):.8 7.42 (in, 3 7.18 (in, 2 4.34 Hz, 2H), 2.96 (q,J=7.7 Hz, 2H), 2.84 (q,J=7.7 Hz, 2H), 2.28 2 1.34 (in, 9 1.09 (in, 4 0.76 (t,J 7 Hz, 3 FAB-MS: calculated for (C21H29N0) 311, found 312 mp 76-77TC. Rf OS0: (50% ethyl acetate/hexane).

169 WO 98/04528 PCTIUS97/13248 0 EXAMPLE 8 HO

N'

2 6 -Diethyl-3-hydroxymethyl-4phn1..5.(1.ethenvl)pyrid.n The title compound was prepared from ethyl propionylacetate, benzaldehyde and methyl triphenyiphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDCI 3 5 7.40 (in, 3 7.20 (in, 2 6.36 (dd, J=11; 18 Hz, 1 5.22 (dd,J -11, 2 Hz, 1 5.00 (dd, J=18, 2 Hz, 1 4.41 J=6 Hz, 2 2.96 (in, 4 H), 1.35 (in, 7 FAB-MS: calculated for (C18H21NO) 267, found 268 Anal.

Calcd for C18H21NO: 80.86; H, 7.92; N, 5.24. Found: C, 80.65; H, 8.06; N,5.09.

mp 84-85 0 C. Rf =0.4 (50% ethyl acetate /hexane).

EXAWvfLE 9 HO

N

The title compound was prepared from 2 6 -diethyl73-hydroxyinethyl.*p phenyl-5-(l-ethenyl)pyridine (Example 8) according to the procedure described in Example 1, Step 1H NMR (300 MHz, CDC1 3 8 7.44 (in, 3 7.18 (in, 2 4.33 (d=6 Hz, 2H), 2.97 (q,j 8 Hz2 1,2 8 6 (qJ= 8 Hz, 2 2.36 J= 8 Hz, 2 1.34 (in, 7 0.93 J 8 Hz, 3 FAB-MS: calculated for (C18H23N0) 269, found 270 Anal. Calcd for C18f12 3 N0: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.70; H, 8.54; N, 5.08. mp 100*C. Rf =0.4 (50% ethyl acetate/hexane).

170 WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAMPLE 2 ,6-Diisopropyl- 3 The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and butyl triphenyiphosphomium bromide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDC13): 6 7.35 (in, 3 7.14 (in, 2 5.99 (mn, 1 5.35 (mn, 1 4.41 (in, 2 3.36 (in, 2 1.89 1.70 (2q, j 7 Hz, 2 1.24 (mn, 15 0.80 0.72 (2t, J 7 Hz, 3 FAB-MS: calculated for (C23H31N0) 337, found 338 Anal. Calcd for C23H31N0: C, 81.85; H, 9.26; N, 4.15. Found: C, 81.88; H, 9.22; N, 3.93. mp 67-73*C. Rf =0.1 ethyl acetate /hexane).

EXAMPLE 11 HO

N

015 2,-ispoy--yrxmty--hnl5(-ehI1poe~)prdn The title compound was prepared from ethyl isobutyry lacetate, benzaldehyde and isopropyl triphenyiphosphonium iodide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDCl13): 6 7.32 (in, 3 7.11 (in, 2 5.75 1 4.43 (bs, 2 3.46 (sept, J 6.6 Hz, 1 3.18 (sept, I 6.6 Hz, 1 1.57 :3 1.31 (in, 1.5 FAB-MS: calculated for (C22H29N0) 323, found 324 (M Anal. Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.59; H, 8.94; N, 4.29. mp 93-95*C. Rf =0.1 (1 0% ethyl acetate /hexane).

171 ~m;-n WO 98/04528 PCT/US97/13248 0 EXAMPLE 12 HO

N

2,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-(l-propenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and ethyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1 H NMR (300 MHz, CDC13): 5 7.4 3 C 7.2 2 6.0 1 5.5 5.4 (2m, 1 4.4 2 3.4 3.2 (2m, 2 H), 1.6 2 1.4 7 1.3 7 FAB-MS: calculated for (C21H27NO) 309, found 310 Anal. Calcd for C21H27NO: C, 81.53; H, 9.98; N, 3.96. Found: C, 79.06; H, 9.65; N, 3.61. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 13 HO

AN,

2 6 Diisopropl-3-hydroxvmethyl-4-phenyl-5-(1buteny)pyridin The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDCI3): 5 7.4 3 7.2 2 6.0 1 5.4 1 4.4 2 3.3 3 1.9 1.7 (2m, 2 1.3 12 0.7 3 FAB-MS: calculated for (C22H29NO) 323, found 324 Rf 0.4 (20% ethyl acetate/hexane).

172 WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAMPLE 14 2,6-Diisopropyl-3-hvdroxymethyl-4-phenyl-5-pentylpyridine The title compound was prepared from 2,6-diisoproyl-3-hydroxymnethyl-4phenyl-5-(1-pentenyl)pyridine (Example 10) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDCl3) 8 7.41 (in, 3 7.18 (in, 2 H), 4.33 2 3.42 (sept, j 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.26 (in, 2 H), 1.32 (in, 13 1.11 (in, 5 0.76 J= 7 Hz, 3 FAB(HR)-MS calcd for C23H33N0 339.2640; found 340.2640 mp 81-82*C. Rf =0.1 (10% ethyl acetate/ hexane).

EXAMPLE 2 6 -Diisopropyl-3-hvdrpxyinethyl4phenl..5(l..hexeniyl)pvridine The title compound was prepared from ethyl isobutyrylacetate, benzaldehyde and pentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-C. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1 H 'NMR (300 MHz, CDC13): 5 7.35 (mn, 3 7.14 (in, 2 5.99 (mn, 1 5.35 (in, 1 4.40 (in, 2 3.36 (in, 2 1.92 1.70 (2mn, 2 1.20 (in, 17 0.80 (mn, 3 FAB-MS: calculated for (C24H33N0) 351, found 352 Anal. Calcd for C24H33N0: C, 82.00; H, 9.46; N, 3.98.

Found: C, 81.58; H, 9.50; N, 4.62. Rf 0.1 (10% ethyl acetate/hexane); 173 WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAMPLE 16 2 6 -Diisopropyl-3-hydroxymethyl4phenyl.5-hexWlpyridine The title compound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl4.

phenyl-5-(1-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. 1 H NMR (300 MI-z, CDCI3): 8 7.40 (in, 3 7.18 (mn, 2 4.33 I 5 Hz, 2 3.42 (septet, J 7 Hz, 1 3.23 (septet, I 7 Hz, 1 2.26 (in, 2 1.31 (mn, 13 1.12 (in, 8 0.80 J 7 Hz, 3 FAB-MS: calculated for (C24H35N0) 353, found 354 Anal. Calcd for C24H35N0: C, 81.53; H, 9.98; N, 3.96. Found: C, 79.06; H, 9.65; N, 3.61. mp 71-72*C. Rf =0.1 (10% ethyl acetate /hexane).

EXAMPLE 17 HO

IN

The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl4phenyl-5-(1-propenyl)pyridine (Example 12) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDCl3): 8 7.41 (in, 3 7.17 (in, 2 H), 4.33 2 3.42 (sept, J 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.25 (in, 2 H), 1.33 J 6.6 Hz, 6 1.30 J 6.6 Hz, 6 .1.27 (in, 2 1.20 (in, 1 0.74 j -7 Hz, 3 FAB-MS: calculated for (C21H20N0) 311, found 312 Anal.

Calcd for C21H29N0: C, 80.98; H, 9.38; N, 4.50. Found: C, 80.72; H, 9.47; N, 4.38.

mp 89-90*C. Rf 0.4 (20% ethyl acetate /hexane).

174 WO 98/04528 PCTIES97/13248 EXAMPLE 18 2 6 -Diisopropyl-3-hydroxymethyl-4-phenyl-5-butylpyridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl-4phenyl-5-(1-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDC13): 8 7.41 3 7.17 2 4.33 2 3.42 (sept, J 6.6 Hz, 1 3.24 (sept, J 6.6 Hz, 1 2.28 2 1.33 (d, J 6.6 Hz, 6 1.31 J 6.6 Hz, 6 1.28 2 1.14 3 0.71 J 7 Hz, 3 FAB-MS: calculated for (C22H31NO) 325, found 326 Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30. Found: C, 81.28; H, 9.87; N, 4.07. mp 83- 84'C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 19 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-hexenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and pentyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 6:4 trans:cis isomers; gummy oil. 1H NMR (300 MHz, CDC13): 8 7.10 4 5.98 1 5.42 (dt, J 7,11.4 Hz, 0.4 5.29 (dt, 7,16.2 Hz, 0.6 4.40 J 5.5 Hz, 2 3.44 1 3.36 (sept, 6.6 Hz, 0.6 3.24 (sept, I 6.6 Hz, 0.4 1.94 1 1.36 6 1.23 8 1.12 4 0.82 3 FAB- 175 WO 98/04528 PCT/US97/13248 0 MS: calculated for (C24H32FNO) 369, found 370 Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 2 6-Diisopropvl-3- hvdroxvmethyl-44u o -(1-butenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and propyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1 H NMR (300 MHz, CDC13): 5 7.10 4 5.97 1 5.39 (dt, J 7, 11.4 Hz, 0.5 5.32 (dt, J 7, 16.2 Hz, 0.5 4.41 J 5.5 Hz, 2 3.45 1 3.36 (sept, J 6.6 Hz, 0.5 3.24 (sept, I 6.6 Hz, 1.95 1 1.70 1 1.35 J 6.6 Hz, 3 1.34 I 6.6 Hz, 3 H), 1.25 7 0.79 I 7.5 Hz, 1.5 0.78 I 7.5 Hz, 1.5 FAB-MS: calculated for (C22H28FNO) 341, found 342 Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 21 o

C

4 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-propenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and ethyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a 176 WO 98/04528 PCTIUS97/13248 o mixture 1:1 trans:cis isomers. 1 H NMR (300 MHz, CDCl3): 5 7.11 (in, 4 6.04 (d, J 11.7 Hz, 0.5 5.96 J 16.1 Hz, 0.5 5.53 (mn, 0.5 5.33 (mn, 0.5 4.41 (in, 3 3.42 (in, 1.5 3.20 (sept, J 6.6 Hz, 0.5 1.61 j 6 Hz, 2 1.3 (mn, 13 FAB-MS: calculated for (C21H26FN0) 327, found 328 Anal. Calcd for C21H26FN0: C, 77.03; H, 8.00; N, 4.28. Found: C, 77.15; H, 8.07; N, 4.11. mp 46-47*C. Rf =0.4 (20% ethyl acetate /hexane).

EXAMPLE 22

F

HO

N'

The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and methyl triphenyiphosphonium bromi de/sodium amide according to the procedures described in'Example 1, Ste ps A-G. 1 -H NM.R MHz, CDCl3): 5 7.12 (mn, 4 H)j,6-35 (dd, 1 11.5, 18 Hz, 1 5.24 (dd, J 1.5, 11.4 Hz, 1 4.97 (dd, J 1.5, 18 Hz, 1 4.41 (dJ Hz, 2 3.44 (sept, .J 66 Hz, 2 1.35 J 6.6 Hz, 6 1.28 J 6.6 Hz, 6 H)1;1.25 (mn, 1 FAB-MS: calculated for (C2OH24FNO) 313, found 314 Anal. Calcd for C20H24FNO: C, 76.65; H, 7.72; N, 4.47. Found: C, 76.87; H, 7.79; N, 4.33. mp 119-120tC. Rf =0.4 (209% ethyl acetate/hexane).

EXAMPLE 23 WO 98/04528 PCTJUS97/13248 0 2 6 -DiisoprppVl-3hydroxymethy1..{.(4.fluorophenVl)5hexvlpVridn The title compound was prepared from 2 6 -diisopropyl-3-hydroxy.ethy..4 4 -fluorophenyl)-5-(l-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDCl3): 8 7.14 (in, 4 4.33 2 3.41 (sept, J 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.26 (mn, 2 1.33 (d, J 6.6 Hz, 6 1.30 j 6.6 Hz, 6 1.26 (in, 1 1.14 (mn, 7 0.82 J 7 Hz, 3 FAB-MS: calculated for (C24H34FN0) 371, found 372 mp 93-95*C. Rf =0.4 (20% ethyl acetate /hexane)..

EXAMPLE 24

F

HO

N

2 6 Diisopropl3hdro xyiethV4(4fluorophen The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl..4. 4 -fluorophenyl)-5-(1-butenyl)pyridmne (Example 20) according to the procedure described in Example 1, Step H. 1H NMR (300 MI-z, CDCl3): 8 7.15 (in, 4 4.33 (d,J 5.2 Hz, 2 3.41 (sept,J 6.6 Hz, 1 3.23 (sept, J =6.6 Hz, 1 2.27 (mn, 2 1.34 J= 6.6 Hz, 6 1.30 J 6.6 Hz, 6 1.27 (in, 1, 1.16 (in, 3 0.73 J= 7 Hz, 3H). FAB-MS: calculated for (C22H30FN0) 343, found 344 Anal. Calcd for C221130FN0: C, 76.93; H, 8.80; N, 4.08. Found: C, 76.93; H, 8.70, N, 3.96. mp 45-50*C. Rf =0.4 (20% ethyl. acetate/hexane).

WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE

HO

2 ,6-DiisopropYI-3-hydroxymethyl-4-(4-fluorophenyl)-5-propylpyridine The title compound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl)-5-(1-propenyl)pyridine (Example 21) according to the procedure described in Example 1, Step H. 1 H NMvR (300 MHz, CDCl3): 8 7.15 (in, 4 4.33 2 3.41 (sept, I 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.25 (in, 2 1.33 (d, J=6.6 Hz, 6 H),I 1.30 J=6.6 Hz, .6 1.27 (in, 1 1.19 (in, 1 0.76 (t,J1 =7 Hz, 3 FAB-MS: calculated for (C21H28FN0) 329, found 330 Anal. Calcd for C21H28FNO: C, 76.56; H, 8.57; N, 4.25. Found: C, 76.55; H, 8.48; N, 4.11. mp 49-54 Rf 0.4 (20% ethyl acetate/ hexane).

EXAMPLE 26

F

HO

N-I

N-

2 6 -Diisopropyl-3-hydroxymethyl4(4fluorophenl).5..ethlpvridine The title compound was prepared from 2,6- ,diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl).-5-ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. 1 H NMR (300 Mliz, CDCl3): 8 7.15 (in, 4.33 J 3.6 Hz, 2 3.41 (sept, I 6.6 Hz, 1 3 .26 (sept, J 6.6 Hz, 1 2.34 j 7.35 Hz, 2 1.33 j=6.6 Hz, 6 1.31 J= 6.6 Hz, 6 1.19 (in, 1 0.93 J -7.35 Hz, 3 FAB-MS: calculated for (C20H26FNO) 315, found 316, Anal.

WO 98/04528 PCTIUS97/13248 0 Calcd for C2OH26FNO: C, 76.16; H, 8.31; N, 4.44. Found: C, 75.74; H, 8.50; N, 4.27.

mp 126-129*C. Rf =0.4 (20% ethyl acetate/hexane).

EXAMLE 27

HO

2 6DiisoprOyl-3hdrx.hyox -methV14(4fluorl)-5 3 ehylbutenvl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and isobutyl triphenyiphosphonium bromide according to the procedures described in Example 1, Steps A-G. 1 H NmR (300 141Hz, CDCl3): 8 7.07 (in, 4 5.92 J 10.7 Hz, 1 5.20 (dd, J 10.7, 11.4.Hz, 1 4.42 (bs, 2 3.45 (sept, J 6.6 Hz, 1 3.30 (sept, J 6.6 Hz, 1 2.06 (in, 1 1.35 j 6.6 Hz, 6 1.31 (in, 1 1.24 (in, 5 0.69 (bs, 6 FAB-MS: calculated for (C23H30FNcO) 355, found 356 Anal. Calcd for C23H3OFNO: C, 77.71; H, 8.51; N, 3.94. Found: C, 77.94; H, 8.59; N, 3.79. mp 112*C. Rf 0.3 (20% ethyl acetate /hexane).

0 EXAMPLE 28 2 6 DiisoproPvl-3-hydroxymeth yl-4-(4-lo henI)5(4-mehli Pentenyl)pyridine 180 S 5 5 S -5-5 5-~55 WO 98/04528 PCT/US97/13248 0 The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and isoamyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product is obtained as a 6:4 mixture of trans:cis isomers. 1 H NMR (300 MHz, CDC13): 8 7.11 4 6.04 (dt, J 1.5, 11 Hz, 0.4 5.96 (dt, J 1.5,16 Hz, 0.6 5.47 (dt, J 7, 11 Hz, 0.4 5.32 (dt, J 7,16 Hz, 0.6 4.41 2 3.44 0.8 3.38 (sept, J 6.6 Hz, 0.6 H), 3.24 (sept, J 6.6 Hz, 0.6 1.84 1 1.45 1 1.35 6 1.24 7 H), 0.79 I 6.6 Hz, 2.4 0.73 J 6.6 Hz, 3.6 FAB-MS: calculated for (C24H32FNO) 369, found 370 Anal. Calcd for C24H32FNO: C, 78.01; H, 8.73; N, 3.79. Found: C, 78.14; H, 8.62; N, 3.50. mp 48-50°C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 29

F

HO

N

2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenvl)-5-(3-methylbutvl)pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl)-5-(3-methyl-l-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDC13): 8 7.14 (m, 4 H) 4.33 J 5.5 Hz, 2 3.41 (sept, J 6.6 Hz, 1 3.22 (sept, J 6.6 Hz, 1 H), 2.27 2 1.35 1 1.33 J 7 Hz, 6 1.30 J 7 Hz, 6 1.17 3 0.70 J 6.6 Hz, 6 FAB-MS: calculated for (C23H32FNO) 357, found 358 Anal. Calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.34; H, 9.15; N, 3.69. mp 43-45°C. Rf 0.2 (20% ethyl acetate/hexane).

WO 98/04528 PCTIUS97/13248 EXAMPLE 2 6 Diisopropl- 3hdroxmethy (4-fuorhl)-5( 4 -ehI nyorde The title compound was prepared from 2 6 -diisopropy1-3hydroxymethyl.4- 4 -fluorophenyl)5-(4-methy11..pentenyl)pyridin (Example 28) according to the procedure described in Example 1, Step H. 1 H NM (300 MI-z, CDCI3): 8 7.14 (in, 4 4.33 J=5 Hz, 2 3.41.(sept, J=6.6 Hz, 1 3.22 (sept, J 6.6 Hz, 1 H), 2.23 (in, 2 1.38 (in, 1 1.33 J 6.6 Hz, 6 1.30 J 6.6 Hz, 6 1.27 (in, 1 1.17 (mn, 1.00 (in, 3 0.76 I 6.6 Hz, 6 FAB-MS: calculated for (C24H34FN0) 371, found 372 Anal. Calcd for C24H34FN0: C, 77.59;

H,

9.22; N, 3.77. Found: C, 77.63; H, 9.39; N, 3.58. mp 101-103*C. Rf =0.3 (20% ethyl acetate /hexane) EXAMPLE 31

F

HO

N

2 6 -DiisopropVl- 3-hvdroxvmethvl-4-(4-fluophn I) 5 ylpetl idenemethylene)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and cyclopentyl triphenyiphosphonium bromide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MIHz, CDCl3): 7.13 (in, 2 7.07 (in, 2 5.88 1 4.43 j 5.5 Hz, 2 3.44 (sept, J 6.6 182 WO 98/04528 PCT/US97/13248 0 Hz, 1 3.21 (sept, J 6.6 Hz, 1 2.11 2 1.75 2 1.47 4 1.34 J 6.6 Hz, 6 1.29 1 1.21 J 6.6 Hz, 6 FAB-MS: calculated for (C24H30FNO) 367, found 368 Anal. Calcd for C24H30FNO: C, 78.44; H, 8.23; N, 3.81. Found: C, 78.46; H, 8.18; N, 3.63. mp 97-98°C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 32

F

HO

2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-heptenVl)-pridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-hexyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1 H NMR (300 MHz, CDC13): 8 7.11 4 5.99 1 5.42 (dt, J= 7,11 Hz, 0.5 5.30 (dt, J 7, 16 Hz, 0.5 4.41 J 5.5 Hz, 2 3.45 1 3.37 (sept, J 6.6 Hz, 0.5 3.24 (sept, J 6.6 Hz, 1.94 1 1.35 6 1.29 1 1.26 J 6.6 Hz, 3 H),.1.22 6 H), 1.15 4 0.86 3 FAB-MS: calculated for (C25H34FNO) 383, found 384 Anal. Calcd for C25H34FNO: C, 78.29; H, 8.93; N, 3.65. Fouid: C, 78.37; H, 8.88; N, 3.57. Rf= 0.4 (20% ethyl acetate/hexane).

EXAMPLE 33

F

HO f'N WO 98/04528 PCT/US97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-octenyl)-pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and n-heptyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-G. The product was obtained as a mixture 1:1 trans:cis isomers; gummy oil. 1 H NMR (300 MHz, CDCI3): 8 7.11 4 5.98 1 5.42 (dt, J 7, 11 Hz, 0.5 5.30 (dt, I 7, 16 Hz, 0.5 4.41 J 5.5 Hz, 2 3.44 1 3.37 (sept, I 6.6 Hz, 0.5 3.24 (sept, J 6.6 Hz, 1.94 1 1.35 6 1.30 1 1.26 J 6.6 Hz, 6 1.22 4 H), 1.16 5 0.87 3 FAB-MS: calculated for (C26H36FNO) 397, found 398 Anal. Calcd for C26H36FNO: C, 78.55; H, 9.13; N, 3.52. Found: C, 78.63; H, 9.16; N, 3.48. Rf 0.4 (20% ethyl acetate/hexane) EXAMPLE 34

F

S.

HO

N 2,6-Diisopropyl-3-hydroxymethyl(4-fluorophenyl)-5-[2(E)-phenylethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDC13): 8 7.21 9 6.70 J 16.5 Hz, 1 6.26 J 16.5 Hz, 1 H), 4.45 J 5.5 Hz, 2 3.48 (sept, J 6.6 Hz, 2 1.37 I 6.6 Hz, 6 1.31 I 6.6 Hz, 6 1.29 1 FAB-MS: calculated for (C26H28FNO) 389, found 390 Anal. Calcd for C26H28FNO: C, 80.17; H, 7.25; N, 3.60. Found: C, 79.89; H, 7.28; N, 3.49. mp 107-110 0 C. Rf 0.3 (20% ethyl acetate/hexane).

184 WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE C x 2,6-Diisopropyl- -hVdroxymethVl-4-(4-fluorophenyl)-5-heptylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (4-fluorophenyl)-5-(1-heptenyl)pyridine (Example 32) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): 8 7.13 (in, 4 4.33 2 3.41 (sept, J =6.6 Hz, 1 3.22 (sept, J=6.6 Hz, 1 2.26 (in, 2 1.33 (d, J 6.6 Hz, 6 1.30 j 6.6 Hz, 6 1.22 (in, 3 1.11 (in, 8 0.85 1 =7 Hz, 3 FAB-MS: calculated for (C25H36FN0) 385, found 386 Anal. Calcd for C25H36FN0: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.86; H, 9.66; N, 3.59. mp 73- 0 C. Rf =0.3 (20% ethyl acetate /hexane).

EXAMPLE 36 2 6 -Diisopropvl-3-hydroxvinethyl-4-(4-fluorophenyl).5-octy~pyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl)-5-(1-octenyl)pyridine (Example 33) according to the procedure described in Example 1, Step H. 1 H NMR (300 MI-z, CL)C13): 8 7.14 (in, 4 4.33 J 5.5 Hz, 2 3.41 (sept, J 6.6 Hz, 1 3.23 (sept, J 6.6 Hz, 1 2.26 (in, 2 1.33 J 6.6 Hz, 6 1.30 I 6.6 Hz, 6 1.25 (in, 3 1.15 (in, 10 H), 0.87 17 Hz, 3 FAB-MS: calculated for (C26H38FN0) 399, found 400 185 WO 98/0528P C T 1 U S7/ 13248 0 Anal. Calcd for C26H38FN0: C, 78.15; H, 9.59; N, 3.51. Found: C, 78.27; H, 9.81; N, 3.43. Gummy oil; Rf =0.3 (20% ethyl acetate/hexane).

EXAMPLE 37

F

X

2 6 Diisopropvl3hdrox me thi--(-luoro.(4..floro(phenl5 2 thl)id.

The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethylA..

4 -fluorophenyl)-5-[2(E).phenylethenyllpyridjne (Example 34) according to the procedure described in Example 1, Step H. 1 H NMR (300 MI-Iz, CDC13): a 7.9 (in, 7 6.86 (in, 2 4.36 J 5.5 Hz, 2 3.44 (sept, J 6.6 Hz, 1 3.35 (sept, I 6.6 Hz, 1 2.58 (mn, 4 1.35 J 6.6 Hz, 6 1.34 J 6.6 Hz, 6 1.19 j Hz, 1 FAB-MS: calculated for (C26H3OFNO) 391, found 392 Anal.

Calcd for C26H3OFNO: C, 79.76; H, 7.72; N, 3.58. Found: C, 79.57; H, 7.61; N, 3.44.

mp 158-159*C. Rf =0.3 (20% ethyl acetate/hexane).

EXAMPLE 38

F

HO

C

a 6.00 56 0 0 00' 0 *0 S

S

00550

S

*SS*

0000

S

*000 500 so 0

S

2 6 DiisopropVI-3hvdroxymeth A..(4fluoophe el)-5 4 hllbutenyL)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and 3 -phenylpropyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps A-C. The. product was obtained as a mixture 5:1 trans:cis isomers; gummy oil. 1 H NMR (300 NIHz, WO 98/04528 PTU9134 PCTIUS97/13248 o CDC13): 8 7.26 (in, 2 7.19 (in, 1 7.09 (in, 6 6.05 J 11 Hz, 0.2 5.98 J 16 Hz, 0.8 5.47 (dt,JI 7, 11 Hz, 0.2 5.33 (dt, J 7, 16 Hz, 0.8 4.40 1= 5 Hz, 2 3.43 (in, 1 3.26 (sept, J 6.6 Hz, 1 2.51 (in, 2 2.29 (in, 1.6 2.05 (in, 0.4 1.34 (in, 6 1.25 (mn, 1 1.22 j 6.6 Hz, 6 FAB-MS: calculated for (C28H32FN0) 417, found 418 Anal. Calcd for C28H32FN0: C, 80.54; H, 7.72; N, 3.35. Found: C, 80.56; H, 7.56; N, 3.32. Rf =0.3 (20% ethyl acetate /hexane).

-EXAMPLE 39 2 6 -Diisopropyl-3hydroxymethylb4.(4..fluorophenVl)-5(4phenbutvl)pvridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxyinethyl-4- 4 -fluorophenyl)-5-(4-phenyl-l-butenyl)pyridine (Example 38) according to the procedure. described in Example 1, Step H. Gummy oil; 1H NMR (300 MIHz, CDCl3): 8 7.24 (in, 3 7.08 (in, 6 4.31 J 5.5 Hz, 2 3.40 (sept, J 6.6 Hz, 1 3.17 (sept, J 6.6 H-z, 1 2.46 J 7.5 Hz, 2 2.29 (in, 2 1.47 (in, 2 H), 1.32 6.6 Hz, 6 1.30 (in, 2 1.27 J 6.6 Hz, 6 1.15 J 5.5 Hz, 1 FAB-MS: calculated for (C28H34FNO) 419, found 420 Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.06; H, 7.94; N, 3.28. Rf =0.3 ethyl acetate/hexane).

EXAMPLE

F

HO WO 98/04528 PCTIUS97/13248 0 2 6 Diisopropl3hydroxymethI.4(4.fuorohenyl)5 me)thyl phenyl~ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4 -fluorobenzaldehyde and 2-methylbenzyl triphenyiphosphonium bromide according to the procedures described in Example 1, Steps A-G. 1 H NMR (300 MHz, CDCl3): 8 7.22 (in, 3 7. 10 (in, 5 6.62 J= 17 Hz, 1 6.45 I 17 Hz, 1 4.45 j 5.5 Hz, 2 3.48 (in, 2 2.12 3 1.37 I 6.6 Hz, 6 H), 1.33 I 6.6 Hz, 6 1.31 (in, 1 FAB-MS: calculated for (C27H30FN0) 403, found 404 Anal. Calcd for C27H3OFNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.23; H, 7.23; N, 3.44. mp 108-111'C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 41

F

HO

N

2 6 -DiiopropVl3hdroxvmethv .4.&loohnl 2 3 thl phenvl)ethenvllrpyridine The title compound was prepared from ethyl isobutylrylacetate, 4 -fluorobenzaldehyde and 3 -methylbenzyl triphenyiphosphonium chloride accordig to the procedures described in Example 1, Stepd A-G. 1 H NMR (300 lvI~z, CDCl3): 8 7.18 (in, 3 7.1.1 (in, 2 7.00 (in, 3 6.68 I 17 H4z, 1 H), 6.23 (di I= 171-k, 1 4.44 J= 5.5 Hiz, 2 3 .47 2 2.32 3 1.37 I -6.6 Hz, 6 1.31 J=6.6 Hz, 6 1.28 (mn, 1 FAB-MS: calculated for (C27H3oFNO) 403, found 404 Anal. Calcd for C27H30FN0: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.38; H, 7.45;.N, 3.45. mp 97-99*C. Rf =0.3 (20% ethyl acetate/hexane).

188 WO 98/04528 WO 9804528PCTfUS97/13248 EXAMPLE 42

HO

2 6 -Diisopropyl-3-hydroxymetyl-4-(4-fluorophenyl)-5[2(E..(4-mefiy.

Phenvl)ethenyllpyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and 4-methylbenzyl triphenyiphosphonium. bromide according to the procedures described in Example 1, Steps A-C. 1 H NMR (300 MHz, CDCl3): 8 7.18 (in, 2 7.08 (in, 6 6.63 J 17 Hz, 1 6.23 J=17 Hz, 1 4.43 1 =5 Hz, 2 3.47 (sept,JI 6.6 Hz, 2 2.31 3 1.36'(d, I 6.6 Hz, 6 1.30 I 6.6 Hz, 6 1.26 (in, 1 H)..'FAB-MS: calculated for (C27H30FN0) 403, found 404 Anal. Calcd for C27H30 FN0: C, 80.36; H, 7.49; N,3.47. Found:. C, 79.93; H, 7.34; N, 3.47.'mp 131-133*C Rf =0.3 (20% ethyl acetate/hexane).

EXAMPLE 43 2 6 -Diisppropyl-3-hydroxymethyl4(4-fuorphevl.5[2.(2iethI..

Phenylethyllpyridine The title comtpound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl-4- 4 -fluoropheny1)-5-[2(E)-(2-methylphenyl)eth.enylpyridine (Example 40) according to the procedure described in Example 1, Step H. 1H NMR (300 MI-z, CDCl3): 8 189 WO 98/04528 PCT/US97/13248 0 7.16 4 7.06 3 6.81 1 4.35 J 4 Hz, 2 3.42 (sept, J 6.6 Hz, 2 2.57 4 1.97 3 1.36 J 6.6 Hz, 6 1.35 J 6.6 Hz, 6 H), 1.19 1 FAB-MS: calculated for (C27H32FNO) 405, found 406 Anal.

Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 80.08; H, 8.05; N, 3.46.

mp 125-126'C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 44

F

HO

N~

2 6-Diisopropyl-3-hydroxylo l)[ 2 3 methyl-4-(4-fluo o l)[ 2 3 phenyl)ethyllpyridine The title compound was prepared 2 6 -diisopropyl-3-hydroxymethyl-4-(4fluorophenyl)-5-[2(E)-(3-methylphenyl)ethenylpyridine (Example 41) according to the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDCl3): 6 7.18 J 7 Hz, 4 7.10 1 6.97 1 6.65 2 4.36 2 3.44 (sept, J 6.6 Hz, 1 3.35 J 6.6 Hz, 1 2.57 4 2.28 3 1.35 I 6.6 Hz, 6 1.34 I 6.6 Hz, 6 1.20 1 FAB-MS: calculated for (C27H32FNO) 405, found 406 Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45.

Found:, C, 79.30; H, 8.10; N, 3.36. mp 148-150'C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE

F

HO

N

190 WO 98/04528 WO 9804528PCTIUS97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-2-(4-methyl.

p2henyl)ethyllpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl)-5-[2(E)-(4-methylphenyl)ethenyllpyridine (Example 42) according to the procedure described in Example 1, Step H. 1 H NMR (300 MlHz, CDCl3): 8 7.17 (in, 4 7.02 J=7.7 Hz, 2 6.75 1 7.7 Hz, 2 4.36 1=4 Hz, 2 H), 3.43 (sept, J 6.6 Hz, 1 3.34 (sept, I=6.6 Hz, 1 2.55 (in, 4 2.29 3 H), 1.34 1=6.6 Hz, 6 1.33 J -6.6 Hz, 6 1.20 (in, 1 FAB-MS: calculated for (C27H32FN0) 405, found 406 Anal. Calcd for C27H32FN0: C, 79.96; H, 7.95; N, 3.45. Found: C, 79.40; H, 7.84; N, 3.44. mp 121-123*C. Rf =0.3 ethyl acetate /hexane).

EXAMPLE 46 4-fluorobenzaldehytie and 2 -(l,3-dioxolan-2-yl)ethyljtriphenylphosphortium bromide according to the-procedures described in Example 1, Steps A-G. 1H NMR (300.-Lffz, CDCl3): 8 7.16 (in, 4 4.63 1 =4 Hz, 1 4.33 J= 5 Hz, 2 3.88 (in, 2 3.77 (in, 2 H4), 3.41 (bin, 1 3124 (bin, 1 2.34 (in, 2 1.47 (in, 4 H), 1.32 (in, 12 1.18 (in, 1 FAB-MS: calculated for (C24H32FN03) 401, found 402 mp 90-91 0 C. Rf 0.2 (20% ethyl acetate/hexane).

191 WO 98104528 PCTIUS97/13248 0 EXAMPLE 47

F

HOS<

N c 2 6 Dii sopropl3hdroxymethyl4.(4fluorophenyI)5[(Ph tho)methylipyridine Step A: Methyl 2,-isvov--4fuLqhnl--vr~ehI3 pyridinecarboxylate Prepared from methyl isobutyrylacetate, 4 -fluorobenzaldehyde and ammonium acetate by the procedures described in Example 1, Steps A-D.

Step B: MtV- ior Methl~26diiopvpl.4(4.fluorophenl)5bromthl- 3 pyridinecarboxylate A solution of the intermediate obtained in Step A (20 g, 57.9 mmol) 'in acetonitrile (500 mL) was stirred at 0'C and treated with dibromotriphenyiphosphorane (36.7 g, 86.9 mmcil) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 -hr. The solvent was removed in vacuo and the. residue partitioned between diethyl ether (400 mL) and water (350 mL). The ether layer was washed with brine (150 mL), dried (MgSO4) and conicentrated. 'Purification by chromatography through silica diethyl ether/hexane) gave a white solid (20.6 g, 50.5 mmol, 1 H NMR -(300 MHz,

CDCI

3 8 7.31 (in, 2 7.12 (in, 2 4.29 3.49 3H), 3.41 (sept, J 6.6 Hz, 1 3.06 (sept, J 6.6 Hz, 1 1.33 (in, 12 mp 109-111T. Rf 0.6 CH2CI2/hexane).

Step C: 2 6 Diisoproyl3hdroxyethy4(4fluorophl)S5 f(phenylthiOmethyllp ine~ A solution of the intermediate obtained in Step B.(200 mng, 0.47 mmol) in anhydrous TIF (5 mL), stirred under argon, was treated with benzenethiol (73 uL, WO 98/04528 PCT/US97113248 0 0.71 mmol) and N-methylmorpholine (0.26 mL, 2.4 mmol). The reaction mixture was stirred at reflux for 14 hr, allowed to cool to room temperature and treated with lithium aluminum hydride (1.9 mL, 1.9 mmol, 1.OM in THF). The reaction mixture was heated at reflux for 1 hr then allowed to cool to room temperature.

The mixture was quenched by the successive addition of water (80 uL), 20% NaOH (80 uL) and water (240 uL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography ethyl acetate/hexane) afforded a white solid (160 mg, 0.39 mmol, 1 H NMR (300 MHz, CDC13): 8 7.23 5 7.11 4 4.36 J 5.5 Hz, 2 3.81 2 H), 3.45 (sept, J 6.6 Hz, 1 3.43 (sept, J 6.6 Hz, 1 1.35 J 6.6 Hz, 6 1.33 (d,J 6.6 Hz, 6 1.21 J 5.5 Hz, 1 FAB-MS calcd for (C25H28FNOS) 409, found 410 Anal. Calcd for C25H28FNOS: C, 73:32; H, 6.89; N, 3.42; S, 7.83.

Found: C, 73.24; H, 6.90; N, 3.35; S, 8.01. mp 119-121°C. Rf 0.3 (20% ethyl Sacetate/hexane).

EXAMPLE 48

F

HO S

CF

3

N

2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[((3-trifluoromethyl)phenyl)thiolnethylpyridine The title compound was prepared from 3-trifluoromethyl-thiophenol according to the procedures described in Example 47. 1H NMR (300 MHz, CDC13): 8 7.34 2 7.24 4 7.10 2 4.36 J 5.5 Hz, 2 3.85 2 H), 3.45 (sept, J 6.6 Hz, 1 3.38 (sept, J 6.6 Hz, 1 1.35 J 6.6 Hz, 6 1.34 J 6.6 Hz, 6 1.23 J 5.5 Hz, 1 FAB-MS calcd for (C26H27F4NOS) 477, found 478 Anal. Calcd for C26H27F4NOS: C, 65.39; H, 5.70; N, 2.93; S, 6.71. Found: C, 65.39; H, 5.76; N, 2.88; S, 6.62. mp 110-111C. Rf 0.3 (20% ethyl acetate/hexane).

193 sw.**fcws,-. WO 98/04528 PCTIUS97/13248 EXAMPLE 49

HO'

2 6 Diisopro~vl3hvdroxymethl-4(4fluorophel)S[-( 4 -fluo Phenyl)thio~methylpvridine The title compound was -prepared from 4 -fluorothiophenol according to the procedures described in Example 47. 1 H NMR (300 MHz, CDC1 3 8 7.24 (in, 2 H), 7.12 (in, 4 6.93 (mn, 2 4.35 I=5.5 Hz, 2 3.76 2 3.44 (sept, I=6.6 Hz, 1 3.40 (sept, I 6.6 Hz, 1 1.34 I 6.6 Hz, 1.33 J 6.6 Hz, 6 H), 1.22 J 5.5 Hz, 1 FAB-MS calcd for (C25H27F2NOS) 427, found 428 Anal. Calcd for C25H27F2N0S: C, 70.23; H, 6.37; N, 3.28; S, 7.50. Found: C, 70.22; H, 6.41; N, 3.22; S, 7.39. mp, 119-121"C. Rf =0.3 (20% ethyl acetate/hexane).

EXAMPLE 2 6 DiisoPrOVl-3-hdovhvlxvmethv14(4fluol)r((ehl) Phen Ivthio meth~ylpVridine The title compound was prepared from p-thiocresol according to the procedures described in Example 47. 1 H NMR (300 MHz, CDCI3): 8 7.27 (mn, 2 H), 7.13 (in, 2 7.03 (in, 4 4.35 IJ 5.5 Hz, 2 3.77 2 3.44 (in, 2 2.31 3 1.34 I 6.6 Hz, 6 1.33 IJ 6.6 Hz, 6 1.22 J 5.5 Hz, 1 H).

FAB-MS calcd for (C26H30FNOS) 423, found 424 Anal. Calcd for WO 98/04528 PTU9134 PCTIUS97/13248 o C26H3OFNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 74.00; H, 7.15; N, 3.36; S, 7.32. mp 90-91*C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 51

F

HO

2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l-naphthylthio).

methylpyridine The title compound was prepared from 1-naphthalenethiol according to the procedures described in Ex ample 47. 1 H NMR (300 MHz, CDC13): 5 8.01 1 Hz, 1 7.82 J 8.5 Hz, 1 7.74 J 8 Hz, 1 7.46 (in, 3 7.34 (mn, 1 H), 7.20 (mn, 2 7.06 (mn, 2 4.34 J 5.5 Hz, 2 3.82 2 3.51 (sept, J 6.6 Hz, 1 3.45 (sept, J 6.6 Hz, 1 1.36 J=6.6 Hz,* 6 1.35 J= 6.6 Hz, 6 H), 1.19 Hz, 1 FAB-MS calcd for (C29H30FNOS) 459, found 460 Anal. Calcd for- C29H3OFNOS: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.36; H, 6.52; N, 2.91; S, 6.74. mp 77-79*C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 52 s<'j HO' 2 6 -Diisopropyl-3-hydroxvmethyl-4-(4-fluorophenvl)-5-(2-naphthylthio)inethylpyridine WO 98/04528 PCT/US97/13248 0 The title compound was prepared from 2 -naphthalenethiol according to the procedures described in Example 47. 1 H NMR (300 M~z, CDC1 3 8 7.77 j 9 Hz, 1 7.68 J 9 Hz, 2 7.52 j 1.5 Hz, 1 7.45 (in, 2 7.25 (in, 2 H), 7.17 (dd, J 1.8,8.5 Hz, 1 7.07 (in, 2 4.35 J 5.5 Hz, 2 3.91 2 3.45 (sept, J 6.6 Hz, 2 1.35 J 6.6 Hz, 6 1.34 J 6.6 Hz, 6 1.21 J Hz, 1 FAB-MS calcd for (C29H3OFNOS) 459, found 460 Anal. Calcd for C29H30FNOS: C, 75.78; H, 6.58; N, 3.05; S, 6.98. Found: C, 75.55; H, 6.60; N, 2.95; S, 6.91. mp 127-129*C. Rf 0.4 (20% ethyl acetate /hexane).

EXAMPLE 53

F

FN'

F

HO S

F

F

N

2 6 Diisoropl3hdroxvmethl.4(4..fluorophl)...[( 2 3 ,5 6 -tt fluorophenyl)thiolmethylpvridine The title compound was prepared from pentafluorothiophenol according to the procedures described in Example 47. 1 H NMR (300 MHz, CDCl3): 8 7.27 (in, 2 7.11 (in, 2 6.99 (in, 1 4.35 J 5.5 Hz, 2 3.84 2 3.44 (sept, J 6.6 Hz, 1 3.43 (sept, J1=6.6 Hz, 1 1.34 1 =6.6 Hz, 6 1.33 =6.6 Hz, 6 1.23 J 5.5 Hz, 1 FAB-MS calcd for (C25H24F NOjS) 481, found 482 Anal. Calcd for C25H24F5N0S: C, 62.36; H, 5.02; N, 2.91; S, 6.66; F, 19.73.

Found: C, 62.40; H, 4.96; N, 2.82; S, 6.74; F, 19.49. mnp 109-110*C. Rf =0.4 ethyl acetate/hexane).

EXAMPLE 54

F

HO S

OCH

3 WO 98/04528 WO 9804528PCT[US97/13248 0 2 ,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenvl)-5-(3-methoxv.

Pjxenvl)thiolmethvlpvridine The title compound was prepared from 3-methoxybenzenethiol according to the procedures described in Example 47. 1 H NMR (300 MHz, CDCl3): d 7.24 (in, 2 7.13 (mn, 3 6.72 (in, 2 6.62 (mn, 1 4.35 J= 5.5 Hz, 2 3.81 2 H), 3.75 3 3.44 (sept, J 6.6 Hz, 1 3.42 (sept, J =6.6 Hz, 1 1.34 J 6.6 Hz, 6 1.33 J 6.6 Hz, 6 1.23 J 5.5 Hz, 1 FAB-MS calcd for (C26H30FN02S) 339, found 440 Anal. Calcd for C26H30FN02S: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.94; H, 6.77; N, 2.96; S, 7.41. mp 93-94*C. Rf= 0.4 (20% ethyl acetate /hexane).

0 EXAMPLE ja

OH

2 -ispoy--hdoyehl4-4fur ey)5f4hdov phenyl)thiolmethylpyridine The title compound was prepared from 4-hydroxythiophenol according to the procedures described in Example 47. 1 H NMR (300 MHz, 5:1 CDCl3/CD3OD): .8 7.15 (in, 2 H,7.06 (in, 2 6.97 J .5 Hz, 2 6.64 J 8.5 Hz, 2 A4.27 2 3.66 2 3.40 (in, 2 1.29 J 6.6 Hz, 6 1.28 j 6.6 Hz, 6 H).

FAB-MS calcd for o(C25H28FN02S) 425, found 426 Anal. Calcd for C25H28FN02S: C, 70.56;*H, 6.63; N, 3.29; S, 7.53. Found: C, 70.29; H, 6.34; N, 3.12; S, 7.44. mp 178-179*C. -Rf 0.3 (30% ethyl acetate /hexane).

WO 98104528 PCTIUS97/13248 0 EXAMPLE 56

F

'o S 'OCH 3 HO

S

N

2 1 6 Diisopropv-3hdroxmethv.4-(4fluorophen)f( 4 thoy phenyl)thiolmethvlpvridine The title compound was prepared from 4 -methoxybenzenethiol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): 8 7.23 (in, 2 7.12 (in, 4 6.77 1 =9 Hz, 2 4.35 J=5.5 Hz, 2 3.79 3 3.73 2 3.44 (sept, J 6.6 Hz, 2 1.34 I 6.6 Hz, 6 1.33 I 6.6 6 H), 1.21 J=5.5 Hz, 1 FAB-MS calcd for (C26H3oFN0 2 S) 339, found 440 Anal. Calcd for C26H3OFNO 2 S: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.96; H, 6.90; N, 3.15; S, 7.35. mp, 92-93*C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 57

F

HO

N

2 6 Diiorpyldrox~3.ymet intA(~lh 3 hy Phenyl~thiolmethylpiime The title compound was prepared from m-thiocresol according to the procedures described in Example 47. 1H NMvR (300 MHz, CDCI3): 5 7.25 (in, 2 H), 7.11 (in, 3 7.00 (in, 1 6.94 (in, 2 4.36 J 5.5 Hz, 2 3.81 2 3.45 (sept, J=6.6 Hz, 1 3.43 (sept, J 6.6 Hz, 1 2.28 3 1.35 J 6.6 Hz, 6 1.34 I 6.6 Hz, 6 1.22 j 5.5 Hz, 1 FAB-MS calcd for 198 WO 98/04528 WO 9804528PCTIUS97/13248 o (C26H3oFNOS) 423, found 424 Anal. Calcd for C26H30FNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.76; H, 7.09; N, 3.27; S, 7.42. mp 92-93*C. Rf =0.4 ethyl acetate /hexane).

EXAMPLE 58

F

011 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluoropheny)-5-[(2-mefiy.

phenyl)thiolmethylpyridine The title compound .was prepared from o-thiocresol according to the procedures described in Example 47. 1 H NMR (300 MHz, CDC13): 8 7.25 (in, 2 H), 7.11 (in, 6 4.36 J 5.5 Hz, 2 3.74 2 3.45 (sept, J 6.6 Hz, 2 2.26 3 1.35 J=6.6 Hz, 12 1.21 J 5.5 Hz, I FAB-MS calcd for (C26H30FNOS) 423, found 424 Anal. Calcd for C26H3OFNOS- C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.54; H, 7.09; N, 3.06; S, 7.37. mp 140-141*C. Rf= 0.4 (20% ethyl acetate /hexane).

EXAMPLE 59 a F 2 6 -Diisopropyl-3-hydroxmethyl-4-(4-fluorophen1)-5-(3.fluoro.

Phenvl)thiolmethylpyr idine WO 98/04528 PCTIUS97/13248 0 The title compound was prepared from 3 -fluorothiophenol according to the procedures described in Example 47. 1 H NM (300 MHz, CDCl3): 5 7.27 (in, 3 H), 7.11 (in, 2 6.87 (in, 2 6.78 (mn, 1 4.36 J=5.5 Hz, 2 3.82 2 3.45 (sept, I 6.6 Hz, 1 3.38 (sept, I 6.6 Hz, 1 1.35 j 6.6 Hz, 6 1.33 I 6.6 Hz, 6 1.23 I 5.5 Hz, 1 FAB-M4S calcd for (C25H27F2N0S) 427, found 428 Anal. Calcd for C25H27F2N0S: C, 70.23; H, 6.37; N, 3.28; S, 7.50.

Found: C, 70.22; H, 6.31; N, 3.20; S, 7.41. mp 99-100*C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE OCH 3 2 6 Diisopropv1-3-hdroxy neth- 4(4 uoe 2 ehoxr phenylthiolmethylvvridine The title compound was prepared from 2 -methoxythiophenol acco rding to the procedures described in Example 47. 1H NMR (300 MI-z, CDCI3): 6 7.22 (in, 3 7.07 (mn, 3 6.83 (in, 2 4.34 J 5.5 Hz, 2 3.78 3 3.75 2 H), 3.49 (Sept, J 6.6 Hz, 1 3.43 (s'ept, J 6.6 Hz, 1 1.34 j 6.6 Hz, 12 1.19 J 5.5 Hz, 1 FAB-MS calcd for (C26H30FN0 2 S) 339, found 440 Anal.

Calcd for C26H30FN0 2 S: C, 71.04; H, 6.88; N, 3.19; S, 7.29. Found: C, 70.93; H, 6.67; N, 3.12; S, 7.48. rnp 129-131 0 C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE-61 200 WO 98/04528 PTU9134 PC"r[EJS97/13248 0 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[(3,5-dimethylphenyl)thiolmethylpyridine The title compound was prepared from 3,5-dimethyithiophenol according to the procedures described in Example 47. 1 H NMIR (300 MHz, CDCl3): 8 7.24 (in, 2 7.11 (in, 2 6.80 1 6.69 2 4.35 J 5.5 Hz, 2 3.79 2 H), 3.44 (sept, J 6.6 Hz, 1 3.42 (sept, J 6.6 Hz, 1 2.23 6 1.34 J 6.6 Hz, 6 1.33 J 6.6 Hz, 6 1.21 j' 5.5 Hz, 1 FAB-MS calcd for (C27H32FNOS) 437, found 438 Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 74.18; H, 7.22; N, 3.13; S, 6.86. mp 109-110*C. Rf= 0.5 (20% ethyl acetate /hexane).

EXAMPLE 62

F

HO

N

2,6-Diisopropyl-3-hydroxyinethVl-4-(4-fl-uorophenyl)-5-[(4-ethyl- Phenvl)thiolmethvlpvridine The title compound was prepared from 4-ethyithiophenol according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): 8 7.24 (mn, 2 H), 7.05 (in, 6 4.35 J 5.5 Hz, 2 3.77 2 3.43 (in, 2 2.60 J 7.7 Hz, 2 1.34 J 6.6 Hz, 6 1.32 J 6.6-,Hz, 6. 1.21 (in, 4 FAB-MS calcd for (C27H32FNOS) 437, found 438 Anal. Calcd for C27H32FNOS: C, 74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 74.07; H, 7.23; N, 3.09; S, 7.23. mp 102-103*C. Rf (20% ethyl acetate/hexane).

WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 63 2 6 -Diisopropvl-3-hvdroxymethyl-4-(4-fluorophenylys...[(4-isopropylphenyl)thiolmethylpvridine The title compound was prepared from 4 -isopropylthiophenol according to the procedures described in Example 47. 1 H NMR (300 MI-z, CDCl3): 5 7.25 (in, 2 7.06 (in, 6 4.35 I 5.5 Hz, 2 3.79 2 3.43 (in, 2 2.86 (sept, J 7 Hz, 1 1.34 J 6.6 Hz, 6 1.32 J 6.6 Hz, 6 1.22 (d,J1 7 Hz, 6 1.20 J 5.5 Hz, 1 FAB-MS calcd for (C28H34FNOS) 451, found 452 Anal.

Calcd for C28H34FN05: C, 74.46; H, 7.59; N, 3.10; S, 7.10. Found: C, 74.51; H, 7.48; N, 3.04; S, 6.85. mp 108-109 0 C. Rf 0.5 (20% ethyl acetate/ hexane).

EXAMPLE 64 The title compound was prepared from benzyl mercaptan according to the procedures described in Example 47. 1H NMR (300 MHz, CDCl3): 8 7.23 (mn, 5 H), 7.08 (in, 4 4.31 J=5.5 Hz, 2 3.55 2 3.40 (sept, J 6.6 Hz, 1 3.24 2 3.19 (sept, J=6.6 Hz, 1 1.31 (d,j 6.6 Hz, 6 1.24 j 6.6 Hz, 6 1.17 J= 5.5 Hz, 1 FAB-MS calcd for (C26H3OFNOS) 423, found 424 Anal. Calcd for C26H3OFNOS: C, 73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.58; 202 WO 98/04528 WO 9804528PCTIUS97/13248 o H, 7.25; N, 3.05; S, 7.45. mp 150-151*C. Rf 0.5 ethyl acetate /hexane).

EXAMPLE -7

NJ

(13 2 6 -Diisopropyvl-3-hydroxymethyl-4-(4-fluorophenyl).54[(Phenethyl)thiomethyllpyridine The title compound was prepared from phenethyl mercaptan according to the procedures described in Example 47. 1 H NMR (300 MHz, CDC13): 5 7.28 (in, 7.11 (in, 4 4.34 J=5.5 Hz, 2 3.39,(in, 4 2.70 (mn, 2 2.61 H), 1.33 I 6.6 Hz, 6 1.32 J 6.6 Hz, 6 1.20 J 5.5 Hz, 1 -FAB-MS calcd for (C27H32FNOS) 437, found 438 Anal. Calcd for C27H32FNOS:

C,

74.11; H, 7.37; N, 3.20; S, 7.33. Found: C, 73.99; H, 7.46; N, 2.96; S, 7.23. Gummy oil.

Rf 0.5 (20% ethyl'acetate/hexane).

EXAMP'LE 66

HO'

2 6 -Diisopropvl-3-hydroxynethyl-4-(4-fluorophenl)5.(2ropvthio).

methylpyridine The title compound was prepared from propyl mercaptan according to the procedures described in Example 47. 1 H NWR (300 MUz, CDCI3): 8 7.30 (in, 2 H), WO 98/04528 PCTIUS97/13248 0 7.14 (in, 2 4.34 1 5.5 Hz, 2 3.41 (in, 2 3.37 (mn, 2 2.31 I 7.0 Hz, 2 1.31 (in, 15 0.89 J 7.4 Hz, 3 FAB-MS calcd for (C22H30NFOS) 375, found 376 Anal. Calcd for C22H30NOFS: C, 70.36; H, 8.05; N, 3.73; F, 5.06; S, 8.54. Found: C, 70.32; H, 7.97; N, 3.58; F, 4.76; S, 8.49. mp 98'C Rf =0.3 ethyl acetate /hexane).

EXAMPLE 67

F

HO

-~S

S

N

2 6 -Diisopropyl-3h droxxnehy(-lA(4fluorohl)(mehlhio)methylpyridine The title compound was prepared from methyl mercaptan according to the procedures described in Example 47. 1 H NMR (300 MJ-z, CDCl3): 6 7.30 (in, 2 H), 7.16 (mn, 2 4.35 J 5.5 Hz, 2 3.43 (in, 2 3.38 (in, 2 Hf), 1.95 3 1.30 (in, 12 FAB-MS calcd for (C20H26NFOS) 347, found 348 Anal. Calcd for C2OH26NOFS: C, 69.13; H, 7.54; N, 4.03; F, 5.47. Found: C, 69.29; H, 7.54; N, 3.91; F, 5.45. mp 49*C Rf =0.2 (10% ethyl acetate /hexane).

EXAMPLE 68

F

NO

2

HO

I

N

thiolinethvlpyridine 204 WO 98/04528 PCT/US97/13248 0 Ste A: 2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)5 f(t-butvldimethylsiloxv)methylpyridine A solution of 3 g (8.3 mmol) of methyl 2 ,6-diisopropyl-4-(4-fluorophenyl)-5hydroxymethyl-3-pyridinecarboxylate (Example 47, Step A) in anhydrous DMF mL), was treated at room temperature with imidazole (1.3 g, 19 mmol), 4dimethylaminopyridine (50 mg, 0.4 mmol) and t-butyldimethylsilyl chloride (1.4 g, 9.3 mmol). The reaction mixture was allowed to stir at room temperature for 48 hr.

The solution was diluted with diethyl ether (200 mL) and washed with water (2 x 100 mL), 1 N HCI (100 mL), sat..NaHCO3 (50 mL) and brine (100 mL), dried (MgSO4) and concentrated to 4 g as an oil: Rf 0.4 (10% ethyl acetate/hexane).

This intermediate (4 g) was dissolved in anhydrous THF (100 mL), stirred under argon and treated with lithium aluminum hydride (17 mL, 17 mmol, 1.OM in THF). The reaction mixture was stirred at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the successive dropwise addition of water (0.6 mL), 20% NaOH (0.6 mL) and water (1.9 mL). The resulting suspension was filtered through a cake of celite and concentrated. Purification by flash silica gel chromatography ethyl acetate/hexane) afforded a colorless resin (1.8 g, 4.2 mmol, 1 H NMR (300 MHz, CDC13) 5 7.25 2 7.12 2 H), 4.38 J 5 Hz, 2 4.28 2 3.44 (sept, I 6.6 Hz, 1 3.39 (sept, J 6.6 Hz, 1 1.33 J 6.6 Hz, 12 1.24 J 5.5 Hz, 1 0.84 9 -0.08 6 H).

FAB-MS calcd for (C25H38FNSiO 2 431, found 432 Anal. Calcd for C25H38FNSiO 2 C, 69.56; H, 8.87; N, 3.24. Found: C, 69.70; H, 8.82; N, 3.12. Rf 0.2 (10% ethyl acetate/hexane).

Ste B: 2,6-Diisopropl-3-bromometh-4-(4-fluorophenyl)-5f(t-butyldimethylsilox)methyl]pvridine The intermediate obtained in Step A (1.7 g, 3.9 mmol) was dissolved in acetonitrile (50 mL) at O'C and treated with dibromotriphenylphosphorane (2.6 g, 6.2 mmol) in portions. The suspension was then allowed to warm to room temperature and stirred for 2 hr. The solvent was removed in vacuo and the residue partitioned between diethyl ether (150 mL) and water (100 mL). The ether layer was washed with brine (50 mL), dried (MgSO4) and concentrated.

Purification by chromatography through silica diethyl ether/hexane) afforded a viscous oil (1.4 g, 2.8 mmol, 72%) which slowly solidified on standing: 1 H NMR (300 MHz, CDC13): 8 7.28 2 7.13 2 4.23 4 3.37 2 1.34 J 6.6 Hz, 6 1.30 J 6.6 Hz, 6 0.83 9 -0.09 6 FAB-MS calcd for (C27H37BrFSiNO) 493, found 494 mp 72-73C. Rf 0.5 (10% ethyl acetate/hexane).

205 WO 98/04528 PCTIUS97/13248 0 Step C: 2 6 Di isopropvl-3-hvdroxymethV1-4.(4..fluorophenvl)S[-( 4 nitrophenyl)thiolmethylpyridine The intermediate obtained in Step B (200 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL), stirred .under argon at room temperature and treated with 4 -nitrothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and N-methylmorpholine (0.2 mL, 1.8 mmol). The reaction mixture was allowed to stir at reflux for 18 h, then cooled to room temperature. The mixture was treated with tetrabutylammonium fluoride (0.8 -ML, 0.8 mmol, 1.OM in THF) and allowed to stir at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with 1N HCl (50 mL), sat. NaHCO 3 mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient 5-10% ethyl acetate /hexane) afforded the title compound as a lightly colored solid (130 mg, 0.28 mmol, 1 H NMR (300 MHz, CDCl3): S 8.08 J=8.5 Hz, 2 7.27 (in, 2 7.13 (in, 4 H), 4.37 I 5.5 Hz, 2 3.91 2 3.46 (Sept, I 6.6 Hz, 1 3.33 (Sept, J 6.6 Hz 1H) 1.3(d, J= 6.6 Hz, 6H)134(dj 6.6 Hz 6

H)

2 7 (tJ 5H;

H).

FAB-MS calcd for (C25H27FSN 2 0 3 454, found 455 mp 178-180*C. Rf 0.3 ethyl acetate /hexane).

EXAMPLE 69

F

HO 0

N

2 6 Diisopropl3hVdroxth1-- -lurhetlA..4lororp hln methyl)pyridine Step A: Me hv1-26diisopropVl.4-(4- uorophen1)5(mophlio eh Pyridinecarboxylate A solution of mehl26diorpl4(-lurpey)5booehl3 pyridinecarboxylate (Example 47, Step.B) (500 mg, 1.22 minol) in CH2CI2 (20 mL) 206 WO 98/04528 PCT/US97/13248 0 was treated with morpholine (0.14 mL, 1.61 mmol) under argon. The reaction was stirred at room temperature for 48 hours. It was then diluted with CH2C12 mL), washed with saturated NaHCO3 (2 x 40 mL), water (1 x 40 mL), and brine (1 x mL). The organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid (495 mg, 1.2 mmol, 1 H NMR (300 MHz, CDCl 3 6 7.16 2 7.07 2 3.54 J 4.4 Hz, 4 3.49 4 3.27 2 2.98 (septet, J 6.6 Hz, 1 2.19 J 4.8 Hz, 4 1.30 12 FAB-MS calcd for (C24H31N2F03) 414, found 415 Anal. Calcd for C24H31N20 3 F: C, 69.54; H, 7.54; N, 6.76; F, 4.58. Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. mp 132-134'C. Rf 0.2 (20% diethyl ether/hexane).

Step B: 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5- (morpholinomethyl)pyridine The intermediate obtained in Step A (375 mg, 0.905 mmol) was dissolved in dry THF (50 mL), treated dropwise with lithium aluminum hydride (1M/THF, 1.81 mL) and the reaction stirred at reflux for 24 hours. The reaction was quenched by the successive dropwise addition of water (0.lml), NaOH 20% (0.1ml), and water again (0.3ml). Concentration in vacuo afforded a white residue which was partitioned between CH2C12 and water. The organic layer was dried with MgSO4, filtered, and concentrated to afford an oil. The product was passed through a pad of silica (40% diethyl ether/hexanes) yielding an oil which slowly solidified to give the title compound as a white solid (295 mg, 0.76 mmol, 1 H NMR (300 MHz, CDC13): 7.14 4 4.35 2 3.53 J 4.8 Hz, 4 3.45 2 3.18 2 2.18 J 4.5 Hz, 4 1.26 13 FAB-MS calcd for (C23H31N2F02) 386, found 387 Anal. Calcd for C23H31N202F: C, 71.47; H, 8.08; N, 7.25; F, 4.92 Found: C, 71.55; H, 8.16; N, 7.05; F, 4.70. mp 93.5-95.5°C. Rf 0.4 (40% diethyl ether/hexane).

EXAMPLE

F

HO

ND

N

207 IptTi.^te a "i-^^aaii&wK WO 98/04528 PCTIUS97/13248 0 2 6 -Diisopropyl3hydroxymethy1.4(4.fluorphenv).5(Piperidinometh).~rdn .The title compound was prepared from piperidine according to the procedures described in Example 69. 1 H NMR (300 MHz, CDCl3): 8 7.05 (in, 4 4.27 J 5.5 Hz, 2 3.38 (mn, 2 3.01 2 2.02 (mn, 4 1.22 (in, 24 H).

FAB-MS calcd for (C24H33N2F0) 384, found 385 Anal. Calcd for C24H33N20F: C, 74.96; H, 8.65; N, 7.28; F, 4.94. Found: C, 75.13; H, 8.48; N, 6.92; F, 4.77. Gummy oil. Rf =0.5 (40% diethyl ether/hexane).

EXAMPLE 71

F

HO

NN

rnethyl)pyridine The title compound was prepared from pyrrolidine according to the procedures described in Example 69. 1 H NMR (300 Mffz, CDCl3): 8 7.13 (mn, 4 4.34 (d J 4.8 Hz, 2 3.52 (septet, J=6.6 Hz, 1 3.42 (septet, I=6.6 Hz, 1 3.28 2 2.22 J= 6.3 Hz, 4 1.60 J=3.3 Hz, 5 1.27 (in, 12 H).

FAB-vS calcd for (C23H31N2F0) 370, found 371 Anal. Calcd for C23H3 jN 2 cjF: C, 74.56; H, 8.43; N, 7.56; F, 5.13. Found: C, 74.67; H, 8.72; N, 7.35; F, 5.01. mp 122-124 0 C. Rf =0.3 (40% diethyl ether/hexane).

EXAMPLE 72

F

HO- -N 208 WO 98/04528 WO 9804528PCT[US97/13248 0 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-54.phenylpiperidiw1..

yl)methyllpyridine The title compound was prepared from 4-phenylpiperidine according to the procedures described in Example 69. 1 H NMR (300 MHz, CDCl3): 8 7.29 (in, 2 H), 5 7.15 (in, 7 4.36 J 5.2 Hz, 2 3.48 (mn, 2 3.19 2 2.71 I 11 .0 Hz, 2 2.38 (in, 1 1.86 (in, 2 1.71 (mn, 2 1.58 (in, 2 1.58 (in, 13 FAB- MS calcd for (C30H3jN2F0) 460, found 461 Anal. Calcd for C23H31N20F: C, 78.22; H, 8.10; N, 6.08; F, 4.12. Found: C, 78.01; H, 8.21; N, 5.96; F, 4.41. mp 66- 68 0 C. Rf 0.5 (40% diethyl ether/hexane).

EXAMPLE 73 MeO Mehl26diorpI4(-loohpl-5(-ieiinpprdnlV~ehl3 pyridinecarboxylate The title compound was prepared from 4-piperdinopiperidine according to the procedure described in Example 69 (Step IH NMR (300 MHz, CDCl3): 8 7.16 (in, 2 7.04 (in, 2 3.51 (septet, J=5.5 Hz, 1 3.47 3 3.20 2 H), 2.98 (septet, J=6.6 Hz, 1 2.65 J 11.0 Hz, 2 2.44 (in, 4 -2.05 (mn, 1 H), 1.62 (in, 10 1.31 (mn, 16 FAB-MS calcd for (C30H42N3F02) 495, found. 496 Anal. Calcd for C30H42N302F: C, 72.69; H, 8.54; N, 8.48; F, 3.83. Found: C, 72.43; H, 8.56; N, 8.37; F, 3.74. mp 59-61 0 C. Rf 0.1 (70% diethyl ether/hexane 1 drop MeOH).

209 WO 98/04528 PCT1US97/13248 0 EXAMPLE 74

F

HO

~ND-N

N

2 6 Diisoproppyl3hdroxymeth 4(4 forophnl-ipe1)S[(pipidin-l yl)methyllpyridine The title compound was prepared from 4 -piperidinopiperidine according to the procedures described in Example 69. 1H NMR (300 MHz, CDCl3): 8 7.12 (in, 4 4.34 J=3.7 Hz, 2 3.45 (in, 2 3.10 (in, 2 2.63 J=11.0 Hz, 2 H), 2.44 (in, 4 2.03 (mn, 1 1.44 (mn, 29 FAB-MS calcd for (C29H42N3F0) 467, found 468 Anal. Calcd for C29H42N 3 0p: C, 74.48; H, 9.05; N, 8.98; F, 4.06.

Found: C, 74.93; H, 9.35; N, 8.39; F, 3.83. mp 143-145 0 C. Rf =0.1 (50% diethyl ether/hexane 2 drops of MeOH). EXAMPLE

F

H 0~ N N

NA

2 6 Diisopro YI-3hydroxmethl (4fluorophel)5f( 4 helperzvl)methlpvridine The title compound was prepared from 4 -phenylpiperazine according to the procedures described in Example 69. 1 H NMR (300 MJ-Iz, CDC1 3 8 7.16 (in, 6 H), 6.85 (in, 3 4.36 I 5.2 Hz, 2 3.47 (in, 2 3.24 2 3.04 f 4.8 Hz, 4 2.35 J 4.8 Hz, 4 1.29 (in, 13 FAB-MS calcd for (C29H36N3F0) 461, found 462 Anal. Calcd for C29H36N30F: C, 75.46; H, 7.86; N, 9.10; F, 4.12.

210 -7 WO 98/04528 WO 98/4528 CT/US97/13248 o Found: C, 75.35; H, 7.82; N, 8.80; F, 3.99. mp 111-113TC. Rf 0.5 (40% diethyl ether/hexane).

EXAMPLE 76 2 6 -Diisopropyl-3-hydroxymethVl-4-(4-fluorophenyl)-5-(imidazo1.y).

methylpyridine The title compound was prepared from imidazole according to the procedures described in Example 69. 1 H NMR (300 MHz, CDCl3): .8 7.01 (in, 6 6.57 1H), 4.84'(s, 2 4.39 2H), 3.49 (septet, J =6.6 Hz, 1 3.23 (septet, J -6.6 Hz, 1 1.70 1.36 J 6.6,Hz, 6 1.27 J 6.6 Hz, 6 FAB- MS calcd for (C22H26N3F0) 367, found 368 Anal. Calcd for C22H26N30F: C, 71.91; H, 7.13; N, 11.43;:F, 5.17. Found: C, 71.26; H, 7.24; N, 11.03; F, 5.35. mp 184-186 0 C. Rf= 0.1 (50%,diethyl ether/hexane w/ 2 drops MeGH).

EXAMPLE 77 k 2 6 -Diisopropyl-3-hvdroxmethyl-4(4fluorophen1)5-(ccloprop1..

amino)methylpyridine The title compound was prepared from cyclopropylamine according to the WO 98/04528 PCT/US97/13248 o procedures described in Example 69. 1 H NMR (300 ivz, CDC13): 8 7.04 (in, 4 H), 4.21 2 3.35 2 3.26 (septet, J 6.6 Hz, 2 1.78 (in, 1 1.17 (in, 13 H), 0.153 (in, 2 -0.006 (in, 2 FAB-MS calcd for (C22H29N2F0) 356, found 357 Anal. Calcd for CI22H29N2OF: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found: C, 74.29; H, 8.62; N, 7.93; F, 4.90. mp 81-83 0 C. Rf =0.3 (40% diethyl ether/hexane).

EXAMPLE 78

HO'

2 6 Diisopropl3hydrox neth I...4lorpenlSl amino)inethylpvridine The title compound was prepared from cyclohexylainine according to the procedures described in Example 69. 1H NMR (300 MlHz, CDC1 3 8 7.25 (in, 2 7.1 3 (in, 2 4.34 2 3.38 (in, 4 2.16 (in, 1 1.58 (in, 5 1.23 (in, 16 H), 0.936 (in, 2 FAB-MS calcd for (C25H35N2F0) 398, found 399 Anal.

Calcd for C25H35N20F: C, 74.12; H, 8.20; N, 7.86; F, 5.33. Found: C, 74.29; H, 8.62; N, 7.93; F, 4.90. mp 131-133'C. Rf 0.1 (40% diethyl ether/hexane).

EXAMPLE 79

S

2 6 -Diisopropvl-3-hydroxymeth yl..4.(4fluoro-henvi)5(dimthylan)inethVIpyridine 212 WO 98/04528 PCT/US97/13248 0 The title compound was prepared from dimethylamine hydrochloride according to the procedures described in Example 69. 1H NMR (300 MHz, CDC13): 8 7.12 4 4.25 2 4.09 1 3.68 (septet, J 6.6 Hz, 1 3.41 (septet, J 6.6 Hz, 1 2.18 1 1.69 J 4.1 Hz, 1 1.26 12 0.947 I 6.3 Hz, 3 0.555 J 7.0 Hz, 1 FAB-MS calcd for (C22H30NF02) 359, found 360 Anal. Calcd for C22H30N02F: C, 73.51; H, 8.41; N, 3.90; F, 5.28.

Found: C, 73.69; H, 8.40; N, 3.82; F, 5.04. mp 77-79 0 C. Rf 0.2 (40% diethyl ether/hexane).

EXAMPLE

F

HO -N

N

2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(dibutylamino)methylpyridine The title compound was prepared from dibutylamine according to the procedures described in Example 69. 1 H NMR (300 MHz, CDC13): 8 7.11 4 H), 4.33 J 5.5 Hz, 2 3.62 (septet, J 6.6 Hz, 1 3.62 (septet, J 6.6 Hz, 1 H), 3.24 2 2.12 J 7.0 Hz, 4 1.55 1 1.33 J 6.6 Hz, 6 1.26 6.6 Hz, 6 1.16 8 0.796 J 6.6 Hz, 6 FAB-MS calcd for (C27H41N2FO) 428, found 429 Anal. Calcd for C27H41N20F: C, 75.66; H, 9.64; N, 6.54; F, 4.43. Found: C, 75.91; H, 9.83; N, 6.26; F, 4.33. Gummy oil. Rf= 0.6 diethyl ether/hexane).

EXAMPLE 81

F

HO 213 WO 98/04528 PCTIUS97/13248 0 2 6 Diisop ropvl3hdroxymethV1A..(4-fluorophenl)5meth 14riin -A solution of methyl- 2 6 diisopropyl4.(4fluorophenyl)5bromthyl- 3 pyridinecarboxylate (Example 47, Step B) (300 mg, 0.7 mmol), in anhydrous

TI-IF

mL) was stirred under argon at room temperature and treated dropwise with lithium aluminum hydride (2.1 mL, 1.0 M in THF, 2.1 mmol). The reaction mixture was heated at reflux for 1 hr, then allowed to cool to room temperature. The reaction was quenched by the dropwise sequential addition at room temperature of water (80 20% NaOH (80 uL) and water (240 uL). The resulting suspension was filtered through a pad of celite anid concentrated. Purification by chromatography through silica ethyl acetate/hexane) afforded the title compound as a white solid (182 mg, 0.6 mmol, 1 H NMiR (300 MHz, CDCI3): 8 7.15 I=7 Hz, 4 4.36 I=5.5 Hz, 2 3.42 (sept, I=6.6 Hz, 1 3.26 (sept, I=6.6 Hz, 1 1.94 3 1.33 J 6.6 Hz, 6 1.29 J 6.6 Hz, 6

Q

1.19 J 5.5 Hz, 1 FAB-MS calcd for (C19H24FN0) 301, found 302 Anal. Calcd for C19H24FN0: C, 75.72; H, 8.03; N, 4.65. Found: C, 75.62; H, 8.02; N, 4.57. mp 127-128*C. Rf =0.3 (20% ethyl acetate /hexane)...

EXAA4IPLE 82 2 6 Diisoprpl3drox1 mthyrox-ethfloro4fluorl)-5 3 hnlpropenyl)pvridine Step A: Methvl-26diisoropvl4(4fuorop henV1)5-(-o thl)- 3 Pyridinecarboxylate Methoxymethyl triphenylphosphoniur chloride (1.15 g, 3.35 mmol) was suspended in 25 mL -of dry, distilled TI-I under argon and stirred at -78'C.

Butyllithium (1.6 M/hexane, 1.2 2.1 mL) was added dropwise and then the reaction mixture was allowed to stir at OTC for 1.0 hour. The solution was cooled 214 WO 98/04528 PCT/US97/13248 0 again to -78 0 C, treated dropwise with a solution of 5-carboethoxy-2,6-diisopropyl- 4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) (1 g, 2.8 mmol) in mL of dry THF, and then warmed to room temperature and stirred overnight.

The reaction was quenched 2 mL water and the THF was evaporated in vacuo.

Diethyl ether was added and washed with water (2 x 40 mL), brine (1 x 40 mL), and dried with MgSO4. The residue was dissolved in THF (20 ml), treated with a solution of concentrated HC1 and stirred at room temperature for lh. The reaction mixture was diluted with diethyl ether (150 ml) washed with water (50 ml), brine ml), dried with MgSO4 and evaporated in vacuo. Flash chromatography ethyl acetate/hexane) afforded 335 mg (0.9 mmol, 32%) of product. 1 H NMR (300 MHz, CDC13): 8 9.62 1 7.09 4 3.97 J 7 Hz, 2 3.60 2 3.06 (sept, J 6.6 Hz, 1 3.00 (sept, J 6.6 Hz, 1 1.32 J 6.6 Hz, 6 1.27 J 6.6 Hz, 6 0.97 J 7 Hz, 3 FAB-MS: calcd for (C22H26FN03) 371, found S 372 Anal. Calcd for C22H26FN03: C, 71.14; H, 7.06; N, 3.77. Found: C, 70.91; H, 6.91; N, 3.63. mp 69-71C. Rf 0.3 (10% ethyl acetate/hexane).

Step B: 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-phenyl-2propenyl)pyridine The title compound was prepared from the intermediate obtained in Step A and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1 H NMR (300 MHz, CDC3):-8 7.19 8 6.96 (m, 1 6.32 J= 11 Hz, 0.4 6.09 (dt, J 5.5, 16 Hz, 0.6 5.96 J 16 Hz, 0.6 5.45 (dt, J 7, 11 Hz, 0.4 4.37 J 5 Hz, 1.25 4.33 J 5.5 Hz, 0.75 H), 3.41 1.6 3.25 2 3.08 0.4 1.35 5 1.30 I 6.6 Hz, 5 H), 1.21 3 FAB-MS: calcd for (C27H30FNO) 403, found 404 Anal.

Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26.

mp 72-73C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 83

F

HO

215 WO 98104528 PCTfUS97/13248 0 2 6 Diisopropl3hydroxymethy4(4.fluorophenl)53phenylptropyl)pyridn The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethy14.

4 -fluorophenyl)-5-(3-pheny1-2.propenyl)pyridine (Example 82) according to the procedure described in Example 1, Step H. 1 H NMR (300 MI-Iz, CDCl3): 5 7.11 (in, 9 4.31 2 3.40 (sept, J 6.6 Hz, 1 3.12 (sept, J 6.6 Hz, 1 2.46 J 7.35 Hz, 2 2.29 (mn, 2 1.62 (mn, 2 1.32 J 6.6 Hz, 6 1.26 I 6.6 Hz, 6 1.16 (bin, 1 FAB-MS: calcd for (C27H32FN0) 405, found 406 mp 137-140*C. Rf =0.3 (20% ethyl acetate/hexane).

EXAMPLE 84

C-)

2 6 DiisoproPyl-3hdroxmethl4(4.fluorophenVl)5[3-(2-methyl phenyl)propyllpyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4floohnl--2ootyl--yiieabxlt (Example 82, Step and 2methylbenzyl triphenylphosphorui bromide according to the procedures described in Example 1, Steps F-H. 1 H NM (300 MHz, CDCl3): 8 7.07 (in, 7 H), 6.90 (in, 1 4.31 2 3.39 (sept, J=6.6 Hz, 1 3.15 (sept, J 6.6 Hz, 1 H), 2.43 J 7.5 Hz, 2 2.34 (in, 2 2.17 3 1.56 (in, 2 1.31 J 6.6 Hz, 6 1.27 J 6.6 Hz, 6 1.15 (in, 1 FAB-MS: calcd for (C28H34FN0) 419, found 420 Anal. Calcd for C28HMIFNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.01; N, 3.25. mp 65-70*C. Rf =0.4 (20% ethyl acetate/hexane).

216 W;w v W WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 2 6 -Diisopropyl-3-h droxymethyl-4(4-fluorophenyl)..5[3-(3-methlphentyl)propyljpyridine, The title compound was prepared from methyl-2,6-diisopropyl4-(4-.

fluorophenyl)-5-(2-oxoethyl)3pyridinecarboxylate (Example 82, Step A) and 3methylbenzyl triphenyiphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1 H NMR (300 MI-Iz, CDCl3): 8 7.09 (in, 5 H), 6.98 (in, 1 6.78 (mn, 2 4.31 2 3.39 (sept, J 6.6 Hz, 1 3.12 (sept, J 6.6 Hz, 1 H),,2.42 J 7 Hz, 2 2.30 3 2.28 (i,2 1.58 (in, 2. 1.31 j -6.6 Hz, 6 1.26 J 6.6 Hz, 6 1.15 (i,1 FAB-MS: calcd for '(C28H34FN0O) 419, found 420 Anal. Calcd for C28H34FN0: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.23; H, 8.17; N, 3.23. mp, 68-70*C. Rf DA0. (20% ethyl acetate /hexane).

EXAMPLE 86 2 6 -DiisO~ropy-3hdroxymethyl4.(4fluorophenvl)-5F[3(4-methylphenyl)propyll yridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4floohnl--2ootyl--yiieabxlt (Example 82, Step A) and 4methylbenzyl triphenyiphosphonium bromide according to the procedures 217 WO 98/04528 PCT/US97/13248 0 described in Example 1, Steps F-H. 1 H NMR (300 MHz, CDC13): 8 7.08 4 H), 7.01 J 8 Hz, 2 6.85 J 8 Hz, 2 4.30 2 3.39 (sept, J 6.6 Hz, 1 H), 3.13 (sept, J 6.6 Hz, 1 2.41 J 7 Hz, 2 2.31 3 2.27 2 1.58 (m, 2 1.31 J 6.6 Hz, 6 1.26 I 6.6 Hz, 6 1.15 1 FAB-MS: calcd for (C28H34FNO) 419, found 420 Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80 0 C. Rf 0.4 (20% ethyl acetate/hexane).

EXAMPLE 87

F

HO

N

2,6-Diisopropyl-3-hydroxvmethvl-4-(4-fluorophenyl)-5-(2-propenyl)-pyridine The title compound was prepared from methyl-2,6-diisopropyl-4-(4fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1 H NMR (300 MHz, CDC13): 8 7.13 4 5.73 1 H), 4.81 (dd, J= 4.8,1.8 Hz, 2 4.35 2 3.43 (septet, J= 6.6 Hz, 1 3.21 (septet, J 6.6 Hz, 1 3.07 J 1.8 Hz, 2 1.24 13 FAB-MS: calcd for (C21H26FNO) 327, found 328 Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59 0.7 H20. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69- 71'C. Rf 0.35 (15% ethyl acetate/hexane).

EXAMPLE 88

F

HO I, OH 218 WO 98/04528 PCT[US97/13248 0 2,6-Diisopropvl-3-hydroxvmethyl-4-(4-fluorophenVl)-5-(4-hvdroxy-butvl)pvridine To a solution of 2 6 -diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[ 3 (1, 3 -dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) was added 2N aq. HCI (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in vacuo and the residual suspension carefully neutralized to pH 7 with sat. aq. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded a white solid (1.5 g, 4.2 mmol, 1 H NMR (300 MHz, CDC13): d 9.57 1 7.16 4 4.33 J Hz, 2 3.42 1 3.24 1 2.33 2 2.27 (dt, J 1.8, 7.4 Hz, 2 H), 1.61 2 1.32 12 1.20 1 FAB-MS: calcd for (C22H30FN02) 359, found 340 Rf 0.3 (20% ethyl acetate/hexane).

This intermediate (200 mg, 0.56 mmol) was dissolved in absolute ethanol mL) and treated at room temperature, with stirring, with sodium borohydride (32 mg, 0.85 mmol). After stirring for 1 hr, the reaction was quenched by the dropwise addition of 2N HCI (3 mL). The solution was stirred 5 min, then neutralized by the careful addition of sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 50 mL), the combined extracts dried (MgSO4) and concentrated.

Purification by chromatography through silica (20% ethyl acetate/hexane) afforded the title.compound as a white solid (88 mg, 0.25 mmol, 1H NMR (300 MHz CDC13): 8 7.16 4 4.33 J 5 Hz, 2 3.46 2 3.41 1 2.23 (m, 1 2.32 2 1.40 4 1.32 12 1.19 1 1.09 1 FAB- MS: calcd for (C22H30FNO 2 359, found 360 Anal. Calcd for C22H30FNO 2 C, 73.51; H, 8.41; N, 3.90. Found: C, 73.37; H, 8.41; N, 3.72. mp 135- S 137'C. Rf 0.4 (50% ethyl acetate/hexane);

F

HO

N

219 A I TINI W" lq yn"-mr a WO 98/04528 WO 9804528PCTIUS97/13248 o 2 6 -Diisopropyl-3-hydroxymethylA4-(4fluorohenyl)5...(3-.dimethylamino)propyllpyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl4(4fiuorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and (2dimethylaminoethyl)triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1 H NUR (300 MHz, CDCl3): 8 7.17 (in, 4 H), 4.33 2 3.41 (sept, J 6.6 Hz, 1 3.21 (sept, I 6.6 Hz, 1 2.32 (m,2 2.16 (il, 2 2.14 6 1.49 (in, 2 1.32 (in, 13 FAB-MS: calcd for (C23H33FN20) 372, found 373 mp 50-510C. Rf =0.35 ethanol /CH2C2).

EXAMPLE

F

HO N. (CH 2 7

-N

N C 2 6 -DiisopropVl-3hyroxyinethyl-4-.(4fuorophenv)5[(3-dimethvlamino~heptyllpyridine Step A: 2 6 -Diisopropl-3-hydroxymeffyl4(4..fluorophenl)-5-(4 oxobutvl)pvridine To a solution of 2 6 -diisopropyl-3-hiydroxymethyl-4(4..fluorophenyl).s..[3..

(l, 3 -dioxolan-2-yl)propyllpyridine (Example 46) (2 g, 5 inmol) in TI-I (50 mL) was added 2N aq. HC1 (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in vacuo and the residual suspension carefully neutralized to pH 7 with sat. NaHCO3. The aqueous phase was extracted with diethyl ether (3 x 100 mL), the combined ether extract washed with brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography. through silica (step gradient, 10%-20% ethyl acetate/hexarie) afforded a white solid (1.5 g, 4.2 mmol, 1H NMR (300 MHz, CDC13): 5 9.57 1 7.16 (in, 4 4.33 I Hz, 2 3.42 (in, 1 3.24 (in, 1 2.33 (in, 2 2.27 (dt, J=1.8, 7.4 Hz, 2 H), 1.61 (in, 2 1.32 (mn, 12 1.20 (in, 1 FAB-MS: calcd for (C22H28FN02) 357, found 358 Rf =0.3 (20% ethyl acetate /hexane).

220 WO 98/04528 WO 9804528PCT/US97/13248 Step B: 2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)54(3dimethylamino)heptyllpyridine The intermediate prepared in Step A was treated with (3dimethylamino)propyl triphenyiphosphonium. bromide according to the procedures described in Example 1, Steps F-H, to afford the title compound as a solid. 1 H NMR (300 MHz, CDCl3): 5 7.16 (in, 4 4.32 2 3.41 (sept, J 6.6 Hz, 1 3.22 (sept, J =6.6 Hz, 1 2.28 6 2.26 (in, 4 1.43 (in, 2 1.33 I 6.6 Hz, 6 1.30 j 6.6 Hz, 6 1.27 (in, 3 1.31 (in, 6 FAB-MS: calcd for (C27H41FN20) 428, found 429 mp 85-87*C. Rf =0.1 EtOH/CH2C2).

EXAMPLE 91 2 ,6-Diisopropl-3-hydroxymethyl14(4fluorOphenl)5(8carboxheptvl)pyridine The title cornpound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl)-5-(4.-oxobutyl)pyridine (Example 90,' Step A) and carboxybutyl)triphenylphosphoniuin bromide .according to the procedure described in Example 90, Step 1 H.NMR (300 MEIIz, CD3O0D): 8 7.17 (in, 4 4.23 2 3.44 (sept, J=6.6 Hz, 1 3.23 (sept, J=6.6 Hz, 11H), 2.28'(mn, 2 2.14 (t, 7.5 Hz, 2 1.54 (in, 2 1.28 I.J 6.6 Hz, 6 1 .24 J 6.6 Hz, 6 1.22 (in, 4 1.17 (in, 2 1.10 (in, 4 EI-MS: calcd for (C27H38FN03) 443, found 443 mp 240*C (dec). Rf 0.3 (50% ethyl acetate/hexane).

WO 98/04528 PCT/US97/13248 0 EXAMPLE 92

F

HO

CO

2

H

N

2,6-Diisopropyl-3-hydroxymethvl-4-(4-fluorophenyl)-5-(3-carboxypropvl)pyridine To a solution of 2 ,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[3- (1, 3 -dioxolan-2-yl)propyl]pyridine (Example 46) (2 g, 5 mmol) in THF (50 mL) was added 2N aq. HCI (10 mL). The solution was allowed to stir for 17 hr at room temperature. The THF was removed in vacuo and the residual suspension carefully neutralized to pH 7 with sat. NaHCO 3 The aqueous phase was extracted with diethyl ether (3 x 100 mL), and the combined ether extract washed with brine mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient, 10%-20% ethyl acetate/hexane) afforded 1.5 g of the intermediate as a white solid: Rf 0.3 (20% ethyl acetate/hexane).

280 mg of the intermediate was dissolved in dry pyridine (5 mL), stirred at room temperature under argon and treated with acetic anhydride (0.37 mL, 3.9 mmol). The reaction mixture was allowed to stir at room temperature for 17 hr.

The pyridine was removed in vacuo, and the residue dissolved in diethyl ether mL), washed with sat. CuSO4 (10 mL), water (20 mL), sat. NaHCO3 (20 mL) and brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (20% ethyl acetate/hexane) afforded 220 mg as a viscous yellow oil: Rf =0.6 (50% ethyl acetate/hexane).

200 mg of the oil was dissolved in acetone (5 mL), stirred at room temperature and treated with Jones reagent (2 mL, prepared from 67 g Cr03, 125 mL H20 and 58 mL con. H2S04). The reaction mixture was stirred 0.5 hr, quenched by the addition of 2 -propanol, filtered through a short pad of silica and concentrated. The residue was dissolved in MeOH (5 mL), treated with 20% NaOH (2 mL) and stirred 14 hr at room temperature. After neutralizing to pH 7 with aq.

HC1, the solution was saturated with NaCl and extracted with CHC13 (3 x 20 mL).

The combined extract was dried (MgSO4) and concentrated. Purification by chromatography through silica (1:1 ethyl acetate/hexane) afforded the title 222 WO 98/04528 WO 9804528PCT1US97/13248 o compound as a white foam (22 mg). 1 H NMR (300 Mffz, CD3OD): 8 .7.18 4 H), 4.24 2 3.46 (sept, J 6.6 Hz, 1 3.33 (sept, J 6.6 Hz, 1 2.34 (in, 2 H), 1.99 J 7 Hz, 2 1.60 (in, 2 1.29 j 6.6 Hz, 6 1.26 J 6.6 -Hz, 6 H).

FAB-MS: calcd for (C22H28FN03) 373, found 374 mp 160*C. Rf 0.3 ethyl acetate /hexane).

EXAMPLE 93

F

OH

HO

N

ethyl)vyridine Step A: W±)-Ethyl-2,6-diisopropyl-4-(4.fluorophenyl)-5-( -hydroxy-ethyl)-3pyridinecarboxylate TO 5-carboethoxy-2,6-diisopropy4(4.fluoropheny)-.3..pyridinecarboxaldehyde (Example 1, Step E) (1 g, 2.91 mmol) in TIF (30 mL) was added methyllithium (1.4 M, 1.0. eq., 2.08 mL) dropwise at -78*C under. argon. The reaction was stirred for 2 hours, then quenched with water and the THIF evaporated to afford a white solid. The product was partitioned between diethyl ether and water, The. organic layer was then dried with -MgSO4q, -filtered, and concentrated to afford a white solid. The product was passed through, a plug of silica ethyl acetate/hexane) to afford a white'solid (857 mg, 2,4 minol, 82%).

1H1 NMR (300 MHz, CDCl3): 8 7.14 (in, 4 4.86 (dq, 1 3.7 J= 6.6 Hz, 18H), 3.80 (septet, I=6.6 Hz, 1 3.47 3 2.96 (septet, J 6.6'Hz, 1 1.65 J 3.7 Hz, 25 1 M, 1.46 I=6.6 Hz,-3 1.27 12 PAB-MS: calcd for (C21H26NF03) 359, found 360 Anal. Calcd for C21H26N0 3 F: C, 69.54; H,7.54; N, 6.76; F, 4.58.

Found: C, 69.55; H, 7.43; N, 6.50; F, 4.45. MP 169-1710C. Rf =0.2 (10% ethyl acetate /hexane).

WO 98/04528 PCT/US97/13248 0 Step (±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(l hydroxvethyl)pyridine The intermediate obtained in Step A (300 mg, 0.835 mmol) was dissolved in mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.67 mL, 2 The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water(70 gL), 20% NaOH (70 LL), and water (140pL). After filtration, the solvent was evaporated to afford a white residue. The product was subjected to flash chromatography (20% ethyl acetate/hexane) which afforded the title compound as a white solid (84 mg, 0.25 mmol, 1 H NMR (300 MHz, CDCl 3 8 7.15 4 4.71 (dq, J= 3.7, 1 6.6 Hz, 1 4.30 2 H), 3.79 (septet, J 6.6 Hz, 1 3.42 (septet, 6.6 Hz, 1 1.62 J 3.68 Hz, 1 H), 1.58 1H), 1.43 J 6.6 Hz, 3 1.28 16 FAB-MS: calcd for (C20H26NF0 2 331, found 332 Anal. Calcd for C20H26N0 2 F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 184-186C. Rf 0.2 (20% ethyl acetate/hexane).

EXAMPLE 94

F

OH

HO

N

±-26-Diisorop -hydroxmethl-4-4-fluorophenl-5-(-hydropropyl)pyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. 1 H NMR (300 MHz, CDCl3): 8 7.15 4 4.40 (dq, J 3.7, J= 5.2 Hz, 1 4.30 J 5.5 Hz, 2 3.72 (septet, J 6.6 Hz, 1 3.42 (septet, I 6.6 Hz, 1 1.88 1 1.63 (t, J 5.5 Hz, 1H), 1.27 14 0.804 J 7.36 Hz, 3 FAB-MS: calcd for (C21H28NF0 2 345, found 346 Anal. Calcd for C21H28N02F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175C. Rf 0.2 (20% ethyl acetate/hexane); 224 WO 98/04528 WO 9804528PCT/US97113248 EXAMPLE

OH

(±-,-ispoy--~rxmtVI4(-loohnl--lhdoy peqtvl)pyridine The title compound was prepare d from 5-carboethoxy-2,6-diisopropylb4-(4fluo'rophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and n-butyllithium, according to the procedures described in Example 93. 1 H NMiR (300 Mliz, CDCl3): 8 7.16 (in, 4 4.49 (in, 1 4.31 J=5.5 Hz, 2 3.74 (septet, J 6.6 Hz, 1 H), 3.42 (septet, I=6.6 Hz, 1 (in,1 H) 1.58 J 3.3.Hz, 1 1.18-(in 18 H), 0.821 1=4.1 Hz, 3 FAB-MS: calcd for (C23H32NF0 2 373, found1374 Anal. Calcd for C23H32N02F:- C, 73.96; H, 8.64; N, 3.75; F, 5.09. -Fountd: C, 73.81; Hj, 8.60; N, 3.58; F, 5.02. mp 166-1680C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 96

HO

(±-,-ispoy--yrxmtvl4(-loohnl--hdoy phenylmethvl)pvridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. 1 H NMIR (300 MIHz, CDC13): 225 1 4 1 WO 98/04528 PCT[US97/13248 0 8 7.23 (in, 7 7.06 (mn, 2 5.71 I=5.14 Hz, I 4.38 J 5.5 Hz, 2 3.47 (septet, I 6.6 Hz, 1 3.12 (septet, J Hz, 1 2.12 J 5.1 Hz, 1 1.57 (s, 1H), 1.29 (in, 10 0.797 j 6.6 Hz, 3 FAB-MS: calcd for (C25H28NF0 2 393, found 394 Anal. Calcd for C25H28N0 2 F: C, 76.84; H, 8.69; N, 3.90.

Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204*C. Rf =0.2 (20% ethyl acetate /hexane).- EXAMLE 97

F

OH

HO 0

N

2 6-Diisopro~l3.hydroetvme4-V1A(4luothel)5[(lhydroxv methYlDpropyllpyridine The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4(4fluorophenyl)-37.yridinecarboxaldehyde (Example 1, Step E) and isopropyl magnesium bromide, according to the procedures described in Example 93. 1

H

NMR (300 MHz, CDC13): 8 7.14 (Mn, 4 4.35 2 3.53 J 4.8 Hz, 4 3.45 (in, 2 3.18 2 2.18 J 4.5 Hz, 4 1.26 (in, 13 FAB-MS: calcd for (C23H3jN 2 F0 2 386, found 387 Anal. Calcd for C23H31N202F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 139-140*C. Rf =0.3 ethyl acetate/hexane) EXAMPLE 98

F

OCH

3 H O

-CI

N

226 'O -CFC _i WO 98/04528 WO 9804528PCTIUS97/13248 0 (±)-2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenl).5.(lmethoxy.

ethyl)pvridine Step A: Methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-methoxyethyl)-3 prwidinecarboxylate (±)-Ethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(1-hydroxyethyl).3pyridinecarboxylate (Example 93, Step A) 487 mg, 1.36 mmol) was dissolved in mL of dry THF, treated with NaH (-0.20 g, 8.13 mnmol) under argon, stirred for min. and treated with methyl iodide (0.34 mnL, 5.24 mmol). The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature,. quenched with water, and concentrated to. afford a watery residue. The product was partitioned between diethyl ether and water, the organic layer was dried with MgSO4, filtered, and concentrated to afford a white solid. The product was passed throuigh a pad of silica ethyl acetate/hexane) to yield aw white solid (495 mg, 1.33 mmol, 1

H

NMR (300 MHz, CDCI3): 8 7.13 (in, 4 4.25 J 6.6 Hz, 1 3.80 (septet, J 6.6 Hz, 1 3A48 3 3.10 3 2.97 (septet, J 6.6 Hz, 1 1.41 j 6.6 Hz, 3-H),'1.29 (in, 12 FAB-MS: calcd for (C22H31FN03) 373, found 374 Anal. Calcd 'for C24H31N203F: C, 70.75; H, 7.56; N, 3.75; F, 5.09. Found: C, 70.70; H, 7.63; N; 3.59; F, 4.77'. mp 132-134*C. Rf =0.5 (10% ethyl acetate/hexane).

Step2 B: 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-fluorOphenl).5(.

methoxyethyl)pyridme The intermediate obtained in Step A (359 mg,, 0.9.61 mmol) was dissolved in mL of dry THF, for a dropwise addition of a solution of LAH (1 M/THF, 1.92 mL, 2 The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water (80 jiL), 20% NaOH (80 J.LL), and water (160 Ai). After filtration, the solvent was evaporated to afford a residue which was ifitered through to a pad of silica (10% ethyl acetate/hexane) to Afford the'title compound as a white solid (281 mng, 0.72 inmol, 1 H NMR (300 MIHz, CDCl3): 8 7.13 (in, 4 4.32 (dq, J=5.2 J=11.4 Hz, 1 4.11 J 6.3 Hz, 1 3.77 (septet, J=6.6 Hz, 1 3.42 (septet, J 6.6 Hz, 1 3.10 3 1.29 (in, 16 H).

FAB-MS: calcd for (C21H28FN02) 345, found 346 Anal. Calcd for C21H28N0 2 F: C, 76.84; H, 8.69; N, 3.90. Found: 76.67; H, 8.76; N, 3.77. mp 151- 1530C. Rf =0.4 (20% ethyl acetate /hexane).

227 WO 98/04528 PTU9/34 PCTIUS97/13248 EXAMPLE 99 -propyl)pvridine The title -compound was prepared from 2 6 -diisopropyl-3hydroxymethyl-4(4fluorophenyl)5(1..hydroxypropy)pyridine (Example 94) according to the procedures described in Example 98. 1 H NMvR (300 MHz, CDC13): 8 7.11 (in, 4 4.32 (in, 2 3.83 (in, 1 3.74 (septet, I 6.6 Hz, 1 3.41 (septet, J=6.6 Hz, 1 3.12 2 1.88 (in, 1 1.56 (in, 2 1.27 (in, 12 H), 0.776 J= 3.7 Hz, 3 H1). FAB-MS: calcd for (C22H30NF02) 359, found. 360 Anal. Calcd for C22H30N02F: C, 73.51; H, 8.41; N, 3.90; F, 5.28. Found: C, 73.55; H, 8.54; N, 3.75; F, 5.06. mp 147-149*C. Rf 0.5 (20% ethyl acetate/hexane).

EXAMPLE 100 -pentvl)pyridine The title compound was prepared from (±)-2,6-diisopropyl-3hyrxmty--4furpeyl--ihdoyetlprdm (Example according to the procedures described in Example 98. 1 H NMLR (300 MHz, CDCl3): 8 7.10 (in, 4 4.32 (in, 2 3.92 (in, 1 3.76 (septet,; 7.0 Hz, 1 3.42 228 WO 98/04528 PTU9134 PCT[US97/13248 o (septet, J=6.6 Hz, 1 3.12 3 1.87 (in, 1 1.52 (in, 2 1.19 (in, 16 H), 0.821 J=7.4 Hz, 3 FAB-MS: calcd for (C24H34NF02) 387, found 388 Anal. Calcd for C24H34N02F: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.38; H, 8.82; N, 3.45; F, 4.90. mp 121-123*C. Rf 0.5 (20% ethyl acetate/hexane).

5 EXAMPLE 101

F

OH

o

N

(±-,-ispov--lhdovty)4(-loohnl--rplprdn Step A: 2 6 -Diisopropyl4(4-fluorophenyl)-5-propyl-.3pyridinecarboxaldehyde To -a solution of 2 6 -diisopropyl-3-hydroxymethylA..(4..fluorophenyl)-5 propylpyridmne (Example 25) (5.7 g, 17 mmol) in dichioromethane (250 mL) was added Brockman I, neutral a lumina (3.5 g, 34 rnmol). The suspension was stirred at room temperature, and treated with pyridiniuin chlorochromnate (PCC) (7.5 g, 34 minol). Stirring was continued at room temperature for 1 hr. The suspension was poured into 10% ethyl acetate/hexane (500 mL), filtered through a pad of silica and concentrated int vacuo to *afford (4.2 g/12.8 mhmol, 74%) as a waxy solid. 11H NMR (CDCl3, 300 MWz): 1 7.15 (in, 4 3.83 (sept, J 6.6 Hz, 1 3.28 (sept, J 6.6 Hz,, 1 2.31 (mn, 2 1.30 (mn, 14 0.78 (t,J 7.4 Hz, 3 FAB- NIS: calcd for (C2jH26FN0) 327, found 328 mp 81-83*C. Rf 0.6 ethyl acetate/ hexane).

Step B: 2 6 -Diisopropyl-3-(l-hvdroxvethyl)-4-(4.fluorophenyl).5.

propylpyridine The intermediate obtained in Step A (400 mg, 1.22 minol) in THF (10 mnL) at 78*C under argon atmosphere was added dropwise MeLi (1.4 M, 1.2 eq, 1.05 ML).

The reaction was stirred for 20 min, then another 0.5 eq. of. MeLi was added, as starting material was still present. After. 20 min., the reaction was quenched with 229 WO 98/04528 PCTIUS97/13248 0 water (2 mL) and the THF is evaporated in vacuo to afford an oil. The product was partitioned between water and CH2C12 (50 mL) and the organic layer was dried with MgSO4, filtered, and concentrated to yield a gummy solid. Flash Chromatography using silica gel (60% CH2Cl2/hexane) to afford an oil which slowly solidified to give the title compound as a solid (0.387 g/1.13 mmoll 1

H

NMR (300 MHz, CDCI 3 8 7.10 (in, 4 4.66 (dq, I 3.3,6.6 Hz, 1 3.75 (septet,

J

6.6 Hz, 1 3.20 (septet, J 6.6 Hz, 1 2.17 j 1.5 Hz, 2 1.58 J 5.2 Hz, 1 1.41 J 6.6 Hz, 3 1.29 (mn, 14 0.74 j 7.4 Hz, 3 FAB-MS: calcd for (C22H3OFNC)) 343, found 344 Anal. Calcd for C22H30FN0: C,' 76.93; H, 8.80; N, 4.08; F, 5.53.* Found: C, 76.98; H, 8.73; N, 3.93; F, 5.80. mp 124.5- 126.5*C. Rf =0.2 (60% CH2Cl2/hexane).

EXMPLE 102

F

OH

N

2 6-Diisoprovl3(hvdroxvethvl)4-fluooheny)-5trplprd The enantiomeric mixture of 2 6diisopropyl3(1hydroxrethyl)..ip4fluorophenyl)..s..propylpyridine.(Example 101) was separated by chiral HPLC with a Chiralpak AD coltumn, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiorner to elute was obtained in 99% ee, Inp 103-104'C, [aID +40.4%.

EXAMPLE 103

F

OH

N

230 WO 98/04528 WO 9804528PCT[US97/13248 0 2 6 -Diisopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenvl)-5-propyl-pvridine The enantiomeric mixture of (±)-2,6-diisopropyl-3-(1-hydroxyethyl)-4-(4.

(Example 101) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 90% ee. mp 95-97C.

EXAMPLE 104

.F

(±-,-ispoy--lhdovty)4(-loohnl--uv.prdn The title compound was prepared from 2 ,6-ciisopropyl-3-hydroxymethyl-4- 4 -fluorophenyl).75-butylpyridine (Example 24) according to the procedures described in.ExampleO 16. H NMR (300 MIHz, CDC13): S 7.1 (in, 4 4.7 (dq, 1=3 Hz, 1 3.7 (septet, I 7 Hz, 1 3.2 (septet, J =7 Hz, 1 2.2 J 1L5 Hz, 2 H), 1.6 5 Hz, 1H), 1.4 7 Hz, 3H), 1.3 16 0.8 7 Hz 3 FAB- MS: calcd for (C23H32FN0) 357, found 358 mp 103-104*C. Rf 0.2 CH2Cl2/hexane).

EXAMPLE 105 The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- WO 98/04528 PCTIUS97/13248 0 4 -fluorophenyl)-5-pentylpyridine (Example 1) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCI 3 S 7.10 (in, 4 4.65 (dq, I 2.8, 6.6 Hz, 1 3.75 (septet, J 6.6 Hz, 1 3.20 (septet, J 6.6 Hz, 1 2.19 J 8.1 Hz, 2 1.63 J= 2.6 Hz, 1 1.40 J 7.0 Hz, 3 1.31 (in, 14 1. 11 (in, 4 0.79 J 6.6 Hz, 3 FAB-MS: calcd for (C24H34FN0) 371, found 372 Anal. Calcd for C24H34FN0: C, 77.59; H, 9.22; N, 3.77; F, 5.11. Found:

C,

77.59; H, 9.34; N, 3.75; F, 5.26. mp 99-101*C. Rf 0.2 (70% CH2CI2/hexane).

EXAMPLE 106 The enantiomeric mixture. of 2 6 -diisopropyl.3.(1.hydroxyethyl)4( 4 (Example 105) was separated by chiral HPLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The first enantiomer to elute was obtained in 99% ee. mp 83TC.

EXAMPLE 107 The enantiomeric mixture of 2 6diisopropy13(1hydroxyethyl)-4-(4- (Example 105) was separated by chiral HPLC with a 232 4 WO 98/04528 WO 9804528PCT/US97/13248 o Chiralpak AD column, isocratic elution (99% hexanemethyl t-butyl ether). The second enantiomer to elute was obtained in 93% ee. mnp 84-86 0

C.

EXAMPLE 108 The title compound was prepared from 2 1 6 -diisopropyl-3-hydroxymethyA..

4 -fluorophenyl)-5-hexylpyridine (Example 23) according to the procedures described in Example 101. 1 H NMR (300 MHz, CDCl3): 8 7.13 (in, 3 7.04 (in, 1 4.65 (in, 1 3.73 (sept, I=6.6 Hz, 1 3.19 (sept, J 6.6 Hz, 1 2.18 (in, 2 1.39 I 6.6 Hz, 3 1.30 (in, 13 1.18 (mn, 4 1.09 (in, 4 0.81 I=7 Hz, 3 FAB-MS: calcd for (C25H36FNO) 385, found 386 Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.84; H, 9.49; N, 3.65. mp 96- 99-C. Rf 0.3 (10% ethyl acetate/hexane).

EXAMPLE 109 2,-isvo~4(-vrxe ohnl--eypfdn The enantiorneric mixture of 2 6 -diisopropyl-3-(1-hydroxyethyl)-4-(4.

(Example 108) was separated by chirg. HIPLC with a Chiralpak AD coliumn, isocratic elution (99% hexkane/methyl t-butyl ether). The first enantiomer to elute was obtained in 98% ee. mp 75-77C.

233 h WO 98/04528 PCTIUS97/13248 EXAMPLE 110 2,-ispoy--lhdoytv)4(-loohnl--eyprdn The enantiomeric mixture of 2 6 -diisopropy-3-(l-hydroxyethyl)4(4- (Example 108) was separated by chiral I-PLC with a Chiralpak AD column, isocratic elution (99% hexane/methyl t-butyl ether). The second enantiomer to elute was obtained in 88% ee. mp 66-68*C.

EXAMPLE ill 2 6 DiisopropVI-3[1lhvdrox-2-((S)toluvlsulfoxy)ethvl1A-4( 4 Pentvlpvridine A solution of lithium diisopropylamide was prepared by the addition of nbutyllithium (3.5 mL, 2 eq., 1.6 M/hexane) to a solution of diisopropylamnine (0.73 mL, 5.57 mmol) in anhydrous tetrahydrofuran (50 mL) at 0CC. To this was added a solution of (S)-(-)-methyl p-tolylsulfoxide (0.863 g, 5.60 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise, with stirring. The mixture was stirred at 0*C for 2 hr, then treated with a solution of 2 6 -diisopropyl-4(4.fluorophenyl)-5pentyl.

3 -pyridinecarboxaldehyde (Example 114, Step A) (1.0 g, 2.80 mmol) in anhydrous.

tetrahydrofuran (20 mL) dropwise and with stirring. After stirring 15 min at 0 *C, the reaction mixture was quenched by the addition of sat. NH4Cl (1 mL). The 234 7 WO 98/04528 PCT/US97/13248 0 solvent was removed in vacuo and the residue partitioned between CHCl3 (150 mL) and water (50 mL). The organic phase was washed with sat. NaHCO3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude product consisted of a 1.2:1 ratio of diastereomers. Flash chromatography (step gradient 5%-10%-20% ethyl acetate/hexane) afforded 740 mg of the first diastereomer to elute. 1 H NMR (CDC13, 500 MHz): 8 7.4 4 7.0 2 6.7 2 5.1 1 4.6 1 3.8 2 2.6 (sept, J 6.6 Hz, 1 2.5 3 H), 2.3 1 2.1 2 1.4 18 0.8 3 FAB-MS: calcd for (C31H40FNO2S) 509, found 510 Anal. calcd for C31H40FNO2S: C, 73.05; H, 7.91; N, 2.75; S, 6.29. Found: C,-72.88; H, 7.95; N, 2.50; S, 6.38. mp 170-171'C. Rf 0.3 (20% ethyl acetate/hexane).

EXAMPLE 112

F

O OH 2, 6 -Diisopropyl-3-l1-hydroxy-2-(S)-toluylsulfoxyethyl1-4-(4-fluoro-phenyl)-5pentlpyridine From the flash chromatography described in Example 111, the second diastereomer to elute afforded 600 mg of the title compound. 1 H NMR (CDC13, 500 MHz): 8 7.4 2 7.2 2 7.0 3 6.8 1 4.8 1 3.8 1 3.7 1 3.2 (sept, J 6.6 Hz, 1 3.1 1 2.7 1 2.4 3 2.1 2 1.3 18 0.6 3 FAB-MS: calcd for (C31H40FNO2S) 509, found 510 Anal. calcd for C31H40FNO2S: C, 73.05; H, 7.91; N, 2.75; S, 6.29. Found: C, 72.90; H, 7.95; N, 2.50; S, 6.54. mp 190°C. Rf 0.1 (20% ethyl acetate/hexane).

235 N -V WO 98/04528 PCTIUS97/13248 EXAMPLE 113 jo methylpyridine The title compound was prepared from 2,6-diisopropyl-3-(1h>'droxymethyl)A4-(4..fluorophenyl)..5..(phenylthio)methylIpyridine (Example 47) according to the procedures described in Example 101. 1 H NMR (300 MIHz, CDCl3): 8 7.19 (in, 4 7.09 (in, 5 4.67 (in, 1 3.74 (in, 3 3.38 (sept, I=6.6 Hz, 1 1.58 I 4 Hz, 1 1.41 J 6.6 Hz, 3 1.31 (in, 12 FAB-MS: calcd for (C26H3OFNOS) 423, found 424 Anal. Calcd for C26H3OFNOS:

C,

73.72; H, 7.14; N, 3.31; S, 7.57. Found: C, 73.52; H, 7.12; N, 3.20; S, 7.51. mp 125- 128 0 C. Rf 0.5 (20% ethyl acetate /hexane).

EXAMPLE 114 0 .000** ha a 2 6DiisopoPyl3l.3.(1.y-2 rony)4-426roV1envll)Stlprdn Step A: 2 6 -Diisopropyl4.(4-.fluoEophen1yl) 5 pen tvl-3- *rdi carboxaldehyde 2,-ispoy--yrxmty--4furpey)5pnyprdn (Example 1) (2.30 g, 6.43 minol) was dissolved in 175 ml, of CH2Cl2 under argon 236 WO 98/04528 PCT/US97/13248 0 atmosphere and treated with 2 eq. of alumina (neutral, 1.31 g, 12.87 mmol) followed by 2 eq of pyridinium chlorochromate (PCC) (2.77 g, 12.87 mmol). The reaction was stirred at room temperature for 1.5 h. The suspension was added to 500 mL of 1:1 hexane/diethyl ether, then filtered through a pad of silica (300 g).

The pad was washed with 100 mL diethyl ether and the filtrate was combined and concentrated in vacuo to afford a solid. Flash chromatography (60:40, CH2Cl2/hexane) using silica afforded 1.84 g of an off-white solid (5.2 mmol, 1 H NMR (300 MHz, CDC13): 8 9.74 1 7.17 4 3.85 (septet, 6.6 Hz, 1 3.30 (septet, J 6.6 Hz, 1 234 J 5.2 Hz, 2 1.30 14 1.15 4 0.80 J 6.6 Hz, 3 FAB-MS: calcd for (C23H30FNO) 355, found 356. Anal.

Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94; F, 5.34 Found: C, 77.91; H, 8.47; N, 3.83; F, 5.42. mp 75.5-77.5'C. Rf 0.4 (50% CH2Cl2/hexane).

Step B: 2 6 -Diisopropyl-3-(1-hydroxy-2-propenyl)-4-(4-fluorophenyl)-5pentylpyridine To a solution of the intermediate obtained in Step A (100 mg, 0.281 mmol) in THF (10 mL) at -78 0 C under argon was added vinyl magnesium bromide (1 MN, eq., 0.42 mL) dropwise. After 1 a saturated solution of NH4CI (2 mL) was added and the aqueous phase was extracted with diethyl ether. A precipitate formed when the NH4C1 was added and was filtered off. The ether layer was dried with MgSO4, filtered and concentrated to yield a gummy oil. Flash chromatography CH2Cl2/hexane) afforded the title compound as a solid (38 mg, 0.1 mmol, 1H NMR (300-MHz, CDCl3): 8 7.11 4 6.06 =17.4 Hz, J 10.3Hz, J 4.0 HzI, 1H), 5.08 (q,J 1.5 Hz, 1 5,00 2 3.51 (septet, 6.6 Hz, 1 H), 3.21 (septet, J =6.6 Hz, 1 2.21 J= 4.4 Hz, 2 1.74 J= 4.1 Hz, 1.27 (m, 14 1.11 4 0.783 J 6.6 Hz, 3 FAB-MS; calcd for (C25H34FNO) 383, found 384 Anal. Calcd for C25H34NOF: C, 78.29; H, 8.93; N, 3.65; F, 4.95.

Found: C, 78.28; H; 8.97; N, 3.53; F, 5.04. mp 83-85C. Rf 0.2 CH2Cl2/hexane).

EXAMPLE 115

F

OH

N

237 p WO 98/04528 PTU9/34 0 (±-,-ispov--lhdovety)4(-loohnl-:etlprdn The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethy.4- 4 -fluorophenyl)-5-pentylpyridine (Example 1) and butyllithium according to the procedures described in Example 114. 1 H NMR (300 MHz, CDCl3): 8 6.95 (in, 4 H), 4.33 (in, 1 3.59 (septet,*J 6.6 Hz, 1 3.09 (septet, J 6.6 Hz, 1 2.08

J=

5.2 Hz, 2 1.75 (mn, 2 1.47 (in, 2 1.04 (in, 22 0.719 j 7.0 Hz, 3 H), 0.674 J=7.0 Hz, 3 FAB-MS: calcd for (C27H4OFNO) 413, found 414 Anal. Calcd for C27H40FN0: C, 78.41; H, 9.75; N, 3.39; F, 4.59. Found: C, 77.84; H, 9.51; N, 3.27; F, 5.08. mp 66-68'C. Rf 0.2 (50% CH2Cl2/hexane).

EXAMPLE 116 The title compound was prepared from 2 6 -diisopropy-3hydroxyiethyl4 4 -fluorophenyl)-5-pentylpyridine (Example 1) and aflylmagnesium bromide according to the procedures described, in Example 114. 1 H NMR (300 M1Hz, CDCl3): 8 7.09 (in, 4 6.58 (in, 1 5.06 1 5.01 (in,'1 4.4-7 (in, 1 3.71 (septet, J =6.6 Hz,, 1 3.20 (septet, I 6.6 Hz, 1 2.59 (in, 1 2.35 (in, 1 H), 2.18 j=4. 8 Hz, 2 1.72 12.9 Hz, 11H), 1.28 (mn, 14 1.11 (in,.4 0.783 J 6.6 Hz, 3 FAB-MS: calcd for (C26H36FN0) 397, found 398 Anal.

Calcd for C26H36F140: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 78.10; H, 9.21; N, 3.43; F, 4.89. mp 70-72*C. Rf =0.2 (50% CH2Cl2/hexane).

238 WrO 98/04528 PCTIUS97/13248 EXAMPLE 117

OH

2 6 -Diisopropyl-3-(l-hydroxy-2-propyl)-4-(4-fluorophenyl)-5-pentVlpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- (Example 1) and ethylmagnesium chloride according to the procedures described in Example 114. 1 H NMR (300 MHz, CDCl3): 8 7.10 4 4.35 (dq, I= 3.7, 8.8 Hz, 1 3.68 (septet, I 6.3 Hz, 1 H), 3.20 (septet, J 6.6 Hz, 1 2.18 J 5.2 Hz, 2 1.86 (septet, I 5.5 Hz, 1 H), 1.63 2 1.28 14 1.09 4 0.789 6 FAB-MS: calcd for (C25H36FNO) 385, found 386 Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63; F, 4.93. Found: C, 77.44; H, 9.37; N, 3.35; F, 4.87. mp 77-79*C. Rf 0.2 CH2CI2/hexanes).

EXAMPLE 118 (±)-2,6Diisoprop l-3-(2,2,2-trifuo-lhdaetl4--fluoro-phey)5 Pentvlpvridine A stirred solution of 2 6 -diisopropyl-4-(4-fluorophenyl)-5-pentyl-3pyridinecarboxaldehyde (Example 114, Step A).(190 mg, 0.53 mmol) in anhydrous THF (5 mL), under argon at 22*C, was treated with trimethyl(trifluoyomethyl)silane (5.3 mL, 2.65 minol, 0.5M in THF) followed by tetrabutylammonium fluoride (100 239

'Y

WO 98/04528 PCTIUS9713248 0 uL, 1.OM in THF). After stirring at 22°C for 5 min, tetrabutylammonium fluoride (3 mL, 3 mmol, 1.0 M in THF) was added and the reaction mixture stirred for 17 hr.

The solvent was removed in vacuo, the residue dissolved in diethyl ether (50 mL), washed with 1N HCI (50 mL), saturated NaHCO3 (50 mL), water (50 mL), brine mL), dried (MgSO4) and concentrated. Purification by flash silica gel chromatography ethyl acetate/hexane) afforded 153 mg of the title compound as a white solid. 1 H NMR (300 MHz, CDC13): 6 7.11 4 4.90 (bs, 1 3.64 (bs, 1 3.21 (sept, J 6.6 Hz, 1 2.35 1 2.15 2 1.30 J 6.6 Hz, 6 1.29 J 6.6 Hz, 6 1.26 2 1.10 4 0.77 J 6.6 Hz, 3 FAB-MS: calcd for (C24H31.F4NO) 425, found 426 Anal. Calcd for C24H31F4NO: C, 67.75; H, 7.34; N, 3.29; F, 17.86. Found: C, 67.82; H, 7.13; N, 3.02; F, 18.05. mp 88-89"C. Rf 0.35 (10% ethyl acetate/hexane).

EXAMPLE 119

F

HO "T Nr 2,6-Diisopropyl-3-(2-hydroxyethyl)-4-(4-fluorophenyl)-5-pentylpyridine Ste

A

2,6-Diisopropyl-3-(2-oxoethvl)-4-(4-fluorophenyl)-5-pentylpyridie A solution of (methoxymethyl)triphenylphosphonium chloride (350 mg, 0.985 mmol) in THF (30 mL) was treated with butyllithium (1.6 M, 1.2 eq., 0.74 mL) at -78 0 C. The reaction was stirred at 0 C for 1 h. and then is cooled to -78 0 C again.

2,6-Diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (350 mg, 0.985 mol) in THF (5 mL) was added dropwise and the reaction mixture allowed to come to room temperature. After 24 the reaction was quenched with water and the THF evaporated in vacuo. The residue was partitioned between ether and water. The organic layer was dried with MgSO4, filtered, and concentrated to yield an oil. Flash chromatography CH2Cl2/hexanes) afforded an oil (172 mg).

The oil (172 mg) was taken up in THF (15 mL) and treated with 4 mL cone.

240 WO 98/04528 PCT/US97/13248 0 HC1. The solution was stirred for 1.5 hours and then diluted with ether (150 mL).

The reaction was washed with NaHCO3 (2 x 50 mL) and dried with MgSO4.

Filtration and concentration yielded a solid (20 mg, 0.054 mmol, The product was taken directly to the next step without further purification.

Step B: 2,6-Diisopropyl-3-(2-hydroxyethyl)-4-(4-fluorophenyl)-5pentylpyridine To the intermediate obtained in Step A (20 mg, 0.054 mmol) in dry THF mL) was added dropwise LAH (2 eq., 1 M, 0.11 mL) under argon and the mixture was stirred at reflux for 1 h. The reaction was quenched with water (3.9 gL), NaOH (3.9 gL), and water (7.8 gL) again. Concentration afforded a white solid.

The product was subjected to a pad of silica gel (CH2C12) to afford the title compound as a white solid (14 mg, 0.038mmol, 1 H NMR (300 MHz, CDC13): 8 7.39 2 7.12 2 3.52 J 5.5 Hz, 2 3.23 2 2.60 J 2.9 Hz, 2 2.20 J 3.7 Hz, 2 1.30 14 1.11 4 0.771 J 6.3 Hz, 3 FAB-MS: calcd for (C24H34FNO) 371, found 372 Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.57; H, 9.44; N, 3.05. mp 81- 83°C. Rf 0.6 (10% ether/hexane).

EXAMPLE 120

F

N-

H

2 6 -Diisopropyl-3-methvlaminomethyl-4-(4-fluorophenyl)-5-pentyl-pyridine Methylammonium chloride (37.99 mg, 0.563 mmol) was added to a stirred solution of methylamine in methanol (2 M, 0.28 mL) under argon in an oven-dried round bottom flask equipped with a stir bar. Then sodium cyanoborohydride (4 eq., 10.60 mg, 0.169 mmol) was added and 2,6-diisopropyl-4-(4-fluorophenyl)-5pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (100 mg, 0.281 mmol) was added as a solution in methanol (2 mL). The reaction was refluxed for 18 hours and then quenched with water. Concentration and addition of CH2C12 (25 mL) allowed WO 98/04528 PCTIUS97/13248 0 washings with water (2 x 15 mnL), brine (1 x 25 mL), following which the solution was dried with MgSO4, filtered, and concentrated to afford a clear oil. Flash chromatography using silica gel (40% ether/CH2CI 2 yielded the title compound as a white solid (21 mg, 0.057 mmol, 1 1H NMR (300 MHz, CDC13): 8 7.13 (in, 4 3.26 (in, 4 2.24 (mn, 5 1.20 (in, 19 0.783 J= 6.6 Hz, 3 FAB-MS: calcd for (C24H35FN 2 370, found 371 mp 77-79*C. Rf =0.2 ether/CH2CI2).

EXAMPLE 121

F

The title compound was prepared from 2 6 -diisopropyl.A44fluorophenyl)..s.

pentyl- 3 -pyridinecarboxaldehyde (Example 114, Step A) and NH4OAc, according to the procedures described in Example 120. 1 H NMR (300 MHz, CDC13): 8 7.10 (in, 4 2.61 (mn, 4 2.20 J5.5 Hz, 2 1.17 (mn, 20 0.776 J 6.6 Hz, 3 H).

FAB-MS: calcd for (C23H33FN 2 35.6,' ,found 357 Anal. Calcd for C23Hi33N2F: C, 77.48; H, 9.33; N, 7.86;j, 5.33. Found: C, 77.42; H, 9.12; N, 7.64; F, 5.51. mp 47-459C. Rf =0.6 (50% CH2CL2/hexans) EXAMPIILE 122

N

WO 98/04528 WO 9804528PCTIUS97/13248 o 2,6-Diisopropvl-3-(dimethylamino)methyl-4-(4-fluorophenyl)-5-2entyl-pyridine The title compound was prepared *from 2,6-diisopropyl-4-(4-fluorophenyl)-5pentyl-3-pyridmnecarboxaldehyde (Example -114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. 1 H NMR (300 MHz, CDC13): 8 7.09 (in, 4 3.49 (septet, I 6.6 Hz, 1 3.21 (septet, I 6.6 Hz, 1 3 .05 2 2.22 j 5.2 Hz, 2 1.99 6 1.18 (in, 18 0.790 j 6.3 Hz, 3 FAB-MS: calcd for (C25H37FN2) 384, found 385 Anal.

Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66; N, 7.12; F, 5.25. mp 69-71*C. Rf 0.4 (20% ether/CH2CI2).

EXAMLE 123 2 ,6-Diisopropyl-3-(ethylamino)methy1-4-(4-fluorophenyl)-57pentrlp~yridine The title compound was prepared from i2,6-diisopro yl-4-(4-fluorophenyl)-5pentyl-3-pyridinecarboxaldehyde (Example 114, Step and ethylamine, according to the procedures described in Exai'nple 120. 1HN NMR (300 MHz, CDC13): 8 7.06 (in, 4 3.18 (in, 4 2.32 (q,J 7.4 Hz, .2 2.15 j 5.2 Hz,, 2 1.13 (mn, 18 0.839 J= 7.4 Hz, 3 0.698 J=6.6 Hz, 3 FAB-MS: calcd for (C25H37FN2) 384, found 385 Anal. Cakcd for C23H37FN2: C,,78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.50; N, 6.99;'F, 4.79. mp 48-50*C. Rf 0.1 ether/CH-2C12).

EXAMPLE 124 WO 98/04528 PCT[US97/13248 0 (±)-2,6-Diisopropyl-3-(1, 2 -dihydroxyethyl)-4(4-fluorophenyl)-5pentyl-pyridine Ste 2,6-Diisopropyl-3-ethenyl-4-(4-fluorophenyl)-5-pentylpridine Methyl triphenylphosphonium bromide was suspended in 15 mL of dry THF under argon and stirred at -78 0 C. Butyllithium (1.6 M, 0.42 mL) was added dropwise over 2 min. and then the reaction mixture was allowed to stir at 0 C for hours. The solution was cooled again to -78 0 C, treated dropwise with a solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarbox-aldehyde (Example 114, Step A) in 5 mL of dry THF, and then stirred at 0°C for 2.5 hours. The reaction was quenched with water (10 mL) and the THF evaporated in vacuo. Diethyl ether was added and the mixture was washed with water (2 x 20 mL), brine (1 x 20 mL), and dried with MgSO4. Filtration, concentration and flash chromatography CH2Cl2/hexanes) yielded a solid (0.132 g, 0.37 mmol, 1 H NMR (300 MHz, CDC13) 8 7.08 J 1.1 Hz, 4 6.34, 6.28 J 11.4 Hz, J 11.4 Hz, 1 5.19 J 1.8 Hz, 1 4.96 J 1.8 Hz, 1 3.39 (septet, J 6.6 Hz, 1 3.24 (septet, J 6.6 Hz, 1 2.30 J 5.2 Hz, 2 1.20 J 2.2 Hz, 18 0.979 J =6.0 Hz, 3 FAB-MS: calcd for (C24H32FN) 353, found 354 Anal. Calcd for C24H32FN: C, 81.54; H, 9.12; N, 3.96; F, 5.37. Found: C, 81.46; H, 9.06; N, 3.78; F, 5.59. mp 44-46 0 C. Rf 0.7 (30% CH2Cl2/hexanes). StepB: 6 -Diisopropyl-3-(1,2-dihydroxvethyl)-4-(4-fluorophenyl)-5pentylpyridine To an oven-dried round bottom flask equipped with a stir bar was added the intermediate obtained in Step A (150 mg, 0.424 mmol), in pyridine (10 mL) under argon. The solution was stirred and Os04 (0.129 g, 0.509 mmol) was added in one portion. The reaction turned black as stirring continued at room temperature.

After 3 hours, the pyridine was evaporated in vacuo and the residue was dissolved o inCH2Cl 2 (10 mL) and sat. NaHSO3 (10 mL). The resulting heterogenous solution was stirred very rapidly for 18 hours. The layers were separated and the aqueous layer was extracted several times with CH2C1 2 The combined organic layers were dried (MgSO4), filtered, and concentrated to give a white solid. The product was subjected to a pad of silica (65/35; CH2Cl2/ether) to yield a white solid (70 mg, 0.18 mmol, 1 H NMR (300 MHz, CDC13): 8 7.08 4 4.57 J 1.5 Hz, 1 H), 3.85 1H), 3.65 (septet, J 6.6 Hz, 1 3.50 1 3.20 (septet, J 6.6 Hz, 1 2.19 2 1.96 1 1.24 14 1.07 4 0.780 J 6.6 Hz, 3 FAB-MS: calcd for (C24H34FNO) 387, found 388 Anal. Calcd for C24H34FNO: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.60; H, 9.03; N, 3.83; F, 5.04. mp 175-177°C. Rf 0.5 (65/35; CH2Cl2/ether).

244 I I I i -715r ii-in WO 98/04528 WO 9804528PCT[US97/13248 0 EXAMPLE 125 2 6 -Diisopropyl-3-hydroxymethyl-4-[(4trifluoromethl)phenyl-5(pent-l enyl)2yridine Step A: DiethVl 1 ,4-dihydro-2,6-diisopropyl-4-(4.trifluoro.

Following the procedure of Chucholowskj Patent 4,950,675);. to a solution of 18.0 g (0.11 mol) of ethyl. isobutyrylacetate and 9.9 g (56.8 mnmol) of 4- (trffluoromethyl)berizaldehyde in ethanol (25 m4) was added concentrated ammoni um hydroxide (3.0 mL). This reaction mixture was heated at reflux for 12 hrs. After cooling to room temperature, the reaction mixture was concentrated under vacuum to yield a yellow oil. The crude product was taken directly to the next step without purification.

Step Diethyl 2,6Ldiisopropyl-4-[(4-trifluoromethyl)phenyl1..pyridine-3,5..

dicarboxylate Prepared from the intermediate obtained in Step A by the procedure described in Example 160, Step B. 1H NWI (3*00* MHz, CDCl3): 85 0.92 J=7.0 Hz, 6H), 1.33 J=6-6 Hz, 12H), 3.14 (in, 4H), 4.0 J=7.0 Hz, 4H),'7.42 J=8.0 Hz, 2H). mnp 100-101*C.

Step C: Ethyl 2 6 -diisO~ropyl-4 hydroxvmethylp-yridine.3-carboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step D. 1H NMR (300 MI-Lz, CDCl3): 5 0.91 J=70. Hz, 3H), 1.32 J=6.6 Hz, 6H), 1.35 J=6.6 Hz, 6H), 3.08 (in, 1H), 3.50 (in, 1H), 3.96 (q, Hz, 4.43 J=4.0 Hz, 2H), 7.44 J=8.0 Hz, 2H), 7.68 J=8.0 Hz, 2H).

mp 102-103 0

C.

245 WO 98/04528 PCTIUS97/13248 0 Step D: 5-Ethoxycarbonyl-2,6-diisopropyl4.[('4-.trifluoromethyl)phenyllpyridine-3-carboxaldehyde To a solution of the intermediate obtained in Step C (1.9 g, 4.6 mmol) in dichioromethane (50 mL) was added Celite (2.0 The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (2.0 g, 9.3 mmol) in three portions. The suspension was stirred at room temperature for 1 hr, then poured into 1:1 diethyl ether/hexane (250 mL), filtered through a pad of silica, the pad washed with diethyl ether- (250 mL) and the combined eluent concentrated to afford 1.7 g of the product as a viscous oil which slowly solidified. 1

H

NMR (300 MJ.-z, CDCl3): 8 0.94 J=7.0 Hz, 3H), 1.33 J=6.6 Hz, 6H), 1.34 (d, J=6.6 Hz, 6H), 3.14 (in, 1H) 3.88 (in, 1H), 4.0 J=7.0 Hz, 2H), 7.42 J=8.0 Hz, 2H), 7.71 J=8.0 Hz, 2H1), 9.86 1H). mp 105-106*C.

Step E: Ethyl 2 6 diisopropVl-4.(4trifluoromethvl)phenyl5(pent-l enyl)Pyridine-3-carboxylate Prepared from the intermediate obtained in Step D by the procedure described in Example 1, Step D. 1H1 NMR (300 MHz, CDCl3): 5 0.69 "J=7.0 Hz, 3H), 0.90 J 7.0 Hz, 3H); 1.09-1.34 14H), 1.92 J=14.0, 7.0, 1.5 Hz, 2H), 3.07 (in, 1H), 3.38 (mn, 1H1), 3.96 J=7.0 H4z, 2H), 5.29 (in, 1H1), 6.05 (mn, 1H), 7.31 Hz, 2H), 7.59 J=8.0 Hz, 2H1). mp 70-72 C.

Step F: 2 6 Diisopropvl-3hydroxmethvl4(4-trifluoroinethvl)phen11l5-0 (Pent-l-enyridine The intermediate obtained in Step E 2.0 .4 iniol) was diss olved in anhydrous THE (100 mnL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 10 mL, .10 mmol). The reaction mixture was stirred .at reflux for 1 hr, cooled to room temperature and quenched by the sequential addition of H120, 20% aqueo us NaOH and H120. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by flash chromatography through silica ethyl acetate/n-hexane) to afford 0.77 g (1.90 minol, 93%) of the title compound as 'a white foam. 1H1 NMvR (300 MIz, CDCl3): *8 0.68 J-"7.0 Hz, 311), 1.05- ,1.40 (in, 14H1), 1.90 J=14- 7, Hz, 211), 3.34 (in, 1H), 3.45 (mn, 1H), 4.37 J=5.5 Hz, 211), 5.26 (in, 111), 5.95 (in, 111), 7.30 J=8-0 Hz, 7.65 J=8.0 Hz, 2H1). Rf=-0.36 (10% ethyl acetate/nhexane). mp 77-78*C.

246 WO 98/04528 PTU9134 PCT/US97/13248 EXAMPLE 126

CF

3 2 6 -Diisopropyl- 3 -hydroxymethyl-4[(4-trifluoromethl)Phen11.5..pentWpyridine To 0.59 g (1.46 mmol) of the comp ound 2,6-diisopropyl-3-hydroxymethyl-4.

4 -trifluoromethyl)phenyl]-5-(pent-l-enyl)pyridine (Example 125) was dissolved in absolute ethanol (50 mL) and treated with 10% palladium on carbon (0.1 eq). The reaction flask was purged under aspirator vacuum and filled with hydrogen gas The reaction mixture was stirred under a hydrogen atmosphere for .6 hr.

After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed by concentration under vacuum and the crude product was purified by flash chromatography (10% ethyl acetate/nhexane) to yield 0.58 g (1.41 mmol, 97%) of the title compound as a white solid. 1

H

NMR (300 MI-z, CDCl3): 5 0.78 J=7.0 Hz, 3H), 1.12 (in, 4H), 1.31 (mn, 14H), 2.26 (mn, 2H), 3.25 (mn, 1H), 3.42 (in, 1H), 4.29 2H), 7.34 J=8.0 Hz, 2H), 7.72 Hz, 21H). Rf=-0.36 (10% ethyl acetate/n-hexane). mp 99-100*C.

EXAMPLE 127 2 6 -Diisopropyl-3-hydroxyJmethyl.4(3.fluoo~henVl).5.(pent..1.envl)..pyridine Step A: Ethyl 2 6 -diisopropyl-4-(3-fluorophenyl)-5(pent-i-enyl).pyridine-3carboxylate WO 98/04528 PCTIUS97/13248 0 Prepared from 3-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MHz, CDCI3): (reporte 'd as a mixture of olefin isomers): 8 0.76 (in, 3H), 0.97 J=7.0 Hz, 3H), 1.13-1.37 (in, 14H), 1.95 (in, 2H), 3.07 (in, 1H), 3,21-3.45 (in, 1H), 4.0 (in, 2H), 5.30-5.60 (in, 1H), 6.06 (mn, 1H), 6.90-7.03 (in, 3H), 7.27 (in, 1H).

Step B: 2 6 -Diisopropyl-3hdroxvmethyl..4-.(3.fluorophenl)5(Pentl enyl)pyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1 H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): 8 0.78 (in, 3H), 1.13-1.37.(in, 14H), 1.93 (in, 2H), 3.41 (in, 2H), 4.40 2H), 5.28-5.45 (in, 1H), 6.0 (in, 1H), 6.87-7.07 (mn, 3H), 7.34 (in, Rf=-0.36 (10% ethyl acetate/n-hexane). mnp 117-118*C.

EXAIVILE 128 2 6 Diisopropl3hdroxvmethyl.4.(flurophefv)5petlpridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxyinethyl4.

3 :fluorophenyl)-5-.(pent-1-enyl)pyridmie (Example 127) by the procedure described in Example 126. 114I NMR (300 MHz, CDCl 3 8 0.79 J=7.0 Hz, 3H), 1.10-1.35 (in, 18H), 2.28 (mn, 2H), 3.24 (mn, 1H), 3.42 (in, 1H), 4.33 6.96 (in, 2H), 7.12 (in, 11H), 7.40 (in, 1H). mp 117-118*C. Rf"=0.36 (10% ethyl acetate/n-hexane).

248 WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAM[PLE 129 2 6 -Diisopropyl-3-hydroxymethyl-4-4-methlphen1)-5-(Pent-l-eny)-.pyridjne Step A: Ethyl 2,6-diisopropyl-4-(4-metylphenyl)-5-(pent-l-eny1l)pyidin-3carboxylate' Prepared from 4-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium h ydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 ML-z;CDCl3): 80.75 (tJ=7.4 Hz, 3H), 0.95 (tJ=7.4, 3H), 1.20-1.40 (in, 14H), 1.95 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 2.35 3H), 3.10 (in, 1H), 3.40 (in, 1H), 3.99 J=7.4, 2H), 5.30-5.40 (in, 1H),-'6.05 (dt, 1.5 Hz, 1H), 7.0-7.2 (mn, 4H). mp 74-77TC.

Step B: 2 6 -Diisopropyl-3-hydroxmethl4-(4-methylphenyl)-5-(pent-lenyl)-Ryridine The title compound was prepared- from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCI3) (reported as a mixture of olefin isomers): 8 0.77 J=7.0 Hz, 3 1.1-1.3 (mn, 15 H), 2.27 (in, 2 2.42 3H), 3.4 (in, 2 4.34 J=6.0 Hz, 2 5.30-5.40 (in, 1 H), 5.90 J=16.0 Hz, 1 7.0 J=8.0 Hz, 2 HI), 7.18 J=8.0 Hz, 2 FA-B-MS: calculated. for C24H33N0 352; found 352 100%). Rf=0.38 (106/ ethyl acetate/n-hexane). mp 72-75*C.

249 WO 98104528 PCT[US97/13248 EXAMPLE 130

HO

2

I

6 -Diiopropl3-'hydroxmethyl4(4methlphenyl)5penlvidin The title compound was prepared from 2 6 -diisoprpyl-3.hydroxmethyl-4(4.

(Example 129) by the procedure described in Example 126. 1 H NMR (300 MHz, CDCI3):S 0.77 J=7.0 Hz, 3 1.10-1.40 (in, 19 2.27 (mn, 2 2.42 3 3.22 (in, 1 3.41 (in, 1 4.34 J=6.0 Hz, 2 H), 7.10 J=8.0 H~z, 2 7.20 J=8.0 Hz, 2 FAB-MS: calculated for C24H35N0 354; found 354 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 92-94*C EXAMPLE 131

HO

CH

2

CH

3 00 I I 2 6 Diisopropvl3hvdromethvl Step A: Ethyl 2 6 diisopropvI-4-(4efflhenV)-5.pentenl)prdine-3carboxylate Prepared from 4 -ethylbenzaldehyde, ethyl isobutyrylacetate and concentrated amnmonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MHz, CDCI 3 8 0.78 J=7.4 Hz, 3H), 0.90 J=7.4 Hz, 3H), 1.10-1.40 (mn, 17H), 1.94 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.64 J=7.7 Hz, 2H), (mn, 1H), 3.40 (mn, 1H), 3.96 J=7.4 Hz, 2H), 5.35 (in, 1H), 6.08 (dt, J=16.2, 1.5 Hz, 1H), 7.10 (in, 4H). mp, 67-68 0

C.

250 WO 98/04528 WO 9804528PCTfUJS97/13248 o Step B: 2,6-DiisopropYI-3-hVdroxymethV-4-(4-ethylphenyl)-5-(pent-lenyl)pyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1 H NMR (300 MvHz, CDCl3) (reported as a mixture of olefin isomers): 8 0.73 J= 7.0 Hz, 3H), 1.10-1.40 (in, 18H), 1.91 (tdd, J=7.0, 7.0, 1.0, 2H), 2.68 J=7.4 Hz, 2H), 3.3-3.5 (in, 2H), 4.41 J= Hz, 2H), 5.20-5.40 (mn, 1H), 6.0 (dt, J=16.0, 1.0 Hz, 1H), 7.0 J=8.5 Hz, 2H), 7.23 J= 8.5 Hz, 2H). FAB-MS: calculated for C25H35N0 366; found 366 100%).

Rf=0.31 (10% ethyl acetate/ n-hexane).

EXAMPLE 132 2 6 -Diisopropyl- 3 -hVdroxymethl-4-(4-ethylphenyl)-5-penylpvridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 4 -ethylphenyl)-5-(pent-1-enyl)pyrime (Example 131) by the procedure described in Example 126. 1 H NMR (300 MHz, CDCl3): 5 0.77 J=7.0 Hz, 3H), 1.0-1.40 (in, 22H), 2.28 (in, 2H), 2.73 J= 7.5;Hz, 2H), 3.35 (in, 1H), 3.45 (in, 1H), 4.35 2H), 7.10 J=8.0 Hz, 2H), 7.18-7.34 J=8.0 Hz, 2H). FAB-MS: calculated for C25H37N0 368; found 368 100%). Rf=0.31 (10% ethyl acetate/n-hexane).

mp 87-88 0

C.

E)(AMPLE 133

H

3

C,,,CH

3 -c WO 98/04528 PCT[US97/13248 0 2 6 Diisoproppl3hvdroxymethy-4-(4-isopropvlphenVl)-5-(pent-l-enyl)pvri-dine Step A: Ethyl 2,-ispov--4iorplhev)5(etle~~yiie3 carboxylate Prepared from 4 -isopropylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-B. 1 H NMR (300 MHz, CDCI3): 8 0.70 J=7.7 Hz, 3H), 0.84 J=7.4, 3H), 1.10-1.40 (in, 20H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.80-3.10 (in, 2H), 3.40 (mn, 1H), 3.94 J=7.4 Hz, 2H), 5.30 (mn, 1H), 6.10 (dt, J=15.8, 1.5 Hz, 1H), 7.0-7.20 (in, 4H).

mp 4-45*C.

Step B: 2 6 -Diisoropv1-3hdroxyieth 4(4sopropvhenl)-5( t-1 envl)pvridine( The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. IH NMvR (300 MHz, CDCl 3 (reported as a mixture of olefins): 5 0.68 J=7.4 Hz, 3 1.0-1.4 (in, 21 1.90 (tdd, J=7.0, 7.0, 1.5 Hz, 2 2.9 (in, 1H), 3.3-3.5 (in, 2 4.43 J=6.0 Hz, 2 H), 5.20-5.35 (in, 1 6.0 (dt, J= 16.0', 1.5 Hz, 1 7.0 J=8.0 Hz, 2 7.25 Hz, 2 FAB-MS: calculated for C26H37N0 380; found 380 100%). Rf=-0.40 (10% ethyl'acetate/n-hexane).

EXAMPLE 134

H

3 0

OH

3

HO

N

The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl-4-.

4 -isopropylphenyl)-5-(pent-l-..eny)pyidne (Example 133) by the procedure described in Example 126. 1 H NMR (300 MHz, CDdl3): 5 0.74 J= 7.0 Hz, 3 H), 1.0-1.40 (in, 25 2.25 (in, 2 2.95 (mn, 1 3.25 (mn, 1 3.40 (in, 1 4.35 (d, 252 WO 98/04528 CIS7I38 PCTIUS97113248 o J=6.0 Hz, 2 7.1, J=8.5 Hz, 2 7.25 J= 8.5 Hz, 2 FAB-MS: calculated for C26H39N0 382; found 382 100%). Rf=0.40 (10% ethyl acetate/n-hexane).

*mp42-44*C.

EXAMPLE 135 2,6-Diisopropyl-'3-hydroxymethiyl-4r4-(phenyl)phen11-5-(Pent4-lenvl)pvridine Step A: Ethyl 2,6-diisopropyl-4-[4-(phenyl)phenVI]-5-(pent-1-envl)pyridine-3carboxylate Prepared from 4-phenylbenzaldehyde, ,ethyl isobutyrylacetate and concentrated 'ammonium hydroxide by the procedures described in Example 125, Steps.A-E. 1H NM (300 MIHz, CDCl3):' 8 0.73 J=7.4 Hz, 3H), 0.93 J=7.0 Hz, 3H), 1.10-1.40 (in, 14H), 1.97 (tdd,'J=7.0, 7.0, 1.1 Hz, 2H), 3.10 (in, 1H), 3.45 (in, 1H), J=7.4 Hz, 2 5.40 (in, 1H), 6.10 (dt, J=16.2, 1.1 Hz, 1H), 7.20-7.70 (in, 9H).

mp 104-106*C.

Step B: 2 6-Diisopropyl-3-hvdroxymethvl-4-[4-(phenyl)phenyll-5-(pent-lenylpyridine The title compound wAs prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMvIR (300 MlHz,, CDCl3) (reported as a mixture of olefin isomers): 'S 0.70 7.0 Hz, 3H), 1.10-.40 (in, 1.90 (tdd, J=7.0, 7.0, 1.5, 2HM, 3.30-3.50 (mn, 2H), 4.40 J=6.0 Hz, 2H), 5.35 (mn, 1H), 6.05 (dt, J-"16.0, 1.5 Hz, 1H), 7.20-7.24.(mn, 2H), 7.35-7.70 (mn, 7H). FAB-MS: calculated for C29H35N0 414; found 414 (MI+H, 100 ).Rf 0.15 ethyl acetate/n-hexane). mp 50-52*C.

253 WO 98/04528 PCTIUS97/13248 0 EXAMPLE 136

HO

2 6 -Diisopropyl- 3 -hydroxymethy4[4(Phenyl)phenv11..5.pentlpyridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl-4-[4- (phenyl)phenyl]-5-(pent-l-enyl)pyridine (Example 135) by the procedure described Q in Example 126. 1 H NMR (300 MHz, CDC13): 5 0.76 J=7.0 Hz, 3H), 1.0-1.40 (m, 19H), 2.31 2H), 3.25 1H), 3.44 1H), 4.40 J=5.9 Hz, 2H), 7.22-7.70 (m, 9H). FAB-MS; calculated for C29HN37N0 416; found 416 100 Rf=0.34 ethyl acetate/n-hexane). mp 56-58*C.

0 EXAMPLE 137

Q"

2,6Diisopl-3-hhdroxvmethyl--2-fluoro Step A: Ethyl 2,6-diisoroyl-4-(2-fluorophenyl)-n (i 3 carboxylate Prepared from 2-fluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-B. 1H NMR (300 MHz, CDC3): (reported as a mixture of olefin isomers): 8 0.70 3H), 0.92 J= 7.0 Hz, 3H), 1.05-1.40 14H), 1.90' 2H), 3.10 1H), 3.35 1H), 3.97 2H), 5.29-5.50 1H), 6.16 1H), 7.08-7.32 4H).

9- 9- 9A99-A09A99-'Cj.9-9-9-$99~ 9 9 WO9 98/04528 PCT/US9713248 Step B: 2 ,6-Diisopropyl-3-hydroxymethyl--(2-fluorophenvl)5.(p-ent-lenyl)pyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1 H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): 8 0.69-0.82 3H), 1.09-1.40 14H), 1.90 2H), 3.20-3.45 2H), 4.40 2H), 5.25-5.45 1H), 6.08 1H), 7.08- 7.41 5H). Rf=0.24 (10% ethyl acetate/n-hexane).

EXAMPLE 138

F

HO

2,6-Diisopropyl-3I- hydrox ymethVI-4-(2-fluorpey)5pnyprdn The title compound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl74- 2 -fluorophenyl)-5-(pent-l-enyl)pyridine (Example 137) by the procedure described in Example 126. 1 H NMR (300 MHz, CDC13): 8 0.78 J=7.0 Hz, 3H), 1.07-1.40 (m, 18H), 2.29 20H), 3.26 1H), 3.46 1H), 4.34 2H), 7.20 3H), 7.42 (m, 1H). Rf=0.24 (10% ethyl acetate/n-hexane).

EXAMPLE 139

CH

3 2,6-Diisprpv3-hydroxymetfivl-4-(3-methvp~nl--1etley)prd Step A: Ethyl 2 6 -diisopropvl-4-(3metyvphetnyl)-(pent1-nl)..pyridine3.

carboxylate 255 s WO 98/04528 PCTIUS97/13248 0 Prepared from 3-methylbenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MHz, CDCI3): 8 0.74 J=7.4 Hz, 3H), 0.92 J=7.0 Hz, 3H), 1.10-1.40 (in, 14H), 1.95 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 2.32 3H), 3.10 (mn, 1H), 3.40 (mn, 1H), 3.96 J=7.4 Hz, 2H), 5.40 (mn, 1H), 6.05 (dt, J=16.2, 1.5 Hz, 1H), 6.90- 7.20 (mn, 4H).

Step B: 2,-istrpl3hdoyehl4(-mt enyl)pyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1 H NMvR (300 MiHz, CDCl 3 (reported as a mixture of olefins): 8 0.73 J=7.0 Hz, 3 1.10-1.40 (in, 15H), 1.90 (tdd, J=7.0, 7.0, 1.0, 2H), 2.36 3H), 3.30-3.50 (in, 2H), 4.40 J= 4.0 Hz, 2H), 5.20- 5.40 (mn, 1H), 5.95 (dt, J=16.0, 1.0 Hz, 1H), 6.90 (in, 211), 7.10-7.30 (in, 2H). FAB-MS:(7 calculated for C24H33N0 352; found 352 100%). Rf=-0.34 (10% ethyl acetate /n-hexane). mp 94-97C.

EXAMIPLE 140 The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl.4- 3 -methylphenyl)..s.pentlenyl)pyridine (Example 139) by the procedure described in Example 126. IH NMR (300 MHz, CDCl 3 8 0.77 J=7.0 Hz, 3 1 .0- 1.40 (mn, 19H), 2.25 (mn, 2H), 2.39 314), 3.23 (in, 1H), 3.44 (mn, 1H), 4.34 211), 6.97 (in, 211), 7.18-7.34 (mn, 2H). FAB-MS: cialculated for C24H35N0. 354; found 354 100 Rf=-0.34 (10% ethyl acetate/n-hexane). mp 88-90*C.

256 s- WO 98/04528 WO 9804528PCr1US97/13248 0 EXAMPLE 141 Step A: Ethyl 2,-ispoy--2mtvpeyl--pn--nl-yiie3 carboxylate Prepared from 2 -methylbenzaldehyde, ethyl isobutyrylacetate and conce ntrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MHz, CDCl3): 8 0.70 J=7.4 Hz, 3H), 0.88 J=74)0 Hz, 3H), 1.0-1.40 (in, 14H), 1.90 (td, J=7.0, 7.0 Hz, 2H), 2.0 3H), 3.10 (in, 1H), 3.40 (mn, 1H), 3.90 (mn, 2H), 5.30-5.40 (in, 1H), 6.0 (in, 1H), 7.0-7.20 (in, 4H).

Step B: 2 6 -Diisopropyl-3-hydroxymethVI-4(2-ethylphenl)5(pent1..

en)pwdine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Exam pie.125, Step 1H NMR (300 MHz, CDC13) (reported as a mixture of olefin isomers): 8 0.70 J= 7.5 Hz, 3H), 1.10-1.40 (mn, 1.87 (tdd, J=7.5, 7.5, 1.5, 2H), 1.95 3H), 3.30-3.50,(m, 4.20 (in, 1H), 4.45 (in, 1H), 5.30 (in, 1H), 5.93 (in, 6.90-730, (in, 4H). FAB-MS: -calculated for C24H33N0 352; found 352 Rf=-0.32 (10% ethyl acetate/n-hexane).

MP 76-79 0

C.

EXAMPLE 142 HO WO 98/04528 PCT/UJS97/13248 0 2 6 -Diisopropvl-3-hVdroxymethyl..4.(2-.methlphenyl)5pen~ylpyridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl.4 2 -methylphenyl)--(pentlenyl)pyridine (Example 141) by the procedure described in Example 126. 1 H NMR (300 MHz, CDCl3): 8 0.76 J=6.6 Hz, 3H), 1.40 (in, 19H), 1.97 2.0 (mn, 1H), 2.35 (in, 1H), 3.22 (mn, 1H), 3.42 (mn, 1H), 4.16 (dd, J=12.0, 5.0 Hz, 1H), 4.40 (dd, J=12.0, 5.0 Hz, 1H), 7.0-7.10 (mn, 1H), 7.20-7.40 (in, 3H). FAB-MS: calculated for C24H35N0 354; found 354 100%). Rf=-0.32 ethyl acetate/n-hexane). mp 81-83*C.

EXAMPLE 143

CC,

2 6 DiisopropVl-3-hydroxymethvl.4..(4horoph5(pn-eyl)ptid.n 0- Step A: Ethyl 2,-ispov--4clrpeyl--pn-7nl-yiie3 carboxylate Prepared from 4 -chlorobenzaldehyde, ethyl isobutyrylacetate and concentrated amnmonium hydroxide by -the procedures described in Example 125, Steps Ak-E. 1 H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): 8 0.76 (in, 3M), 0.98 (in, 3M), 1.15-1.35 (in, 14H), 1.95 (in, 2H), 3.05 (in, 1H), 3.39 (in, 1H), 4.0 2H), 5.29-5.48 (in, 1H), 6.03 (in, 1H), 7.11 (in, 2H), 7.30 (mn, 2H).

Step B: 2,-ispoy--vrxmty-4(-hoohnl--pnenylpyridine- The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 M[Hz, CDC13) (reported as a 6:1 mixture of olefin. isomers): 8 0.73-0.83 (in, 3M), 1.10-1.40 (14H), 1.91 (in, 2H), 3.93 (in, 21H), 4.39 J=5.0 Hz, 5.25-5.45 (mn, 1M1, 5.98 (mn, 1H), 7.11 (in, 2H), 7.35 (in, 2H). Rf=0O.36 (10% ethyl acetate/n-hexane).

258 11- 11-- 7 777-77 7 7, WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 144 2 6 -Diisopropyl-3-hydroxVmethyl-4-(4-chlorophenVl)-5-pentylpvyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 4 -chlorophenyl)-5-(pent-1-enyl)pyridmne (Example 143) by the procedure described in Example 126. 1H NNM (300 MfHz, CDCI3): 8 0.79 J=7.0 Hz, 3H), 1.08-1.38 (in, 18H), 2.26 (in, 2H), 3.22 (in, 1H), 3.40 (mn, 1H), 4.31 J=5.0 Hz, 1H), 7.13 (d Hz, 2H), 7.42 J=8.0 Hz, 2H). mp 83-85*C. Rf=-0.36 (10% ethyl acetate/n-hexane).

EXAMPLE 145 2 6 -Diisopropyl-3-hydroxvmethyl-4-(3-chlorophenyl)5-(pent-l-enyl)..pyridine Step A: Ethyl 2 6 -diisoPMropy-4-(3-chlorophenyl)-5-(pent-l-enyl)-pyridine-3carboxylate Prepared from 3-chlorobenzaldehyde, ethyl isobutyrylacetate and ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MIHz, CDCl3): 8 0.75 J=7.4 Hz, 3H), 0.98 J=7.0 Hz, 3H), 1.20-1.40 (mn, 14H), 1.96 (tdd, J=7.0, 7.0, 1.5 Hz, 2H), 3.05 (in, 1H), 3.40 (mn, 1H), J=7.0 Hz, 5.45 6.05 (dt, J=16.2, 1.5 Hz, 1H), 7.0-7.30 (in, 4H1).

259 WO 98/04528 PCTIUS97/13248 0 Step B: 2,-isvoy--vrxmty--3clr enyl)pvridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. IH NMR (300 MHz, CDCl 3 (reported as a mixture of olefin isomers): 5 0.75 J=7.5 Hz, 3H), 1.10-1.40 (in, 1.93 (tdd, J=7-0, 7.0, 1.0 Hz, 2H), 3.30-3.50 (in, 2H), 4.37 J=12.0 Hz, 1H), 4.43 (d, J=12.0 Hz, 1H), 5.20-5.40 (mn, 1H), 5.9 (dt, J=16.0, 1.1 Hz, 1H), 7.0-7.40 (in, 4H). FAB- MS: calculated for C23H30N0C1 372; found 372 100%). Rf=0.26 (10% ethyl acetafe/n-hexane). mp 101-104*C.

EXAMPLE 146 2 6 Diiso rol-3hydroxeh et3-h~lor3c~h rol)Stlvrdn The title compound was prepared from 2

I

6 -diisopropy3hydroxmeffyl-4 (3-chlorophenyl)-s.(pent1..enyl)pyridine (Example 145) by the procedure described in Eampl 126 1 H NMR (300 MIHz, CDCl3): 8 0.80 J=7.0 Hz, 3H),1.-40(n 19H), 2.26 (in, 2H), 3.23 (in, 1H), 3.41 (mn, 1H), 4.34 (in, 2H), 7.05-7.45 4H). FA- MS: calculated for C23H32N0C1 374; found 374 100%). Rf 0.26 (10% ethyl acetate /n-hexane). mp 94-95*C.

EXAMPLE 147OC- 260 WO 98/04528 WO 9804528PCT/tJS97/13248 o 2 ,6-Diisopropvl-3-hydroxymethl-4-(2,4-dichloropheYl)5-(pent-l-eny1)pyridne Step A: Ethyl 2 ,6-diisopropyl-4-(2,4-dichlorophenyl)-5-(pent-l-enyl)pyridine- 3-carboxylate Prepared from 2,4-dichlorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDCl3) (reported as a 1:1 mixture of olefin isomers): 8 0.79 (in, 3H1), 0.99 (in, 3H1), 1.12-1.38 (in, 14H), 1.91 (in, 2H), 3.12 (in, 1H), 3.32 (mn, 1H), 4.0 (in, 211), 5.20 -5.60- (mn, 1H), 6.09 (in, 1H), 7.05-7.41 (in, 3H).

Step B: 2 6 -Diisopropyl-3-hydroxinethw-4-(2,4-dichdorophenyl).5..(Rent-l.

enyl)pyridine The title compound was prepared from the, intermediate obtained in Step A by the procedure described in Example 125, Step F. H NMR (300 MHi, CDCl3) (reported as a 1:1 mixture of olefins): 8 0.75-0.87 (in, 1.13-1.37 (in, 14H), 1.65- 2.0 (in, 2H), 3.20-3.651 (in, 211), 4.30 (in, 1H1), .4.42 (in, 111), 5.31-5.50. 6.0 (in, 1H1), 7.05 (in, 1H1), 7.28 (in, 11), 7.47 (in, Rf 0.38 (10% ethyl acetate/n-hexane).

EXAMPLE 148 2 4 -dichlorophenyl)-5-(pent-1-enyl)pyridine (Example 147) by the procedure described in Example 126. 1H1 NMR (300 MHz, CDCl3): 8 0.80 J=7.0 Hz, 311), 1.12-1.48 (in, 1811), 2.12 (in, 111), 2.35 (in, 111), 3.26 (in, 111) 3.45 (in, 111), 4.31 (AB, J=12.0 Hz, 211), 7.16 J=8.0 Hz, 1H), 7.36 (dd, J=8.0, 2.0 Hz, 111), 7.54 J=2.0, 111).

Rf 0.38 (10% ethyl acetate/ni-hexane).

WO 98/04528 PCTIUS97/13248 0 EXAMPLE 149 2 6 DiisopropVI-3hVdroxvmethvl.4(3,4dichorophen)(t 11ny)prdn Step A: Ethyl 2,-ispov--34dclrpey)5(etley~viie 3-carboxylat Prepared from 8, 4 -dichloroberizaldehyde, ethyl isobutyrylacetate. and concentrated ammonium hydroxide by the procedures described in Example.160, Steps A-E. 1 H NMR (300 NMz, CDCl3) (reported as a 6:1 mixture of olefin isomers): 5 0.78 (in, 3H), 1.04 (in, 3H), 1.16-1.35 (in, 14H), 1.98 (in, 2H), 3.04 (in, 1H), 3.57 (in, 5.31-5.58 (mn, 1H), 6-.02 (mn, 1H), 7.04 (mn, 1H), 7.28-7.42 (in, 2H). Step B: 2 6 -Diiso r~..hroox-3hdrxmehy e-(,-dcl(34dihen enylpyridine The title compound was prepared- from the intermediate obtained in Step A by the procedure 'described in Example 125, Step F. 1 H NMR (300 MIZ, CDCl3) (reported as a 6:1 mixture of olefin isomers;): 80.80 (mn, 3H), 1.16-1.57 (in, 14H), 1.95 (in, 2H), 3.40 (in, 2H), 4.41 (in, 21H), 5.28 5.42. (in, 1H), 6.0 (in, 1H), 7.05 1H), 7.30 1H), 7.45 (mn, 1H). mp 46-48*C. Rf=0.38 (10% ethyl acetate/n-hexane).

EXAMPLE 150

F

F

HO I~ 262 WO 98/04528 WO 98/4528 CT1US97/13248 o 2 6 -Diisoproppl-3-hydroxymethy-4-(2,4-difluorophny)-5.(pent-l-.enyl)pvridine Step A: Ethyl 2 6 -diisopropyl-4-(2,4-difluorophenyl)-5-(pent-1-enylrpyridine.

3-carboxylate Prepared from 2,4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1 H NMR (300 MHz, CDCl3): 8 0.75 J=7.4 Hz, 3H), 1.0 J=7.0 Hz, 3H), 1.10-1.40 (in, 14H), 1.93 (tdd, J=7.4, 7.4, 1.5 Hz, 2H), 3.10 (mn, 1H), 3.35 (in, 1H), J=7.0 Hz, 2H), 5.30 (dt, J=15.0, 7.0 Hz, 1H), 6.10 (mn, 1H), 6.80-7.20 (in, 3H).

Step B: 2 6 -Diisoropl-3-hydroxymethyl-4-(2,4difluorohenyl)5(pent-l.

enyl)pyridinet The title compound was prepared from the -intermediate obtained in Step A by the procedure described in -Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): 8 0.75 J=7.5,Hz, 3H), 1.10-1.40 1.92 (tdd, J=7.0, 7.0, 1.5, 2H), 3.3-60 (in, 2 4.34 (dd, J=12.0, 6.0 Hz, 1H), 4.43 (dd, J=12.0, 5.0 Hz, 1H), 5.3 (in, 1H), 6.05 J=16.0, Hz, 1H), 6.80-720' (rfi, 3H).

FAB-MS: calculated. for C23H29N0F2 374; found 374 100%) Rf 0.24 ethyl acetate /n-hexane). mp 59-62*C.

EXAMPLE 151

~F

The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 2 4 -difluorophenyl)-5-(pent-1-enyl)pyiidine (Example 150) by the procedure described in Example 126. 1 H NMR (300 MHz, CDCl3): 8 0.79 J=7.0 Hz, 3H), 1.10-1.40 (in, 18H), 2.30 (in, 2 3.20 (mn, 1H1), 3.40 (mn, 1H), 4.30 J=12-0 Hz,.

1H),4.36 J=12.0 Hz, 1H),-6.90-7.20 (in, FAB-MS: calculated for C23H31F2N0 376; found 376 100%). Rf 0.24(10% ethyl acetate/n-hexane). mp 93-95*C.

WO 98/04528 WO 9804528PCT/US97/13248 0 EXAMPLE 152

~I

Step A: Ethyl 2 6 -diisopropyl4-(3benzloxp,henvl)-5(entenvl)vidin 3-carboxylate Prepared from 3 -benzyloxybenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 160, Steps A-E. 1H1 NMR (300 MHz, CDCl3): 8 0.75 J=7.4 Hz, 3H), 0.93 J= 2 Hz, 311), 1.25 (in, 14H), 1.93 (tdd, J=7.4, 7.4, 1 .1 Hz, 2H), 3.07 (in, 1H1), 3.40 (in 1H), 3.97 (in,211), 5.04 (bs, 211), 5.35 (in, 6.06 (dtJ=16.2, 1.5 Hz,l11), 6.79 (fi,2H), 6.89 (in, 111), 7.31 (mn, 6H). Step B: 2,-ispoy--vrxmty-4(-ezlxpey)5(etl enyl)pyrjdine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 111 NUvR (300 MHz, .CDC13) (reported as a mixture of olefin isomers): 8 0.74 J=7.4 Hz, 311), 1.25 (in, 1411), 1.90 (in, 2H), 3.39 (in, 211), 4.39 J=6.0 Hz, 211), 5.07 211), 5.32 (in, 111), 5.97 (mn, 1H1), 6.74 6.95 (in, 111), 7.35 (mn, 711). FAB-MS: calculated for C30H37N02, 444; found 444 100%). Elemental analysis: calculated for C30H37N02: C 81.22; H 8.41;. N 3.16,* found: C 80.51; H 8.41; N 3.36. Rf 0.5 (25% ethyl acetate/n-hexane).

EXAMPLE 153

<OH

WO 98/04528 WO 9804528PCTIUS97/13248 0 A,6-Diisopropyl-3-hydroxymethyl-4-(3-hydroxyphenyl)-5-pentylpyridine The title compound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl-4- (3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 152) by the procedure described in Example 126. 1 H NNM (300 MHz, CDCl3): 5 0.78 J=7.0 Hz, 3H), 1.28 (in, 18H), 2.28 (in, 2H), 3.22 (in, 1H), 3.39 (mn, 1H), 4.34 (in, 2H), 5.52 1H), 6.63 (mn, 1H), 6.71 J=8.0 Hz, 1H), 6.81 (in, 1H), 7.26 (mn, 1H). FAB-MS: calculated for C23H33N02 356; found 357 100%). Elemental analysis: calculated for C23H33N02: C 77.70; H 9.36; N 3.94, found: C 76.51; H 9.49; N 3.85. Rf 0.21 ethyl acetate /n-hexane). mp, 121-122 0

C.

EXAMPLE 154 (7.3 2 6 -Diisopropyl-3-hydroxyiethyl-4-(3-trifluoromethyl)Rhenyl..-(pent-l.

enyl)pvridine Step A: Ethyl 2 6 -diisopropvl4-(3-trifluoromethl)phenyl-5.(pent-lenvl)pvridine-3-carboxylate Prepared from 3-(trifluoromethyl)benzaidehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-E. 1H NMvR (300 MIHz, CDC13) (reported as a 6:1 mixture of olefin isomers): 8 0.72 (in, 3H), 0.94 (mn, 3H), 1.10-1.40 (mn, 14H), 1.94 (in, 2H), 3.07 (in, 1H), 3.4.1 (in, 1H), 3.97 (in, 2H), 5.33 (in, 1H), 6.05 (in, 7.29-7.60 (Mn, 4H).

Step B: 2 6 -Diisopropvl-3-hydroxyinethyl-4-(3-trifluoronethl)henyl-5- (Pent-1-envl)Pyridine The title compound was prepared from the intermediate. obtained in Step A by the procedure d escribed in Example 12.5, Step F. 1H NUR (300 MhHz,. CDCl3) (reported as a 6:1 mixture of olefin isomers): 8 0.67-0.87 (in, 3H), 1.08-1.38 (in, 14H), 1.90 (in, 2H), 3.20-3.50 (in, 2H), 4.39 (qd, J=12.0, 5.0 Hz, 2H), 5.24-5.50 (mn, 1H), 5.93- WO 98/04528 PCT1US97/13248 o 6.02 (in, 1H), 7.37-7.62 (in, 3H). mp 100-103 0 C. Rf 0.36 (10% ethyl acetate/nhexane).

EXAMEPLE 155 2 6 DiisopropVl-3hydroxymethy1.4(3..trifluoromethv)2hnpentlpWLid The title compound was prepared from 2 6 -diisopropyl-3-hydroxymetyl4.

3 -trifluoromethyl)phenyr..s.(pent1..enyl)pyridjfle (Example 154) by the procedure described in Example 126. 1 H NMR (300 MHz, CDC13): 8 0.75 J=6.5 Hi, 3H), 1.07-1.39 (in, 18H), 2.24 (in, 2H), 3.24 (in, 1H), 3.42 (in, 1H), 4.31 (qd, J=12.0, 5.0 Hz, 2H), 7.42 J=8.0 Hz, 1H), 7.50 1H), 7.57(t, J=8.0 Hz, 1H), 7.67 J=8.0 Hz, 1H).

mp 96-97*C. Rf 0.36 (10% ethyl acetate/n-hexane).

EXAMPLE 156

HK

HO

Step A: Diethyl. 46diS o 2idpcnv~viii-,-iabxl Prepared from 2-iodobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 125, Steps A-B. 1 H NMR (300 MJ-hl CDCl 3 6 0.94 J= 7.0 Hz,- 6H), 1.30 J= 6.6 Hz, 6H), 1.34 J= 6.6 Hz, 6M, 3.19 (septet, 6.6 Hz, 2H), 4.0 J= .7.0 Hz, 4H), 7.40 (in, 3H), 7.85 (in, 1H).

WO 98/04528 PCT/US97/13248 0 Step B: Diethyl 2 ,6-diisopropyl-4-[(2-trimethylsilylethynyl)phenvl]pyridine- A solution of 1.50 g (3 mmole) of the intermediate obtained in Step A in toluene was treated with 1.48 g (15 mmole) of trimethylsilyl acetylene, 87.1 g (0.86 mol) of triethylamine, 0.1 g (0.15 mmol) of bis(triphenylphosphine) palladium(ll) chloride, 0.2 g (0.8 mmole) of triphenyl phosphine and 0.2 g (1.17 mmole) of copper iodide. This reaction mixture was stirred at rt for lhr and heated at 90°C, in a sealed reaction vessel, for 16 .hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which upon purification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. 1 H NMR (300 MHz, CDC13): 8 0.0 9H), 0.93 J= 7.0, 6H), 1.32 J= 6.6 Hz, 6H), 1.33 J=6.6 Hz, 6H), 3.18 (septet, J= 6.6, 2H), 3.90 J= 7.0 Hz, 4H), 7.20-7.50 4H).

Step C: Diethyl 2;6-diisopropyvl-4-(2-thynylphenyl)pyridine-35-dicarboxylate A solution of 5.68 g (11.9 mmole) of the intermediate obtained in Step B in 800 mL ethanol was treated with 2.8 g (20.3 mmole) of potassium carbonate and the reaction-mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride, brine 'and separated. The organic layer was dried over miagnesium sulfate, filtered aind concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10 ethyl acetate/n-hexane, to give 3.95 g (9.6 mmole) of the product. 1 H NMR (300 MHz, CDCI3): 8 0.90 J= 7.0 Hz, 6H), 1.32 12H), 2.97 1H), 3.21 (septet, J=6.6, 2H), 3.90 J= 7.0, 4H), 7.2-7.6 4H).

Step D: Ethyl 2,6-diisopropvl-4-(2-ethynvlphenl)-5-(pent-l-enyl)-pyridine-3carboxylate Prepared from the intermediate obtained in Step C by the procedures described in Example 125, Steps A-E. 1H NMR (300 MHz, CDC13): 8 0.68 J=7.4 Hz, 3H), 0.88 (td, J=7.0, 2.4 Hz, 3H), 1.20-1.40 14H), 1.88 (tdd, J=7.0, 7.0, 1.1 Hz, 2H), 2.92 J= 2.4 Hz, 1H), 3.0-3.40 2H), 3.90 2H), 5.28 (dt, J=16.2, 7.0 Hz, 1H), 6.15 (dt, J=16.2,1.5 Hz, 1H), 7.10-7.60 4H).

Step E: 2,6-Diisopropyl-3-hvdroxvmethyl-4-(2-ethynylphenyl)-5-(pent-lenyl)pyridine The title compound was prepared from the intermediate obtained in Step D 267 i WO 98/04528 PCTIUS97/13248 o by the procedure described in Example 125, Step F. 1 H NMvR (300 MiHz, CDCl 3 (reported as a mixture of olefin isomers): 8 0.81 J= 7.4 Hz, 3H), 1.0-1.40 (in, 1.75 (mn, 2H), 2.98 J= 3.3 Hz, 1H), 3.20-3.60 (in, 2H), 4.20-4.50 (in, 2H), 5.40 (in, 1H), 6.0 (mn, 1H), 7.0-7.60 (mn, 4H). Rf=0.23 (10% ethyl acetate/n-hexane).

EXAMPLE 157 ispoyl3hdoyetV--2eh~lhnl--pnVprdn ~The title compound was prepared from ethyl 2 ,6-diisop .ropyl-3hyrxmty--2ehnlhnl--pn--nlp~dn--abxlt by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): B. 0.60-0.90 (in, 3H), 1.0-1.40 (in, 15H),, 1.60-1.90 (in, 3.20-3.50 (in, 2H), 4.20-4.40 (mn, 5.14 (dt, J= 11.0, 1.0 Hz, 1H), 5.40 (in, 1H), 5.90 (in, 1H), 6.30 (in, 1H), 7.0-7.70 (in, 4H). FAB-MS:. calculated for C25H33N0 363. found- 364 100%). Rf 0.28 (10% ethyl .acetate/n-hexane).

C

EXAMPLE 158 2,6-Diisoj2ropyl-3-_hydroxymethVI-4-(3,4-difluoroDhenVl)-5-(vent-l-envl)pvridine Step A: Ethyl 2,-is~OV--34dfurphni--Pn--ev~viie 3-carboxylate 268 CT., WO 98/04528 WO 9804528PCTIUS97/13248 0 Prepared from 3/4-difluorobenzaldehyde, ethyl isobutyrylacetate and concentrated ammonium hydroxide by the procedures described in Example 1, Steps A-E. 1 H NMR (300 MI-z, CDCl3) (reported as a 8:1 mixture of olefin isomers): 8 0.78 (in, 3H), 1.03 (in, 3H), 1.18-1.33 (in, 14H), 1.97 (mn, 2H), 3.04 (in, 1H), 3.38 (mn, 1H), 4.04 (in, 2H), 5.30-5.45 (mn, 1H), 6.02 (mn, 1H), 6.89-7.17 (mn, 3H).

Step B: 2 6 -Diisopropyl-3-hydroxymethy-4-(34difluorophenl)5(Pent-lenylDpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1 H NMR (300 MI-z, CDC13) (reported as a mixture of olefin isomers): 8 0.75 (in, 3H), 1.05-1.38 (in, 14H), 1.90 (mn, 2H), 3.35-(mk, 2H), .4.35 (in, 2H), 5.25 (in, 1H), 5.91 (in, 1H), 6.80-7.20 (in, 4H). mp 105-106*C. Rf=-0.30 (10% ethyl acetate /n-hexane).

EXAMPLE 159

~F

The title compound was prepared fromn 2 ,6-diisopropyl-:3-hydroxymethyl-4- 3 4 difluorophenyj)--(pent--enyl)pridini- (Example 158) by the procedure described in Example 126.- 1 H NMR (300 MHz, CDC13):B 0.81 J=7.0 Hz., 3H), 1.12 (mn, 4H), 1.30 (in, 14H), 2.27 2H), 3.24 (in, 1H), 3.41 (in; 1H), 4.32 J=4.0 Hz, 2H), 6.95 (in, 1H), 7.06 (in, 7.25 (mn, 1H). mp, 106-107*C. Rf 0.30 (10% ethyl acetate/n-hexane).

269 WO 98/04528 PCT/US97/13248 0 EXAMPLE 160 OCH2Ph

HO

2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzvyoxyphenyl)-5-(pent-l-enyl)pyrdi.ne Step A: Diethyl 1,4-dihvdro-2,6-diisopropyl-4-(4-benzl Pyridinedicarboxylate To 4 -benzyloxybenzaldehyde (24.3 g, 114 mmol) and ethyl isobutyryl acetate (37.8 g, 239 mmol) were added ethanol (50 mL), acetic acid (1 mL), and piperidine (1.7 mL). The mixture was stirred under an argon atmosphere at for 12 hours. Freshly prepared sodium ethoxide in ethanol 15 mL) was then added and the reaction mixture was stirred at 25 0 C for 2 hours. To this mixture was added a solution of ammonium acetate (13.1 g, 171 mmol) in acetic acid (100 mL). The reaction was heated at reflux for 14 h and was then cooled to 25 0

C,

during which time a white precipitate developed. To the mixture was added a 40% solution of 2 -propanol in water. The mixture was stirred for 0.5 hours at 0 C and was then cooled to -20 0 C for 2 hours. The white solid was collected by filtration with vacuum and washed with a 50% solution of isopropanol in water to provide the product (41.8 g, 85 mmol, 75%) as a pure white solid (mp 140- 141"C). 1 H NMR (300 MHz, CDC13): 8 1.14-1.29 18H), 4.10 J 6.9 Hz, 4H), 4.19(sept, J 6.9 Hz, 2H), 4.95 1H), 5.01 2H), 6.12 1H), 6.82 J 8.7 Hz, 2H), 7.17 J 8.7 Hz, 2H), 7.27-7.45 tep B: Diethyl 2,6-diisopropyl-4-(4-benzvloxyphenyl)-35-pyridinedicarboxylate To a solution of the intermediate obtained in Step A (39.72 g, 81 mmol) in acetone (400 mL) stirred under argon at 25 0 C was added an aqueous solution of ammonium cerium(IV) nitrate (1M, 162 mL). The mixture was stirred at for 0.5 hours and the acetone was then removed under reduced pressure.

The resultant mixture was diluted with dichloromethane (400 mL) and poured into 270 WO 98/04528 PCT/US97/13248 0 water (100 mL). The organic layer was saved and the aqueous layer is extracted with dichloromethane (100 mL). The combined organic layer was washed with a saturated solution of sodium. chloride (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the product as a white powder (39.51 g, 100%) (mp 87 0 1 H NMR (300 MHz, CDCI3): 5 0.96 J 6.9 Hz, 6H), 1.31 J 6.6 Hz, 12H), 3.10 (sept, J 6.6 Hz, 2H), 4.01 J 7.5 Hz, 4H), 5.09 (s, 2H), 6.95 J 8.7 Hz, 2H), 7.21 J 8.7 Hz, 2H), 7.32-7.46 Step C: Ethyl 2,6-diisopropyl-4-(4-benzyloxyphenyl)-5-(pent-l-enyl)-3pyridinecarboxylate Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Steps D-F. 1H NMR (300 MHz, CDC13): 8 0.77 J 7.2 Hz, 3H), 0.95 J 7.2 Hz, 3H), 1.21-1.34 14H), 1.96 J 7.2 Hz, 2H), 3.05 (septet, J 6.6 Hz, 1H), 3.42 (septet, J 6.6 Hz, 1H), 3.94-4.03 2H), 5.06-5.12 (m, 2H), 5.32-5.42 1H), 6.03-6.15 1H), 6.94 J 9.0 Hz, 2H), 7.10 J 9.0 Hz, 2H), 7.34-7.47 Step D: 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-1enyl)pyridine The intermediate obtained in Step C (6 g, 12.35 mmol) was dissolved in anhydrous tetrahydrofuran (130 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride M in THF, 24.7-mL, 24.7 mmol). The reaction mixture was stirred at reflux for 3 hr, cooled to room temperature and quenched by the addition of 0.9 mL H20, 0.9 mL 20% aqueous NaOH, and 2.7 mL H20. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by chromatography through silica ethyl acetate/hexane) to afford 4.76 g of the title compound as a colorless wax. 1H NMR (300 MHz, CDC13): 8 0.73-0.83 3H), 1.37-1.70 14H), 1.56 (s, 1H), 1.92 (dq, J 0.90, 6.90 Hz, 2H), 3.41 J 6.60,13.20, 24.60 Hz, 2H), 4.43 J 5.1 Hz, 2H), 5.10 2H), 5.27-5.37 1H), 5.97 J 15.90 Hz, 1H), 6.97-7.09 (m, 4H), 7.35-7.48 271 WO 98/04528 PCTIUS97/13248 EXAMPLE 161

OH

HO

2,6-Diisopropyl-3-hvdroxymethvy-4-(4-hydroxyphenyl)-5-pentylpyridin 2,6-Diisopropyl-3-hydroxymethyl-4-(4-benzyloxyphenyl)-5-(pent-lenyl)pyridine (Example 160) (500 mg, 1.13 mmol) was dissolved in absolute ethanol mL) under argon, treated with 10% palladium on carbon (15 mg), then stirred under a hydrogen atmosphere for 14 h. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the residue is purified by flash chromatography methanolmethylene chloride) to yield 371 mg of the title compound as a waxy solid (mp 158.5 1H NMR (300 MHz, CDC1 3 8 0.79 J 6.6 Hz, 3H), 1.06-1.36 21H), 2.24-2.31 2H), 3.22 (sept, J 6.6 Hz, 1H), 3.40 (sept, J 6.6 Hz, 1H), 4.36 J 5.4 Hz, 2H), 4.85 1H), 6.89 J 8.4 Hz, 1H), 7.05 J 8.7 Hz, 1H).

'C'

C'

r io EXAMPLE 162 6-Diisopropyl-3-hydroxymethy-4-2-benzyloxphenyl)-5-(pent-l-enl)pridine The title compound was prepared as a waxy solid from 2-benzyloxybenzaldehyde by the procedures described in Example 160. 1H NMR (300 MHz, CDCl3): 8 0.69-0.74 3H), 1.07-1.38 14H), 1.69-1.79 1H) 1.84-1.99 2H), 3.26-3.54 2H) 4.28-4.46 2H), 4.90-5.09 2H), 5.26-5.47 1H), 6.00 (dd, J 15.9,1.2 Hz, 1H), 7.05-7.10 5H), 7.24-7.36 4H).

272 ~i i ritl WO 98/04528 WO 9804S28PCTIUS97113248 EXAMPLE 163

HO

2 6 -Diisopropyl- 3 -hydroxymethyl-4-(2-hydroxypheny)-5-pentylpyridine The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 2 -benzyloxyphenyl)-5-(pent-l-enyl)pyridine (Example, 162) by the method detailed in Example 161. 1 H NMR (300 MHz, CDCl3): 8 0.75-0.7'3 (mn, 3H), 1.09-1,.15 (in, 4H), 1.30-1.37 (mn, 14H), 1.70-1.73 (mn, 1H), 2.16-2.28 (in, 1H), 2.32-2.42 (in, 1H), 3.22-3.32 (in, 1H), 3.39-3.51 (in, 1H), 4.29-4.35 (in,1H), 4.48-4.54 (in, 1H), 5.14 (hr s, 7.02- 7.05 (in, 3H), 7.28-7.36 (in, 1H). FAB-MS: calcd for (C23H33N02) 355, found 356 (M Anal. caic. for C23H33N02: C, 77.70; H, 9.6; N, 3.94. Found:, C, 77.63; H, 9.12; Nf 3.75. mp 125.5 0

C.

EXAMPLE 164

OH

3 2 6 -Diisopropvl-3-(l-hydroxyethyl)-4-(2-hyvdronphenyl).5-pentvlpvridine Step A: 2 ,6-Diisopropl-(2-benzlxvpheny)-5pentVI-.3-.p iinecarboxaldehyde 2,-ispoy--yrxmty--2bnyoyhnl--pn-ley) pyridine (Example 162) (680 ing, 1.53 mnmol) was dissolved in 15 mU of methylene chloride under an argon atmosphere and treated with a mixture of Celite (661 mng) and pyridinium, chlorochromate (661 mng, 2 eq). The reaction was stirred at 273 WO 98/04528 PCT/US97/13248 0 room temperature for 1.5 h. The suspension was filtered through a pad of silica and the pad was washed with 50 mL CH2C1 2 and the filtrate was combined and concentrated in vacuo to afford 572.4 mg of product 1H NMR (300 MHz, CDC1 3 8 0.70 J 7.2 Hz, 3H), 1.08-1.35 15H), 1.85-1.93 1H), 3.26-3.45 (m, 1H), 3.87-3.97 1H), 4.97-5.06 2H), 5.27-5.50 1H), 6.01-6.10 1H), 6.94- 7.34 9H), 9.82 J 3.6 Hz, 1H).

Step 2,6-Diisopropyl-3-(l-hdroxvethl-4-(2-benzvloxpheny)-5-(pent-1enyl)pyridine Prepared as a separable mixture of two diastereomers from the intermediate from Step A by the method detailed in Example 101, Step B. The two diastereomers were separated by flash chromatography on silica eluting with ethyl acetate-hexane.

Diastereomer 1: colorless oil, 1 H NMR (300 MHz, CDCI3): 8 0.68-1.91 (m, 23H), 3.19-3.40 1H), 3.77 (sept, J 6.6 Hz, 1H), 4.69-4.79 1H), 4.94 (dd, J 12.3, 3.9 Hz, 1H), 5.05 J 12.3 Hz, 1H), 5.20-5.43 1H), 5.90-6.05 1H), 6.94- 7.38 9H). FAB-MS: calcd for (C31H39N0 2 457, found 458 (M 1).

Diastereomer 2: colorless oil, 1 H NMR (300 MHz, CDC13): 8 0.69 J 7.2 Hz, 3H), 1.05-1.40 17H), 1.67-1.73 1H), 1.80-1.88 2H), 3.18-3.41 1H), 3.68-3.80 1H), 4.84-5.08 3H), 5.25-5.42 1H), 5.86-6.08 1H), 6.90-7.38 9H). FAB-MS: calcd for (C31H39N0 2 457, found 458 (M 1).

StepC: 2,6-Diisopropyl-3-(1-hydroxyethyl-4-(2-hydroxyphenvl)-5 pentylpyridine The diastereomeric mixture of intermediates from Step B (39 mg) was dissolved in absolute ethanol (1.5 mL) under argon, treated with 10% palladium on carbon (4 mg), then stirred under a hydrogen atmosphere for 8 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford 32 mg of the title compound as a colorless solid. Preparative thin layer chromatography ("prep TLC") using a 20% ethyl acetate-hexane mixture as the eluent provided the two diastereomers.

Diastereomer 1 (Dl) (11.2 mg): 1 H NMR (300 MHz, CDC13): 8 0.68 J 7.30 Hz, 3H), 0.99-1.03 4H), 1.19-1.34 17H), 1.62 J 3.60 Hz, 1H), 1.97- 2.07 1H), 2.16-2.26 1H), 3.14 (septet, J 7.30 Hz, 1H), 3.67 (septet, J 7.30 Hz, 1H), 4.72 (br s, 1H), 4.83 (dq, J 4.20, 6.60 Hz, 1H), 6.89-6.97 3H), 7.19-7.25 1H). FAB-MS: calcd for (C24H35N0 2 369, found 370 (M 1).

274 WO 98/04528 WO 9804528PCT[US97/13248 0 Diastereomer 1 (Dl) could be resolved into the constituent enantiomers as follows. A Waters Prep LC 2000 HPLC. system was equipped with a chiral HPLC column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 mL/min. The sample was dissolved in mobile phase (20 mg/mL) and 5 mL aliquots were injected at 30 minute intervals. The effluent was monitored at 280 nm and two fractions (corresponding to the enantiomers) were collected at (15-17 min, 100% ee) and (19-26 min, >99% ee), respectively.

Diastereomer 2 (D2) (11.8 mng): 1 H NMR (300 MIHz, CDCl3): 8 0.68 J 6.60 Hz, 3H), 0.99-1.03 (in, 4H), 1.16-1.32 (in, 17H-), 1.86 (br s, 1H), 2.00-2.10 (in, 1H), 2.19-2.29 (mn, 1H), 3.14 (septet, J 6.60 Hz, 1H), 3.67 (septet, J 6.60 Hz, 1H), 4.57 (q, J 6.60 Hz, 1H), 4.76 (br s, 1H), 6.84-6.93 (in, 3H), 7.19-7.24 (in, 1H). FAB-MS: calcd for (C24H35N02),369, found 370 1).

EXAMPLE 165 OH OH'

CH

3 f

N-

2,6-Diisopropyl-3-(l-hydroxyethyl)-4-(2-hydroxvphenyl)-5-propylpyridine Step A: Diethyl-2,6-diisopropyl-4-(2-benzyloxyphe Sdicarboxylate Prepared from 2-benzyloxybenzaldehyde by the. methods detailed in Example 160, Steps A-B. 1 H NMR (300 MHz, CDCl3): 'S 0.87 J 6.9 Hz, 6H), 1.32 J 6.6 Hz, 6H), 1.33 J 6.6 Hz, 6H), 3.19 (sept, J =6.6 Hz, 2H),,.3.97 J 7.2 Hz, 4H), 5.01 2H), 6.88 J= 8.1 Hz, 6.94(dtJ 7.2, 0.6 Hz, 1H), 7.16 (dd, J 1.8 Hz, 1H), 7.14-7.30 (mn, 6H).

Step B: 5-Ethoxvcarbonyl-2,6-diisopropyl.4-(2-benzvloxvphenyl)-3pVridinecarboxaldehyde Prepared from the intermediate from Step A by the methods detailed in Example 1, Steps D-E. 1 H NMR (300 MI~z, CDCl3): 8 0.91 J =6.6 Hz, 3H), 1.30- 275 WO 98/04528 PCT/US97/13248 0 1.39 12H), 3.18 (septet, J 6.0 Hz, 1H), 3.91-4.03 3H), 5.04 (dd, J 6.6, 12.6 Hz, 2H), 6.96-7.05 2H), 7.17-7.28 6H), 7.34-7.40 1H).

tep C: 2,6-Diisopropl-4-(2-b enyl)pyridine Ethyltriphenylphosphonium bromide (4.01 g, 10.8 mmol) was suspended in anhydrous THF (130 mL) under argon and stirred at -78 0 C. A 1.6 M solution of nbutyllithium in hexanes (6.75 mL, 10.8 mmol) was added dropwise. The reaction mixture was allowed to come to 0 C and stirred at that temperature for 1 hr. The resulting brightly colored solution was cooled again to -78 0 C and treated dropwise with a solution of the intermediate obtained in Step B (4.0 g, 9.0 mmol) in THF mL). The reaction mixture was allowed to stir at 25 0 C for 3 hrs, then quenched by the addition of water (5 mL). The THF was removed in vacuo, the residue partitioned between ethyl ether (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated. Flash chromatography through silica ethyl acetate/hex) afforded 4.1 g of the-product Z mixture) as a viscous oil. 1 H NMR (300 MHz, CDCl 3 6 0.86-0.92 3H), 1.40-1.21 (m,15H), 3.06-3.28 2H), 3.91-4.01 2H), 5.00 (br s, 2H), 5.29-5.56 (m, 1H), 6.10-6.19 1H), 6.89-6.97 2H), 7.08-7.12 1H), 7.15-7.19 2H), 7.22- 7.29 4H).

Step D: 2, 6 -Diisopropyl-3-hydroxvmethyl-4-(2-benzyloxyphenyl)-5-(prop-l enyl)pyridine Prepared from the intermediate from Step C by the method detailed in Example 160, Step D. 1 H NMR (300 MHz, CDCl3): 5 1.21-1.60 15H), 1.90-1.95 1H), 3.18-3.53 4.26-4.58 2H), 4.87-4.94 1H), 5.06 J 12.3 Hz, 1H), 5.27-5.57 1H), 5.95-6.05 1H), 7.00-7.06 5H), 7.22-7.37 4H).

Step E: 2 6 Diisopropvl-3-(1-hydroxvethyl)-4-(2-hdroxphenyl)-5propylpyridine The intermediate from Step D was converted into the title compound by the methods detailed in Example 164, Steps A-C. The diastereomers were separated by radial band chromatography using a gradient eluent of 100% hexane to 5% ethyl acetate-hexane.

Diastereomer 1 1 H NMR (300 MHz, CDC13): 8 0.66 J 7.50 Hz, 3H), 1.15-1.34 15H), 1.59 (br s, 1H), 1.96-2.06 1H), 2.15-2.25 1H), 3.15 (sept, J 6.60 Hz, 1H), 3.56 (sept, J 6.60 Hz, 1H), 4.70 (br s, 1H), 4.81-4.87 1H), 6.90-6.97 3H), 7.19-7.26 1H). FAB-MS: calcd for (C22H31NO2) 341, found 342 276 WO 98/04528 PCT/US97/13248 0 Diastereomer 1 (Dl) was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC column (BRB-9466AD; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 25% hexane and 75% of a mixture of (15% THF in heptane) at 150 mL/min. The sample was dissolved in mobile phase (10 mg/mL) and 5 mL aliquots were injected at 35 min intervals. The effluent was monitored at 280 nm.

Peaks overlapped and were thus shaved. Mixed fractions were then evaporated and reinjected. The collected enantiomers were assayed off line on an analytical column (BRB-9705A) at 1.5 mL/min with a mobile phase of 1% acetic acid in ethanol) and 99% hexane. The low Rt enantiomer from the preparative column was the high Rt enantiomer on the analytical column with Rt 8.80 min; 98.8% ee.

The high Rt enantiomer from the preparative column was the low Rt enantiomer on the analytical column with Rt 3.71 min; 81% ee.

0 Diastereomer 2 1 H NMR (300 MHz, CDC13): 5 0.72 J 7.50 Hz, 3H), 1.22-1.36 15H), 2.03-2.15 1H), 2.23-2.33 1H), 2.56 J 3.0 Hz, 1H), 3.21 (septet, J 6.60 Hz, 1H), 3.73 (septet, J 6.60 Hz, 1H), 4.56-4.63 (dq, J 3.0, 6.0 Hz, 1H), 5.66 (br s, 1H), 6.88-6.99 3H), 7.25-7.28 1H). FAB-MS: calcd for (C22H31N0 2 341, found 342 EXAMPLE 166

F

OH

HO

N

2,6-Diisopropyl-3-hydroxymethl-4-[(4-fluoro-2-hydrox Step A: 2 -Benzyloxy-4-fluorobromobenzene To a solution containing 2 -bromo-5-fluorophenol (50 g, 0.26 mol) in 500 mL acetone was added potassium carbonate (54.2 g, 0.39- mmol) and benzyl bromide (34.3 mL, 0.288 mol). The reaction was heated at reflux under an argon atmosphere for 2 h and then allowed to cool to 25°C. The acetone was removed under reduced pressure and the residue was taken up in ether (400 mL). The organic layer was 277 WO 98/04528 PCT/US97/13248 0 washed with water (5 x 100 mL) and brine (1 x 100 mL) and then dried (MgSO4).

The solution was then concentrated under reduced pressure and subjected to flash chromatography using hexane as the eluent. In this manner, 2-benzyloxy-4fluorobenzene was obtained as a white solid. H NMR (300 MHz, CDC13): 8 5.14 2H), 6.57-6.63 1H), 6.69 (dd, J 2.7,10.2 Hz, 1H), 7.32-7.52 6H).

Step B: 2 -Benzyloxy-4-fluorobenzaldehyde To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A (1 A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux.

After completion of addition the reaction was allowed to proceed until it cooled to C and was then heated at reflux for 1 h. The reaction was allowed to cool to C and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25 0 C and was then filtered through a plug of Celite. The THF was removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HC1 (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of 2 -benzyloxy-4-fluorobenzaldehyde. 1 H NMR (300 MHz, CDC13): 8 5.16 2H), 6.70-6.76 2H), 7.34-7.44 5H), 7.87-7.92 1H), 10.43 1H). FAB-MS: calcd for (C 14

H

1 1 0 2 F) 230; found 231 Step C: 2 6 -Diisopropyl-3-hydroxymethyl-4-[(2-benzyloxy-4-fluoro)phenyll- Prepeared from the intermediate obtained in Step B by the methods described in Example 160, Steps A-D. 1 H NMR (300 MHz, CDC1 3 8 0.73 J 7.4 Hz, 3H), 1.09-1.36 14H), 1.63-1.73 2H), 1.89 J 6.9 Hz, 1H), 3.25 (septet, J 6.6 Hz, 1H), 3.46 (d septet, J 2.7,6.6 Hz, 1H), 4.29-4.42 2H), 4.89-5.06 2H), 5.24-5.47 1H), 5.95-6.00 1H), 6.70-6.79 3H), 7.00-7.07 5H). FAB-MS: calcd for (C30H36N02F) 461, found 462.

Step D: 2 6 -Diisopropyl- 3 -(hydroxymethyl)-4-[(4-fluoro-2-hydroxv)phenyll-5pentvlpvridine The title compound was prepared as a racemate from the intermediate obtained in Step C by the method detailed in Example 161. 1H NMR (300 MHz, 278 WO 98/04528 WO 9804528PCTIUS97/13248 o CDCl3): 8 0.78 J 6.6 Hz, 3H), 1.09-1.35 (in, 18H), 1.65 J 5.0 Hz, 1H), 2.13- 2.23 (in, 1H), 2.28-2.38 (mn, 1H), 3.24 (sept, J 6.6 Hz, 1H), 3.39 (sept, J 6.6 Hz, 1H), 4.29 (dd, J 11.1, 5.0 Hz, 1H), 4.52 (dd, J 11.1, 5.1 Hz, 1H), 5.45 (bs, 6.71-6.78 (in, 2H), 6.95-7.00 (in, 1H). FAB-MS: calcd for (C23H32N02F) 373, found 374 (M Rf =0.15 (20% ether-hexanes). mp, 152 0

C.

EXAMPLE 167 2 6 -DiisopropVl-3-(l-hydroxyethyl).4-[(4.fluoro-2.hydrox)henyl.5.

pentylpyridine The6 title compound was prepared, as two separable diastereomers from 2,6diisopropyl3-hdroxymethy4-(2benyoxy4.nuoro)phenyJ..5(pet.1.

Fnyl)pyridine (Example 166, Step C) by the methos. detailed in Example 164, Steps A-C. The. diastereorners were separated by radial band chromatography using a gradient eluent of 100% hexane to 20% ether-hexane.

Diastereomner 1 1 H NMR (300 MHz, CDCl 3 6 0.80 J 6.6 Hz, 3H), 1.10-1.42 (in, 21H), 1.64 J 3.6 Hz, 1H), 2.03-2.13 (in, 1H), 2.21-2.31 (in, 1H1), 3.15- 3.26 (septet, 1H), 3.54-3.65 (septet, 1H), 4.89-4.98 (in, 1H), 4.99 (br s, 1H), 6.69-6.75 (in, 2H), 6.94-6.99 J 2.7,6.5,6.5 Hz, 1H). FAB-MS: calcd for (C24H34N02F) 387, found 388 (M Rf 0.41 (40% ether-hexanes). mp 124-126 0

C.

Diastereomer 1 (Dl) was -resolved into its constituent enantiomners as follows. A Waters Prep LC 2000 HPLC system was equipped with a chiral HPLC column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 2% acetic acid, 99% ethanol) and 98% hexane at a flow rate of 175 mL/min. The sample was dissolved in mobile phase (50 mg/mL) and 5 mL aliquots were injected at 30 min intervals. The effluent was monitored at 280 nin and two fractions (corresponding to the two enantioiners) were collected at (13-18min,100% ee) and (18.5-27 min, >99%ee), respectively.

279

I

WO 98/04528 PCT/US97/13248 0 Diastereomer 2 1 H NMR (300 MHz, CDC13): 8 0.78 J 6.5 Hz, 3H), 1.06-1.40 21H), 1.75 (d,J 3.6 Hz, 1H), 2.06-2.16 1H), 2.26-2.37 1H), 3.21 (septet, J 6.6 Hz, 1H), 3.74 (septet, J 6.6,1H), 4.59-4.67 m, 1H), 4.83 (br s, 1H), 6.68-6.75 2H), 6.86-6.91 J 3.0, 6.6, 6.6 Hz, 1H); FAB-MS: calcd for (C24H34NO 2 F) 387, found 388 (M Rf 0.24 (40% ether-hexanes). mp 157- 159 0

C.

EXAMPLE 168 OCH3

HO'

N

2,6-Diisopropl-3-hydroxvmethvl-4-(4methoxyphenl)-5-(pent-l-enl)pridine The title compound was prepared from 4 -methoxybenzaldehyde by the methods detailed in Example 125. 1 H NMR (300 MHz, CDC13): 8 0.76 and 0.81 J 7.2 Hz, 3H), 1.12-1.39 14H), 1.60-1.80 (bs, 1H) 186-1.97 2H), 3.33-3.50 (m, 2H), 3.85 3H), 4.43 2H), 5.27-5.48 1H), 5.93-6.05 1H), 6.92 J 8.4 Hz, 2H), 7.07 J 8.4 Hz, 2H). FAB-MS: calcd for (C24H33N0 2 367, found 368 EXAMPLE 169

OCH

3

I

v ~os? 11~5 ouon u

J

o u 2,6-Diisopropl-3-hydroxymethl-4-4-methoxyphenyl)-5-pentyl-pyridine 280 -Vt4a8se37 V V* 3 WO 98/04528 PTU9134 PCTIUS97/13248 0 The title compound was prepared as a white solid from 2,6-diisopropyl-3hydroxymethyl-4-(4-methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 168) by the methods detailed in Example 126. 1 H NMR (300 MHz, CDCI3): 8 0.80 J 6.6 Hz, 3H), 1.08-1.19 (in, 4H), 1.24-1.38 (in, 15H), 2.27-2.33 (in, 2H), 3.24 (sept, J 6.6 Hz, 1H), 3.42 (sept, J 6.6 Hz, 1H), 3.87 3H), 4.35 J 5.7 Hz, 2H), 6.97 J 8.7 Hz, 2H), 7.11 J 8.7 Hz, 2H). FAB-MS: calcd for (C24H35N02) 369, found 370 (M mp 47-49*C.

EXAMPLE 170 The title compound was prepared from '3-methoxybenzaldehyde by the methods detailed in Example 125. 1 H NMR (300 MHz, CDCl3): .8 0.78 J 7.5 Hz, 3H), 1,17-1.41 (in, 14H), 1.65 1H), 1.97 J 14.0, 7.2, 1.5 Hz, 2H), 3.39-3.55 (in, 2H), 3.81 3H), 4.45 2H), 5.35-5.50 (in, 1H), 6.01-6.09 (mn, 1H), 6.73-6.77 (in, 2H), 6.89 J 8.1, 2.1, 0.9 Hz, 1H), 7.30 J 8.0 Hz, 1H). FAB-MS: calcd for (C24H33N0 2 367, found 368 (M mp 71-75 0

C.

EXAMPLE 171 The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4- 281 WO 98/04528 WO 9804528PCTIUS97/13248 o 3 -methoxyphenyl)-5-(pent-1-enyl)pyridine (Example 170) by the methods detailed in Example 126. 1 H NM (300 MIHz, CDCI3): 8 0.79 J 6.6 Hz, 3H), 1.09-1.33 (in, 7H), 1.30 J 6.6 Hz, 6H), 1.33 J 6.6 Hz, 6H), 2.25-2.31 (in, 2H), 3.23 (sept, J 6.6 Hz, 1H), 3.42 (sept, J 6.6 Hz, 1H), 3.82 3H), 4.35 J 6.0 Hz, 2H), 6.73 (dd, J 2.4, 1.5 Hz, 1H), 6.76 (dt, J 7.5, 1.4 Hz), 6.93 J 8.4, 3.6, 1.2 Hz, 1H), 7.34 J =8.1 Hz, 1H). FAB-MS: calcd for (C24H35N0 2 369, found 370 (M mp 65-660.

EXAMPLE 172

OCH

3 2 6 Diisopropyl3hydroxymethl4..( The title compound was prepared from 2 -methoxybenzaldehyde by the methods detailed in Example 125. 1H NMR (300 MHz, CDCl3): 6 0.82 and 0.72 J =7 Hz, 3H), 1.05-1.47 (in, 15H), 1.80-2..00 (in, 1H), 2.05 (bs, 1H), 3.21-3.60 (mn, 2H), 3.75 and 3.76 3H), 4.27 J 11.4 Hz, 1H), 4.43 J 11.4 Hz, 1H), 5.25-5.44 (in, 1H), 6.01-6.07 (mn, 1H), 6.93-7.03 (in, 3H), 7.29-7.37 (mn, 1H).

EXAMPLE 173

OCH

3 2 6 Diisopropvl-3..hvdroxcvmethyliA (2methox The title compound was prepared from 2 ,6-diisopropyl-3-hydroxymethyl-4- (2mtoyhnl--pn--nlprdn (Example 172) by the methods detailed in Example 126. 1 H NMR (300 MI-Iz, CDC13): 0.77 J 6.6 Hz, 3H), 1.06-1.11 (in, 4H), 1.22-1.38 (in, 14H), 1.87 (dd, J 9.3,3.3 Hz, 1H), 2.14 -2.40 (in, 21H), 3.25 (sept, J 282 WO 98/04528 PCT/US97/13248 0 6.6 Hz, 1H), 3.46 (sept, J 6.6 Hz, 1H), 3.76 3H), 4.19 (dd, J 11.7, 3.0 Hz, 1H), 4.39 (dd, J 11.7,9.0 Hz), 7.00-7.08 (mn, 3H), 7.35-7.42 1H).

EXAMPLE 174

HO

2, 6 -Diisopropvl- 3 -hydroxymethyl-4-4-(methylthio)henl-5-(pent-1-enVl)pVridine The title compound was prepared as a thick colorless oil from 4- (methylthio)benzaldehyde by the methods detailed in Example 125. 1 H NMR (300 MHz, CDCl3): 8 0.66 and 0.72 J 7.5 Hz, 3H), 1.05-1.32 14H), 1.51-170 (bs, 1H), 1.80-1.89 2H), 2.43 3H), 3.12-3.41 2H), 4.32 (bs, 2H), 5.17-5.40 (m, 1H), 5.85-5.97 1H), 6.99 J 8.1 Hz), 7.18 J 8.1 Hz, 2H).

EXAMPLE 175

HO'

2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl-5-(pent-1enyl)pyridine 2 6 -Diisopropyl-3-hydroxymehyl[44-(methylthio)phenyl]-5-(pent-1enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at OOC under an argon atmosphere. To this mixture was added a solution containing 3 -chloroperoxybenzoic acid ("mCPBA") 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0'C and is quenched with the addition of a saturated aqueous solution of NaHSO3 I 7 S WO 98/04528 PCT/US97/13248 0 (3 mL). The reaction mixture was further diluted through the addition of water mL) and then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (52 mg, 50%) as a white solid, mp 133-135 0 C. 1 H NMR (300 MHz, CDC13): 8 0.77 and 0.69 J 7.5 Hz, 3H), 1.08-1.36 14H), 1.70-1.92 3H), 2.75 and 2.76 3H), 3.19-3.51 2H), 4.32-4.40 2H), 5.20-5.45 1H), 5.93-6.00 1H), 7.31-7.38 2H), 7.59-7.70 2H). Anal. calc. for C24H33N0 2

S:

C, 71.86; H, 8.29; N, 3.39; S, 7.73. Found: C, 72.14; H, 8.32; N, 3.51; S, 8.02.

EXAMPLE 176 SO2CH3 HO 2,6-Diisopropyl-3-hydroxymethl-4-4(methylsulfonlhenv-5-(ent-1enyl)pyridine 2,6-Diisopropyl-3-hydroxymethyl-4-[4-(methylsulfinyl)phenyl]-5-(pent-- Senyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0°C under an argon atmosphere. To this mixture :-was added a solution containing 3-chloroperoxybenzoic acid ("mCPBA") 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0 0 C and quenched with the addition of a saturated aqueous solution of NaHSO3 (3 mL). The reaction mixture was further diluted through the addition of water mL) and is then extracted with methylene chloride (3 x 10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (31.1 mg, 1H NMR (300 MHz, CDC13): 8 0.69 and 0.79 J 7.2 Hz, 3H), 1.08-1.37 14H), 1.45 J 4.2 Hz, 1H), 1.86-1.93 2H), r WO 98/04528 WO 9804528PCTIUS97113248 o 3.10 and 3.11 3H), 3.25-3.50 (in, 2H), 4.34-4.36 (in, 2H), 5.20-5.50 (in, 1H), 5.93- 6.00 (in, 1H), 7.41 J 8.4 Hz, 2H), 7.96.(d, J 8.4 Hz, 2H). Anal. caic. for C24H33N03S: C, 69.28; H, 7.91; N, 3.18; S, 7.50. Found: C, 69.36; H, 8.00; N, 3.37; S, 7.71.

EXCAMPLE 177 2 6 -Diisopropvl-3-hvydroxvinethvl-4.(4-fluoro-3.hydroxymethvl)phenyll-5.

Pentylpyridine Step A: 2,6-Diisopropyl-3..[(tbutyldimethVlsilox)methyl4(4.fluorophenyl).

Toa olutioni of 2 i-diisopropyV.3-hydroxyT~ethyl.4{4-fluoropheny),.s.

pentylpyridine (3.14 g, 8.78 minol)'(Examrple- 1, Step H) in methylene chloride mnL) were -added imidazole (0.9 g, 13.17 mmol, 1.5 e and, t-butyl-dimethylsilyl chloride (2.0 g, 13.17 inmol, 1.5 eq). A whitepeiiaebn t ofr imnmediately. The nu'xture was stirred for 14 h .at-*25 0 C and-was then-diluted with methylene chloride (100 rnL) and washed sequentially with. 10% hydrochloric acid jft_ (20 mL), saturated aqueous, sodium. bicarbonate (20 an.brine.(20 The -organic layer was conicentrated under reduced pressure and. the resultant. residue was .recrystallized from methanol'to provide the product (3.27 g& 79%) as. a white fluffy crystalline solid. 1 H NMvR(300 MHzCDCl3): 8 -0.19 0.79,(t, J =6.9 Hz, 3H4), 0.83 9H4), 1.07-1.20 (in, 4H), 1.29-1.32 (in, .14HM, 2.23-2.30, 12H), 3121 (sept, J =6.6 Hz, IM, 3.35 (sept, J 6.6 Hz, 1H), 4.24 2H), 7.05-7.18: (in, 4H).

-Anal. caic. for 629H461NOFSi: C, 73.83; H, 9.83; N, 2.97. Found: C, 73.82; H, 9.95; N, 2.86.

Step B: 2 6 -Diisopropl- 3 -(t-butldimethylsioxv)iethl14[(4-fluor-3- To a solution of the intermediate from Step A (5.4 g, 11.4 inmol) in THF 285 WO 98/04528 PCT/US97/13248 0 mL) was added sec-butyllithium (1.3 M, 26.4 mL, 3 eq) at -78 0 C under an argon atmosphere. The yellow solution was stirred for 1 h at -78 0 C and quenched through the addition of of water (50 mL). The mixture was allowed to warm to 0 C and extracted with ethyl acetate (3 x 50 mL) and the organic layer was washed with water (50 mL) and brine (50 mL), dried (Na2SO 4 and concentrated under reduced pressure to afford the crude intermediate. (6.41 g).

This intermediate (3.2 g) was dissolved in THF (50 mL) and stirred at 0°C as lithium aluminum hydride (1M in THF, 25.7 mL, 25.7 mmol) was added to it. The resultant mixture was stirred at 0°C for 1.5 h and quenched through the sequential addition of water (1 mL), 1N aqueous sodium hydroxide (1 mL), and water (3 mL). The resultant mixture was filtered and the precipitate rinsed with ether (100 mL). The combined organic layer was washed with water (25 mL) and brine (25 mL), dried (Na2SO 4 and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography using a 10% ether-hexane mixture as the eluent. In this manner, 1.1 g of the product was obtained. 1H NMR (300 MHz, CDC1 3 8 -0.09 6H), 0.83 9H), 1.07-1.20 4H), 1.29-1.33 17H), 1.96-2.02 1H), 2.22-2.31 2H), 3.23 (sept, J 6.6 Hz, 1H), 3.36 (sept, J 6.6 Hz, 1H), 4.22-4.32 2H), 4.70-4.90 2H), 7.09-7.12 2H), 7.23-7.28 1H), tep C: 26-Diisopropl-3-hdroxvmethyl-4(4-fluoro-3-hydroxy To a.solution of the intermediate from Step B (123 mg, 0.245 mmol) in THF mL) was added tetrabutylammonim fluoride (1M in THF, 0.7 mL, 0.7 mmol) at under an argon atmosphere. The mixture was stirred for 14 h at 25°C and is Sthen diluted with water mL) and extracted with methylene chloride (3 x 5 mL).

The combined organic layer was washed with brine (5 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by flash -chromatography using a 40% ethyl acetate-hexane mixture as the eluent. In this manner, the'title compound (79 mg, 83%) was produced as a colorless oil. 1 H NMR (300 MHz, CDC13): 8 0.78 J 6.6 Hz, 3H), 1.10-1.17 4H), 1.24-1.35 14H), 2 .10- 2 .40 2H), 2.73 (bs, 1H), 3.22 (sept J 6.6 Hz, 1H), 3.34 (sept, J =6.6 Hz, 1H), 385 (bs, 1H), 4.06 J 11.4 Hz, 1H), 4.35 J 11.4 Hz, 1H), 4.48 J 14.1 Hz, 1H), 4.73 J 14.1 Hz, 1H), 7.00-7.06 2H), 7.25 J 7.2 Hz, 1H).

286 WO 98/04528 WO 98/452.8PCTIUS97/13248 0 EXAMPLE 178 2,6-Diisopropyl-3-hydroxymethvl-4-[( 4 pentvlpyridine Step A: 2,-ispoy--(-uVdmtyslx~eh~--(-loo3 To a solution of 2 6 -diisopropyl-3-(t-butyldimethylsiloxy)methyij-4-(4fluoro-3-hydroxymethyl)phenylJ-5-pentylpyridine (Example 177, Step B) (1.09 g, 2.18 mmol) in methylene chloride (100 mL) was added a mixture of PCC (0.94 g, 4.35 mmol, 2 eq) and Celite (0.94 The resultant mixture was stirred for 2 h at C and then filtered through a pad of silica gel. The silica gel pad was rinsed with a 10% ethyl acetate-hexane mixture (200 mL) and the combined organic layer was concentrated to afford -the crude product (0.78 g) as a white waxy solid..

Step B: .26Diorpl3[tbt~iehlioVmtyl4(-loo3 To a -solution of the intermediate from Step A (82 mg, 0.164 mmol) in methanol.(3P mL) were added potassium cyanide (53 mg, 0.82 mmol) and activated manganese dioxide (71 mg, 5 eq). -The mixture was stirred at 25 0 C for 14 -h and is.

then filtered through a pad of Celite. .The Celite pad was rinsed' With ethyl acetate mL) and 'the combined organic layer was washed "With -brine mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to provide the intermediate (70. mg). 1 H NMR (300 MHz, CDCl3): 8 -0.13 6H), 0.75 J 6.6 Hz, 3H), 1.06-1.40 (in, 27H-), 2.20- 2.35 (in, 2H), 3.20 (sept, J 6.6 Hz, 1H), 3.32 (sept, J -6.6 Hz, 1H), 4.15 J 10.8 Hz, 1H), 4.25 J 10.8 Hz, 1H), 7.15-7.25 (mn, 7.40-7.50 (in, 1H4), 7.69 (dd, J 6.6, 2.4 Hz, 1H), 10.41 1H). FAB-MS: calcd for (C30H46NO2FSi) 499, found 500 287 _t 7

J

WO 98/04528 WO 9804528PCTIUS97/13248 0 Step C: 2 6 -Diisoropyl-3-hydroxymethyl-4-[(4-fluoro.3-methoxv- The title compound was prepared from the intermediate obtained in Step B by the method detailed in Example 177, Step C. 1 H NMR (300 MI-z, CDCl3): 8 0.78 J 6.6 Hz, 3H), 1.08-1.16 (in, 4H), 1.23-1.34 (in, 15H), 2.20-2.30 (mn, 2H), 3.22 (sept, J 6.6 Hz, 1H), 3.40 (sept, J 6.6 Hz, 1H), 3.93 3H), 4.25-4.39 (in, 2H), 7.12 (dd, J= 10.3, 8.5 Hz, 1H), 7.28 J= 8.5, 4.8, 2.2 Hz, 1H), 7.69 (dd, J= 6.6, 2.2 Hz, 1H).

EXAMPLE 179 Step A: 2 6 -Diisopropvl-3-[(t-butyldimethylsiloxy)inethVI144&(4-.fluioro-3 To a solution of 2 6 -diiLsopropyl-3-[(t-butyldimefiylsiloxy)inethyl]p4[(4- (Example 178, Step A) (200 mg, 0.40 mmol) in TI-F (10 mL) was; added a butyltriphenyiphosphoniuin bromide/sodium amide mixture (Fluka, 0.55 g, 3 eq) under an argon atmosphere. The reaction was stirred at 250C for 1'.5 h and is, quenched by dropwise addition of water (3 mL) and further diluted with brine (5 mL). The mixture was extracted with ethyl acetate (2 x mL) and the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was subjected to flash chromatography to yield the intermediate (205 mng). 1 H NIVI (30.0 MlHz, CDCl3): 8 -0.13 6H), 0.75-1.47 (in, 35H), 2.13-2.33 (in, 4H), 3.21 (septet, J 6.6 Hiz, 1H), 3.34 (septet, J 6.6 Hz, 1H), 2.7 J 2.7 Hz, 2H), 5.75-6.31 (in, 1H), 6.41-6.59 (in, 1HM, 6.98-7.09 (mn, 3H). FAB-MS: calcd for (C341-I54NOFSi) 539, found 540 (M 1).

288 WO 98/04528 WO 9804528PCTIUS97/13248 o Step B: 2,6-Diisop~ropyl-3-[(t-butvldimethylsiloxv)methyl-.4-(4-fluoro-3- The intermediate from Step A (200 mg) was dissolved in ethanol (10 mL) and the mixture purged with argon. A quantity of 10% Pd-C (20 mg) was then added and the mixture was purged with hydrogen and stirred under a hydrogen atmosphere at 250C for 16 h. The mixture was then filtered through a pad of silica and the silica pad is& rinsed with ethanol (25 mL). The organic layer was concentrated under reduced pressure and the resultant residue was subjected to flash chromatography using hexane as the eluent to afford the intermediate (150 mg, 1 H NMR (300 MHz, CDCl3): 8 -0.11 6H), 0.76-1.65 (in, 39H), 2.17-2.33 (in, 2H), 2.51-2.78 (mn, 2H), 3.21 (septet, J 6.6 Hz, 1H), 3.35 (septet, J 6.6 Hz, 1H), 4.42 (dd, J 10.2, 16.2, 2H), 6.92-7.05 (in, 3H). FAB-MS: calcd for (C34H56NOFSi) 541, found 542 Step C: 2 6 -Diisopropl-3-hvdroxymethyl-4-[(4-fluoro.3-pent1)phenyl..5.

pentylpyridine The title compound was prepared as a colorless oil from the intermediate from Step B by the method detailed iri rx-ample 177, Step C. 1H NMR (300 MIHz, CDC13): 8 0.77 J 6.9 Hz, 3H), 0.88 J 6.9 H4z, 3H), 1.08-1.34 (in, 24H), 1.57- 1.65. (in, 1H), 2.22-2.29 (mn, 2H), 2.57-2.75 (in, 2H), 3.21 (septJ 6.6 Hz, 1H), 3.40 (sept, J =6.6 Hz, 1H), 4.33 (dd, J 1.4 Hz, 2H), 6.93-77.09 (mn, 3H). FAB-MS: calcd for (C28H42N0F) 427, found 428 (M Rf-= 0.42 (20% ether-hexanes).

EXAMPLE 180 2 ,-Diisopropvl-3-hvdroxvmethyl-4f(4-fluoro.3-ethvl)phenvl1.5-pentvlpyjidne The title compound-was prepared as a white wax from 2,6-diisopropyl-3+[tbutyldimethyLsiloxy)inethyl1-4[(4-fluoroforyl)phenyl] (Example 178, Step A) (200 mg, 0.40 mmol) and 'an ethyltrihenylphosphoniuin 289 WO 98/04528 PCT/U5S97/13248 0 bromide/sodim amide mixture (Fluka) by the methods detailed in Example 179, Steps A-C. 1 H NMR (300 MU-z, CDCl3): 8 0.77 J 6.9 Hz, 3H), 1.10-1.33 (in, 22H), 2.17-2.33 (in, 2H), 2.60-2.80 (in, 2H), 3.21 (sept, J 6.6 Hz, 1H), 3.40 (sept, J 6.6 Hz, 1H), 4.34 (dd, J 5.7, 1.8 Hz, 2H), 6.94-7.09 (mn, 3H). FAB-MS: calcd for (C25H36N0F) 385, found 386 Rf 0.38 (20% ether-hexanes).

EXAMPLE 181 2 6 Diisopoy--roxVmthvdro4x[ethy14[4fluohro3( 4 flobe pentylpyridine Oct- Step A :2 Di s p o y "3 u v d m t v sl l x m h -4 fl o hydroxv.;4-fluorobenzv1)phenvll1.5entvlpvvridin To' a'solution of 2 6 -diisopropyl..3-(t-.butyldiinethylsiloxy)methyl]A4[( 4 (160 mg, 0.321 mmol) (Example 178, Step A) in THF (10 mL) was added 4 -fluorophenyl magnesium bromide (1.0 M in THF, 0.4 mL, 2.5 eq) under an argon atmosphere at 25 0 C. The mixture was stirred for mmn and then quenched by the dropwise addition of water (5 inL). The mixture was extracted with ether (2 x 10'mL) and the combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography using a 10% ether-hexane mixture as the eluent to provide 150 mg of the intermediate. 1 H NMR (300 MHz, CDCl3): 8 -0.19 6.3 Hz, 3H), -0.10 J= 7.2 Hz, 3H), 0.71-1.30 (in, 30 H4), 2.17- 2.28 (in, 3H), 3.18 (septet, J 6.6 Hz, 1H), 3.25-3.40 (in, 1H), 4.04-4.38 (in, 2H), 6.14 (dd, J= 4.4, 17.9 Hz, 1H), 6.97-7.38 (mn, 7H). FAB-MS: calcd for (C36H51NOF2Si) 595, found 596 (M 1).

S tep B i s p o y y r x m t y -4 f u r a h d o y 4 fluo 290 WO 98/04528 WO 9804528PCTIUS97113248 0 The title compound was prepared from the intermediate from Step A by the method detailed in Example 177, Step C. 1 H NMR (300 Mliz, CDCI3): 8 0.72-1.45 (in, 22H), 2.13-2.36 (in, 2H), 2.65 J 4.2 Hz, 1H), 3.21 (sept, J 6.6 H-z, 1H), 3.39 (sept, J 6.6 Hz, 1H), 4.21-4.39 (in, 2H), 6.1 4-6.17 (in, 1H), 6.98-7.12 (mn, 4H), 7.35- 7.42 (in, 3H). FAB-MS: calcd for (C30H37N02F2) 481, found 482 (M Rf 0.21, 0.51 (50% ether-hexanes). mp 118-120 0

C.

EXAMPLE 182 F OH p4entvlpyridine The title compound was prepared as an. oil from 2,6-dijsopropyl-3-[tbutyldimethylsiloxy)nethl]4-(4-fluoro-3-.formyl)phienyl].s.pe ,lpyridine IS (Exanffi''e 178, Step A) and methylinagnesium bromide by the methods detailed in Example 181, Steps A-B. 1 H NMR (300 MHz, CDC13): 8.0.76 J 6.0 Hz, 3H), 1-0941.53'(mn, -21H4),1.84 (br s, 1H,21-.2,i,2H), 2.87 brs. 1 3.20 (sptt J 6.6 Hz, 1H), 3.37 (septet, J 6.6 Hz, 1H), 4.16 J= 11.4 Hz, 1H), 4.28-4.35 (in, 1H), 5.16-5.19 (in, 1H), 7.01-7.07 (in, 2H4), 7.25-7.34 (in, 1H). FAB-MS: calcd for (C25H36NO2F) 401, found 402 (M Rf 0'32 and 0.20 (50% ether-hexanes).

EXAILE 183

F

H

HO

291 WO 98/04528 WO 9804528PCT/US97113248 0 2 6 -Diisopropyl-3-hydroxymethvl-4-[4-fluoro.3((N.((pvridin-2yl-)- Step A: 2

I

6 -Diisopropyl-3-[(tbutvldimethylsiloxy)methvl..4-.fluoro3((N- To a solution of 2 6 -diisopropyl-3-[(t-butyidimethylsiloxy)methylp4-[(4fluoro- 3 -formyl)phenyl]-5-pentylpyridine (500 mg, 1 mmol) (Example 178, Step A) in methanol (10 mL) and ether (2 mL) was added 2 -methylaminopyridine (0.42 mL, 4 inmol, 4 eq) under an argon atmosphere at 25*C. To this solution were added ZnCI2 (68.1 mg, 0.5 eq) and sodium cyanoborohydride (62.8 mg, 1 eq) in methanol (6 mL). The reaction was allowed to stir for 20 h and was then quenched with the addition of aqueous sodium hydroxide (0.1N, 7 mL). The methanol was removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (10 mL) and brine (10 mb) 1 dried (Na2SO4), and concentrated under reduced pressure. The resultant. residue was subjected to flash chromatography using a 60% ether-hexane mixture as the eluent to provide the intermediate (260 mng, 1 H NMR (300 MHz,, CDC13): 8 0.12 6H), d;72-0.81 (mn, 12H), 1.80 (br s, 1H7) 1.07-1.15 (mn, 414), .1.274.31 (in, 14H), 2.23-2.29 (in, 2H), 3.20 (septet, J 6.6Hz, 1H), 3.34 (septet, J 6.6 Hz, 1H), 3.83-4.03 4H),4.25 (dd, J =10.5,'27.6 Hz, 2H), v.064.-33 (in, 7.64(5, J 7.5 Hz, 1H)f. 8.54-8.56 (in, 114). FAB-MS: calcd for (C36H'54N3OFSi) 591, found 592 (M 1).

Step B: 2 6 -Diisooropl-3-hvdroxVmethyl14.[4-fluoro-3.((N((pyridin-2 The title compound was 'prepared as a colorless oil from the intermediate ,;obtained in Step A by the method'detailed in Example 177, Step C. 1H NWR (300 NMilz, iCDC3. 506.75 J 6.9 Hz, 3H), 1.07-1.36 (mn, 18H), 1.75 (bs, 2H), 2.19-2.36 2H), 3.20 (sept, J 6.6 Hiz, 1H), 3.47 (sept, J 6.6 Hz, 1H), 3.74 J 14.1 Hz, 1H), 3.79 J 13.5 Hz, 1H), 3.89 J 13.5 Hz, 1H), 4.07 J 14.1 Hz, 1H), 4.20 J 11.4 Hz, 1H), 4.41 J 11.4 Hz, 1H), 7.02-7.25 (in, 4H), 7.38 J 7.8 Hz, 1H), 7.66 J 7.5, 7.5, 1.8 Hz, 1H), 8.47 (in, 1H). FAB-MS: calcd for (C30H40N30F) 477, found 478 (M Rf 0.4 (ethyl acetate).

292 WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 184

HO

pentVlpyridine The title compound was prepared from 2,6-diisopropyl-3-[(t-butyldiehlioymty]4[4fur--omlpeyl5pnyprdn (Example 178, Step A) by the methods detailed in Example 183, Steps A-B. 1 H NMR (300 M~ffz, CDCl3): 8 0.77 J= 6.6 Hz, 3H), 1.054131 18 1.75-1.85 (in, 5 2.23- '2.29 (Mn, 2H'1), 2.56-3.50 4H), 3.10 (sept, J= 6.6 Hz, 1H), 3.41 (sept, J 6.6 Hz, 1H), 3.7lV'(d, J 12.9'Hz, 1H), 3.82 J= 12.9 Hz, 1H), 4.29 (dd, J 20.4 Hz, 2H), 7.03-7.13 (in, 2H), .7.26-7.30 111). FAB-MS: calcd for (C28H41N20F) 440, found 441 (M Rf =0.2 (ethyl acetate).

EXAMP'LE 185

N

H

HO'

pentylpyridine The title compound was prepared from 2,6-diisopropyl--[t-butyldhehlioymty]4[4fur-3frnlpeyl5pnyprdn (Example 178, Step A) by the methods detailed in Example, 183, Steps 1 H NMR (300 MHz, CDCI3): 8 0.79 J 6.8 Hz,* 3 H4), 0.91 J= 7.4 Hz, 3 1.10-1.61 (mn, 24 H), 293 WO 98/04528 PCTIUS97/13248 0 2.25-2.31 (in, 2 2.62 J 7.2 Hz, 2 3.23 (sept, J 6.6 Hz, 1 3.42 (sept, J 6.6 Hz, 1H), 3.89 2H), 4.32 (dd, 11.7 Hz, 2H), 7.04-7.20 (in, 3 FAB-MS: calcd for (C28H43N 2 0F) 442, found 443 (M Rf 0.33 (ethyl acetate).

EXAMPLE 186 The title compound was prepared as, an oil from ethyl isobutyryl acetate, ammonium acetate and pyridinie-3-carboxaldehyde in 0.56% yield by the miethods, described in Example 125. FAB-MS: calculated for Q22H 3 2

N

2 O 340; fountd 341 1 H &M (300 ML-z, CD 3 OD): 8 0.77 J 6.5 Hz, 3H), 1.08-1.32 (mn, 18H), 2.27-233 (in, 2H), 128 (septet, J 6.6 Hz, 1H), 3.48 (septet, J 6.6 Hz, 1H), 4.25 2H), 7.52-7.57 (in, 1H), 7.73-7.76 (in, 1H), 8.42-8.43 (mn, 2H), 8.59 (dd, J 5.1, 1.5 Hz, 1H). Anal. caic for C22H32N20: C, 77.60; H, 9.47; N, 8.23. Found: C, 75.96; H, 9.32; N, 7.88. Rf =0.40 (diethyl ether).

EXAMPLE 187 200 Substituting 2 i 3 -dichloro-5,&-dicyano.1,4..benzoquinmone (DDQ) for ceric ammonium nitrate (CAN) to oxidize the dihydropyridine intermediate to the phenyl pyridine, the title- compound was prepared as a mixture of E and Z isomers E:Z) from -ethyl isobutyryl acetate, ammioniumn acetate and furan-3carboxaldehyde, in 10% yield by the methods described in Example 125. FAB-MS: 294 V WO 98/04528 WO 9804528PCT1US97/13248 o calculated for C 21

H

29 N0 2 327; found 328 1 H NMR (300 MHz, CD 3 OD): 0.84 J =7.4 Hz, 3H), 1.17-1.38 (in, 14H),'2.01-2.04 (in, 2H), 3.39 (septet, J 6.6 Hz, 1H), 3.47 (septet, J 6.6 Hz, 1H), 4.44 2H), 5.40-5.58 (in, 2H), 6.11-6.25 (in, 1H), 6.38-6.40 (in, 1H), 7.41-7.54 (in, 2H).

EXAMPLE 188 2 6 -Diisopropyl-3-hydroxymethyl-4(3furW1)-5.pentWlpyridine The title compound was prepared from 2 6 -diisopropyl-3-hydroxymethyl-4- 3 -furyl)-5-(pent-1-enyl)pyridine (Example 187) in yield by the methods described in Example 125.- FAB-MS: calculat&1 for -C 21

H

31

NO

2 329; found 330 1 H NMR (300 MHz, CD 3 OD): 8 0.83 J= 6.8 Hz, 3H), 1.19-1.36 (in, 19H), 2.42-2.48 (in, 2Ht), 3.25 (sepfet,-j 6.6 Hz, 1H), 3.45 (septet, J =6.6 Hz, 1H), 4.38 (s, 2H), 6.42 (in, 1H), 7.45-7.46 (in, 1H), 7.61-7.62jt, 1j.7 Hz, 1H). Anal. caic for C21H3iN0 2 C/76"55; 9.48; N, 4.25. Found: C, 76.41; H, 9.76; N, 4.24. Rf =0.59 EtOA'C/hex). mp 98400tC.

EXAMPLE 189 2 0

~S

The title compound *was prepared as a mixture of E and Z isomers (5.5:1, from ethyl isobutyrylacetate, ammonium acetate and thiophene-3carboxaldehyde in 7% oyield by the methods described in Example 125. FAB-MS: 295 WO 98/04528 PCT1US97113248 0 calculated for C 21

H

29 N0S 343; found 344 1 H NMR (300 MlHz, CDCI 3 8 0.78-0.84 (in, 3H), 1.22-1.37 (in, 15H), 1.96-2.00 (in, 2H), 3.37-3.50 (mn, 2H), 4.47 J= 5.7 Hz, 2H), 5.32-5.43 (mn, 1H1), 6.02-6.12 (mn, 1H1), 6.95-6.97 (in, 1H1), 7.12-7.13 (mn, 1H), 7.35-7.38 (in, 1H). Anal. caic for C21H29N0S: C, 73.43; H, 8.52; N, 4.08; S, 9.32.

Found: C, 73.38; H, 8.75; N, 3.97; S, 9.03. Rf 0.65 (20% EtOAc/hex). mp 85-87 -C.

EXAMPLE 190 Ste2 A: 1( 2 -Methoxvethoxv)iethox.ethl24diisopropyl5 hydroxvmethVlbenzene A mixture of 1,-~~yixmt3l-24diorplezn (0.947 g, 4.26 minol) (prepared by '.the method of' Fey, et al U.S. Patent 5,138,090), methoxyethoxymethyl chloride (0.49 mL, 4.29 mmol), and diis opropylethylamine (1.1 mL, 6.31 mmol) in CH2Cl2 (9.6 mL) was stirred overnight. The mixture was diluted with water (50 mL) and extiracted with CH2Cl2 (3 x 50 mL). Silica gel chromatography (67:33 hexanes/ethyl acetate) provided a colorless oil (0.679 g, H NUR (CDC13, 300 MfiIz): 8 7.31 7.29 1H), 4.83 211), 4.72 (s' 2H), 4.66 211), 3.76 (in, 211), 3.60 (mn, 2H1), 3.43 3H), 3.26 (in, 2H), 1.27 Hz, 1211). EL-MS: calculated for C18H300 4 310; found 292 (M-H20, 221 (100%).

Step B: 3 2 -Mhethoxvmetioxymeth,-,-itVdisp o lbzldhyd Prepared from the intermediate obtained in Step A by the procedure described 'in Example 1, Step E. 1H NAMI (CDC13, 300 MHz): 8 10.29 111), 7.80 (s, 111), 7.39 111), 4.83 211), 4.70 211), 3.98 (sept, 6.8 Hz, 111), 3.76 (in, 211), 3.59 (in, 2H), 3.42 3H), 3.26 (sept, 6.8 Hz, 111), 1.30 7.0 Hz, 6H), 1.28 7.0 Hz, 6H).

FAB-MS: calculated for C18H2 80 4 308; found 309 (Mi-H).

WO 98/04528 WO 9804528PCT1US97/13248 0 Step C: N-PhenVl 3-(2-methoxyethoxv)methoxvmethyl-4,6-diisopropylbenzimine A mixtureof the intermediate from Step B (2.35 g, 7.62 mmol), aniline (700 mL, 7.68 mmol), p-toluenesulfonic acid (58.8 mg, 309 mmol), and molecular sieves (20.7 g) in toluene was' refluxed overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (65 mL) and washed with saturated aqueous NaHCO3 solution (50 mL) and water (50 mL), dried (MgSO4), and concentrated to give an orange oil (2.78 g, The product was used in the next step without purification. 1 H NMR (C6D6, 300 MHz): 8 8.70 1H), 8.48 1HM, 7.31 1H), 7.17 (in, 4H), 7.00 (mn, 1H), 4.61 2H), 4.60 (s,MQ), 3.56 (in, 2H), 3.46 (sept, 6.8 Hz, 1H), 3.29 (in, 2H), 3.20 (sept, 6.8 Hz, 1H), 3.07 (s, 3H), 1.17 7.0 Hz, 6H), 1.12 7.0 Hz, 6H).

Step D: Bis[(2-N-phenylmethlimino)-3,5- diisopropl..6(2.

methoxyethoxcy)methoxymethylphenVlldipalladiumn A mixture of the intermediate from Step C (2.78 g, 727 mmol) and Pd(OAc)2 (1.63 g, 7.26 mmol) in acetic acid (34 mL) was reflu) ed fbrl 1 h. *The mixture was cooled, to rt, poured into-.Water (135 mL), and filtered through a medium porosity fitted funnel. The filtrate was lyophilized. The residlue w -as dissolved in ethyl acetate (100 mL) and washed with saturated aqueous NaHCO3 (50 inL) and saturated aqueous NaCl-(50 rnL), dried;(MgSO4), and.,concgntrated to give a brown solid. The solid was mixed with 50:50 petroleum _ether/ethyl acetate (17 mL) and cooled in the freezer. The resulting precipitate was collected and dried to give a brown solid (0.951.g, 1 H NMR (C6D6, 300 Mffz): -t-7.70 1H),-7.65 1H), 7.63 1H), 7.11 1H), 7.08 1H), 6.99 (in, 1H), 6.73 1H), 5.33 2H), 5.08 (s, (in, 2H), 3.35 (in, 2H), 3.04 3H), 2.68 (sept, 6.8 Hz, 1H),'2.15- (sept, 6.8 Hz, 1H), 1.01 7.0 Hz,: 6H), 0.96 7.0 Ili, 6H). FAB-MS: calculated for C48HM4N2O6Pd2 976; found 488 Step E: 3,-ispo~l2fml6(-etovtix.r ehxmtOC fluoro-1,1'-biphenyl A mixture of 1j2-dibromoethane (80 mL) and magnesium turnings (0.349 g, 14.4 inmol) in diethyl ether (1 mL) was heated to reflux for several "'minutes. The mixture was diluted with diethyl ether and a solution of 1-bromo-4-7fluorobenzene (950 mL, 8.65 minol) and 1,2-dibromoethane (160 mL) in dieithyl ether'(3 mL) was added over several minutes. The reflux was -continued for 1 h then the mixture was cooled to room temperature.' The supernatant liquid was added via cannula to a -297 WO 98/04528 PCT/US97/13248 0 solution of the intermediate obtained in Step D (0.951 g, 973 mmol) and triphenylphosphine (2.02 g, 7.71 mmol) in benzene (19 mL) and the mixture stirred overnight. Aqueous 6N HCI (6 mL) was added and the mixture stirred for 2 h. The mixture was filtered and the solids washed with diethyl ether (75 mL). The combined filtrates were washed with saturated aqueous sodium chloride solution (50 mL). Silica gel chromatography provided a colorless solid (0.413 g, 1

H

NMR (CDC13, 300 MHz): 8 9.70 1H), 7.50 1H), 7.26 2H), 7.11 2H), 4.59 2H), 4.30 2H), 3.89 (sept, 6.8 Hz, 2H), 3.55 2H), 3.44 2H), 3.37 3H), 1.33 6.6 Hz, 6H), 0.96 7.0 Hz, 6H). FAB-MS: calculated for C24H3 1

FO

4 402; found 403 Step F: 35-Diispropl-2-(2-meth )methoxymethyl-6-(pent-l-enl)- 4 '-fluoro-1,1'-biphenyl Prepared from the intermediate obtained in Step E by the procedure

C

described in Example 1, Step F. The olefin was a mixture of cis and trans isomers in a ratio of 9:91. 1H NMR (CDC13, 300 MHz): 8 7.32 1H), 7.12 2H), 7.01 (m, 2H), 5.95 16.2 Hz, 1H), 5.23 (dt, 16.2 Hz, 7.0 Hz; 1H), 4.57 2H), 4.29 2H), 3.53 2H), 3.43 3.37 3H), 3.31 2H), 1.89 2H), 1.32 6.6 Hz, 6H), 1.23 7.0 Hz, 6H), 1.2 2 0.74 7.4 Hz, 3H). FAB-MS: calculated for C28H39FO 3 442; found 442.(M+).

Ste G. 3,5-Diisopropyl-22-2methoxyethoxy)riethoxvmethyl-6-peyl-4'fluoro-1,1'-biphenyl Prepared from the intermediate obtained in Step F by the procedure described in Example 1, Step H. 1 H NMRh(CDCl 3 300 MHz): 8 7.29 1H), 7.19 2H), 7.07 2H), 4.52 2H), 4.21 2H), 3.51 2H), 3.41 2H), 3.37 (s, 3H),.3.27 (sept, 6.8 Hz, 1H), 3.16 (sept, 6.8 Hz, 1H), 2.27 2H), 1.30 7.0 Hz, 6H), 1.27 2H), 1.23 7.0 Hz, 6H), 1.10 4H), 0.77 6.8 Hz, 3H). FAB-MS: calculated for C28H4 1 F0 3 444; found 445 Step: 35iisopropl-2acetoxymethyl-6-pent-4fluoro-'-bipheiyl Chiorotrimethylsilane (110 mL, 867 mmol) was added to a cooled (0°C) mixture of the intermediate from Step G (62.4 mg, 140 mmol) and Nal (132 mg, 880 mmol) in CH3CN (1.4 mL). After 25 min. the mixture was filtered through silica gel (5:1 hexanes/ethyl acetate) and the filtrate concentrated. A mixture of the residue and sodium acetate (122 mg, 1.49 mmol) in dimethyl formamide (2.3 mL) was heated to 80 0 C overnight. The solvent was removed and the residue dissolved in water (15 mL) and extracted with CH2C12 (3 x 15 mL). Silica gel 298 WO 98/04528 WO 9804528PCT1US97/13248 o chromatography (95:5 hexane/ethyl acetate) provided a colorless oil (38.2 mg, 1 H NMR (CDCl3, 300 MHz): 8 7.31 1H), 7.15 (in, 2H), 7.07 (in, 4.76 (s, 2H1), 3.18 (sept, 6.8 Hz, 1H1), 3.12 (sept, 6.8 Hz), 2.28 (in, 2H), 1.97 3H), 1.29 6.6 Hz, 6H), 1.29 (mn, 2H1), 1.29 6.6 Hz, 6H), 1.14 1.07 (in, 4H1), 0.78 6.8 Hz, 3H).

FAB-MS: calculated for C26H35F02 398; found 338 (M-AcOH).

Step I: 3 ,S-Diisopropyl-2-hydroxymethyl-6-pentv1-4'..fluoro11'-biphenvl A solution of the intermediate obtained in Step H (11.2 mg, 28.1 minol) and potassium hydroxide (109 mg, 1.65.mmo1) in methanol (2 mL) was heated at 50 0

C

for 3 h. The solvent was removed, and the residue dissolved in saturated aqueous ammonium chloride (15 mL) and extracted with diethyl ether (3 x 15 inL. Silica gel chromatography (5:1 hexane/ethyl acetate) provided the title compound as a colorless crystalline solid (12.0 mg, 120%). 1H1 NMR (CDCI3, 300 MHz): 8 7.30 (s, 1H1), 7.19 (mn, 211), 7.11 (in, 2H), 4.32 2H), 3.37 (sept, 6.9 Hz, 1H1), 3.16 (sept, 6.9 Hz, 1H1), 2.26 (mn, 2H), 1.31 6.6 Hz, 6H), 1.29 (in, 2H), 1.28 7.0 Hz, 6H), 1.17 1.03 (mn, 4H), 0.77 6.8 Hz, 3H). FAB-MS: calculated for C24H33F0 356; found 356 Rf 0.33 (83:17 hexanes/ethyl acetate). Anal. calculated for C24H33F0: C, 80.85; H, 9.33 Found: C, 80.63; H, 9.40. mp 98-99'C.

EXAMPLE 191 Step A: 3 ,-Diisopropvl- 2 -formyl..&pe ntvl-4'fluoro.1,1'..biphenvl Prepared from 3 ,5i 5 soproprl-2-hydroxymtl-6pentyl.4'.fluoro-1,1 biphenyl (Example 190) by the procedure described in Example 1, Step 1H NivR (CDCl3, 300 MHz): 8 9.70 1H1), 7.42 7.23-7.10 (in, 4H), 3.88 (sept, 6.8 Hz, 1H), 3.23 (sept, 6.8 Hz, 1H), 2.34 (mn, 211), 1.31 6.6 Hz, 611), 1.29 -7.0 Hz, 611), 1.28 (in, 211), 1.14 (mn, 4H), 0.79 6.6 Hz, 3H). FAB-MS: calculated for C24H31F0 354; found 355 (Mdl).

299 SV WO 98/04528 PCTIUS97/13248 0 Step B: 3 ,5-Diisopropl2(1.hdroxethVl).6penlAfluo1'-bip~henvl The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 101, Step B. 1 H NMR (CDCl3, 300 MI-z): 7.32 1H), 7.19-7.06 (in, 4H), 4.70 (dq, 7.0 Hz, 2.9 H-z, 1H), 3.88 (sept, 6.8 Hz, 1H), 3.13 (sept, 6.8 Hz, 1H), 2.20 (in, 2H), 1.63 2.9 Hz, 1H), 1.40 6.6 Hz, 3H), 1.30 (d, Hz, 6H), 1.3 (mn, 2H), 1.27 7.0 Hz, 6H), 1.08 (in, 4H), 0.78 6.8 Hz, 3H). FAB- MS: calculated for C25H35F0 370; found 370 Rf =0.36 (83:17 hexanes/ethyl acetate). mp, 126*C.

EXAMPLE 192

F

In a separate experiment, the title compound was prepared by the methods described in Example 191. 1 H NMR (300 Mfiz, CDCF3): 8 0.76 0.80 (in, 3H), 1.04 1.31 (in, 19H), 1.40 J 6.6 Hz, 3H), 2.17 2.22 (in, 2H), 3.11 3.16 (in, 1H), 3.86 3.90 (in, 1H), 4.66 4.73 (in, 1H), 7.06 7 7.22 (in, 4H), 7.32 1H). 13 C NMR MHz, CDCI3) d 13.87, 22.01, 23.37, 24.22, 24.55, 24.61, 25.08, 28.66, 28.94, 29.91, 31.02, 32.22, 68.89, 114.65 115.15 (2d, 2Q, 124.25, 130.33 .131.28 (2d, 2C), 135.51, 136.96,137.72, 139.00, 145.80 161.67 J 245.7 Hz, 1C). FAB-MS: calculated z' for C25H3,50F 370; 'found 370 Anal. caic for C25H350F: C, 81.03; H, 9.52.

Found: C, 81.05; H, 9.70. Rf 0.37 (9:1 hexanes:ethyl acetate). HPLC: (C-18,

A-

0.05 aqueous tiifluoroacetic acid, B CH3CN; linear gradient: 75% 100 %B over min; 254 nin, 1 mL/min): R.T. 20.0 min. (91.1 area (Daicel Chiralcel'

OD-H;

isocratic 99:1 hexanes:inethyl t-butyl ether; 254 run, 1.5 mL/min); R.T. =5.83 min (49.0 area 7.67 min.(51 area mp l 2 4.0-125.0*C.

300 WO 98/04528 PTU9134 PCT/US97/13248 0 EXAMPLE 193 (+)-3,5-Diisopropyl-2-(l-hvdroxyethyl)-6-pentyl-4'-fluoro-1 ,1'-biphenyI Step A: 3,5-DiisopropVl-2-(l-hydroxyethyl)-.67pentyl-4'fluoro-1 ,1 '-biphenyl, hemi-phthalate ester A solution of 1.90 g (5.36,mmol) ,of .3,5-diisopropyl-2-formyl-6-pentyl-4'fluoro-1,1'-biphenyl (Example 191, Stepp A) in 36 mL of tetrahydrofuran at -78*C under an argon atmosphere was treated with a dropwise addition of 4.6 mL (6.43 mrnol) of a 1.4 M solution of methyllithiunt in ether. The, reaction mixture was allowed to warm toToom temperature over, one hour., 1.0.3 mmol) of phthalic anhydride. was -then added as a solid and .stirring. was continued for another hour. The 'reaction was quenched with 3, mL saturated- aqueous ammoniumn chloride and. extracted. with 60 mL., ethyl acetate. Separated. organic phase was washed again :with 30 mL sturated. aqueous:.ammonium chloride.

Combined aqueous portions w ipeextracted with several portions of 20 mL of ethyl acetate. Combined organic portions were dried (Na2SO4) and concentrated in vacuo. The crude mixture. was purified by flash columnnchromatography on silica using hexanes:ethyl acetate:acetilc. acid (75:24:1)- as elueit -to, provide 2.55. g (4.94 mmol, 97 of the product. FAB-MS: calculated for C33H3904F 518; found 519 1H NMR (300MHz, CDCl3): 80.77 J 7.0 Hz, 3H 1.03 1.30 (mn, 18H), 1.53 J 7.0 Hz, 3H), 2.16 2.22,(in, 2H), 3.05 3.20 (in, 1H), 3.53 3.65 (mn, 1H), 5.87 5.93 (in, 1H), 7.05 7.37 (in, 4H), 7.54 8.06 (in, 5H). Rf: =,0.47 (75:24:1 hexanes:ethyl acetate:acetic acid).

Step B: (+)-3,5-Diisopropyl-2-(l-hydroxyethyl)-6..pentyl-4'-fluoro.1 biphen I A solution of 2.54 g (4.90 minol) of the hemi-phthalate ester from Step A in mL of hexane and 0.5 mL of methanol at reflux was treated with 0.63 mL (4.90 iniol) of (R)-(+)-a-methylbenzylamine. Reflux was continued until solids began to 301 WO 98/04528 PCT/US97/13248 0 precipitate. At this point, the flask was removed from the hot plate and allowed to cool. Further cooling was achieved by placing the flask in a freezer (-25 0

C)

overnight. Crystals were harvested via filtration and washed with hexane. The amine salt crystals were then suspended in hexane and methanol was added at reflux until the crystals dissolved. Reflux was continued until solids began to precipitate. At this point, the flask was removed from the hot plate and allowed to cool. Further cooling was not necessary and the salt crystals were harvested as above. The salts were crystallized a third time via the second method described, and the harvested crystals were placed in a vacuum oven overnight at 50°C to afford 0.57 g (0.89 mmol, 18 of crystalline amine salt. A solution of 0.57 g (0.89 mmol) of the amine salt in 5 mL dioxane was treated with a 20% solution of and was held at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was diluted with 20 mL of ethyl acetate. The separated aqueous phase was extracted with ethyl acetate (2 x 10 mL). Combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by flash column chromatography on silica using hexanes:ethyl acetate (19:1) and the resulting material placed in a vacuum oven overnight (at 50 0 C) to afford 0.26 g (0.70 mmol, 79%) of the title compound as a white solid. 1 H'NMR (300 MHz, CDC13): 8 0.75 0.80 (mi, 3H), 1.02 -1.31 19H), 1.40 J 6.6 Hz, 3H), 2.17 2.22 2H), 3.08 3.18 1H), 3.83 3.92 1H), 4.66 4.73 1H), 7.05 7.23 4H), 7.32 1H). 1 3 C NMR (75 MHz, CDCI3): 8 13.88, 22.02, 23.38, 24.23, 24.56, 24.63, 25.09, 28.68, 28.96, 29.92, 31.04, 32.23, 68.91, 114.66 115.16 (2d, 2C), 124.27, 130.34 -131.30 (2d, 2C), 135.53, 136.98,137.74, 139.02, 145.82 161.68

J

245.4 Hz, 1C). FAB-MS: calculated for C25H350F 370; found 370 Anal. calc for C25H350F: C, 81.03; H, 9.52. Found: C, 81.15; H, 9.68. Rf 0.36 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 20.0 min (93.9 area (Daicel Chiralcel OD-H; isocratic 99:1 hexanes:methyl t-butyl ether; 254 nm, 1.5 mL/min); R.T. 5.23 min.(98.0 area 8.37 min. (0.89 area 98.2 e.e. [a]D +26.90 (c 0.00196 g/mL, CH2C12).

mp 95.0-96.0 0

C.

WO 98/04528 WO 9804528PCT/US97/13248 EXAMPLE 194 3 ,5-Diisopropyl-2-hydroxymethVl-6-(pent-1-enyl)-4'-fluoroll'-biphenyl The title compound was prepared from the -intermediate obtained in Example 190, Step F by the procedures described in Example 190, Steps H and I.

The oleOiAwas a mixture of cis and trans isomers in a ratio of 17:83. 1 H NMR (CDCI3, 300 MHz): 5 7.33 1H), 7.15-7.02 (in, 4H), 5.95 16.2 Hz, 1H), 5.24 (dt, 16.2 Hz, 7.0 Hz,, 1H), 4.40 2H), 3.41 (sept, 6.8 Hz, 1H), 3.30 (sept, 6.8 Hz, 1H), 1.89 (dt, 7.2 Hz, 7.21Hz, 2H), 1.33 6.6 Hz, 6H), 1.24 7.0 Hz, 6H), 1.2 (in, 2H), 0.74 (t, 7.4 Hz, 3H). FAB-MS: calculated for C24H31F0 354; found 354 Rf 0.36 (83:17 hexanes/ethyl'acetate). Anal, calculated for C24H 31F0: C, 81.31; H, 8.81 Found: C; 81.04; H, 8.65. mp 85-95'C.

EXAMPTLE 195 3 ,5Dimethyl-2-(l-hvdroxvethl)7.6.provyl-4'.fluor-1 ,1 '-biphenyl Step A: 2 -Allyloxy-4,6-dimethylacetophenone A solution of 2 -hydroxcy- 4 ,6-dimethylacetophenone (4.99 g, 30.4 inmol) in dimethylformamide (31 mL) was added to a cooled (0 0 C) suspension of sodium hydride -(0.772 g, 32.1 minol) in dimethylformamide mL). The mixture was warmed to room temperature for 2.5 h. The mixture was recooled to 0 0 C and allyl 303 WO 98/04528 PCT/US97/13248 0 bromide (5.4 mL, 62.4 mmol) added. The mixture was warmed to room temperature and stirred 25 h. The mixture was diluted with saturated aqueous sodium chloride solution (150 mL) and extracted with diethyl ether (250 mL 2 x 125 mL). The combined organic phase was washed with 1 N KOH (2 x 125 mL) and saturated aqueous sodium chloride solution. Silica gel chromatography provided a colorless oil (5.74 g, 1H NMR (CDC13, 300 MHz): 8 6.64 1H), 6.56 1H), 6.03 (ddt, 17.3 Hz, 10.7 Hz, 5.2 Hz, 1H), 5.38 17.3 Hz, 1H), 5.27 10.7 Hz, 1H), 4.55 5.0 Hz, 2H), 2.51 3H), 2.31 3H), 2.22 3H).

StepB: 2 -Hvdroxv-3-(prop-2enyl)-4,6-dimethylacetophenone A solution of the intermediate obtained in Step A (6.30 g, 30.8 mmol) and 2 6 -di-t-butyl-4-methylphenol (71.9 mg, 326 mmol) in xylenes was degassed by three freeze-pump-thaw cycles. The mixture was heated in an oil bath at 225 0 C for 8 h. The mixture was cooled to room temperature and concentrated in vacuo.

Silica gel chromatography provided a yellow oil (5.47 g, 1 H NMR (CDCl3, 300 MHz):' 13.09 1H), 6.56 1H), 5.93 1H), 4.95 2H), 3.42 6.0 Hz, 2H), 2.65 3H), 2.55 3H), 2.27 3H). El MS: 204 70), 189 (100).

Step C: 2 Ace tl- 3 ,5-dimethyl-6-(prop2-enyl)phenyltriflate A solution of friflic anhydride (1.10 mL, 6.54 mmol) in CH2C12 (3.8 mL) was added to a cooled (-10 0 C) solution of pyridine (0.58 mL, 6.54 mmol) in CH2C12 (9.6 mL). After 35 min. a solution of the intermediate obtained in Step B (0.271 g, 1.33 mmol) in CH2C1 2 (6.4 mL) was added and the mixture allowed to warm to room temperature. After 5 h the mixture was poured into ice water and extracted with CH2C2 (2 x 15 mL). Silica gel chromatography provided a yellow oil (0.426 g, 1H NMR (CDC13, 300 MHz): 8 7.09 1H), 5.86 1H), 5.09 10.3 Hz, 1H), 4.93 17.1 Hz, 1H), 3.51 5.6 Hz, 2H), 2.52 3H), 2.34 3H), 2.30 3H).

3,5-Dimethyl-2-acetvl-6-(rop-2-enyl)-4-fluoro-1,1'-biphenyl A mixture of the intermediate obtained in Step C (3.25 g, 9.68 mmol), 4- fluorophenylboronic acid (2.06 g, 14.7 mmol), Pd(PPh 3 4 (1.13 g, 976 mmol), K3P04 (4.10 g, 19.3 mmol), and KBr (1.97 g, 16.6 mmol) in 1,4-dioxane (50 mL) was heated at 85 0 C for 16.5 h. The mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with diethyl ether (100 mL 2 x 75 mL). Silica gel chromatography (95:5 hexanes/ethyl acetate) provided a yellow oil (1.03 g, 38%).

1H NMR (CDC1 3 300 MHz): 8 7.18 2H), 7.06 3H), 5.76 1H), 4.97 10.2 Hz, 1H), 4.72 17.0 Hz, 1H), 3.15 5.5 Hz, 2H), 2.32 3H), 2.24 3H), 1.91 (s, 3H).

304 I~ ~iii~iii;i~.i ;l~p "i~r3~ i. WO 98/04528 P~U9I34 PC17[US97/13248 0 Step E: 3,5-Dimethyl-2-acetVl-6-propyl-4'-fluoro-1 ,1 '-biphenvl Prepared from the intermediate obtained -in Step D by the procedure described in Example 1, Step H. 1 H NMR (CDCl3, 300 MHz): 8 7.19 (in, 2H), 7.07 (in, 3H), 2.36 (in, 5H), 2.22 3H), 1.91 3H), 1.32 (in, 2H), 0.75 7.2 Hz, 3H).

FAB-MS: calculated for C19H21F0 284; found 285 (M H).

Step F: 3,5-Dimethyl-2-(l-hydroxvethyl)-&-propyl-4'-fluoro-1,1 '-biphenvl A mixture of the intermediate obtained in Step E (21.0 mg, 73.8 mmol) and lithiumn aluminum hydride (31.0 mg, 0.818 mmol) in tetrahydrofuran (2 mL) was refluxed overnight. Aqueous hydrochloric acid 1 mL) was added and the mixture stirred 1h. The mixture was diluted with 5% aqueous hydrochloric acid mL) and extracted with diethyl ether (3 x. 15 mL). Silica gel chromatography provided the title compound as a colorless crystalline solid (15.7 mg, 74/6). 1

H

NMR (CDCl3, 300 NMz): 5 7.19-7.01 (in, 5H), 4.71 (dq, 6.7 Hz, 3.2 Hz, 1H), 2.56 (s, 3H), 2.32 3H), 2.20 (in, 2H), 1.52 3.3 Hz, 1H), 1.38 7.0 Hz, 3H), 1.28 (in, 2H), 0.73.(t, 7.2 Hz). EI-MS: calculated for C19H23FO 286; found 286 29), 225 (100).

Rf 0.31'(83:17 hexanes/ethyl'acetate). 'Anal. calculated for C19H23F0: C, 79.68; H,"8.10 found: C, 79.46; H, 7.95. mp 98-9T 0 EXAMPLE 196

F

HO 3 ,S-Dimethvl-2-(l-hydroxvethyl)-6-(prop-2-enyl)-.4'-fluoro..1,1'biphenyI The title compound was prepared from the intermediate .obtained in Example 195, Step D by the procedure described in Example 195, Step F. 1 H NMR (CDKl3, 300 MHz): 8 7.16-7.02; (in, 5H), 5.66* (mn, 1H), 4.90 10.2 Hz, 1H), 4.75-4.62 (in, 2H), 2.99 5.5 Hz, 2H), 2.57 3H), 2.28 311), 1.50 3.7 Hz, 1H), 1.38 (d, Hz, 3H). Rf =0.27 (83:17 hexanes/ethyl acetate). Anal. calculated for C19H21F0: C, 80.25; H, 7.44 Found: C, 80.14; H, 7.36. mp 92TC.

305 WO 98/04528 PCTIUS97/13248 0 EXAMPLE 197 2 -Isopropyl 3 hdroxmethVl4(4.fluorohenl)5penyl6meth~l rdin Step A: 2 -IsoprovI-3carboethoxy.4(4.fluorophenVl)5carbomethoy 6 methyl-i ,4-dihydropyridie A mixture of methyl 3 -aminocrotonate (13 g, 114 mmol) and 4-carboethoxy- 4 -fluoropheny)-2-methypentzt.en.2.one (30 g, 114 mmol) (prepared by the method of Angerbauer, et al. U.S. Patent 5,169,857) in absolute ethanol (300 mL) was refluxed overnight. The mixture was concentrated in vacuo and the crude product taken to the next step without purification.

S tep B: 2 -Iso~ro~l-3-carboetho)-4(4fluorOp2henyl)5(pent-lenyl)- 6 methvlpvrid ne Prepared from the intermediate obtained in Step A by the procedures described in Example 1, Steps C-F. The olefin was obtained as a mixture of cis and trans isomers in a ratio -of 34:66. 1H1 NMR (300 M4Hz, CDCl 3 8 7.16 (in, 2H), 7.04 (in, 2H), 6.02 (in, 1 5.46 (mn, 1H1), 4.01 (in, 3.06 (in, 1H), 2.61 3H, major isomer), 2.50 3H, minor isomer), 1.99 (in, 1H), 1.67 (in, 1H1), 1.4 1.15 (mn, 8H), 0.98 (mn, 3H1), 0.79 (mn, 3H1).

Step C: 2 -Isopro~vl-3hdro)methV1A.(4fluoro~henl)5(Pentlenvl)z6 inethylpridine A mixture of 1.25 g (3.38 inmol) the intermediate obtained in Step B and, lithium aluminum hydride (0.28 g, 6.8 minol) in tetrahydrofuran (50 mL) was refluxed for 2.5 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate to provide a colorless crystaline solid (1.0 g, The olefin was obtained as a mixture of cis and trans isomers in a ratio of 19:81. 1H1 NI\4R (300 MHz, CDCl 3 8 7.10 (in, 4H), 5.88 16.2 Hz, 1 5.39 (dt, 16.2 Hz, 7.0 Hz, 1H1), 306 WO 98/04528 PCT/US97/13248 0 4.39 5.5 Hz, 2H), 3.44 (sept, 7.0 Hz, 1H), 2.57 3H, major isomer), 2.46 3H, minor isomer), 1.92 2H), 1.4 1.15 4H), 1.33 6.6 Hz, 6H), 0.75 7.4 Hz, 3H). FAB-MS: calculated for C21H26FNO 310; found 326 Rf 0.44 (80:20 hexanes/ethyl acetate). Anal. calculated for C21H26FNO: C, 77.03; H, 8.00; F, 5.80; N, 4.28. Found: C, 77.02; H, 8.14; F, 5.99; N, 4.22. mp 106-108 0

C.

Step D: 2 -Isopropvl-3-hydroxymethyl-4-(4-fluorophenyl)-5-pentyl-6methylpyridine A mixture of the intermediate obtained in Step C (1.3 g) and 10% Pd/C (0.1 g) in absolute ethanol (50 mL) was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of silica gel and the pad washed with ethyl acetate. Silica gel chromatography (80:20 hexanes/ethyl acetate) followed by recrystallization from ethyl acetate afforded the title compound as colorless crystals (650 mg, 1H NMR (300 MHz, CDC13): 8 7.25 2H), 7.23 (s, 2H), 4.43 5.5 Hz, 2H), 3.53 (sept, 7.0 Hz, 1H), 2.69 3H), 2.35 2H), 1.44 (d, 6.6 Hz, 6H), 1.4 2H), 1.2 4H), 0.88 6.6 Hz, 3H). FAB-MS: calculated for C21H28FNO 310; found 328 Rf 0.43 (80:20'hexanes/ethyl acetate).

Anal. calculated for C21H28FNO: C, 76.56; H, 8.57; F, 5.77; N, 4.25. Found: C, 76.71; H, 8.60; F, 6:04; N, 421. mp 83-85 0

C.'

EXAMPLE 198

F

HO

N

2-Isopropvl-3-pentyl-4-(4-fluorophenyl)-5-hydroxvmethl-6-methylpyridine Step A: 2 -Isopropvl- 3 -carboethoxv-4-(4-fluorophenvl)-5-hydroxymethyl-6methylpyridine Prepared from the intermediate obtained in Example 197, Step A by the procedures described in Example 1, Steps C and D. 1 H NMR (300 MHz, CDC13): 8 7.25 2H), 7.09 2H), 4.44 5.1 Hz, 2H), 3.97 7.1 Hz, 2H), 3.04 (sept, 6.8 WO 98/04528 PCTIUS97/13248 0 Hz, 1H), 2.71 3H), 1.53 5.2 Hz, 1H), 1.30 6.6 Hz, 6H), 0.96 7.2 Hz, 3H).

EI-MS: calculated for C19H22FN0 3 331; found 331.

Step B: 2 -isopropvl-3carboethox-4.(fluorophenvl)5(tbutI dimethvlsiloxv)methVI-.6-meffilpvridine A solution of the intermediate obtained in Step A (3.41 g, 10.3 mmol) t-butyldimethylsilylchdoride (1.86 g, 1.2 equiv), and imidazole (1.75 g, 2.5 equiv) in dimethylformamide (6 mL) was stirred overnight. The mixture was diluted with water and extracted with ethyl _acetate. Silica gel chromatography (95:5 hexanes/ethyl acetate) provided a colorless solid (3.5 g, 1H NMR (300 MHz, CD3OD): 8 7.30 (in, 2H), 7.20 (mn, 2H), 4.49 2H), 4.03 7 Hz, 2H1), 3.1 (sept, 1H), 2.72 3H), 1.34 7.0 Hz, 6H), 1.01 7.0 Hz, 3H), 0.90 9H), 0.00 6H). FAB- MS: calculated for C25H,36FNO 3 Si 331; found 446 Step C: 2-spo-l-3(etley)4.(-loohnl--tbtl diinethylsiloxy)inethvl-6-methvlpyridine Prepared from the intermediate, obtained in Step B by the procedures described in Example 1, Steps D, E, and F. 1H NMR (300 MI-Iz,1CD3OD): 8 7.2-7.0 (mn, 4H), 5.99 16.2 Hz, 1H), 5.28 (dt, 15.6 Hz, 7.2 Hz,- 1H)-i 4.30 2H), -3.38 (in, 1H), 2.67 (in, 3H), 1.92 (in, 2H), 1.4-1.2 (in, 8H), 0.85 9H), 0.75 7.4 Hz, 3H1), 0.06 6H1).

S!M D: 2 -Isopropv1-3-(ptlenvlt.. -fophenv~4 lrophedroxythyl- 6 inethvlpyridine Tetrabuyaimnioimi fluoride (1 mL of 1.0 M solution in tetrahydrofuran, 2.5 equiv) was added to a solution of the -intermediate obtained in Step C (200 mng, 0.45 inmol) in tetrahydrofuran (10 mL). After 2 h the mixture was concentrated in vacuo. The residue was dissolved -in water and extracted with ethyl acetate. Silica gel chromatography (80:20 hexanes/ethyl acetate) provided a colorless solid (120 mg, The olefin was obtained as a mixture of cis and trans isomers in a ratio of 8:92. 1H NMR (300 MI-z, C~DC 3 8 7.09 (rn, 4H1), 5.96 16.2 Hz, 1 5.27 (dt, 16.2 Hz, 1H1), 4.38 5.'5 Hz, 2H), 3.36 (sept, 1H1), 2.69 311), 1.90 (in, 211), 1.4 1 .1 (in, 411), 1.25 6.6 Hz, 6H), 0.73 7.4 Hz, 3H). FAB-MS: calculated for C211126FN0 327; found 327 Rf 0.23 (80:20 hexanes/ethyl acetate). Anal.

calculated for C21H26FN0: C, 77.03; H, 8.00; F, 5.80; N, 4.28. .Found: C, 76.92; H, 8.07; F, 5.92; N, 4.15. mp.119-120 0

C.

308 WO 98/04528 WO 9804528PCT/US97/13248 o Step E: 2 -Isopropyl-3-pentvl-4-(4-fluorophenl)-5-hydroxymethl..& methylpyridine The title compound was obtained as a colorless solid in 86% yield from the intermediate obtained in Step D by the procedure described in Example 1, Step H.

1H NMR (300 MHz, CDCI 3 8 7.2 (in, 4H), 4.29 5.5 Hz, 2H), 3.24 (sept, 6.6 Hz, 1H), 2.65 3H), 2.26 (in, 2H), 1.29 6.6 Hz, 6H), 1.25 (in, 4H), 1.1 (in, 4H), 0.76 (t, Hz, 3H). FAB-MS: calculated for C21H28FN0 329; found 328 Rf 0.20 (80:20 hexanes/ethyl acetate). Anal. calculated for C21H28FN0: C, 76.56; H, 8.57; F, 5.77; N, 4.25. Found: C, 76.49;.H, 8.55; F, 5.78; N, 4.21. mp 110-112TC.

EXAMPLE 199

~F

isopropylpyridine Step A~ 2-spo Rentyl-6-inethyllpvridine A solution of the intermedi !ate from Example 197, Step D (50 mng, 0.15 mnmol), t-butyldiphenylsilylchloride (50 mg, 1.2 equiv), and iinidazole (25 mg, equiv) in dimethylformamide (0.5 mL) was stirred for 2 h. The mixture was diluted with water and extracted with ethyl acetate. Silica gel chromtatography (95:5 hexanes/ethyl acetate) provided a colorless solid (64 mg, 1H NMR (300 Mffz, CD3OD): 8 7.41:(in, 6H), 7.33 (in, 4H), 7.05 (in, 4H),.4.25 2H),'3.13 (sept, 6.8 Hz, 1H), 2.57 3H), 2.23 (mn, 2H), 1.3 (mn, 1.17 6.6 Hz, 6H), 1.15 (in, 4H), 0.99 9H), 0.78 6.4 -Hz, 3H).

Step B: 2 -IsoprO~yl- 3 -(t-butvldiphenylsilov)methyl-4-(4fluorophenyl)-..

pentyl-6-methylpyridine N-oxide A mixture of the intermediate from Step A (60 mg, 0.11 innol) and 3- 309 WO 98104528 WO 9804528PCT1US97/13248 o chloroperoxybenzoic acid (52 mg, 1.4 equiv) in chloroform (5 mL) was refluxed for min. The mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 25 mL). The organic phase was filtered through a shoroomn temperature pad of silica gel and concentrated to give a yellow solid (54 mg, 1 H NUR (300 MHz, CDCl 3 8 7.31 (in, 6H), 7.24 (in, 4H), 6.96 (mn, 4H), 4.13 2H), 3.16 (br s,1H), 2.47 2.18 (mn, 2H), 1.33 6.6 Hz, 6H), 1.25 (in, 2H), 1.05 (in, 4H), 0.93 9H), 0.70 6.4 Hz, 3H).

Step C: 2 -Chloromethyl-3-pentl4-(4-fluorophenyl)5.(t-butvldiphenylsiloxv)methyl-6-isopropylpyridine Phosphorus oxychloride(9.5 g) and triethyl amine (8.6 mL) were added simultaneously to a refluxing solution of the intermediate obtained in Step B (15 g, 25.8 mmol) in CH2Cl2 (30 mL). After 3 h the mixture was diluted with CH2l2- (100 inL and washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL). Silica gel chromatography (90:10 hexanes/ethyl acetate) provided a solid (9.4 g, 1 H NMR (300 MvHz, CDCl 3 8 7.41 (in, 6H), 7.32 (mn, 4H), 7.06 (mn, 4H), 4.75 2H), 4.27 2H), 3.15 (sept, 6.8 Hz, 1H), 2.39 (in, 2H), 1.35 (in, 2H), 1.18 6.6 Hz, 6H), 1.12 (in, 4H), 1.00(s, 9H), 0.79 6.6 Hz, 3H).

Step D: 2 -Morpholinonethyl-3-pentyl-4-(4-.fluorophenv)5 (t-butvldiphenylsiloxv)inethyl-6-isopropylpyridine A mixture of the intermediate prepared in Step C (0.5 g, 0.83 iniol), inorpholine (0.108 g, 1.5 equiv), and 4-dimethylaminopyridine (0.172 g, 1.7 equiv) in CH2Cl2 (15 inL was refluxed for 2 h. The mixture was washed with saturated aqueous sodium chloride solution. Silicagel chromatography (90:10 hexanes/ethyl acetate) provided a yellow oil (170 mg, 1 H NMR (300 MHz, CDCI 3 8 7.41 7.34 (in, 4H), 7.05 (mn, 4H), 4.26 2H), 3.71 (in, 4H), 3.67 2H), 3.13 (sept, 6.8 Hz, 1H), 2.61 (in; 4H), 2.35 (in, 2H), 1.15 6.6 Hiz, 6H), 1.1 (in, 4H), 0.99 9H), 0.9 (nm, 2H), 0.78 7.0 Hz, 3H).

Step E: 2 -Morpholinomethyl-3-pentyl-4(4-fluorophenyl).5hydroWinethvl.

6-isopropVlpvridine The title compound was prepared from the intermediate obtained in Step D by the procedure described in Example 198, Step D. 1 H NMR (300 MHz, CDCI 3 8 7.17 (in, 4H), 4.36 5.1 Hz:, 2H), 3.68 (mn, 6H), 3.42 (sept, 6.6 Hz, 1HM, 2.59 (mn, 4H), 2.39 (in, 2H), 1.32 6.6 Hz, 6H), 1.25 (mn, 2H), 1.1 (mn, 4H), 0.78 6.6 Hz, 3H).

FAB-MS: calculated for C25H35FN202 414; found 415 Anal. calculated for 310 WO 98/04528 PCT/US97/13248 0 C25H35FN202: C, 72.43; H, 8.51; F, 4.58; N, 6.76. Found: C, 72.49; H, 8.42; F, 4.71; N, 7.05.

EXAMPLE 200

F

HO

OH

2,5-Bis(hydroxymethyl)-3-pentyl-4-(4-fluorophenyl)-6-isopropylpyridine Step A: 2-Acetoxvmethyl-3-pentyl-4-(4-fluorophenyl)-5-(tbutvldiphenvlsiloxy)methyl-6-isopropylpyridine A mixture of the intermediate obtained in Example 199, Step B (4.8 g, 7.97 mmol) and acetic anhydride (20 mL) was heated to 100 0 C for 20 min. The mixture was poured onto ice and the aqueous phase extracted with ethyl acetate (3 x mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (3 x 50 mL), and saturated aqueous sodium chloride solution (3 x 50 mL). Silica gel chromatography provided a yellow oil (4.4 g, 1 H NMR (300 MHz, CDC1 3 8 7.40 6H), 7.31 4H), 7.06 4H), 5.29 2H), 4.26 (s, 2H), 3.14 (sept, 6.8 Hz, 1H), 2.2 2H), 2.18 3H), 1.2 2H), 1.16 6.6 Hz, 6H), 1.05 4H), 0.99 9H), 0.77 6.8 Hz, 3H).

Step B: 2-Hydroxymethyl-3-pentvl-4-4fluorophenyl)-5-(tbutyldiphenylsiloxy)methyl-6-isopropylpyridine A mixture of the intermediate obtained in Step A (60 mg, 0.096 mmol) and potassium carbonate (5 equiv) in methanol (8 mL) and water (2 mL) was refluxed for 1.5 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Concentration of the organic phase provided a colorless solid (60 mg, 100%) that was used in the next step without purification.

1H NMR (300 MHz, CDC13): 8 7.4-7.2 10H), 7.11 4H), 4.90 2H), 4.39 (s, 2H), 3.34 (sept, 7.0 Hz, 1H), 2.34 2H), 1.25 7.0 Hz, 6H), 1.2 2H), 1.04 (m, 4H), 0.90 9H), 0.68 7.0 Hz, 3H).

WO 98/04528 PTU9/34 PCTfUS97/13248 Step C: 2 iS-Bis(hvdroxymethyl)-3-pent-14(4.fluorophenyl).6iso2ropylpyridine The title compound was prepared from the intermediate obtained in Step B by the procedure described in Example 198, Step D. IH NMR (300 MHz, CD3OD): 5 7.21 (in, 4H), 4.70 2H), 4.30 2H), 3.54 (sept, 6.6 Hz, 1H), 2.28 (in, 2H), 1.32 (d, 6.6 Hz, 6H), 1.25 (mn, 2H1), 1.1 (mn, 4H), 0.75 6.8 Hz, 3H1). FAB-MS: calculated for C21H28FN0 2 345; found 346 Anal, calculated for C21H28FN0 2 C, 73.01; H, 8.17; F, 5.50; N, 4.05. Found: C, 72.89; H, 8.25; F, 5.21; N, 4.41. mp 135-136*C.

EXAMPLE 201 2 -Methox vmthl-etyl(4flphen1 5.(4fl roxhel5tVI-6 diphenylsiloxv)methyl6isotropylpyridine A mixture of the intermediate obtained in Example 200, Step B (0.1 g, 0.17 inmol), methyl iodide (0.013 mL, 1.2 equiv), and sodium hydride (8 mng of a dispersion in mineral'oil,. 1.2 equiv) in tetrahydrofuran (1 mL) was heated -at 40 0

C

for 3 h. The mixture was diluted with water and extracted with ethyl acetate (3 x The combined -organic phase was washed with saturated aqueous sodium chloride solution (3 x 10.mL). Silica gel chromatography provided a colorless solid (40 mng, 'H NMR (300 MHz, CDCI 3 8 7.41 (in, 6H1), 7.32 (in, 411), 7.06 (in, 411), 4.62 2H), 4.27 211), 3.48 311), 3.15 (sept, 6.6 Hz, 1H), 2.36 (in, 2H), 1.27 (in, 211), 1.18 6.6 Hz, 611), 1.12 (mn, 2H), 1.00 9H), 0.87 (in, 2H), 0.78 6.6 Hz, 3H1).

312 WO 98/04528 WO 984528PTIUS97/13248 o Step B: 2 -Methoxymethyl-3-pentyl-4-(4-fluorophenl)-5-hydroxymethyl-6.

isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1 H NMR (300 MI-z, CDCI 3 8 7.14 (in, 4H), 4.62 2H), 4.36 5.2 Hz, 2H), 3.46 3H), 3.44 (sept, 6.6 Hz, 1H), 2.38 (in, 2H), 1.34 7.0 Hz, 6H), 1.23 (in, 2H), 1.12 (in, 4H), 0.77 6.8 Hz, 3H).

FAB-MS: calculated for C22H3OFNO2 359; found 360 Anal. calculated for C22H30FN02: C, 73.51; H, 8.41; F, 5.28; N, 3.90. Found: C, 73.40; H, 8.47; F, 5.19; N, 3.91.

EXAMPLE 202

CF

2-toyehl3pny--4furpeyl--yrxmty--spo~prdn The title compound was prepared from the intermediate obtained in Example 200, Step B by the procedures described in Example 201, Step A, and Example 198, Step D. 1 H NMR (300 MI-z, CDCI1 3 5 7.18 4.68'(s, 2H), 4.35 4.4 Hz, 2H), 3.65 7.0 Hz, 2H), 3.44 (sept, 6.6 Hz, 1H), 2.40, (mn, 2H), 1.4 (in, 2H), 1.34;(d, 6.6 Hz, 6H), 1.26 (t,7.0 Hz, 3M,-1.13 (in, 4H), 0.78 6.6 Hz, 3H). FAB-MS: 4D calculated for C23H32FNO2 373; found 374' Anal. calculated for C3H32N0 2 3.96; Hj, 8.64; F, 5.09; N, 375 Fon:C47.7 8.83; F, 5.33; N, 3.52..

EXAMP'LE 203

F

HO

313 h WO 98/04528 PTU9134 PCT/US97/13248 0 2 -(Prop- 2 -enVloxV)methVI-3-pentl.4-(4.fluoropheny).5..hydroxymethyI 6 isopropylpyridine The title compound was prepared from the intermediate obtained in Example 200, Step B by the procedures described in Example 201, Step A, and Example 198, Step D. 1 H NMR (300 MI-z, CDCl 3 8 7.15 (in, 4H), 5.97 (ddt, 17.1 Hz, 10.5 Hz, 6 Hz, 2H), 5.33 17.3 Hz, 1H), 5.21 10.3 Hz, 1H), 4.68 2H), 4.34 2H), 4.12 5.5 Hz, 2H), 3.44 (sept, 6.8 Hz, 1H), 2.39 (in, 2H), 1.33 6.6 Hz, 6H), 1.29 (in, 2H), 1.10 (mn, 4H), 0.77 6.8 Hz, 3H). FAB-MS: calculated for C24H32FN02 385; found 386 Anal. calculated for C24H32FN0 2 C, 74.8; H, 8.37; F, 4.93; N, 3.63. Found: C, 75.2; H, 8.54; F, 4.90; N, 3.52.

EXAMPLE 204 2 -Benxvloxvmrethyvl-3penv4(4fluorophenvl)s..hydrowmethl 6 isopropylpyridine The title compound was prepared from the intermediate obtained in Examle 200, Step B by the procedures described in Example 201, Step A, and Example 198, Step 1H NNM (300 MIHz, CDCL 3 8 7.43-7.30 (in, 5H), 7.17 (in, 4H), 4.73 2H), 4.66 2H), 4.36 2H), 3.46 (sept, 6.6 Hz, 1H), 2.38 (in, 2H), 1.36 6.6 Hz, 6H), 1.25 (mn, 2H), 1.05 (in, 4H), 0.75 6.6 Hz, 3H). FAB-MS: calculated for C24H32FN0 2 435; found 436 Anal. calculated for C28H34FN02:

C,

77.21; H, 7.87; F, 4.36; N, 3.22. Found: C, 77.26; H, 7.84; F, 4.42; N, 3.11. mp 110- 112 0

C.

314 WO 98/04528 WO 9804528PCT/US97/13248 0 EXAMPLE 205

OH

2 -(l-Hvdroxybut-3-enyl)-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethvl-6isopropvlpyridine Step A: 2 -FormVI-3-pentVl-4-(4-fluoropheny)-5-(t-butyldiphenylsiloxy)methvb.6-isopropvlpyridine Prepared from 2 -hydroxymethyl-3-pentyl-4-(4-fluorophenyl)-5- [(t-butyldiphenylsiloxy)methylJ-6-isopropylpyridine (Examhple 200, Step B) 'by the procedure described in Example 1, Step E: 1 JR NMR (300 MHz, CDCl 3 8 10.20 (s, 1H), 7.41 (in, 6H), 7.33 (mn, 4H), 7.04 (in, 4H), 4.33 2H), 3.23 (sept, 6.6 Hz, 1H), 2.66 1.3-1.4. 1.22 6.6 Hz, 1.01 9H), 0.79 7.0 Hz, 3H).

FAB-MS: calculated for C37H44FNO2Si 581; found 582,(M4+H).

Step B: 2 -(1-HvdroxVbut-3-enV) 3-peAty-4.(4-fluorophenyl)-5.

(t-butvldiphenvlsiloxv)methyl..6-isoropvlpvridine A mixture of the intermediate obtained ,i M'"Step. A (0.2 g, 0.34 minol) and allylmagnesium bromide (1 mL of 1.0 M solu-tion in tetraliydrofuran, 3 equiv) in tetrahydrofuran (10 mL) was r~'fuxed .for 1.5*h. The; mixture was concentrated in vacuo. The residue was dissolved in ethyl aceta~te and washed, with saturated aqueous sodium chloride solution. Silica gel chromatography (97:3 hexanes/ethyl acetate) provided a yellow oil (110 mg, 520/6). 1~INMR-.(300 MHz, CDCl 3 5 7.42 (mn, 6H), 7.2 (in, 4H), 7.06 (in, 4H), 5.94 (in, 1H), 5.14-5.08 (mn, 2H), 4.99-4.90 (mn, 2H), 4.28 2.2 Hz, 2H), 3.16 (sept, 6.8 Hz, 1H), 2.55 (in, 1H), 2.45-2.15 (in, 3H), 1.3 (mn, 2H), 1.20 6.6 Hz, 3H), 1.15 6.6 Hz, 3H), 1.1 (in, 4H), 0.76 6.6 Hz, 3H).

Step C: 2 -(l-Hvldroybut-3-eyl)-3ptl..4(4-fluorophery).5hydroxvm!thyl-6-isopropylpyridine The title compound was prepared from the intermediate obtained in Step B by the procedure described in Example 198, Step D. 1 H NMR (300 M[Hz, CDC1 3 8 315 WO 98/04528 PTU9/34 PCTIUS97/13248 o 7.16 (in, 4H), 5.94 (mn, 1H), 5.13 7.7 Hz, 1H), 5.08 1H), 4.92 2H), 4.38 (in, 2H), 3.47 (sept, 6.7 Hz, 1H), 2.51 (in, 1H),.2.4-2.1 (in, 3H), 1.35 6.6 Hz, 3H), 1.34 6.6 Hz, 3H), 1.29 (mn, 2H), 1.10 (in, 4H), 0.77 6.6 Hz, 3H). FAB-MS: calculated for C24H32FN02 385; found 386 Rj 0.15 (85:15 hexanes/ethyl acetate).

Anal. calculated for C24H32FN02: C, 74.77; H, 8.37; F, 4.93; N, 3.63. Found: C, 74.85; H, 8.53; F, 4.99; N, 3.50.

EXAMPLE 206 F0

OH

2 -(l-Hvdroxpro-2-env1)3-pentVI4..(4-.fluorOhenv)-5hdrovmethl Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step 1 H NMR (300 MIz, CDCl 3 8 7.16 (mn, 4H), 5.89 17.0 Hz, 10.0 Hz, 7.1 Hz, 1H), 5.66 5.5 Hz, 1H), 5.37 16.9 Hz, 1H), 5.26 5.7 Hz, 1H), 5.20 9.9 Hz, 1H), 4.38 4.8 Hz, 2H), 3.49 (sept, 6.7 Hz, 1H), 2.33 (in, 1H), 2.13 (mn, 2H), 1.35 6.6 Hz, 3H), 1.34 6.6 Hz, 3H), 1.2.(in, 2H), 1.10 (mn, 4H), 0.76 6.8 Hz, 3H). FAB-MS: calculated for C23H30FN0 2 371; found.372 Rj 0.15 (85:15 hexanes/ethyl1 acetate). NIP jP13-115*C. Anal, calculated for C23H30FN02: C, 74.36; H, 8.14; F, 5.11; N, 3.77.

pFund: C, 74.16; 5.11; N, 3.60.

EXAMPLE 207

F

HO

HOI OH 316 -s WO 98/04528 WO 9804528PCTIUS97/13248 0 2-(Hydroxy-p-tolyl)methyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxVmethyl-6.

isopropylpyridine, hydrochloride Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. 1 H NMR (CD3OD, 300 Mffz): 8 7.28 (in, 6H), 7.21 (mn, 2H), 6.90 7.7 Hz, 1H), 6.43 1H), 4.48 11.8 Hz, 1H), 4.41 11.8 Hz, 1H), 3.96 (sept, 6.8 Hz, 1H), 2.46 3H), 2.19 (in, 211), 1.61 7.0 Hz, 3H), 1.58 7.0 Hz, 3H), 1.0-0.6 (mn, 511), 0.57 7.0 Hz, 3H), 0.3 (in, 1H).

FAB-MS: calculated for C28H34FN02 435; found 436 Anal. calculated for C28H34FN02-HCI: C, 71.25; H, 7.47; Cl, 7.51; F, 4.02; N, 2.97. Found: C, 71.43; H, 7.49; Cl, 7.48; F, 4.10; N, 2.87. mp 178-180'C.

EXAMPLE 208 2 -(a-HydroXY)benzyl-3-pentyl4(4-fluorophenyl)-5-hydroxymethyl-6.

isopropylpyridine P repared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. 1H NMR (CDCI3, 300 MHz): 8 7.30 (mn, 7.17 (mn, 4HM, 6.43 6.6 Hz, 1H), 5.79 6.6 Hz, 1H), 4.40 (in, 2H1), 3.55 (sept, 6.6 Hz, 1H), 2.21-2.09 (in, 211), 1' .4 6.6 Hz, 3H), 1.43 6.6 Hz, 3H), 1.32 (mn, 1H), 1.14-0.88 (in, 6H), 0.69 3H). FAB-MS: calculated for C27H32FN02 421; found 422 Rf 0.10 (85:15 hexanes/ethyl acetate). Anal.

calculated for C27H32FN02: C, 76.93; H, 7.65; F, 4.51; N, 3.32. Found: C, 76.70; H, 7.86; F, 4.45; N, 3.14.

WO 98/04528 PCT/US97/13248 EXAMPLE 209

OH

2-(4-Fluorophenvl)hdroxymethyl-3-pentyl--4furpe~)5hdoyehl 6-isopropylpyridine Prepared from the intermediate in Example 205, Step A by the procedures described in Example 205, Step B, and Example 198, Step D. 1 H NMR (CDCl3, 300 MHz): 87.24 2H), 7.15 4H), 6.98 2H), 6.40 5.9 Hz, 1H), 5.77 5.5 Hz, 1H), 4.40 2H), 3.55 (sept, 6.6 Hz, 1H), 2.13 2H), 1.43 6.3 Hz, 3H), 1.41 (d, 6.6 Hz, 3H), 1.08 1H), 0.99 6H), 0.69 6.6 Hz, 3H). FAB-MS: calculated for C27H31F2N0 2 439; found 440 Rf 0.15 (85:15 hexanes/ethyl acetate).

Anal. calculated for C27H31F2N0 2 C, 73.78; H, 7.11; F, 8.64; N, 3.19. Found: C, 73.49; H, 7.23; F, 8.45; N, 3.01.

EXAMPLE 210 r r

I

r c r~ r o i~m~ ~tQI, Jv n i 2-(l-H vdroxvethv)-3-Pentyl -4-(4-fluorphenyl)5-hdroxymethyl& isopropylpYridine Step A: 2 -(l-Hvdroyethl)3-Denyl-4-(4-fluorophenVl)5(tbutI dipenysiloxy)methy1-6-isoprop ypvridine 318 ye ,.*kY'T=~iey--aeyeL<-- WO 98/04S28 WO 9804528PCr[US97/13248 0 Prepared from the intermediate in Example 205, Step A by the procedure described in Example 205, Step B. 1 H NMR (300 MIHz, CDCl 3 8 7.42 (in, 6H), 7.32 (in, 4H), 7.05 (in, 4H), 5.16 7.7 Hz, 1H), 4.99 (mn, 1H), 4.28 2H), 3.16 (sept, 6.8 Hz, 1H), 2.25 (in, 2H), 1.45 6.3 Hz, 2H), 1.19 6.6 Hz, 3H), 1.16 6.6 Hz, 3H), 1.10 (in, 6H), 0.76 6.8 Hz, 3H).

.Step B: 2 -(l-Hvdroxyethl)-3-p2entyl-4-(4-fluorophenvl)..5.hydroxymethl.6isopropylpyridine The title compound was prepared from the intermediate in Step A by the procedure described in Example 198, Step D. 1 H NMR (CDCl3, 300 MHz): 6 7.19- 7.15 (mn, 4H), 5.12 7.0 H, 1H), 4.99 4.38 5.5 Hz, 2H), 3.48 (sept, 6.8 Hz, 1H), 2.27 (in, 2H), 1.43 6.3 Hz, 1H), 1.35 6.6 Hz, 6H), 1.30,(m 2H), 1,09 (in, 7H1), 0.76 6.6 Hz, 3H). FAB-MS: calculated for C22H30FN02 359; found 360 Rf 0.15 (85:15 hexanes/ethyl acetate). Anal. calculated for C22H30FN02: C, 73.5-1; H, 8.41'; FT15.28; N, 3.90. Found: C, 73.24; H, 8.40; F, 5.41; N, 3.85. mp 125- 127 0

C.

EXAMPLE 211

OH

2 -(l-Hvdroxvbutv1)-3-penyl-4-(4-fluorophenyl)-5hydroxyinethyl.6 isopropylpyridine, Prepared from the compound obtained in Example 205 by the procedure described in Example 1, Step H. 1 H NMR (300'MHz, CDC1 3 6 7.17 (mn, 4H), 4.92 (br s, 2H), 4.85 (br s, 2H), 4.37 5.2 Hz, 211), 3.47 (sept, 6.6 Hz, 1H), 2.29-2.23 (in, 2H), 1.62-1.53 1.35 6.6Hz, 3H); 1.34 6.6 Hi,-3H), 1.3(mn, 1H), 111 (in, 0.94 7.0 Hz, 3H1), 0.77 6.4 Hz, 3H). .FAB-MS: calculated for C .24H34FN02 387; found 388 Anal, calculated for C24H34FN02: C, 74.38; H, 8.84; F, 4.90; 3.61. Found: C, 74.11; H, 8.93; F, 4.96;' N, 3.51.

319 WO 98/04528 PTU9/34 PCTIUS97/13248 EXAMPLE 212 isopropylpvridine The title compound was prepared from the intermediate obtained in Example 206 by the procedure described in Example 1, Step H. 1 H NMR (300 MHz, CDCl 3 8 7.18 (in, 4H), 4.94 (br s, 1H), 4.82 (hr s, 1H), 4.39 4.8 Hz, 2H), 3.48 (sept, 6.6 Hz, 1H), 2.3-2.1 (in, 2H), 1.82 (mn, 1H), 1.36 5.5 Hz, 3H), 1.34 6.3 Hz, 3H), 1.11 (in, 8H), 1.02 7.4 Hz, 3H), 0.78 6.6 Hz, 3H). FAB-MS: calculated for C23H32FN0 2 373; found 374 Rf= 0.15 (85:15 hexanes/ethyl acetate). Anal.

calculated for C23H32FN0 2 C, 73.96; H, 8.64; F, 5.09; N, 3.75. Found: C, 73.88; H, 8.57; F, 5.17; N, 3.53. mp, 89-90*C.

EXAMPLE 213 N. OMe 2 2 Methoxphenvl)aminoinethl.3pentyl4-( 4 hvdroxvmethyl-6-isoproplpyfidine

S

Step A: 2 2 -MethoxVphenl)aiinomehvfietvl-W4-.(4-fluoro~henvl-5- (t-butVldiphenysiloxy)methyl-6isoprotvlpvridine 320 WO 98/04528 WO 9804528PCT/US97113248 0 A mixture of the intermediate from Example 205, Step A (60 mg, 0.10 mmol) and m-anisidine (50 mg, 4 equiv) in methanol (10 mL) was treated with a mixture of zinc chloride (7 mg, 0.5 equiv) and sodium cyanoborohydride (6 mng, 1 equiv) in methanol (15 mL). After stirring at room temperature overnight the mixture was quenched with water and extracted with ethyl actetate (3 x 15 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (3 x mL). Silica gel chromatography provided a colorless solid (70 mg, 1 H NMR (300 MHz, CDCI 3 8 7.43 (in, 6H), 7.32 (mn, 4H), 7.16 (in, 1H), 7.06 (mn, 4H), 6.43 (in, 1H), 6.32 (in, 2H), 5.98 (br s, 1H), 4.38 2H), 4.29 2H), 3.83 3H), 3.19 (sept, 6.6 Hz, 1H), 2.28 (in, 2H), 1.25 (in, 2H), 1.22 6.6 Hz, 6H), 1.14 (mn, 2H), 0.99 9H), 0.80 6.8 Hz, 3H).

Step B: 2-N-(2-MethoxVphenVI)aminomethyl-3-pentyl-4-(4-fluorophenyl)-5hydroxVmethVI-6-isopropvlpR~idine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1 H NMR (300 MHz, CDCl 3 8 7.16.(in, 5H), 6.43.(in, 1H), 6.32 (mn, 2H), 4.40 2H1), 4.39 2H), 3.83 3H)" 3.50 (sept, 6.6 Hz, 1H), 2.32 (in, 2H), 1.39 6.6 Hz, 6H), 1.31 (in, 2H), 1.16 (in, 4H), 0.80 6.4 Hz,, 3H). FAB-MS: calculated for C28H35FN202 450; found '451 Anal.

calculated for C28H35FN202: C; 74.64; H, 7.83; N, 6.22. Found: C. 74.44; H, 7.75; N, 6.03. mp 109-110 0

C.

EXAMPLE 214 2 -Ethenvl-3-pentyl-4-(4-fluoophenl)-5..hydroxymethyl..6.isopropylpvridine Step A: 2 -Ethenyl-3-pentWJ.4-(4.-fluorophenyl)-5-(t-butlliphenylsiloxv)methyl-6-isopropvlpv'rdine n-Butyl lithium (0.03 mL of 1.6 M solution in hexanes) was added to a cooled 321 WO 98/04528 PCT/US97/13248 0 (0 0 C) solution of methyltriphenyphosphonim bromide (18 mg) in tetrahydrofuran (3 mL). After 2 a solution of 2 -formyl-3-penty..4(4floohnl--tbtlihnlioymty--spoyprdn (Example 205, Step A) in tetrahydrofuran (1 mL) was added and the mixture warmed to room temperature. After 30 min. the mixture was quenched with water and extracted with ethyl acetate. Silica gel chromatography (95:5 hexanes/ethyl acetate) afforded a colorless solid (20 mg). 1H NMR (CDCI3, 300 MHz): 8 7.44-7.36 (in, 6H), 7.34-7.27 (in, 4H), 7.08-6.98 (in, SH), 6.59 (dd, 16.7 Hz, 2.7 Hz, 1H), 5.48 (dd, 10.5 Hz, 2.8 Hz, 1H), 4.26 2H), 3.16 (sept, 6.6 Hz, 1H), 2.29 (mn, 2H), 1.4-1.2 (mn, 2H), 1.19 6.6 Hz, 6H), 1.15 (mn, 4H), 0.98 9H), 0.78 6.8 Hz, 3H).

Step B: 2 -Ethenvl3penty4.(4uorophenvl)5-hdroxmthl- 6 isopropylp2yridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1 H NMR (CDCI3, 300 MHz): 8 7.17 2H), 7.14 2H), 7.04 (dd, 16.7 Hz 10.5 Hz, 1H), 6.61 (dd, 16.7 Hz,- 2.8 Hz, 1H), 5.51 (dd, 10.5 Hz, 2.8 Hz, 1H), 4.36 3.45 (sept, 6.7 Hz, 1H), 2.32 (mn, 2H), 1.37 6.6 Hz, 6H), 1.34. (mn 2H), 1.15 (mn, 4H), 0.'80 6.6 Hz, 3H). FAB-MS: calculated for. C22H28FN0 341; found 342 Anal. calculated for C22H28FNO: C, 77.38; H, 8.27; N, 4.10. Found: C, 77.15; H, 7.98; N, 4.06.

EXAMPLE-215 2 2 arboetoxethxeth--enl-4-(4- luorphenvfl)Shydro~ehI isopropylpyridine Step A: 2 2 -Carbomethoxvethen -3enl 4 (t-butvldipenylsiloV) eff &ivI~rovsolrdi A mixture of the intermediate obtained in Example 205, Step A (50 ing, 322 WO 98/04528 WO 9804528PCTIUS97/13248 o ramol) and methyl (triphenylphosphoranylidene)acetate (31 mg, 1.1 equiv) in toluene (5 mL) was heated to reflux for 5 h. The mixture was cooled to rt and concentrated in vacuo. Silica gel chromatography provided a yellow oil (60 mg).

1H NMR (CDCI3, 300 MHz): 8 7.96 15.1 Hz, 1H), 7.42 (in, 6H), 7.34-7.21 (mn, 7.05 2H), 7.03 2H), 4.28 2H), 3.84 3H), 3.17 (sept, 6.8 Hz, 1H), 2.38 (in, 2H), 1.31 (in, 2H), 1.19 6.6 Hz, 6H), 1.14 (in, 4H), 1.00 9H), 0.79 6.6 Hz, 3H).

Step B: 2-(2-CarboinethoxVethenyl)-3-pentvl-4-(4-fluorophenvl)-5hydroxymethyl-6-isopropvlpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1H NMR (CDCl3, 300 MHz): d 7.95 15.1 Hz, 1H), 7.25 15.1 Hz, 1H), 7.17 2H), 7.15 2H), 4.3.7 3.7 Hz, 2H), 3.84 3H), 3.45 (se pt, 6.6 Hz, 414), 2.40 (in, 2H), 1.35 6.6 Hz, 6H), 1.3 (in, 4H), 1.14 (mn, 4H), 1.00 9H), 0.79 6.6 Hz, 3H). EI-MS: calculated for C24H30FN03 399; found 399 Anal. calculated for C24H30FN03: C, 72.16; H, 7.57; N, 3.51. Found: C, 71.79; H, 7.50; N, 3.32. mp 82-83 0

C.

EXAMPLE 216 2 -(l-Methoxveffiyl)-3-pentvl-4-(4-fluoropheny1)-5-hvdroxymethvl-6 isopropylpyridine The title compound was prepared from the intermediate obtained in Example 210, Step A by the procedures described in Example 201, Step A, and Example.198, Step D. 1H NMR (CDCl3, 300 MI-z) 8 7.15 (mn, 4H), 4.75 6.3 Hz, 1H), 4.35 3.7 Hz, 2H), 3.44 (sept, 6.4 Hz, 1H), 3.31 3H), 2.4-2.2 (in, 2H), 1.58 (d, 6.3 Hz, 3H); 1.35 6.3 Hz, 3H), 1.34 6.6 Hz, 3H), 1.27 (mn, 2H), 1.11 (in, 4H), 0.78 6.6 Hz, 3H). FAB-MS: calculated for C23H32FN02 373; found 374 Anal.

calculated for C23H32FN02: C, 73.96; H, 8.64; F, 5.09; N, 3.75. Fo und: C,-73.92; H, 8.75; F, 4.93; N, 3.60.

323 t S WO 98/04528 PCTIUS97/13248 EXAMPLE 217 2-lEhxehl--etl4(-loohnl--y.doyehl6 isoPropylpyridine The title compound was prepared .from the. intermediate obtained in Example 210, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. !H NMR (CDCl3, 300 MHz): B 7.16 (in, 4H), 4.83 6.5 Hz, 1H), 4.34 4.4 Hz, 2H), 3.5-3.2 (in, 3H), 2.4-2.2 (in, 2H), 1.57 6.6 Hz, 3H), 1.34 6.6 Hz, 3H), 1.33 6.6 Hz, 3H), 1.27 (m 2H), 1.10 (mn, 4H), 1.20 7.2 Hz, 3H), 0.77 6.8 Hz, 3H). FAB-MS: calculated for C24H34FN0 2 387; found 388 Anal. calculated for C24H34FN0 2 C, 74.38; H, 8.84; F, 4.90; N, 3.61. Found:

C,

74.67; H, 9.00; F, 5.14; N, 3.27.

EXAMPLE 218 Oil

HO'

2-c!I3vnv--4fur~ey)-7yrxmty--s~ovprdn Step A: 2 -Acetl3penW.4..(fophluropenV15..tvldip diilox)etil- 6 -isopropylpyridine I- C WO 98/04528 WO 9804528PCTIIJS97/13248 0 A mixture of the intermediate obtained in Example 210, Step A (210 mg, 0.35 mmol), pyridinium chlorochromate (113 mg, 1.5 equiv), and Celite (110 mg) in CH2Cl2 (13 mL) was stirred overnight. The mixture was filtered through a short pad of silica gel. Silica gel chromatography (95:5 hexanes/ethyl acetate) afforded a colorless solid (120 mg, 1H NM (CDCl3, 300 MHz): 8 7.41 (in, 6H), 7.34 (in, 4H), 7.06 2H), 7.03 2H), 4.29 2H), 3.18 (sept, 6.6 Hz, 1H), 2.75 3H), 2.54 (in, 2H), 1.3 (in, 2H), 1.19 6.6 Hz, 6H), 1.15 (in, 4H), 1.00 9H), 0.77 (in, 3H).

Step B: 2 -AcetVI-3-pentyl-4-(4-fluorophenyl)-5-hvdroxymethyl-6isopropylpyridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1 H NMR (CDC13, 300 MHz): 8 7.17 2H), 7.15 2H), 4.39 5.2 Hz, 2H), 3.48 (sept, 6.8 Hz, 3H), 2.74 3H), 2.55 (mn, 2H), 1.35 6.6 Hz, 6H), 1.3 (in, 2H), 1.1 (in, 4H), 0.77 6.6 Hz, 3H). FAB-MS: calculated for C22H28FN02 357; found 358 Anal. calculated for C22H28FN02: C, 73.92; H, 7.90; N, 3.92. Found: C, 73.89; H, 8.14; N, 3.88. rnp 69- 0

C.

EXAMPLE 219 2 -(1-Hydroxv-1-me hylethyl)-3penyl4(4fluorophenyl)5hydroxiethyl6.

isopropYlpRvidine Step A: 2 -(l-Hvdrox-l-nethylethl)3pntyl-4(4.fluoropheny).5 (t-butyldiphenylsiloxy~methyl-&sopropylpy *.dine Prepared from the intermediate obtained in Example 218, Step A by the procedure described in Example 205, Step B. 1 H NM (CDCI3, 300 MHz): 8 7.41 (in, 6H), 7.32 4H), 7.08 (in, 41H), 4.25 211), 3.13 (sept, 6.8 Hz, 1H), 2.44 (mn, 211), 1.62 6H), 1.2 (in, 211), 1.17 6.6 H-lz, 6H), 1.03 (mn, 4H), 1.01 9H), 0.72 6.8 Hz, 3H).

325 WO 98/04528 PTU9/3 PCT/US97/13248 0 Step B: 2-(l-Hydroxy-l-methylethyl)-3-pentyl-4-(4-fluorophenyl)-5hydroxymethyl-6-isopropylp~yridine The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 198, Step D. 1H NM (CDCl3, 300 MHz): 6 7.19 (in, 4H), 4.36 5.5 Hz, 2H), 3.48 6(sept, 6.6 Hz, 1H), 2.47 (in, 2H), 1.60 6H), 1.35 6.6 Hz, 1.25 (in, 2H), 1.05 (mn, 4H), 0.72 6.6 Hz, 3H). FAB-MS: calculated for C23H32FN02 373; found 374 Anal. calculated for C23H32FN02: C, 73.96; H, 8.63; F, 5.09; N, 3.75. Found: C, 73.88; H, 8.64; F, 4.81; N, 3.59. mp 180-182TC.

EXAMPLE 220 2 -(l-Methoxv-l-methvl)ethyl-3-pentyl-4-(4-fluorophenyl)-5-hydroxymethyl-6.

isopropylpyridine The title compound was prepared from the intermediate obtained in Example 219, Step A by the procedures described in Example 201, Step A, and Example 198, Step D. 1H NMR (CDCL3, 300 MHz): 8 7.26-7.12 (in, 4H), 4.34 Hz, 2H), 3.40 (sept, 6.5 Hz, 1H), 3.12 3H), 2.76 (mn, 2H), 1.67 6H), 1.31 6.6 Hz, 6H), 1.3-0.9 (rii, 6H), 0.72 6.8 Hz, 3H). FAB-MS: calculated for C24H34FN02 387; found 388 Anal. calculated for C24H34FN02: C, .74.38; fl, 8.84; N, 3.61.

Found: C, 74.64; H, 8.97; N, 3.61. mp, 57-591C.

326 WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 221

HO

.QEI

C

isopropvlpyridine The title compound was prepared from. the, .intermediate obtained in Example 219, Step A by the procedures described jn- Example 201, Step A, and Exam :ple 198, Step D. 1 H NMR (CDC13, 300 MHz): 8 7.23-7,11 (in, 4H), 4.33 5.1 Hz, 2H), 3.39 (sept, 6.6 Hz, 1H), 3.28 7.0-Hz, 2H), 2.80 (in, 2H), 1.67 6Hj,), 1.30 0 6.6 Hz, 6H), 1.15 7.0 Hz, 3 1.15-0.9 (Tn, 6H)- 0.71 Hz, 3H). FAB-MS: calculated for C25H36FNO2 401; found 402 Anal. calculated for C25H36FN02: C, 7'4.7'8;H, 9.04; N, 3.49. Found: C, 74.89; H, 9.22; N, 3.24.

EXAMPLE 222 2 6 -Diisoproyl-3-(1hydroxveffil)4(4.fluorophenl)5propVl-pvridine Step A: 2 6 -Diisopropyl-3-1-hdrox.. 2-S)tolulStIfoxveiylA..(4-~ A solution of lithium diisopropylainide was prep'ared by the addition of nbutyllithium (15 mL, 23 inmol, 1.6 M/hexane) to a solution of diilIsopropylainine (3 mL, 23 inmol) in anhydrous tetrahydrofuran (100 mL) at 0 To this was added a 327 V WO 98/04528 PCT/US97/13248 0 solution of (S)-(-)-methyl p-tolylsulfoxide (3.6 g, 23 mmol) in anhydrous tetrahydrofuran (20 mL) dropwise, with stirring. The mixture was stirred at 0°C for 2 hr, then treated with a solution of 2 6 -diisopropyl-4-(4-fluorophenyl)-5propyl- 3 -pyridinecarboxaldehyde (Example 101, Step A) (3.8 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) dropwise and with stirring. After stirring min at 0 the reaction mixture was quenched by the addition of saturated NH4Cl mL). The solvent was removed in vacuo and the residue partitioned between CHCI3 (300 mL) and water (100 mL). The organic phase was washed with saturated NaHCO 3 (100 mL), water (100 mL) and brine (50 mL), dried over MgSO4 and concentrated. The crude product consisted of a 1.3:1 ratio of diastereomers which were separated by flash chromatography (step gradient 5%-15%-20% ethyl acetate/hexane), which afforded 1.5 g of the faster diastereomer followed by 2.7 g of the slower diastereomer (II) and 0.83 g of a mixed fraction. Diastereomer

HI

is recrystallized once from ethanol/hexane to afford fine white needles (1.7 g, 3.5 mmol, 30% yield). I: mp 225-22 7 Rf 0.4 (30% ethyl acetate/hexane); 1 H NMR (CDC1 3 500 MHz): 8 7.23 4 6.95 2 6.63 1 6.55 1 5.03 11.0 Hz, 1 4.53 (s,1 3.79 2 3.11 (sept, J= 6.6 Hz, 1 2.46 3 2.30 (dd, J= L9, 14.1 Hz, 1 H),'2.01 2 1.25 12 1.16 2 0.64 (t, J 7.3 Hz, 3I). FAB-MS: calcd for C29H36FN0 2 S, 481, found 482 (M II: mp 205-206'C; Rf 0.2 (30% ethyl acetate/hexane); 1H NMR (CDC13, 500 MHz): 5 7.38 J 8.2 Hz, 2 7.24 2 7.05 1 7.03 1 6.97 1 6.87 (m 1 4.84 (dt, 2.7,10.8 Hz,1 H)',3.69 (sept, =6.6 Hz, 1 3.49 (dd, J 10.8, 13.1 Hz, 1 3.14 (sept, J= 6.6 Hz, 1 3.00 J 2.5 Hz, 1 2.68 (dd, J 2.5, 13.1 Hz, 1 2.41 3 2.10 2 1.23 14 0.69 J 7.3 Hz, 3 FAB-MS calcd for C29H36FN0 2 S, 481, found 482 Step B I+)-26-Diisopropvl-3-(1-hVdroxeth l )-4-(4-florophenl)-5propylpyridine A suspension of Raney nickel (20 g) in methanol (50 mL) was stirred under a hydrogen atmosphere for 1 hr. The suspension was cooled to 0 *C and treated with a solution of the intermediate II obtained in Step A (1.6 g, 3.3 mmol) in methanol (50 mL). The suspension was stirred vigorously under hydrogen at 0 'C for 16 hr. After purging with argon, the methanolic solution was decanted from the catalyst, the catalyst washed and decanted 3 more times with methanol. The combined decanted solution was filtered through celite and concentrated. Flash chromatography through a plug of silica (10% ethyl acetatehexane) afforded the title compound (99% as a white solid (1.1 g, 3.2 mmol, 1 H NMR (CDC13, 300 MHz): 8 7.11 3H), 7.04 1 4.64 (dq, 6.6 Hz, 1H), 3.73 (sept,

I

328 -r WO 98/04528 WO 9804528PCTIUS97/13248 o 6.6 Hz, 1 3.18 (sept, J 6.6 Hz, 1 2.15 (in, 2 1.56 J 3.7 Hz, 1 1.39 J 6.6 Hz, 3 1.28 (in, 14 0.73. J 7.35 Hz, 3 FAB-MS calcd for C22H30FNO, 343, found 344 Anal. Calcd for C22H3OFNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53. Found: C, 76.98; H, 8.71; N, 3.76; F, 5.73. [aID 41.5* (CHCl3). mp 101-103*C. Rf =0.3 (10% ethyl acetate/hexane).

EXAMPLE 223

F

O H

N

Sp A: 2 ,6-Diis~popI-4-(4-fluoropheny)5propy13-[(l1xo.2toluylstdfoxv)ethyl)lpvridine To a solution of 'diisopropylamnine (4.8 mL, 36.7 mmol) in anhydrous tetrahydrofuran (160 mL) was added .n-butyllithium, (23 m.L. 33.4 mmol, 1.45 at 0 0 C. To the reaction mixture was added a solution of (S)-()-methyl ptolylsulfoxide (5.65 36.7 mmol) in anhydrous tetrahydrofuran (30 mL). The midxture was-stirr Ifor 1-.5 hours, the'n treated -with a solution of 2,6-diisopropyl-4- 4 -fluorophenyl)-5-propyl-3-pyridinecarboxaldehyde (Example 101, Step A) (8.0 g, 24.4 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 0 After stirring minutes' at 0 0 the reaction was quenched by addition of saturated ammonium chloride solution mL). The solvent was removed in vacuo, and the residue dissolved in choroform (480 rnL. The organic phase was washed with water (2 x 160 mL) and brine (160 rnL), dried over magnesium sulfate and. concentrated. The residue was dissolvedl in diahlromethane (8*00 inL) and manganese (IV) dioxide g, 4641minol) is added. The suspension was stirred vigorously with a mechanical stirrer and refluxed for 16 hours. The manganese dioxide was removed by ifitration through celite, washed with dichioromethane,,(100 mL) and the solvent removed in vacuo. Filtration through a pad of silica gel diethyl etherdichloromethane) afforded a white solid (10.2 g, 21.3 inmol, 1H NMR (300 MIHz, CDC13): 8 7.39 (mn, 7.26 (in, 2 7.05 (in, 4 3.72 J 16 Hz, 1 H), WO 98/04528 PCT/US97/13248 0 3.38 J 16 Hz, 1 3.24 (sept, I 6.6 Hz, 1 2.59 (sept, J 6.6 Hz, 1 2.42 (s, 3 2.32 2 1.27 8 1.20 8 0.75 J 7.35 Hz, 3 FAB-MS: calculated for C29H34FN0 2 S, 479, found 480 mp 140-142°C. Rf 0.2 ethyl acetate/hexane).

Step B: 2,6-DiisopropVl-3-(1-hvdroxv-2-(S)-toluylsulfoxyethyl)-4-(4 To a solution of the intermediate obtained in Step A (5.8 g, 12.1 mmol) in anhydrous tetrahydrofuran (145 mL) at -78'C was added rapidly a solution of lithium aluminum hydride (169 mL, 169 mmol, 1.0 M/THF). After 15 minutes the reaction mixture became turbid and was slowly quenched at -78C with water (6 mL) 20% aqueous sodium hydroxide solution (6 mL) and water (18 mL). The reaction mixture was allowed to warm to room temperature and the resulting suspension was filtered through a pad of celite. The solvent was evaporated and the residue purified by silica gel chromatography (10% diethyl ether/dichloromethane) to afford a white solid (4.8 g, 10 m mol, 1 H NMR (300 MHz, CDC1 3 8 7.41 J 8.5 Hz, 2 7.27 2 7.06 J 7 Hz, 2 H), 7.00 1 6.89 1 4.85 (dt, J 2.2, 11 Hz, 1 3.71 (sept, J 6.6 Hz, 1 H), 3.51 (dd, J 11, 13 Hz, 1 3:16 (sept, J =6.6 Hz, 1 3.02 J 2.2 Hz, 1 2.70 (dd, J 2.2, 13 Hz, 1 2.43 3 2.12 2 1.25 14 0.71 J 7.35 Hz, 3 FAB-MS calculated for C29H36FN0 2 S, 481, found 482 mp 204- 206C. Rf 0.2 (30% ethyl acetate/hexane).

Step C: +)-2,6-Diisopropvl-3(l-hydroxvethvl)4-(4-fluorophenyl)propylpyridine A suspension of Raney nickel (40 g, washed with 3 x 100mL ethanol) in ethanol (80 mL) was stirred under hydrogen atmosphere for 1.5 hours. The suspension was treated with a solution of the intermediate obtained in Step B (4.1 g, mmol) in ethanol (180 mL) at room temperature and stirred vigorously for hours. The suspension was carefully filtered through celite and concentrated.

Filtration through silica gel (CH2C12) afforded the title.compound (99% as a white solid (2.74 g, 8 mmol, 94 1 H NMR (300 MHz, CDC13): 8 7.11 3 H), 7.04 1 4.64 (dq, J= 3.7,6.6 Hz, 1 3.73 (sept, J 6.6 Hz, 1 3.18 (sept, J 6.6 Hz, 1 2.15 2 1.56 J= 3.7 Hz, 1 1.39 J 6.6 Hz, 3 1.28 (m, 14 0.73 J 7.35 Hz, 3 FAB-MS calculated for (C22H31FNO, M+H) 344, found 344. Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53; Found: C, 77.20; H, 8.97; N, 4.01; F, 5.60. [a]D +39.4' (CH2C12). mp 104-106C. Rf 0.4 (CH2C1 2 r i il- WO 98/04528 WO 9804528PCTIUS97/13248 0 EXAMPLE 224

F

OH

N

2 6 Diisopropl-3(-hydroxeyl)4(4fluorophen1)5proptvl.din Step A: 2 -ispo~l3(-xehl--(-loohnl--rpl~rdn TO 2 6 -diisopropyl-3(bhydroxyethyl)4(4..fluoropheflyl)-5 propylpyridine (Example 101) (8.03 g, 23.4 mmol) in CH2CI2 (600 mL) was., added pyridinium chlorochromate (10.08 g' 46.76 mmol) and celite (10.1 g) under argon.

The reaction was stirred at room temperature for 16 hours. The reaction was added to a 1:1 mixture of diethyl ether/hexane (1 then filtered through a plug of silica. The pad was washed with 150 mL of diethyl ether and the combined filtrates were concentrated in vacuo to afford a white solid. (7.95 g,i. 23.3 mmol,. 1H NMR (300 MHz,.CDC!3): S 7 1 2(m, 3.26 (septetj 6.6 Hz, 1 H),"2.85 (septet, J -6.6 Hz, 1 2.36 (in, 2 1.97 3 1.33 (in, 14 0.774 I 7.4 Hz, 3 H).

FAB-MS calcd for (C22H28NOF) 341, found 342 mp 131-133 C. Rf CH2CI2/hexane)., proOvlpyridine To a solution of (lS, 2 R)-(+)-N-methylephedr'ine. (31.1 g, 0.174 mol) in, ether (208 mL) was added lithium aluminum hydride (iM/diethyl ether, 1..5 eq.,.174 mL) dropwise at 0 0 C under argon. The reaction was refluxed. for 1.5 h. turning from a 25 dear solution to a white milky solution. The reaction was cooled to room temperature and then -78 0 C. The interm~diate'obtainied in Step A (39.53''-0.116 inmol) was dissolved in 400 mL of dry diethyl ether and cooled to 0 0 C for a dropwise addition to the' reaction xihixture 1(-2 mbL/mmi., the temperature .should not rise above The reaction wa s kept at -78 0 C for 4.0 hours and then allowed to warm overnight. The reaction was quenched at 0 0 C with isopropanol 331 WO 98/04528 PCT/US97/13248 0 (70 mL) and diluted With ether (700 mL), washed With water (4 x 500 mL), 10% HCl (2 x 500 mL), brine (2 x 500 mL) and dried with MgSO4. Filtration and concentration afforded a residue which was filtered through a pad of silica (600 g, diethyl ether/hexane) to give the title compound (97% as a white solid (36.67 g, 107 mmol, 1 H NMR (300 MHz, CDCl 3 7.11 (in, 4 4.67 (dq, J 3.3, 6.6 Hz, 1 3.74 (septet, I 6.6 Hz, 1 3.20 (septet, I=6.6 Hz, 1 2.17 (in, 2 1.61 j 2.9 Hz, 1 1.40 J 7.0 Hz, 3 1.30 (i,14 0.741 j 7.4 Hz, 3 FAB-MS: calcd for (C22H30N0F) 343, found 344 mp 102-104*C.

Rf =0.2 (60% CH2C12/hexane).

EXAMPLE 225 2 -IsoropVl31-h 6xvmethl4.(4fluoro~hen) -pntl-64 2 -t Phenylethyl)pyrjdine Step A: 2 -Bromometh -3pen w1.p(4fluorpnv) 5 (~u 1 diphenylsiogxv)methv1-6isopropV1.yrdin Prepared from the intermediate obtained in Example 200, Step B by the procedure described in Example 47, Step B. 1 H NMR (300 MIHz,

CDCI

3 8 7.40 (mn, 6H), 7.32 (in, 4H), 7.04 (in, 4H), 4.64 211), 4.26 2H), 3.14 (sept, 6.8 Hz, 1H), 2.38 (in, 2H), 1.34 (mn, 2H), 1.17 7.0 Hz, 6H), 1.12 (in, 1.00 9H), 0.78 6.6 Hz, 3H)- 2 5 S tep B 2 i t v t) o p o o m t v e t l 4 -l o o h n l -t butydietvph )mhvl6n o ef I riien~~~ll bu Ldihylsiox iefv1~p A mixture of diethylphosphite (280 ing) and sodium metal (50 mg) in benzene (5 mL) was stirred overnight. A mixture of the sodium diethyiphosphite solution (1 mL) and the intermediate obtained in Step A (110 mng, 0.17 nimol) in benzene (5 mL) was refluxed for 2 h. The mixture was concentrated in vacuo. The 332 r0f~* 09A- WO 98/04528 PCT/US97/13248 0 residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium chloride solution (3 x 10 mL). Silica gel chromatography (70:30 hexanes/ethyl acetate) provided a yellow oil (80 mg, 1H NMR (300 MHz,

CDCI

3 8 7.41 6H), 7.32 4H), 7.04 4H), 4.25 2H), 4.15 (dq, 7.2 Hz, 4H), 3.49 22.4 Hz, 2H), 3.14 (sept, 6.8 Hz, 1H), 2.38 2H), 1.30 7.2 Hz, 6H), 1.25 2H), 1.16 6.6 Hz, 6H), 1.10 4H), 0.99 9H), 0.77 6.8 Hz, 3H).

Step C: 2-(trans-2-Phenylethenyl)-3-pent-4-(4-fluorophenl)-5- (t-butvldiphenylsiloxy)methl-6-isopropylpyridine Sodium hydride (8 mg) was added to a mixture of the intermediate obtained in Step B (90 mg, 128 pmol) and benzaldehyde (20 mg) in THF (2.7 mL). After min. the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Silica gel chromatography (97:3 hexanes/ethyl acetate) provided a yellow oil (100 mg). 1H NMR (300 MHz, CDC1 3 8 8.00 15.4 Hz, 1H), 7.61 2H), 7.45-7.27 14H), 7.04 4H), 4.29 2H), 3.20 (sept, 6.4 Hz, 1H), 2.38 2H), 1.40 2H), 1.25 6.6 Hz, 6H), 1.18 4H), 1.00 9H), 0.81 3H).

Step D: 2 -(trans- 2 -Phenylethenyl)-3-pentyl-4-(4-fluorophenyl)-5hydroxymethyl-6-isopropylpyridine The title compound was prepared from the intermediate obtained in Step C by the procedure described in Example 198, Step D. Silica gel chromatography (94:6 hexanes/ethyl acetate) provided a yellow oil (24 mg, 38%).

1 H NMR (300 MHz, CDC 3 8 8.02 15.5 Hz, 1H), 7.63 2H), 7.43-7.31 4H), 7.16 4H), 4.38 2H), 3.48 (sept, 6.6 Hz, 1H), 2.41 2H), 1.42 6.6 Hz, 6H), 1.4 2H), 1.19 4H), 0.82 6.8 Hz, 3H). FAB-MS: calculated for C28H32FNO 417; found 418 Rf= 0.13 (90:10 hexanes/ethyl acetate). Anal. calculated for C28H32FNO: C, 80.54; H, 7.72; N, 3.35. Found: C, 80.34; H, 7.79; N, 3.10. mp 98- 100 0

C.

EXAMPLE.226

F

HO

N

WO 98/04528 PCT/US97/13248 0 2-Isopropyl-3-hvdroxymethyl-4-(4-fluorophenyl)-5-penyl-6-( 2 -methylpropenyl)pyridine The title compound was prepared as a yellow oil from the intermediate obtained in Example 225, Step B by the procedure described in Example 225, Step C and Example 198, Step D. The product was obtained as an inseparable mixture of the title compound and the corresponding deconjugated olefin in a ratio of 84:16.

111 NMR (300 MHz, CDCl 3 8 7.16 4H), 6.43 1H), 4.82 1H, minor isomer), 4.60 1H, minor isomer), 4.36 2H), 3.58 2H, minor isomer), 3.46 (sept, 6.6 Hz, 1H), 2.26 2H), 2.07 3H), 1.99 3H), 1.82 3H, minor isomer), 1.35 (d, 7.0 Hz, 6H), 1.28 2H), 1.13 4H), 0.79 6.8 Hz, 3H). FAB-MS: calculated for C24H32FNO 369; found 370 Rf 0.16 (90:10 hexanes/ethyl acetate). Anal.

calculated for C24H32FNO: C, 78.01; H, 8.73; N, 3.79.' Found: C, 77.73; H, 8.86; N, 3.97.' EXAMPLE 227

F

HO

2-Isopr l-3-hdro ethvl-4-(4-fluorophenvl)-5-pentvl-6-2-pheny1ethyl)pyridine The title compound was prepared as a yellow oil from the intermediate obtained in Example 225, Step D by the procedure'described in Example 1, Step H.

1H NMR (300 MHz, CDCI 3 8 7.29-7.19 5H), 7.14 2H), 7.12 2H), 4.34 (s, 2H), 3.44 (sept, 6.6 Hz, 1H), 3.18-3.10 4H), 2.20 2H), 1.35 6.6 Hz, 6H), 1.22 2H), 1.08 4H), 0.76 6.8 Hz, 3H). FAB-MS: calculated for C28H34FNO 419; found 420 Rf 0.21 (90:10 hexanes/ethyl acetate). Anal. calculated for C28H34FNO: C, 80.18; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.15; N, 3.24.

I -i C WO 98/04528 WO 9804528PCTIUS97/13248 EXAMPLE 228

HO

2 -Isopropvl- 3 -hdroxmethl-4(4-fluoropheny)5-pentl.&(2-.methvlpropyl)pvridine The title compound was prepared as a colorless crystalline solid from the intermediate obtained in Example 226 by the procedure described in Example 1, Step H. 1 H NMR (300 Mffz, CDCl 3 8 7.15 (in, 4H), 4.33 5.2 Hz, 2H), 3.41 _(sept, 6.6 Hz, 1H), 2.67 7.0 Hz, 2H), 2.34 (mn, 2H), 2.25 (in, 2H), 1.32 6.6 Hz, 1.20 2H), 1.12(in, 4H), 0.99 6.6'-Hz, 6H), 0.78 6.6IHz, 31). FAB-MS:. calculated for C24H34FNO 371; found 372 Rf 0.77 (90:10 hexanes/ethyl' acetate).

Anal. calculated for C24H34FN0: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.4.9; H, 9.20; 3.73.

EXAMPLE 2-29

HO

2 -Isoprop-vl-3hdroxymethyl-4-14.fluorophenivl)$...pentyl-6(3.methvl.

butvl)pvridi ne The., title compound was prepared as -a yellow oil from the intermediate obtained in Example 225, Step B by the procedures described in Example 225, Steps C and D, and Example 1, Step H. 1H NMR (300 MHz, CDCI 3 8 7.14 (i 4H), 4.34 335 m"r Vw o X" WO 98/04528 PCTIUS97/13248 o 3.7 Hz, 2H), 3.41 (sept, 6.8 Hz, 1H), 2.80 (in, 2H), 2.26 (in, 2H), 1.68 (in, 3H), 1.33 6.6 Hz, 6H), 1.29 (in, 2H), 1.12 (in, 0.98 6.3 Hz, 6H), 0.79 6.6 Hz, 3H).

FAB-MS: calculated for C25H36FN0 385; found 386 Rf 0.15 (90:10 hexanes/ethyl acetate). Anal. calculated for C25H36FNO: C, 77.88; H, 9.41; N, 3.63.

Found: C, 77.62; H, 9.13; N, 3.42.

EXAMPLE 230

F

HO

N 2 -IsopropV3hvdrxv nethv-4-(-lA(4forophenl)56788tthdo 8 diMethylauinoine Step A: 2 -f( 4 -Fluorophenvl)methylenel..4-methy1..3.oxopentanoic acid To a solution of ethyl isobutyryl acetate (30 gf 0.190 mol) in ethanol (75 mL) was added cyclohexane (120 rnL), acetic acid (0.6 mL), piperidine (0.6 mL), and 4fluorobenzaldehyde (20.35 mL, 0.190 mol). The reaction was heated at reflux with a Dean-Starck trap for 5 hours. The mixture was poured into 200 mL of diethyl ether and washed with brine (1 x 75 mL). The organic layer was dried with MgSO4, filtered, and concentrated to afford an orange oil. The product was taken directly to the next step without any further purification. Rf 0.1 (50% CH2CI2/hexane).

Step B: 2 -IsO~roPvl-3carboethox4(4fluoropheyl)5678tetrahvdro-8,8 dimethylquinoline To a solution of lithium bis(triinethylsilyl)ainide (1.0 M/THF, 2 eq. 13.6 mL) in THE (15 inL was added 2 2 -dimethylcyclohexanone (1.88 mL, 13.6 minol) at 78*C. The reaction was stirred for 15 minutes, and then the intermediate obtained in Step A (3 g, 11.4 minol) was added dropwise. The reaction was stirred overnight and allowed to warm to room temperature. -To the crude product was added acetic acid (19.4 inL), ammonium acetate (2.62 g, 34.0 minol) and copper acetate (5.14 g, 28.3 mmol). The reaction mixture was heated at 100 0 C and the THEF was removed 336 WO 98/04528 WO 9804528PCTIUS97/13248 o by distillation. The reaction was heated to 130VC and allowed to reflux for 24 hours.

Ethyl acetate (100 mL) was added and washed with sodium bicarbonate (2 x mL), water (2 x 20 mL), brine (2 x 20 mnL), dried with MgSO4, filtered, and concentrated to afford an oil. Flash chromatography (5 ethyl acetate/hexane) afforded a white solid (1.36 g, 3.7 mmol, 1 H NMR (300 MI-z, CDCI3): 8 7.17 (in, 2 7.08 (in, 2 3.98 J 7.4 Hz, 2 3.03 (septet, J 7.0 Hz, 1 2.35 J 5.9 Hz, 2 1.70 (in, 4 1.36 6 1.31 J 4.1 Hz, 6 0.965 J 7.4 Hz, 3 FAB-MS: calculated for (C23FI2BFNO) 369, found 370 mp, 124- 126*C. Rf =0.6 (50% CH2Cl2/hexane).

Step C: 2 -Isopropvl- 3 -hvdroxymiehyl-4-(4-fluorophenVl)-5,6,7,8..tetrahvdro.

8,8-dimethvlguinoline To theitermediate obtained in Step B (1.32 g, 3.6 minol) in THF mL) was added lithium aluminum hydride (1 M/THF, 2 eq., 7.2 mL) dropwise. The reaction was refiuxed for 1.5 hours and cooled to room -temperature. Then the reaction was quenched with water and the THF was evaporated. The residue. was partitined beween d ethyeter (150 rnL) arfid water (100, The organic layer was washed with brine (1 x 100 mb), dried with MgSO4, filtered, and concentrated to.. afford a. solid. Flash chromatography (40% CH2Cl2/hexane) afforded te title compound as a white solid (808 mng, 2.5 inmol, 1 H NMR (300 MHz, CDCl3): 8 7.13 J 7.0 Hz,,4 4.36, I 5.5 HZ, 2 '3.42 (septet, J 6.6 Hz, 1 2.24 J 5.5 Hz,. 2 1.67' -4 1.32 (in, 13 FAB-MS: 'calculated for C21 F0 .327,. found 328 mp! .146-149 0 Rf =0.2 CHF2CI2/hexane). EXAMPLE 2A

F

OH

NI

-N

2 -IsopropVl- 3 -(l-hydroxvethyl)-4-(4-fluorophen1).5,6,7,8.tetrahvdro.88dirnethylquinoline 337 79 WO 98/04528 WO 9804528PCT/US97/13248 0 Step A: 2 -Isopropvl-3-carboxadehyd-4(4fluorophenl)5678tetahdro- 8,8-dimethylcjuinoline To a solution of 2 -isopropyl-3-hydroxymethyl-4(4..fluorophenyl)5,6, 7 8 tetrahydro-8,8-dimethylquinolmne (Example 230) (765 mg, 2.34 mmol) in dichioromethane (30 mL) was added Celite (1.01 g) and pyridinium chlorochromate (1.01 g, 4.69 mmol). The reaction was stirred at room temperature for 2 hours and then added to a 1:1 diethyl ether/hexane solution (500 mL). The solution was passed through a pad of silica and washed several times with diethyl ether.

Concentration yielded a white solid (568 mg, 1.75 mmol, 1 H NMR (300 MI-lz, CDCl3): 8 9.78 1 7.15 (in, 4 3.86 (septet, I 6.6 Hz, 1 2.31 I 5.9 Hz, 2 1.70 (in, 4 1.37 6 1.30 (in, 6 FAB-MS: calculated for (C2jH24FN0) 325, found 326 mp 94-96*C. Rf 0.7 (50% CH2CI2/hexane).

Step B: 2 -Isopropyl3(-hdroxyethyl)44.fluorophenV)-5678tetrh~dr 8 8 -dimethVlguinoline To the intermediate obtained in Step A (508 mg, 1.56 minol) in THF (20 mL was added methylnagnesium bromide (0.57 mL, 3.0 M/ether, 1.1 eq.) dropwise at -78*C. After 2 hours, the reaction was quenched with saturated ammonium chloride (30 mL) and diluted with dichloromethane (100 mL). The solid' was filtered and the mother liquor was washed with water (1 x 50 mL), brine (1 x 50 dried with MgSO4,, filtered, and concentrated to afford a white solid. Flash chromatography (50% o.dichlorometharielhexane) gave a white solid'(205 mng, 0.6 mmol, 1 H NMR (300 MHz, CDCl3): 8 7.13. (in, 3 7.01 (in, 1 4.73, 4.71 (dq, I 3.7, 6.6 Hz, 1 3.74 (septet, I 6.6 Hz, 1 2.13 I 4.4 Hz, 2 1.64 (in, 3 1.31 (mn, 17 FAB-MS: calculated for (C22H27FN0) 341, found 342 mp 56.5-58.5 0 C. Rf =0.2 (50% CH2CI2/hexane).

EXAMPLE-232

F

HOI

*NN

338 WO 98/04528 WO 9804528PCrIUS97/13248 o 2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-( 1-butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobeazaldehyde and 3-methyl-1-phenyl-2-butanone according to the procedures described in Example 230. 1 H NMiR (300 MHz, CDCl3): 8 7.16 (in, 3 H), 6.91 (mn, 6 4.45 I 5.1 Hz, 2 3.52 (sept., J=6.6 Hz, 1 2.86 (sept., j 6.6 Hz, 1 1.55 1 1.36 (in, 6 1.17 J=6.6 Hz, 6 FAB-MS: calculated for (C24H26FN0) 363, found 364 mnp 115-117C. Rf =0.3 CH2l2 /hexane).

EXAMPLE 233

F

OH

NI

2 i 6 -Diisopropyl-3-(l-hydroxvethyl)-4-(4.fuorophenyl)-5.phenylpyridine The title compqundtwas prepared according to the procedures described in Example 231. 1 H.NMR.(300 MHz, CDC13): 8 7.14 (in, 3 6.88 (in, 6 4.80 7.0,3.71Hz, 1 3.84 (sept., I 6.6 Hz, I 2.79 (sept., I=6.6 Hz, 1 1.66 (d,J =3 .7 Hz,,1 1.48 (dj 7.0 Hz, 3H), 1.39i(m, 6H): FAB-MS: (Q19 calculated for (C25H28FN0) 377, found 378 mp155-1570C. Rf =0.4 o" 20 CH2Cl2/hexane).

EXAMPLE 234

F

HO

N

339 WO 98/04528 PCTIUS97/13248 o 2 -Isopropvl-3-hydroxymethV1.4..(4.fluorophenl)77-dimethy1.5Hcvlo penta[blpyridine The title compound was prepared from ethyl isobutyrylacetate, 4 fluorobenzaldehyde and 2 2 -dimethylcyclopentanone according to the procedures described in Example 230. 1 H NMR (300 MHz, CDCL3): 8 7.29 (in, 2 H), 7.14 (mn, 2 4.49 I 5.2 Hz, 2 3.46 (sept., J 6.6 Hz, 1 2.56 J 7.0 Hz, 2 1.90 I 7.0 H-z, 2 1.34 (in, 13 FAB-MS: calculated for (C20H24FNO) 313, found 314 mp 141-143*C. Rf 0.1 (60% CH2CI2/hexane).

EXAMPLE 235

F

OH

N

2 -Isopropyl3(hydroxethvl)4.(4fluorophenVl)7-di difl-Hclo Pentalbipyridine* The title compound was prepared according to the procedures described in Example 231. 1 H NMR(300 MIiz, CDCl 3 8 7.15 (in,4 H$,4.95 (dq, J= 6.6,3.7 Hz, 1 3.77 (sept., J=6.6 Hz,.1 2.44 (in, 2 1.88 J -7.4 Hz, 2U), -1.62 I 3.7 Hz, 1 1.48 I 7.0 Hz, 3 1.32 (in, 12 FAB-.MS: calculated for (C21;H26FN0) 327, found 328 mp.90-92 0 Rf (60% CH2CI2/hexane).

EXAWv.LE- 236

F

HO

N 340 WO 98/04528 WO 9804528PCTIUS97/13248 o 2-Isopropyl-3-hydroxvmethyl-4-(4-fluorophenyl)-5,6-dihydro-.6,6,8 trimethylguinoline The title compound was prepared from ethyl isobutyrylacetate, 4 fluorobenzaldehyde and 2,4,4-trimethyl-2-cyclohexen-1-one according to the procedures described in Example 230. 1 H NM4R (300 MHz, CDCl3): 5 7.16 (in, 4 H), 5.81 1 4.41 I 5.2 Hz, 2 3.45 (sept., I1 6.6 Hz, 1 2.29 2 2.16 (s, 3 1.58 1 1.35 j 6.6 Hz, 6 0.95 6 FAB-MS: calculated for (C22H26FN0) 339, found 340 mp 112-114*C. Rf =0.2 CH2l2 /hexane).

EXAMPLE 237

F

AOH*

N.

2 -Isopropyl-3-(l-hydroxyethyl)-4-(4-fluorophenyl)..5,6dihydro.668-.

trimethylguinoline The title cornpound was prepared according to the procedures described in Example 231. 1 H NNM (300 MHz, CDCl3): 8 7.14 (in, 3 7.00 (mr, 1 5.78 1 4.77 (dq, J 6.6, 3.7 Hz, 1 3.76 (sept.,! 6.6 Hz, 1 2.18 (sj 2 2.14 3 1.61 J=3.7 Hz, 1 1.43 J 6.6 Hz, 3 1.33 6 -0.91 6 FAB-MS: calculated for (C23H28FN0) 353, found 354 mp 117-119*C. Rf 0.3 (60% CH2CI2/hexane).

EXAMPLE 23

F

OH

HO

WO 98/04528 PCTIUS97/13248 0 Step A: 2 6 -Diisopropv1-3hdroxymethy1.4[(2benzox4fluoro)phell- Prepared from the intermediate obtained in Example 166, Step B by the methods described in Example 160, Steps A-D. 1H1 NMR (300 MHz, CDCl 3 a 1.20- 1.34 (in, 12H), 1.56-1.59 (mn, 3H), 1.68-1.74 (in, 1H1), 3.13-3.50 (in, 2H1), 4.23-4.42 (mn, 2H), 4.87-5.05 (in, 2H), 5.25-5.56 (mn, 1H), 5.23-6.03 (in, 1H1), 6.69-6.77 (in, 2H), 6.95- 7.08 (in, 3H), 7.22-7.27 (in, 3H). FAB-MS: calcd for (C28H32N0 2 F) 433; found 434 (M Rf 0.30 (10% ethyl acetate-hexane).

Step B: 2 6 Diiso~ropl3(..hydroxyeffl)-4-(4 4fl propylpyridine The title compound was prepared as two separable diastereomers from the intermediate obtained in Step A by the methods described in Example 164, Steps A- C. The diastereomers; were. separated by radial band chromatography using a gradient eluent of 100% hexane to 20% ether-hexane.

Diastereoiner 1: 1H NMR (300 MHz, CDCl 3 8 0.75 J 7.2 Hz, 3H), 1.27- 1.40 (in, 1711), 1.66 (br s, 1H1), 2.02-2.12 1H), 2.20-2.31 (in, 1H1), 3.21 (sept, J 6.6 Hz, 1H), 3.60 (septj 6.6 Hz, 1H), 4.94 (in, 1H),'5.03' (br s, 1H1), 6.70-6.76 (in, 2H1), 6.94-7.00 (in, 1H1); FAB-MS: calcd for (C22H3ONO2F) 359, found 360 0M+ Rf).

0.29 (20% ethyl acetate-hexane). rup 152-153 0 C. t Diastereomer 1 was resolved into its constituent enantiomers As follows.

A

Waters Prep LC -2000 HPLC system was equipped with a chiral HIPLC column (BRB-9668A;1 6 x 50",ci ID). The system was eq uilibrated, with a mobile' phase cofisisting of 1% acetic acid, 99% ethianol) -and 99% hexane at a flow rate of 150 mL/min. The sample was dissolved in chloroform (50 ing/inL) and 5 mL aliquots were injected at 40 min intervals. The effluent was monitored at 280 run and two fractions (corresponding to the two enantiomners) were collected at (17-23 min,100% ee) and (23-32 inin, 98% ee), respectively.

Diastereomer 2: 1H1 NMR (300 MHz, CDC1 3 8 0.75 J 7.2 Hz, 311), 1.26-~ 1.31 (in, 1411), 1.38 J 6.9 Hz, 311), 1.84-1.87 (in, 111), 2.05-2.14 (in, 111), 2.24-2.34 (in, 111), 3.20 (septet, J 6.6 Hz, 1H1), 3.72 (septet, J 6.6, 1H1), 4.58-4.65 (in, 1H), 5.06 (br s, 1H), 6.67-6.74 (in, 211), 6.85-6.90 (in, 1H1); FAB-MS: calcd for (C22H30N02F) 359, found 360 (M Rf 0.19 (20% ether-hexanes). mrp 157-159 0

C.

342 WO 98/04528 WO 9804528PCTIIUS97/13248 0 EXAMPLE 239

F

~OH

HO0

N

2 6 -Diisopropyl-3-(l-hydroxvmethyl)-4(4-fluoro-2.hydroxypheny).5propylpyridine The title compound was prepared fromr 2 ,6-diisopropyl-3-hydroxymethyl- 2 -benzyloxy-4-fluoro)pheny]-5-.(prp1..lenyl) pyridifle (Example 238, Step A) by the method described in Example 161, Step A (mp 138-141 0 1 H NMR (300 MHz, CDCl3): 8 0.76 J 7.2 Hz, 3H),,1.24-1.35 (in, 1411), 1.82 (br s, 1H), 2.12-2.22 (in, 1H), 2.27-2.37 (mn, 1H), 3,24 (sept, J =6.6 Hz, 1H), 3.39 (sept, J =6.6 Hz, 1H), 4.29 J =11.4 Hz, 1H1), 4.52 J =10.8 Hz, 1H), 5.72 (br s, 1H1), 7.70-6.77 (in, 2H), 6:94-7.00 ABM:acdfr(2H28N02F) 345; found 346 (M Rf -0.30 ethyl acetate-hexane).

The racemate was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HIPLC system was'equipped ,with a chiral HPLC column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated it a mobile phase consisting'of 1%b acetic acid, 99% ethanol).an~d hexane at a flow rate of 100 mfL/min. Th~e sample was dissolved in mobile phase (5 mg/rnL) and 3 mL aliquots were injected at 30 min intervals. The effluent was monitored at 280 run and two fractions (corresponding to the two enantiomners) were collected at (24-36 min,100% 'ee) -and (26-30 min, 95.5% ee), respectively.

EXAMPLE 240

F

OH

HO

WO 98/04528 PCT/US97/13248 0 2,6-Diisopropyl-3-(1-hydroxyethyl)-4-(4-fluoro-2-hydroxyphenyl)-5-ethylpVridine SteA: 2 ,6-Diisopropyl-3-hydroxymethyl-4-[( 2 -benzyloxy-4-fluoro)phenyl]- Prepared from the intermediate obtained in Example 166, Step B by the methods described in Example 160, Steps A-D. 1 H NMR (300 MHz, CDC1 3 8 1.25- 1.33 12H), 1.66-1.70 1H), 3.34-3.50 2H), 4.28-4.41 2H), 4.89-5.18 (m, 4H), 6.29-6.39 1H), 6.67-6.78 2H), 7.23-7.25 3H). FAB-MS: calcd for (C27H30N02F) 419; found 420 (M Rf 0.29 (10% ethyl acetate-hexane).

Ste B: 2 ,6-Diisopropyl-3-carboxaldehyde-4-[(2-benzloxy-4-fluoro)phenyl- Prepared from the intermediate obtained in Step A by the method described in Example 164, Step A. 1 H NMR (300 MHz, CDC13): 8 1.25-1.33 12H), 3.24 (sept, 1H, J 6.6 Hz), 3.89 (sept, 1H, J 6.6 Hz), 4.93-5.04 3H), 5.23 (dd, iH, J 11.4 Hz), 6.40 (dd, 1H, 11.4, 17.7 Hz), 6.7b-7.04 2H), 6.99-7.04 1H), 7.10-7.14 2H), 7.24-7.29 3H), 9.82 1H). FAB-MS: calcd for (C27H28N02F) 417; found 418 (M Rf 0.68 (10% ethyl acetate-hexane).

Step C: 26-Diisopropyl-3-(2-hydroxyethyl)-4-[(2-hydroxy-4-fluoro)phenyl]-5ethyl)pyridine To an oven-dried 250 mL three-neck round bottom flask equipped with a thermometer were added copper(I) iodide (3.21 g, 16.9 mmol) and toluene (40 mL) under an argon atmosphere. The slurry was cooled to an internal temperature of 0°C Methyllithium (1.4M in ether, 25 inL, 0.03314 mol) was added at a rate to maintain reaction temperature The reaction was then allowed to stir at 0°C for 50 min. At the end of this time the intermediate from Step B (1.33 g, 3.19 mmol) in 10 mL toluene was added via syringe at a rate to maintain reaction temperature The syringe was rinsed with an additional 4 mL toluene and this rinse was added to the reaction mixture at a rate to maintain reaction temperature <5 0 C. The reaction was stirred at 0 C for 35 min. The reaction was then quenched by the addition of a saturated solution of ammonium chloride (20 mL) and was allowed to stir for 36 h at 25 0 C. The reaction mixture was poured into a separtory funnel and was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was then concentrated to yield the crude intermediate (1.4 g, yellow oil, 9:1 ratio of diastereomers). The crude intermediate was dissolved in a mixture of ethanol mL) and tetrahydrofuran (10 mL) under argon, treated with 10% palladium on 344 WO 98/04528 WO 9804528PCT1US97/13248 o carbon (140 mg), and was then stirred under a hydrogen atmosphere for 14 h.

After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the residue was purified by flash chromatography (12-15% ethyl acetate-hexane) to yield 1.0 g of the title compound as two separate diastereomers.

Diastereomer 1: 1 H NlM (300 Mffz, CDCl3): 8 0.91 J 7.4 Hz, 3H), 1.28- 1.40 (in, 15H), 1.70 J 3.9 Hz, 1H), 2.12-2.24 (in, 1H), 2.29-2.41 (in, 1H), 3.24 (sept, J 6.6 Hz, 1H), 3.61 (sept, J 6.6 Hz, 1H), 4.89-5.00 (in, 1H), 5.10 (br s, 1H), 6.70-6.76 (in, 2H), 6.96-7.01 (in, 1H); FAB-MS:. calcd for (C21H28N02F) 345, found 346 (M Rf 0.43 (30% ether-hexane). mp 190-191 0

C.

Diastereomer 1 was resolved into its constituent enantiomers as follows. A Waters Prep LC 2000 HPLC systemi was equi pped with a chiral HPLC column (BRB-9668A; 6 k 50 cmn ID). The system was equilibrated with a mobile phase consisting of (1acetic acid;,99% ethanol) and, 99% hexane at a flow rate of 100 inL/min. The sample (1 g) was dissolved in a mixture of CH2CL2 (40 mL), ethanol (1 mL), and 10 mL of the mobile phase.- The mixture was injecied and the effluent was monitored at 280. im- and two .fractions (correspo nding to 'the%* two enantioiners) were collected at (27-29 min, 99.8% ee) and (37-57 min, 99.4% ee), respectively. Fraction 1 (27-29 min): [cX] 25 D +4.70 (c 0.54, CH2CI2).

Diastereomner 2: 1 H NMR (300 MHz, CDC1 3 80.89 j =7.5 Hz, 1.26- 1.38 (in, 15H), 1.92 J 3 Hz, 1H), 2.1-2-2.25 (in, 1H), 2.31,-2.43 1H), 3.23 (septetJ 6.6 Hz, 3.72- (septet, J 6.6, 4.56.4.63 1H), 5.14 (br s'.1H), 6.68-6.74 (ml, 6.85-6.91 (in, FAB-MS: calcd for (C21H28N02F) 345, found 346 (M Rf =0.217(30%. ether-hexane). mp 201-202*C.

EXAMPLE 241

F

OH

HON

3 =-Diisopropvl1-2-hydroxvinetl-6-provvyl4'fluoro-2'-hydroxy..1,1'..biphenYI 345

U

WO 98/04528 PCT/US97/13248 0 Step A: Dimethyl 4 6 -diethyl-2-hydroxy-1,3-benzenedicarboxylate A mixture of dimethyl 1,3-acetonedicarboxylate (200 g, 1.15 mol), heptanedione (140 g, 1.09 mol) and sodium methoxide (70 g, 1.25 mol) in methanol L) was held at reflux overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (1 L) and 10 aqueous hydrochloric acid (1 The separated aqueous layer was extracted with diethyl ether (0.5 L x The combined organic portions were washed with saturated aqueous sodium chloride (0.1 dried over sodium sulfate, filtered through a pad of silica (40 mm x 100 mm) and concentrated in vacuo. The crude oil was purified via vacuum distillation at 0.25 Torr to afford the clean product as translucent yellow oil (bp: 125-145 0 C, 202 g, 70 1 H NMR (300 MHz CDC13): 8 1.20 J 7.4 Hz, 6H), 2.71 2.80 4H), 3.95 6H), 6.64 1H), 11.67 1 3 C NMR (75 MHz, CDC13): 8 15.42, 28.31, 52.27, 115.22, 121.91, 148.63, 159.71, 169.86. EI-MS: calculated for C14H1 8 0 5 266; found 266 Anal. calc for C14H180 5 C, 63.15; H, 6.81. Found: C, 63.23; H, 6.92. Rf 0.38 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 aqueous trifluoroacetic acid, B=CH3CN; -linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 14.4' min (100.0 area Step B: Dimethyl 4,6-diethyl-2-methoxy-1,3-benzenedicarboxylate A mixture of the crude intermediate obtained in Step A (241.6 g, 0.91 mol), .potassium carbonate (204 g, 1.48 mol) and dimethyl sulfate (129 mL, 1.37 mol) in acetone (1 L) was stirred vigorously overnight. After six hours at reflux, the reaction was cooled to room temperature, additional dimethyl sulfate (43 mL, 0.46 mol) was added, and reflux was continued overnight. The mixture was filtered through a pad of Celite, diethyl ether (1 L) was used to wash the Celite pad, and the combined filtrates were concentrated in vacuo. The resulting crude oil was purified via vacuum distillation to afford the pure product as a translucent yellow oil (bp: 180-190°C, 178.1 g, 58 (2 steps)): 1H NMR (300 MHz, CDCl3): 5 1.16-1.25 6H), 2.55-2.66 4H), 3.81 3H), 3.91 6H), 6.89 1H). Rf 0.34 (9:1 hexanes:ethyl acetate).

tep C: Dimethyl 4 6 -diisopropyl-2-methoxy-,3-benzenedicarboxylate A solution of diisopropylamine (26.7 mL, 0.20 mol) in dry tetrahydrofuran (0.2 L) at -78 0 C under an argon atmosphere was treated with slow addition of n-butyllithium (2.47M in hexanes, 85.0 mL, 0.20 mol). After the reaction stirred for fifteen minutes, a solution of the intermediate from Step B (58.0 g, 0.16 mol) in dry tetrahydrofuran (0.2 L) was added to the solution of LDA over 346 WO 98/04528 PCT/US97/13248 0 minutes. Stirring was continued for 80 minutes while the internal temperature was held at -76 0 C. Neat iodomethane (13.2 mL, 0.21 mol) was added to the reaction mixture via syringe; two-thirds of the charge was transferred at the outset, the reaction was allowed to stir for 30 minutes, then the final third of the charge was added, followed by another 30 minutes of stirring. A second pot of LDA (0.2 mol) in dry tetrahydrofuran (0.2 L) was produced by the above procedure and was transferred to the reaction mixture via cannula over 45 minutes. Stirring was continued for 80 minutes at -76 °C then a second portion of neat iodomethane (13.2 mL, 0.21 mol) was added to the reaction mixture using the addition sequence described above. The cooling bath was removed and the reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.4 The mixture was extracted with diethyl ether (3 x 0.4 L) and the combined organic portions were dried over magnesium sulfate, filtered through a plug of silica gel C(7 and concentrated in vacuo to afford the clean product as an off-white solid (60.2 g, 98 1 H NMR (300 MHz, CDC13): 8 1.24 J 6.6 Hz, 12H), 2.84-2.96 2H), 3.82 3H), 3.92 6H), 7.04 1H). 1 3 C NMR (75 MHz, CDCI3): 6 23.72, 31.36, 52.30,63.56, 117.95, 125.66, 148.68, 153.76,168.36. FAB-MS: calculated for C17H240- 308; found 309 Anal. cakl for C17H2 4 0 5 C, 66.21; H, 7.84. Found: C, 66.22 H, 7.94. Rf= 0.3 (9:1 hexanes:ethyl acetate). HPLC:.(C-18, A=0.05 aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 50%-100% B. over 30 min; 254 nm, 1 mL/min): R.T. 16.2 min (97.6 area%). mp 70.5-71;5 6C.

Step D: Diisopropyl 4 6 -diisopropyl-2-methoxy-1 3-benzenedicarboxylate mL), wascautiously added to a flask'charged -with sodium hydride 0.33 g, 13.8 mmol). A solution of the intermediate obtaiined in Step C (8.5 g, 27.6 mmol) in isopropanol (100 mL) was added and the resulting mixture was held at reflux overnight.,Additional sodium hydride 0.33 g, 13.8 mmol) and isopropanol (50 mL) were added to push the reaction to completion. Reflux was continued for five hours then the reaction mixture was cooled to ambient temperature and quenched with 10 aqueous hydrochloric acid, Isopropanol. was removed in vacuo and the residual aqueous layer was extracted with diethyl ether (2 x 150 mL). The combined ethereal extracts were dried over magnesium sulfate, concentrated in vacuo, and chromatographed on silica (300 g) using dichloromethane:hexanes as eluent to provide the cean product 'as a colorless crystalline solid (8.5 g, 85 1H NMR (300 MHz, CDC13): 6 1.25 J Hz, 12H), 1.37 (d,J 6.3 Hz, 12H), 2.90-2.98 2H), 3.85 3H), 5.30 (septet, J 6.3 Hz, 2H), 7.02 1H). 13 C NMR (75 MHz, CDC13): 8 21.77,23.74,31.12,63.59, 68.92, 117.78, 126.44, 148.08, 153.20, 167.40. FAB-MS: calculated for C21H3205 364; found Y"if~E Fr I i~i WO 98/04528 PCT/US97/13248 0 365 Anal. calc for C21H3205: C, 69.20; H, 8.85. Found: C, 69.23; H, 8.86.

Rf 0.42 (9:1 hexanes:ethyl acetate), HPLC: (C-18, A=0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 50%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 24.4 min (96.6 area mp 68.0-69.0°C.

te E Diisopropyl 3,5-diisopropyl-2'-benzyloxy-4'-fluoro-11'-biphenyl-2,6 dicarboxylate A dry flask containing freshly ground magnesium turnings (2.88 g, 120 mmol) and a crystal of iodine was heated until a dark purple iodine atmosphere had formed. The flask was cooled to ambient temperature and a solution of 2bromo-5-fluorophenyl benzyl ether (33.8 g, 120 mmol, Example 166, Step A) in dry tetrahydrofuran (60 mL) was added in several portions over 40 minutes at a rate sufficient to maintain reflux. Reflux was continued for 45 minutes, then the reaction was cooled to room temperature. This solution of Grignard reagent was 0 -transferred via syringe to a second flask containing a solution of the intermediate from Step D (11.0 g, 30.2 mmol) in dry benzene (66 mL). The reaction mixture was held at reflux for one hour, quenched with 10% aqueous hydrochloric acid (300 mL) and extracted with diethyl ether (3 x 300 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a brown oil which was subjected to flash column ihromatography on silica (80 min x 19.5") using- a stepwise gradient elution of dichloromethane:hexanes 1:2, 1:1, 4L each). The fractions containing the product were combined and concentrated to afford an inseparable mixture of the product and an unidentified side product in about a 1:1 ratio as a pale yellow gum (5.3 g, 33% mass balance). This material was not fully characterized and was used without firtherpurification.

StepF: Isopropyl 3 ,5-diisopropyl-6-hydrovxmethyl-2'benzyloxy-4'-fluoro l l'-biphenyl-2-carboxylate A mixture of the intermediate from Step E (5.83 g, 10.9 mrmol) and Red-Al (3.3 mL, 10.9 mmol) in dry tetrahydrofuran (100 mL) was held at reflux for hours. Additional Red-Al was added (in 3.3 mL aliquois) and reflux maintained until the lower Rf spot disappeared (21 hours, total 8 eq. Red-Al; i.e. the by-product from the previous step reacted faster than the desired diester). The reaction mixture was cooled to 0 OC, carefully quenched with water (14 mL), and vigorously stirred for 2 hours. The precipitated solids were removed via vacuum filtration through paper and the collected solids were washed with ethyl acetate (3 x 100 mL) and refiltered. The combined filtrates were washed with a 1:1 mixture of water and saturated aqueous sodium chloride (100 mL), followed by water (75 mL) and 348 W7^ 1 WO 98/04528 PCT/US97/13248 0 saturated aqueous sodium chloride (50 mL). The organic portion was separated, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica (80 mm. x using hexanes:ethyl acetate (19:1) as eluent gave pure diisopropyl 3 ,5-diisopropyl-2'-benzyloxy4fluoroll 1'-biphenyl-2,6dicarboxylate (2.63 g, 4.92 mmol). This was resubjected to the reaction conditions with Red-Al (2.95 mL, 9.84 mmol) in dry tetrahydrofuran (45 mL). Additional Red- Al was added (in 2.95 mL aliquots) and reflux maintained until the reaction was complete (30 hours, total 12 eq. Red-Al). Worked up as above and subjected crude product to flash column chromatography on silica (40 mm x using hexanes:ethyl acetate (19:1) as eluent to provide the desired product as a translucent colorless oil (1.25 g, 55 1 H NMR (300 MIHz, CDCl3): 8 0.91 J 6.6 Hz, 3H), 1.09 J 6.3 Hz, 3H), 1.20-1.33 (in, 9H), 1.35 J 7.0-Hz, 3H), 1.91-2.00 (br s, 1H), 2.94-3.07 (in, 1H), 3.37-3.50 (in, 1H), 4.24-4.46 (mn, 21H), 4.84-5.06 (in, 3H), 6.73-6.87 (in, 2H), 7.01- 7.08 (mn, 2H), 7.14-7.29 (in, 4H), 7.39 1H). FAB-MS: calculated for C30H3504F 478; found 479 Rf 0.23 (9:1 hexanes:ethyl acetate).

Step G: Isovropyl 3%S-diisoropyl-6-formyl.2':bezvloxv-A'fluoro.11'biphenyl-2-carboxylate A chilled (0 0 C) mixture of the intermediate from Step F (0.73 g, 1.52 minol), Celite (1.46 and. pyridinium. chlorochromate (0.61 g, 2.84 minol) in dry dicliloromeiljane (30 mL), was stirred for 5 hours, while warming to room temperature. The mixture was diluted with ethyl acetate (30 mL) and hexane mL) and filtered through a plug of silica (30 mm x Elution was continued with ethyl acetate:hexanes (1:1 mixture, 2 x 120 inL. The- combined ifitrates were concentrated in vacuo to: afford the desired produ&t as a clear colorles's oil (0.72 g, 99 1 H NW1 (300 MHz, CDCI3): 8 0.90 6.3 Hz, 3H), 1.07 J 6.3 Hz, 3H 1.23-1.36 (mn, 12H), 2.99-3.10 (in,1H), 3.92-4.02 (in, 1H), 4.85-5.06 (in, 6.65- 6.76 (in, 2H), 7.15-7.30'(in, 6H), 7.46 1H), 9.84 1H). FAB-MS: calculated for C30H330 4 F 476; found 477 Rf 0.47 (9:1 hexanes:ethyl acetate).

Step H: Isopropyl 3 1 diisopro~y4.&(p rop-l-.enyl)..2'-r ylox-4-fliaoro 1 biphenyl-2-carboxylae A chilled suspension of (ethyl)triphenylphoshonim bromide (0.88 g, 2.37 minol) in dry tetrahydrofuran (6 mL) was treated with dropwise addition of n-butyllithiumn (2.47M in 'hexanes, 1.04 mL, 2.56 inmol). The mixture. was immediately warmed to 0. T, stirred for 90 minutes at 0 TC, and recooled to -70 TC A solution of the intermediate from Step G (0.94 g, 1.97 inmol) in -dry tetrahydrofuran (6 mL) was added to the solution of ylide over several minutes 349 WO 98/04528 PCT/US97/13248 0 and the reaction mixture was warmed again to 0 OC and stirred for one hour. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (25 mL).

The organic portion was washed with saturated aqueous sodium chloride solution (2 x 15 mL). The combined aqueous portions were back-extracted with ethyl acetate (10 mL). The combined organic portions were dried over sodium sulfate and concentrated in vacuo to provide the crude solid which was subjected to flash column chromatography on silica (30 mm x using hexanes:ethyl acetate (19:1) as eluent. The clean fractions were combined and concentrated in vacuo to afford the desired product as a pale yellow oil (0.81 g, 84 1 H NMR (300 MHz, CDC13): 8 0.84-0.92 3H), 1.02-1.59 18H), 2.96-3.31 2H), 4.82-4.97 1H), 4.98 (s, 2H), 5.19-5.52 1H), 6.07- 6.19 1H), 6.57-6.69 2H), 7.05-7.31 7H). FAB- MS: calculated for C32H3703F 488; found 489 Rf 0.58 (9:1 hexanes:ethyl acetate).

Step I: 3,5-Diisopropvl-2-hydroxymethyl-6-(prop-l-enyl)-2'-benzvloxy-4'fluoro-1,1'-biphenyl A reaction flask was charged with a suspension of lithium aluminum hydride 0.14 g, 3.3 mmol) in dry tetrahydrofuran (5 mL) and heated to reflux. A solution of the intermediate from Step H (0.80 g, 1.64 mmol) in dry tetrahydrofuran (10 mL) was added to the refluxing suspension dropwise from a syringe. The reaction mixture was held at reflux for 23 hours, cooled to ambient temperature and quenched using saturated aqueous sodium sulfate solution which was added dropwise until gas evolution stopped. The mixture was then diluted with ethyl acetate (15 mL), stirred for several minutes and filtered through a pad of Celite. The pad was washed copiously with additional ethyl acetate. The combined filtrates were concentrated in vacuo and subjected to flash column chromatography on silica (30 mm x to afford the clean product as a clear oil (0.53 g, 75 1

H

NMR (300 MHz, CD.C13):. 81.05-1.46 15H), 1.68-1.78 (br s, 1H), 3.07-3.49 2H), 4.27-4.47 2H), 4.85-5.05 2H), 5.25-5.52 1H), 5.92-6.08 1H), 6.68-6.76 2H), 6.98-7.13 3H), 7.18-7.29 3H), 7.35 1H). FAB-MS: calculated for C29H3302F 432; found 432 Rf 0.29 (9:1 hexanes:ethyl acetate).

Step 3 ,5-Diisopropvl-2-hydroxymethyl-6-propyl-4'-fluoro-2'-hydroxy-11'biphenyl A mixture of the intermediate from Step I (0.53 g, 1.23 mmol), and Pd/C (53 mg) in methanol (12 mL) was stirred under one atmosphere of hydrogen gas for 18 hours. The reaction mixture was then filtered through a pad of Celite and the pad was rinsed thoroughly with methanol (100 mL). The combined 350 L WO 98/04528 WO 9804528PCTIUS97113248 o- filtrates were concentrated in vacuo, and subjected to flash column chromatography on silica (20 mmn x using hexanes:ethyl acetate as eluent. In this manner, the pure product was obtained as a clear oil which slowly solidified to provide the title compounds as a white solid (0.37 g, 87 1 H NMR (300 MHz, CDCI3): 8 0.76 J 7.4 Hz, 3H), 1.16-1.36 (in, 15H), 2.11-2.42 (in, 2H), 3.12-3.25 (in, 3.30-3.43 (mn, 1H), 4.29-4.47 (in, 2H), 6.69-6.80 (in, 2H), 7.00-7.07 (in, 1H), 7.36 1H). 1 3

C

NMR (75 MHz, CDCl3): 8 14.65,-24.29, 24.34, 24.50, 24.58, 29.21, 32.18, 59.61, 103.6 J=24.4 Hz), 107.6 J=22.0 Hz), 123.50, 123.67 J=2-4 Hz), 131.21 J=9.8 Hz), 134.07, 134.66, 137.42, 146.30, 148.12, 154.26 J=12.2 Hz), 163.01 J=244.2 Hz).

FAB-MIS: calculated .for. C22H2902F 344; found 344 Anal. calc for C22H29O2F: C, 76.71l; H, 8.49. Found: C, 76.66; H, 8.34. Rf 0.41 (4:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05 qeu rfu aeti cd B=CH3CN; linear gradient: 50%-100% B over 30 mmd; 254n, 1, iL/min): RT. 17.1 min (97.5 area mp 127.5 129.0*C.

EXAMPLE 242

H&H

3,-is r~i2(-yrxehl-6 oy-'fur7-'hdoyr,1 ':-biphenyI Step A: 3 ,-Diisopropyl-2-hydroxviethl6-propyl4'-fluoro-2'benzylox..

Xbihen 1 Amixture of the racemnic compoud preare.4 i nple 24 23 gmol), benzyl biomide (1*10g'L, 925 f tinol.),,and .pptas~sium carbonate (303. mg, 2.19 inmol) in acetone (29 mL) ias hdated to reflux fo,3 h.Thmitrwadlue with saturated aqueous ammionium chloride solution (50 m.L) and extracted with Et2O (3 x.50 mL). Silica gel chromatography (90:10 hexane/ethyl acetate) provided a colorless oil (0.369 g, 100%). 1 H NMR (CDC13, 300 MHz): 7.34 1H), 7.23.(in, 3H), 7.12 7.03 (mn, 2H), 6.84-6.75 (in, 2H1),-5.04 1 2.,1 Hz; 1H1), 4.94 12.1.

WO 98/04528 PCT/US97/13248 0 Hz, 1H), 4.38 (dd, 11.4 Hz, 8.5 Hz, 1H), 4.25 (dd, 11.4 Hz, 3.3 Hz, 1H), 3.39 (sept, 6.9 Hz, 1H), 3.18 (sept, 6.9 Hz, 1H), 2.30-2.40 1H), 2.09-2.20 1H), 1.65 (dd, Hz, 3.3 Hz, 1H), 1.26-1.34 14H), 0.72 7.4 Hz, 3H).

Step B: 3,5-Diisopropl-2-forml-6-propy4fluro-2'-benzyloxy-,1'biphenyl Prepared from the intermediate obtained in Step A by the procedure described in Example 218, Step A. Silica gel chromatography (95:5 hexane/EtOAc) provided a colorless crystalline solid (0.323 g, 1 H NMR (CDC13, 300 MHz): 8 9.74 1H), 7.41 1H), 7.22-7.28 3H), 7.06-7.13 3H), 6.72-6.80 2H), 5.00 2H), 3.91 (sept, 6.8 Hz, 1H), 3.23 (sept, 6.7 Hz, 1H), 2.37-2.46 1H), 2.17-2.27 1H), 1.20-1.36 14H), 0.73 7.4 Hz, 3H). FAB-MS: calculated for C29H33F0 2 432; found 433 StepC: 3,5-Diisopropyl-2-(1-hydroxvethvl)-6-propyl-4-fluoro-2-benzyloxy 1,1'-biphenyl Methyl lithium (2.7 mL of 1.4 M solution in Et20, 3.78 mmol) was added dropwise over five minutes to a cooled (ice-water bath) suspension of Cul (715 mg, 3.75 mmol, purified by extraction with THF) in toluene (10.8 mL) such that the internal temperature of the mixture was 53 0 C. The addition produced first a yellow-orange suspension ard then a colorless solution. After 25 minutes the mixture was again a yellow-orange suspension. A solution of the intermediate obtained in Step B (306 mg, 707 mol) in 'toluene (1 mL) was added dropwise over four minutes such that the internal temperature of the mixture was After minutes 1/3 saturated aqueous NH40H solution (40 mL) was added. After an additional 60 minutes the mixture was diluted with saturated aqueous NH4Cl solutionk4O) mL) ind extracted with Et20 (3 x 40 mL). Silica gel chromatography (83:17 hexane/EtOAc) provided a colorless solid (0.290 g, The product was a mixture of diastereomers in a ratio of 93:7 as judged by HPLC. 1 H NMR (CDC13, 300 MHz,- only peaks corresponding to the major diastereomer were visible): 8 7.35 1H), 7.22-7.24 3H), 7.11 (dd, 8.1 Hz, 7.0 Hz, 1H), 7.04 2H), 6.70-6.78 2H), 4.99 2.6 Hz, 2H), 4.83 (qd, Jq=6.8 Hz, Jd=2.8 Hz, 1H), 3.84 (sept, 6.8 Hz, 1H), 3.14 (sept, 6.9 Hz, 1H), 2.29 1H), 2.07 1H), 1.74 2.9 Hz, 1H), 1.25-1.35 17H), 0.70 7.4 Hz, 3H). EI-MS: calculated for C30H37F02 448; found 448

S

te D: 3,5-Diisopropyl-2-(l-hydroxyethyl)-6propyl-4'-fluoro-2'-hydroxy 1,1'-biphenyl 352 WO 98/04528 PCT/US97/13248 0 The title compound was prepared from the intermediate obtained in Step C by the procedure described in Example 1, Step H. Silica gel chromatography (83:17 hexane/EtOAc) provided two colorless solids (0.229 g, 99%).

Diastereomer 1 was obtained as a colorless crystalline solid (0.214 g, 92%).

1 H NMR (CDC3, 300 MHz): 8 7.37 1H), 7.03 1H), 6.72 2H), 4.80-4.89 (m, 2H), 3.79 (sept, 6.8 Hz, 1H), 3.14 (sept, 6.8 Hz, 1H), 2.31 1H), 2.08 1H), 1.64 3.3 Hz, 1H), 1.41 7.0 Hz, 3H), 1.26-1.31 14H), 0.74 7.4 Hz, 3H). FAB- MS: calculated for C23H31F02 358; found 341 mp 149-150°C. Rf 0.25 (83:17 hexane/ethyl acetate).

Diastereomer 1 (212 mg) was resolved into its constituent enantiomers as follows: a Waters Prep LC 4000 HPLC system was equipped with a chiral HPLC column (BRB-9668A; 6 x 50 cm ID). The system was equilibrated with a mobile phase consisting of 1% butanol and 99% heptane at a flow rate of 100 mL/min. The sample was dissolved in dichloromethane (70 mg/mL) and 1 mL aliquots were injected at 40 min intervals. The effluent was monitored at 285 nm and two fractions (corresponding to the two enantiomers) were collected at (19-23 min,100% ee) and (30-37 min, >98% ee), respectively.

Enantiomer 1 was obtained as a colorless solid (78 mg). 1H NMR (CDCl3, 300;MHz): 8 7.37 1H), 7.02 1H), 6.71 2H), 4.77-4.89 2H), 3.77 1H), 3.14 (sept, 6.8 Hz, 1H), 2.31 1H), 2.08 1H), 1.63 2.9 Hz, 1H), 1.41 6.6 Hz, 3H), 1.26-1.31 14H), 0.74 7.2 Hz, 3H). FAB-MS: calculated for C23H31F02 358; found 341 (M-OH).

Enantiomer 2 was obtained as a colorless solid (74 mg). 1H NMR (CDC13, 300 MHz): 8 7.38 1H), 7.03 1H), 6.72 2H), 4.80-4.90 3.79:(sept, 6.6 Hz, 1H), 3.14 (sept, 6.7 Hz, 1H), 2.30 1H), 2.07 1H), 1.63 3.3 Hz, 1H), 1.41 6.6 Hz, 3H), 1.26-1.31 14H), 0.74 7.2 Hz, 3H). FAB-MS: calculated for C23H31F0 2 358; found 341 (M-OH).

Diastereomer 2 was obtained as a colorless crystalline solid (15.3 mg, 1 H NMR (CDC13, 300 MHz): 8 7.37 1H), 6.92 1H), 6.70 5.1 (br s, 1H), 4.64 6.7 Hz, 1H), 3.85 (sept, 6.7 Hz, 1H), 3.14 (sept, 6.8 Hz, 1H), 2.32 1H), 2.09 1H), 1.8 (br s, 1H), 1.37 6.6 Hz, 3H), 1.24-1.30 14H), 0.74 7.2 Hz, 3H).

FAB-MS: calculated for C23H31F0 2 358; found 341 mp 179-180 0

C.

WO 98(04528 PCTIUS97/13248 0 EXAMPLE 243

F

3 S-Diisopropl 2(hdroxvethV6penl 4 flro,,Ibihev Step A: 3 ,5-Diisoprpyl2(oxoethVl)6pen l.4..flo.,,'-biphenyl- A mixture of 3 ,-diisopropyl-2(1.hydroxyethyl)6penty1AI fluoro1,1'biphenyl (Example 192, 13.7 g, 37.1 mmol), Celite (26 and pyridinium chlorochromate (14.9 g, 69.3 mmol) in dichioromethane (750 mL) was stirred..,for minutes. The mixture was diluted with ethyl acetate (750 mL) and hexane (1.5 L) and filtered through a plug of silica (100 mmn x topped with Celi 'te (100 mm x Elution was continued with ethyl acetate:hexanes (1:1 mixture, 3L x The combined filtrates were concentrated in vacuo to afford the desired product as a white solid (13.5 g, 99 1) H NMR (300 MHz-, CDCl3): 8 0.75 0.80 (in, 3H), 1.06 1.31 (iii, 18H), 1.95 3H), -2.33 2.39 2.78 (septet, J 7.0 Hz, 1H), 3.18 (septet, J 7.0 Hz; 1H), 7.03 7.09 (mn, 2H1),. 7.17 7.22. (mn, 2H) 7.26 1H). 1 3

C

NMR (75 Iv1L~z, CDC1b): 8 13.75, 22.02, 24.32, 24.37, 28.99, 29.10, 29.28,130.60,.31.04, 320,303, 114.85'(d, J 20.8 'Hz, 2Q), 1i22.06, 132.03 J 7J3 Hz, 2C), 135.,52 (d, 2A Hz, 1C) 135.58, 135.76, *140.13, 140.85, 147.66 161-99, J 246.6 Hz, 1C), 208.23. EI-MvS: calculated for C25H330F 368; found 368 Anal. caic for C25H330F: C, 80.86; H, 8.96. Found: C, 81.04; H, 9.06. Rf 0.65 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 75o/o,100% B over 30 min; 254 nm, 1 inL/inin): R.T. 22.7 min (94.0 area%) mp 123.0'124.5oC.

Step B: (+)-35Diispropy.2..(l 1...ovhyldroxtetyl-4'-lo biphenyl A mixture of (lS, 2 R)-(+)-N-inethylephedrine (13.9 g, 77.3 inmol) in diethyl ether (225 mL) at 0 'C under an argon atmosphere was treated with slow addition of lithium aluminum hydride (1M in diethyl ether, 77.3 mL, 77.3 iniol). The 354 WO 98/04528 PCT/US97/13248 0 mixture was held at reflux for one hour and then cooled to -75 A solution of the intermediate from Step A (13.5 g, 36.7 mmol) in diethyl ether (500 mL, 50 mL rinse) was then added to the reaction mixture in such a manner that the internal temperature did not rise above -68 The reaction stirred for 3 hours at -75 °C and was warmed to ambient temperature overnight. The reaction was cooled to 0 quenched by adding water (500 mL), and diluted with diethyl ether (750 mL).

The aqueous portion was separated and back-extracted with diethyl ether (200 mL).

The combined organic portions were washed with water (2 x 500 mL), 10 aqueous hydrochloric acid (500 mL), and saturated aqueous sodium chloride (2 x 500 mL), dried over sodium sulfate, filtered through a pad of silica (80'mm x 1.25") and concentrated in vacuo. The resulting solid was recrystallized from ethanol:water and dried in vacuo with several minutes of 'heating to provide the title compound as a fine white powder (11.08 g, 82 1H NMR (300 MHz, CDC13): 8 0.75 0.80 3H), 1.02 1.31 19H), 1.40 J 6.6 Hz, 3H), 2.17 2.22 2H), 3.08 3.18 1H), 3.83 3.92 1H), 4.66 4.73(in, 1H), 7.05 7.23 (m, 4H), 7.32 1H). 13C NMR (75 MHz, CDCl3): 8 13.88, 22.02, 23.38, 24.23,24.56, 24.63,25.09, 28.68, 28.96, 29.92, 31.04,32.23, 68.91, 114.80 (dJ 20.8 Hz, 1C), 115.02 J 20.8 Hz, 1C), 124.27, 130.40 J 8.5 Hz, 1C), 131.25 7.3 Hz, 1C), 135.53,136.98, 137.73 J 2:4 Hzi 1C), 139.02, 145.82 161.68 J' 245.4 Hz, 1C). FAB-MS: calculated for C25H350F 370; found 370 Aial. calc for C25H350F: C, 81.03; H, 9.52. Found: C, 81.15; H, 9.68. Rf 0.36 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A 0.05 aqueous trifluoroacetic acidB CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm; 1 mL/min): R.T. 22.6 min (98.3 area (Daicel Chiralcel OD-H; isocratic 99:1 hexanes:methyl t-butyl ether; 254 nm, mL/min); R.T. 6.20 min.(97.2 area 8.37 min. (0.36 area 99.5 0/o e.e. [a]D +26.90 (c 0.00196 g/mL, CH2Cl2). mp 108.5-109.5 0

C.

EXAMPLE 244

F

OH

(+)-35-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl 1 WO 98/04528 PCT/US97/13248 0 Step A: Dimethyl 4,6-diethyl-2-trifluoromethanesulfonyloxv-1,3benzenedicarboxylate A solution of 90 g (338 mmol) of dimethyl 4,6-diethyl-2-hydroxy-1,3benzenedicarboxylate (Example 241, Step A) in dichloromethane (1 L) was treated with pyridine (109 mL, 1.35 mol). The mixture was stirred under argon at 0°C and treated dropwise with triflic anhydride (83 mL, 507 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. Then was washed with HCI (1.5 water (1 saturated sodium bicarbonate (2 x 500 mL), and dried with MgSO4. Filtration and concentration afforded a dark oil (129.7 g, 326 mmol, Rf 0.4 (10% ethyl acetate/hexane). 1 H NMR (300 MHz, CDC13): 5 7.20 (s, 1 3.93 6 2.74 J 7.4 Hz, 4 1.22 J 4.8 Hz, 6 FAB-MS: calculated for (C15H27F30 7 398, found 399 Ste B: 35-Diethvl-2,6-dicarboxymethyl-4'-fluoro-1'-biphenyl To a solution of the intermediate obtained in Step A (129.7 g, 326 mmol) in dioxane (2.5 L) was added 4-fluorobenzene boronic acid (68.4 g, 492 mmol), potassium phosphate (145 g, 683 mmol), potassium bromide (58.1 g, 488 mmol), tetrakis(triphenylphosphine)palladium (18.8 g, 16.3 mmol), and water (20 mL). The reaction mixture was stirred under argon at reflux for 24 hrs. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The oily residue was filtered, twice through a pad of silica (700 g, 40% dichloromethane/hexane) to afford a yellow solid. Recrystallization from hexane afforded a white solid (52.6 g, 153 mmol, mp 98-99 0 C. Rf 0.4 (10% ethyl acetate/hexane). 1 H NMR (300 MHz, CDCI3): 8 7.26 2 7.17 1 7.04 2 3.49 6 2.67 (q,J 7.7 Hz, 4 1.25 J 7.7 Hz, 6 FAB-MS: calculated for (C20H21F04) 344, fouind 345 Step C: 3,5-Diisopropyl-2,6-dicarboxymethyl-4-fluoro-11'-biphenyl A solution of diisopropylamine (22.7 mL, 0.174 mol) in dry tetrahydrofuran (0.2 L) at -78 0 C under an argon atmosphere was treated with slow addition of nbutyllithium (2.5M in hexanes, 70 mL, 0.174 mol). After the reaction stirred for fifteen minutes, a solution of the intermediate from Step B (46.0 g, 0.133 mol) in dry tetrahydrofuran (0.2 L) was added to the solution of LDA over 15 minutes. Stirring was continued for 30 minutes while the temperature was held at -78 0 C. Neat iodomethane (11.2 mL, 0.180 mol) was added to the reaction mixture via syringe; two-thirds of the charge was transferred at the outset, the reaction was allowed to stir for 20 minutes, then the final third of the charge was added, followed by 356 Vi, WO 98/04528 PCT/US97/13248 0 another 10 minutes of stirring. A second pot of LDA (0.174 mol) in dry tetrahydrofuran (0.2 L) was produced by the above procedure and was transferred to the reaction mixture via cannula over 15 minutes. Stirring was continued for minutes at -78 °C then a second portion of neat iodomethane (11.2 mL, 0.180 mol) was added to the reaction mixture using the addition sequence described above.

The cooling bath was removed and the reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.4 The mixture was extracted with diethyl ether (3 x 0.4 L) and the combined organic portions were dried over magnesium sulfate and concentrated in vacuo to afford an oil, which crystallized upon standing. The white solid was washed with a small portion of hexane (41.7 g, 84 mp 128-130 0 C. Rf 0.5 (10% ethyl acetate/hexane). 1 H NMR (300 MHz, CDCl3): 8 7.33 1 7.26 2 7.03 2 3.49 6 2.97 (sept, J 6.6 Hz, 2 1.29 J 7.0 Hz, 6 FAB-MS: calculated for (C22H25F0 4 372, found -373 Step D: 3,5-Diisopropyl-2-hvdroxymethyl-6-carboxymethyl4'-fluoro-,1'biphenyl To a solution of the intermediate obtained in Step C (37.3 g, 100 mmol) in anhydrous tetrahydrofuran (350 mL) stirred under argon at 0 0 C was added a solution of 3.4M qo sodium bis( 2 -methoxyethoxy)aluminum hydride in toluene (Red-Al) (105 mL, 204 mmol, 65 wt% in toluene) via syringe oer 20 min. The reaction mixture was allowed to stir at room temperature for 24 hr, then cooled again to 0 0 C and carefully quenched by the dropwise. addition of water. The .solution was decanted from the solid which forms and the solvent removed in vacuo. The residue was purified by flash chromatography "(500 g silica) via step gradient. Elution with 5% diethyl ether/hexane affords 9.8 g (26.3 mmol, 28%) of C) recovered starting material and elution with. 40% diethyl Saffords the desired product as a white solid (26.8 g, 77.8 mmmol, mp 124- 126°C. Rf =0.2 (10% ethyl acetate/hexane). 1HNMR (300 MHz, CDCl3): 8 7:35 (s, 1 7.27 2 7.08 2 4.44 J 5.5 Hz; 2 3.43 4 2.92 (sept, J 6.6 Hz, 1 1.59 1 1.28 12 FAB-MS: calculated for (C21H25FO3) 344, found 345 Step E 3 5-Diisopropyl- 2 -carboxaldehyde-6-carboxvmethyl-4-fluoro-1,1'biphenyl.

To a solution of the intermediate obtained in Step D (26.8 g, 77.8 mmol) in dichloromethane (400 mL) was added celite (33.6 The suspension was stirred at room temperature and treated with pyridinium chlorochromate (PCC) (33.6 g, 15.6 357 WO 98/04528 PCT/US97/13248 0 mmol) in three portions. The suspension was stirred at room temperature for 2 hr, then poured into 1:1 diethyl ether/hexane (1 filtered through a pad of silica, the pad was washed with diethyl ether (600 mL) and the combined eluent concentrated to afford an gummy oil (23.3 g, 68.1 mmol, Rf 0.4 (10% ethyl acetate/hexane). 1H NMR (300 MHz, CDC13): 6 9.87 1 7.36 1 7.28 (m, 2 7.15 2 3.48 3 3.89 (sept, J 6.6 Hz, 1 3.10 (sept, I 6.6 Hz, 1 1.35 12 FAB-MS calcd for (C21H23FO 3 342, found 343 Step F: 3,5-Diisopropvl-2-carboxymethyl-6-ethenyl-4'fluoro-11'-biphenyl Methyltriphenylphosphonium bromide (15.5 g, 43.4 mmol) was suspended in anhydrous THF (250 mL) under argon and stirred at -78 0 C. A 1.6 M solution of n;butyllithium in hexanes (25 mL, 40.2 mmol) was added dropwise. The reaction mixture was allowed to come to 0 C and was stirred at that temperature for 1.5 hr.

The resulting brightly colored solution was cooled again to -78 0 C and treated C dropwise with a solution of the intermediate obtained in Step E (11.4 g, 33.3 mmol) in THF (100 mL). The reaction mixture was allowed to stir at 0 C for 1 hr, then quenched by the addition of water (30 mL). The THF was removed in vacuo, the residue partitioned between diethyl ether (400 mL) and water (400 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated. Flash chromatography through silica diethyl ether/hexane) affords a solid (10.3 g, 30.3 mmol, 91%) Z mixture). 1 H NMR (300 MHz, CDC13): 8 7.31 1 7.16 2 7.02 2 6.10 (dd, J 6.3, 11.4 Hz, 1 6.04 (dd, J 1.8,13.6 Hz, 1 5.48 (dd,J 1.8,19.9 Hz, 1 3.46 3 3.35 (sept, I 6.6 Hz, 1 2.93 (sept, 6.6 Hz, 1 1.29 12 EI-MS calculated for (C22H25F02) 340, found 340 mp 58-61 0 C. Rf 0.6 (10% ethyl acetate/hexane).

3,5-Diisopropyl-2-hydroxymethyl-6-ethenyl-4'-fluoro-1 1'-biphenl SThe intermediate obtairied in Step F (10.0 g, 29.4 mmol) was dissolved in anhydrous THF (150 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (1.0 M in THF, 41 mL, 41 mmol). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and quenched by the addition of 30 mL H20. The THF was removed in vacuo, the residue partitioned between diethyl ether (400 mL) and water (3 x 400 mL). The organic layer was washed with brine (300 mL), dried over MgSO4 and concentrated. Flash chromatography through silica diethyl ether/hexane) affords a solid (7.7 g, 24.7 mmol, 1 H NMR (300 MHz, CDC13): 8 7.38 1 H), 7.14 4 6.35 (dd, J 6.3,11.4 Hz, 1 5.20 (dd, J 1.8,13.6 Hz, 1 4.98 (dd, J 1.8,19.9 Hz, 1 4.40 I 5.5 Hz, 2 3.39 2 1.29 12 FAB-MS 358 WO 98/04528 PCT/US97/13248 0 calculated for (C21H25FO) 312, found 312 mp 97-99'C. Rf 0.1 dichloromethane/hexane).

Step H: 3,5-Diisopropyl-2-hydroxymethyl-6-ethyl-4'-fluoro-1,1'-biphenvl The intermediate obtained in Step G (7.7 g, 24.7 mmol) was dissolved in absolute ethanol (200 mL) under argon, treated with 10% palladium on carbon (610 mg, 0.1 eq), then stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite.

The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (7.7 g, 25 mmol, 1H NMR (300 MHz, CDC13): 8 7.32 1 7.15 4 4.33 2 3.39 (septet, J 7 Hz, 1 3.32 (septet, J 7 Hz, 1 2.37 J 7.7 Hz, 2 1.29 13 0.92 J 7.7 Hz, 3 FAB-MS calculated for (C21H27FO) 314, found 314 mp 106-108 0 C. Rf 0.1 dichloromethane /hexane).

Step I: 3,5-Diisopropyl-2-(1-hydroxyethyl)-6-ethyl-4'-fluoro-1,1'-biphenyl The intermediate obtained in Step H (7.65 g, 24.3 mmol) was dissolved in dichloromethane (250 mL), treated with celite (10.5 The suspension was stirred at room temperature and treated with pyridinium chlbrochromate (PCC) (10.5 g, 48.7 mmol). Stirring was continued at room temperature for 2 hrs. The suspension was.poured into 1:1 diethyl:ether/hex (1 filtered through'a pad of silica, the pad washed with diethyl. ether (600:mL) and the combined eluent concentrated to afford a solid (7.25 g, 23.2 mmol, The intermediate (7.25 g, 23.2 mmol) was dissolved in THF (75 mL) at 0 C under argon atmosphere and treated dropwise with Methyl magnesium bromide (3 M, 1.3 eq, 10.1 mL). The reaction was stirred for 1 hr. The reaction was quenched with saturated ammonium chloride (7 mL) and the THF was evaporated in vacuo to afford an oil. The product was partitioned between water (100 niL) and diethyl ether (250 mL) and the organic layer was dried with MgSO4, filtered, and concentrated to yield a white solid. Flash chromatography using silica gel CH2Cl2/hexane) afforded a white solid (71 g, 22 mmol, mp 138-140°C; Rf 0.1 (50% CH2Cl2/hexane); 1H NMR (300 MHz, CDC13): 8 7.34 1 7.15 (m, 4 4.69 (dq, 2.9, 7 Hz, 1 3.88 (septet, J 7 Hz, 1 3.17 (septet, J 6.6 Hz, 1 2.28 J= 7.4 Hz, 2 1.64 J 2.9 Hz, 1 1.39 J 6.6 Hz, 3 1.27 12 0.89 J 7.4 Hz, 3 FAB-MS calcd for (C22H29FO) 328, found 328 359 WO 98/04528 PCT/US97/13248 0 Step: 3 ,5-Diisopropyl-2-(1-oxoethyl)-6-ethyl-4'-fluoro-,1'-biphenyl The intermediate obtained in Step I (7.23 g, 22 mmol) in dichloromethane (100 mL) was added pyridinium chlorochromate (9.49 g, 44 mmol) and celite (9.49 g) under argon. The reaction was stirred at room temperature for 24 hours. The reaction was added to a 1:1 mixture of diethyl ether/hexane (1 then filtered through a plug of silica. The pad was washed with 650 mL of diethyl ether and the combined filtrates were concentrated in vacuo to afford a white solid (7.18 g, 22 mmol, mp 121-23°C; Rf 0.3 (50% CH2C12/hexane); 1 H NMR (300 MHz, CDCl3): 8 7.27 1 7.21 2 7.07 2 3.22 (septet, I 7 Hz, 1 2.78 (septet, J 7 Hz, 1 2.43 J 7.4 Hz, 2 1.96 3 1.28 12 0.930 J 7.7 Hz, 3 FAB-MS calcd for (C22H27FO) 326, found 327 Step K: 3 ,5-Diisopropyl-2-(1-hydroxvethyl)-6-ethyl-4-fluoro-1,1'-biphenyl To a solution of (1S,2R)-(+)-N-methylephedrine (6.29 g, 35.1 mol) in diethyl ether (45 mL) was added lithium aluminum hydride (1M/diethyl ether, 1.5 eq., mL) dropwise at 0°C under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then -78 0 C. The intermediate obtained in Step J (6.64 g, 20.3 mmol) was dissolved in 60 mL of dry diethyl ether for a dropwise addition to the reaction mixture mL/min., the temperature should not rise above The reaction was kept at -78 0 C for 2.0 hours and then allowed to warm overnight. The reaction was quenched at 0°C with water (30 mL) and diluted with diethyl ether (250 mL), washed with water (3 x 200 mL), brine (100 mL) and dried with MgSO4.

Filtration and concentration afford a residue which was filtered through a pad of silica (400 g, 80% dichloromethane/hexane) to give the titled compound (99% e.e.) as a white solid (5.85 g, 17.8 mmol, mp 143-145°C; Rf 0.1 CH2Cl2/hexane); 1 H NMR (300 MHz, CDC13): 8 7.34 7.15 4 4.68 (dq, J 3.3, 7 Hz, 1 3.88 (septet, J 7 Hz, 1 3.18 (septet, J 7 Hz, 1 2.29 (q"j 7.7 Hz, 2 1.68 1 1.37 J 4.8 Hz, 3 1.26 12 0.890 J 7.4 Hz, 3 FAB-MS calcd for (C22H29FO) 328, found 328 Anal. Calcd for C22H29FO: C, 80.45; H, 8.90; F, 5.78. Found: C, 80.19; H, 8.77; F, 5.84; [a] 2 2 +26.6.

360 WO 98/04528 PTU9134 PCTIUS97/13248 EXANPLE 245

F

(+)-3,5-Diisopropvl-2-(l-hydroxvethyl)-6-propyl-4'-fluoro-1,1'-biphe nyI The title compound (99% cc) was prepared from the intermediate obtained in Step E, Example 244 and ethyl triphenyiphosphonium bromide according to the procedures described in Example 244, Steps F-K. 1 H NMR (300 MI-z, CDCl3): 7.33 1 7.14 (in, 4 4.70 (dq, J1=2.9, 7 Hz, 1 3.88 (septet, J=6.62 Hz, 1 H), 3.14 ('septet, J=6.62 Hz, 1 2.18 (in, 27 H) 1.67 j=2.9 Hz, 1 1.37 J 7 Hz, 3 1.29 (in, 14 Ji), 0.719 1=7 Hz, 3 FAB-M4S calcd for (C23H31FO) 342, found 342 Anal. Calcd for C23H31F0: C, 80.66; H,9.12; F, 5.55. Found: C, 80.71; H, 8.99; F, 5.34; [c422 mp 114-116*C; Rf =01(50% CH2CI2/hexane).

EXAMPLE 246

HO

CH

3 3,-ispoy--lhdovty)6ehl4-loo2hdoy11-ihnl Step A: Di-tert-bift'l 4,&-diethyl-2-hydroxv-1,3-benzenedicarboxylate A mixture of di-tert-buityl 1,3-acetonedicarboxylate (10 g, 38.7 inmol), (6.5 g, 50.3 m mol) and s odium methoxide (2.7 g, 50.3 inmol) in WO 98/04528 PCTIUS97/13248 0 methanol (100 mL) was stirred at room temperature overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (100 mL) and 10 aqueous hydrochloric acid (100 mL). The separated aqueous layer was extracted with diethyl ether (50 mL x The combined organic portions were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered through a pad of silica (20 mm x mm) and concentrated in vacuo to yield a yellow oil (13.23 g, 97 1 H NMR (300 MHz, CDC13): 8 1.20 6H), 1.60 18H) 2.74 4H), 6.55 1H), 11.73 1H).

Step B: Di-tert-butyl 3 ,5-diisopropyl-2'-benzyloxy-4-fluoro- ,1'-biphenyl-2,6dicarboxylate The title compound was prepared from the intermediate obtained in Step A by the methods described in Example 241, Steps B, C, and E. 1H NMR (300 MHz, CDC1 3 8 1.15 18H), 1.27 (dd, J=5.15, 1.65 Hz, 12 3.06 2H), 4.95 (s, 2H), 6.65 2H), 7.27 7H).

Step C: 3 ,5-Diisopropyl-2'-benzyloxy-4'-fluoro-1,'-biphenyl-2,6-dicarboxylate To a solution of 14.37 g (25.53 mmol) of the intermediate obtained in Step B in dichloromethane (150 mL) at 0°C was added trifluoroacetic acid (20 mL, 259.60 mmol). This reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated to dryness and the residue was partioned between diethyl ether and aqueous sodium hydroxide. The organic layer was removed, washed with aqueous sodium hydroxide and the two aqueous layers were combined. The combined aqueous layers were washed with diethyl ether (lx) then made acidic by addition of HCI and extracted with diethyl ether The combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield an off-white solid. The crude product was taken directly to the next step without any further purification.

Step D: Dimethyl 3 ,5-diisopropyl-2'-benzyloxy-4'-fluoro-11'-biphenyl-2,6dicarboxylate To a suspension of 7.17 g (15.93 mmol) of the intermediate obtained in Step C in dichloromethane (200 mL) at 0°C was added solid potassium carbonate (10.05 g, 72.71 mmol) followed by iodomethane (5.0 mL, 80.31 mmol). The mixture was allowed to warm to room temperature. After stirring for 1 day the mixture was diluted with water and extracted with diethyl ether The combined extracts were washed with brine dried over magnesium sulfate, filtered and concentrated to yield an off-white solid. 1H NMR (300 MHz, CDC13): 8 1.22 (dd, 362 WO 98/04528PC[J9/34 PCTIUS97/13248 o J=4.41, 2.4 Hz, 12H), 2.94 (in, 2H), 3.39 6H), 4.93 2H), 6.55 (mn, 2H), 7.05 (in, 1H), 7.18 (mn, 6H).

Step E: 3,5-Diisopropvl-2-(l-hydroxyethvl)-6-ethvl-4'-fluoro-2'-hvdroxy-1 biphenyl The title compound was prepared from the intermed iate obtained in Step D by the methods described in Example 241 steps F-I (using ethyl triphenyiphosphonium bromide in Step H) followed by Example 242 steps B-D.

Silica gel chromatography (90% hexane/10% EtOAc) provided two colorless solids (1.129g, 84%).

.Diastereomer 1 was obtained as a colorless crystalline solid (1.029g, 77%).

1H NMR (300 MHz, CDCl3): 8 0.89 J=7.36 Hz, 3H), 1.28 (in, 12H), 1.40 J=6.62 Hz,3H),.1.63 1H), 2.29 (in, 2H), 3.17(m, 1H), 3.78 (in, 1H), 4.84 (in, 1H), 6.70 (in, 2H), 7.03 (in, 1H), 7.38 1H). FAB-MS: calculated for C22H2902F, 344; found 367 mp 174-175*C.

Diastereomer 1 (1.029 g) was resolved into its constituent enantioiners as follows: a Waters Prep LC 4000 HPLC system was equipped* with a chiral HPLC column (BRB-9668A; 6 x 50 cm. ID). The system was equilibrated with a mobile phase consisting of 0.75% butanol and 99.25/o hexane at a flo w rate of 100 inL/nmin.

The sample was dissolved in dichloromethane (20 mg/inL) and the sample was injected in one injection. The effluent was monitored at 285 run and two fractions (corresponding to the two enantioiners) were collected at (26-32 min, >98% ee6) and (34-48 min, ee), respectively.

Enantioiner 1 was obtained as a colorless solid (480 ing). 1H NMR (300 MHz, CDC13): 8 0.89 J=7.54.Hz;;3H), 1.28 (in, 12H),. 1.40 J=5.14 Hz, 3H), 1.65 (bs, 1H),2.19 (mn, 1H), 2.35 (in, 1H), 3.17 (mn, 1H), 3.78 1H), 4.85 (in, 1H), 6.71 (in, 2H), 7.03 (in, 1H), 7.38 I11). mp codndenises; at 57-59*C.

Enantioiner 2 was obtained as a colorless solid (483 ing). 'HNR(300 MHz, CDCl3): 850.89 J=7.36 Hz, 3H), 1.28 (mn, 12H), 1.39 J=-6.99 Hz, 3H), 1.63 (bs 1H, .29(ni .17(i, 1),3.78 (in, 1H), 4.84 (in, 1H), 6.70 (in, 2H), 7.03 (in, IHM, 7.38 1H). FAB-MS: calculated for C22H2902F, 344; found 367 mp condenses at 57-59*C.

Diastereoin-er 2 w 'as obtained as a colorless crystalline solid (100 mng, 1H NMR (CDC13, 300 Mllz): 8 0.88 J=7.54 Fiz, 3H), 1.27'(i, 12H), 1.36 J=6-62 Hz, 3H), 1.8 (bs, 1H1), 2.19 (mn, 1H), 2.39 (in, 1H), 3.16 (mn, 1H4), 3.84 (in. 1H), 4.63 (q, J=6.62 Hz, 1H), 5.09 (bs, 6.69 (mn, 2H), 6.92 J=7.35 Hz, 7.37 1H). mp 183-184 0

C.

WO 98/04528 PCT/US97/13248 0 EXAMPLE 247

F

3,-ispoV--lhdrxehl-- ny-'-loo2-yrx-,'-biphenyl Step A: 3 S-Diisopropl2.rhvdroxmethy6 (Pt-enyen )2benzlxA.

fluoro-1,1 '-biphenyl The desired compound was prepared from dimethyl 3 ,S-diisopropyl-2'benzyloxy-4'-fluoro-1,14-bipheny1.26-dicarboxylate (Example 246, Step D) -by the procedure described in Example 241, Steps F I (using pentyl triphenyiphosphonium bromide in Step The pure product obtained was a clear oil (4.73 g, 52 over 4 steps). 1H -NMR (300 MHz, CDCl3): 5 0.67 0.78 (in, 3H). 1.09 1.34 (mn, 14H), 1.66 1.88 (in, 3H), 3.16 3.46 (in, 2H), 4.29 4.44 (mn, 2H), 4.88 5.04 (mn, 2H), 5.27 5.41 (mn, 1H)j 5.94 6.01 (in, 6.69 6.78 (mn, 2H), 7.00 7.06: (in, 3H), 7.22 7.26 (in, 3H), 7.35 1H). 13 C. NMR (75 MlHz, CDCl3): 8 14.18, 14.52, 22.89, 23.05, 24.39, 24.64, 24.94, 25.11, 25.38, 29.73, 30.50, 30.66, 31.68, 35.85, 60.78, 71.07, 71.45, 102.25, 102.59, 108.08, 108.37, 122.33, 122.54, 127.11, 127.22, 127.92, 128.11, 128.51, 129.16, 132.70, 132.83, 133.39, 134.06, 135.96, 136.96, 137.29, 137.35, 147.48, 147.63, 147.79, 156.90, 156.93, 163.26 J 246.6 Hz, 1Q). FAB-MS: calculated for C31H3702F 460; found 460 Anal. caic for C31H3702F:

C,

80.83; H, 8.10. Fou~nd: C, 80.91; H, 8.01. Rf 0.34 (9:1 hexanes:ethyl acetate).

HPLC: (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 80o/o-100% B over 20 min; 254 rm, 1 mL/min): R.T. 14.8 min (37.7 area V)i 15.2 min (56.0 area );93.7 purity (cis- and trans-).

Step B: 3 ,5-Disoropl2(1..hydroxveffv1)-6 penl-4 flu-2.hvdro 1,1'-biphenyl The title compound was prepared fromn the intermediate obtained in Step A utilizing the procedures outlined in Example 242, Steps B-D. The crude product was subjected to flash column chromatography on silica (50 mm.i -x using hexanes:ethyl acetate (19:1 and 9:1) as eluent to separate the diastereoiners (2.19 g, WO 98/04528 WO 9804528PCT/US97/13248 o 90 75 over 3 steps).- Diastereomer 1 was obtained as awhite solid (2.03 g, 83 1H NMR (300 MlHz, CDCl3): 8 0.78 J 6.6 Hz, 3H), 0.96 -1.23 (in, 19H), 1.41 J 7.0 Hz, 3H), 2.04 2.37 (mn, 2H), 3.09 3.19 (in, 1H), 3.74 3.84 (mn, 1H), 4.81 4.90 (in, 2H), 6.68 6.75 (mn, 2H), 6.99 7.06 (in, 1H), 7.37 1H). 13 C NNM (75 MEHz, CDCl3): 8 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98 J 24.4 Hz, IC), 107.33 J 20.8 Hz, 1Q), 123.58 J 2.4 Hz, 1Q), 125.45, 130.70 J 9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 J 6.1 Hz, 1C), 163.04 J 244.2 Hz, 1C). FAB-MS: calculated for C25H3502F 386; found 409 Anal. caic for C25H3502F: C, 77.68; H, 9..13. Found: C, 77.38; H, 9.20. Rf =0.30 (9A1 hexanes:ethyl acetate). HPFLC: (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 70%-100% B over 30 min; 254 run, 1 inL/min): R.T.,12.9 min (9.1.3 area (silica, A hexanes, B isopropanol, isocratic run: 3 B over 15 min; 254 run, 1 mL/min): R.T. 5.1 min (100 area mp, 122.5-124.0*C.

Diastereomer 1 (1.92 g) was resolved into its constituent enantiomers as follows: a Waters Prep LC 4000 HPLC system was equipped with a chiral-HPLC column (BRB-9668A; 6 x 50 cm ID). The system, was equilibrated with a mobile phase consisting of 0.75% butanol and :99.25% hexane at a flow rate of 100 mL/~min.

Th"e sample was dissolved in dichioromethane .(40 mg/inL) and the sample was loaded in two injections. The effluent was monitored at 285 him and two fractions (corresponding to the two enantiomners) were collected.

Enantiomer 1 was -obtained as a white crystalline soid- (0178 1 H NMR (300 Wiz, CDCI3): 8 0.78 (tJ= 6.6 Hz, 3H), 0.96 1.23 (in, 19H), 1.41 J H4z,3H), 2.04 2.37 (Mn, 2H), 3.09 3.19. (in, 1H), 3.74 3:84j(i, 4.81 4.90 (in, 2H), 6.68 6.75 (in, 2H), 6.99 7.06 (in, 1H), 7.37 1H). 13 C NMvR (75 Mff-z, CDCl3): 8 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98 J 24.4 Hz, 1C), 107.33 J 20.8 Hz, 1C), 123.58 J 2.4 Hz, 1C), 125.45, 130.70 J 9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 J 6.1 Hz, 1C), 163.04 J 244.2 Hz, 1C). FAB-MS: calculated for C25H3502F 386; found 409 Anal. calc for C25H3502F: C, 77.68; H, 9.13.

Found: C, 77.74; H, 9.00. Rf 0.30 (9:1 hexanes:ethyl acetate). HPLC (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 709/0-100% B over min; 254 run, 1 mL/inin): R.T. 12.8 min (94.9 area (BRB-9668, 99 (1 butanol in hexanes), 5 min, 285 run, 2inL/min): R.T. 2.6 min (100 area 100 [aID -14.3- (c 0.00200 g/mL, CH2Cl2). mp 105.0-106.5'C.

Enantiomer 2 was obtained as a white flaky solid (0.73 11f NMR (300 -MHz, CDCI3): 8 0.78 J =1 6.6 Hz, 3H), 0.96 1M3 (mn, 19H), 1.41 J= 7.0 HzM3), 2.04 2.37 (mn, 2H), 3.09 3.19 (mn, 1H), 3.74 3.84 (in, 1H), 4.81 4.90'(mn, 2H), 6.68 365 WO 98/04528 PCT/US97/13248 o 6.75 2H), 6.99 7.06 (mn, 1H), 7.37 1H). 13 C NNM (7,5 MHz, CDC13): 5 13.83, 21.94, 23.83, 24.27, 24.38, 24.50, 24.88, 28.70, 29.05, 29.80, 30.76, 32.20, 68.21, 102.98 J 24.4 Hz, 1C), 107.33 J 20.8 Hz, 1C), 123.58 J 2.4 Hz, 1Q), 125.45, 130.70 J 9.8 Hz, 1C), 131.78, 137.45, 138.55, 146.48, 146.94, 154.29 J 6.1 Hz, 1C), 163.04 J 244.2 Hz, 1C). FAB-MS: calculated for C25H3502F 386; found 409 (M Anal. caic for C25H3,502F: C, 77.68; H, 9.13. Found: C, 77.64; H, 9.06. Rf 0.30 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A 0.05 aqueous trifluoroacetic acid, B CH3CN; linear gradient: 70%-100% B over 30 min; 254 rn, 1 mL/min): R.T. 12.8 min (94.7 area (BRB-9668, 99 (1 butanol in hexanes), 5 min, 285 nan, 2mL/min): R.T. 1.7 min (0.51 area 2.9 min (0.97 area 4.0 min (98.5 area %,98 (aID +16.00 (c =0.00200 g/mL, CH2CI2). mp 103.5-105.5'C.

Diastereomer 2 was obtained as a white solid (0.16 g, 7 1 H NMR (CDCI3, 300 MHz): 8 0.78 J 6.6 Hz, 3H), 0.96 1.33 (in, 19H), 1.37 J 6.6 Hz,3H), 2.05 2.38 (in, 2H), 3.09 3.19 (in, 1H), 3.80 3.89 (mn, 1H), 4.61 4.68 (m, 1H), 4.75 5.25 (br s, 1H), 6.66 6.74 (mn, 2H), 6.90 6.96 7.37 1H). 13

C

NMR (75 MHz, CDC13): 8 13.83, 21.94, 23.43, 24.08, 24.48, 24.56, 24.98, 28.0,--29.04, 29.80, 30.76, 32.19, 68.89, 102.80 J 24.4 Hz, 1C), 107.36 J 22 .0 Hz, 1C), 123;24 J 2.4 Hz, 1C), 125.64, 131.25 J 9. Hz, 1C), 131.56, 137.08, 138.44, 146.81, 146.84, 154.37 J 12.2. Hz, 1C), 163.03 J 244.2 Hz, 1C). FAB-MS: calculated for C25H3502F 386; found 409 Anal. calc for C25H3,502F:

C,

77.68; H, 9.13.. Found: 77.70; H, 9.12. Rf 0.17 (9:1 hexanes:ethyl 'acetate).

HPLC: (C-18, A 0.05 aqueous trifluoroacetic adid, B CH3CN; linear gradient: 70%-100% B over 30 min; 254 rum, 1 mL/mi): R.T. 17.6 min (86.9 area (silica, A -hexanes, B isopropanol, isocratic run: 3 B over 15 min; 254 run, 1 mL/min): R.T. 4.9 min (100 area mp 148.0-150.0* 0

C.

EXAJvIILE 248

F

OH

NNNI

LY1-biphenyl 366 WO 98/04528 PCT/US97/13248 0 StepA: 3,5-Diisopropyl-2-[(p-ethylbenzlox)methyll6-hydroxymethyl4fluoro-1,1'-biphenyl To a solution of 3 ,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'fluoro-1,1'-biphenyl (Example 244, Step D) (4.09 g, 11.9 mmol) in THF (70 mL) was added at room temperature sodium hydride (0.85 g, 35.4 mmol) in portions. The reaction mixture was stirred for 10 min. and then treated with a-bromo-p-xylene (2.64 g, 14.3 mmol). The reaction mixture was heated at reflux for 24 hrs then cooled to room temperature and quenched with water (30 mL). The solvent was removed in vacuo and the residue partitioned between diethyl ether (300 mL) and water (200 mL). The ether layer was dried (MgSO4) and concentrated, the residue was purified through silica (70% CH2Cl2/hexane) which afforded a white solid g, 10.3 mmol, The product was dissolved in THF (40 mL) was treated with lithium aluminum hydride (19.8 mL, 19.8 mmol, 1.OM in THF). The reaction mixture was heated at reflux for 2 hrs then allowed to cool to room temperature.

The mixture was quenched with water (6 mL), and the solvent was removed in vacuo. The residue was partitioned between diethyl ether (200 mL) and water (300 mL). The organic layer was washed with water (3 X 300mL), brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was filtered through a cake of silica (CH2Cl 2 1L) and evaporated to afford a white solid (3.26 g, 7.7 mmol, mp 99-101CO Rf 0.07 (80% CH2Cl2/hexane); 1 H NMR (300 MHz, CDCl3): 6 7.38 1 7 2 7.09 6 4.36 J =5.5 Hz, 2 4.27 2 4.11 2 H), 3.42 (septet, J= 6.6 Hz, 1 3.32 (septet, J= 6.6 Hz, 1 2.35 3 1.60 1 H), 1.22 12 FAB-MS calcd for (C28H33F0 2 420, found 403 (M-OH).

Step B: 3 ,5-Diisopropyl-2-[(p-methylbenzvloxy)methyl]-6-(1 hvdroxyethyl)-4'-fluoro-1,1'-biphenyl S- The title compound was prepared by subjecting the intermediate obtained in Step A to the procedures described in Example 244, Steps I-K. mp 84-86'C; Rf 0.1 CH2Cl2/hexane); 1 H NMR (300 MHz, CDC13): 8 7.39 1 7.27 2 H), 7.09 6 4.76 (dq, J 1.5, 7 Hz, 1 4.22 2 4.03 2 3.89 (septet, J 6.6 Hz, 1 3.26 (septet, J 6.6 Hz, 1 2.35 3 1.66 1 1.40 J 6.6 Hz, 3 1.26 12 FAB-MS calcd for (C29H35F02) 434, found 417 (M-OH); Anal. Calcd for C29H35F02: C, 80.15; H, 8.12; F, 4.37. Found: C, 80.10; H, 8.30; F, 4.24; [a] 22 +30.7.

367 t WO 98/04528 PCT/US97/13248 EXAMPLE 249 biphenyl The title compound was prepared from p-thiocresol and 3 5 -diisopropyl-2hydroxymethy1-6-carboxymefiyl.4'..fluoro..1l1..biphenyl (Example 244, Step D), according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf 0.36 CH2Cl2/hexane); 1 H NMR (300 MHz, CDC 3 8 7.40 1 7.28 (in, 2 7.11 (in, 6 4.76 (dq, J 1.8, 7 Hz, 1 3.92 (septet, I 6.6 Hz, 1 3.78 2 3.26 (septet, J 6.6 Hz, 1 2.36 3 1.66 1 1.40 I 6.6 Hz, 3 1.28 (in, 12 FAB-MS calcd for (C28H33F0S) 436, found 436 Anal. Calcd for C29H35FOS: C, 77.02; H, 7.62; S, 7.34; F, 4.35. Found: C, 76.90; H, 7.77; S, 7.30; F, 4.37; 22 +32-1.

C

EXAMPLE 250 0

OCH

3 3 S-Diisopropl24(4ethoxtho WheIopehynvl-methydroxhdthl)-A'flu 1,1-biphertyl WO 98/04528 PCT/US97/13248 0 The title compound was prepared from 4-methoxy thiophenol and propyl- 2 -hydroxymethyl-6-carboxymethyl-4'-fluoro-l1,'-biphenyl (Example 244, Step according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf 0.23 CH2Cl2/hexane); mp 140-2 0 C; 1 H NMR (300 MHz, CDCl3): 8 7.36 1 7.30 (m, 2 7.08 4 6.75 2 4.72 J 7 Hz, 1 3.89 (septet, J 7 Hz, 1 H), 3.78 3 3.68 2 3.38 (septet, J 7 Hz, 1 1.57 1 1.40 J 6.6 Hz, 3 1.31 12 FAB-MS calcd for (C28H33F02S) 452, found 452 Anal. Calcd for C28H33F02S: C, 74.30; H, 7.35; S, 7.08; F, 4.20. Found: C, 74.06; H, 7.46; S, 6.87; F, 4.09; [a] 2 2 +24.5.

EXAMPLE 251

F

OH

SSCH

3 O H s (+)-35-Diisopropl-2-(4- ethliophenyl)-methyl-6-(l-hdroethvl)-4fluoro-1,1'-biphenyl The title compound was prepared from 4 -(methylthio)phenol and propyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-,1'-biphenyl (Example 244, 20 Step according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf 0.52 CH2Cl2/hexane); mp 157-9°C; 1H NMR (300 MHz, CDCI3): 6 7.37 1 7.30 (m, 2 7.12 6 4.71 j 7 Hz, 1 3.90 (septet, J 7 Hz, 1 3.75 J 11 Hz, 1 3.70 11 Hz, 1 3.33 (septet, J 7 Hz, 1 2.46 3 1.58 1 1.40 J 6.6 Hz, 3 1.29 12 EI-MS calcd for (C28H33FOS2) 468, found 468 Anal. Calcd for C28H3 3

FOS

2 C, 71.76; H, 7.10; S, 13.68; F, 4.05.

Found: C, 71.54; H, 7.22; S, 13.26; F, 4.17; [a]2 2 +40.6.

369 WO 98/04528 PCT/US97/13248 EXAMPLE 252

.CF

3 3 5-Diisoropyl2[(4trifluoromeththiophenvl)methl6(lhydr eh)- 4'-fluoro-1,1 '-biphenyl The title compound was prepared from 4 -(trifluoromethyl)benzene thiol and 3,-ispoy--ydoyehl6croymty 'fur-,'-biphenyl (Example 244, Step according to the procedures described in Example 47, Ste PS B and C, followed by the procedures described in Example 244, Steps I-K. Rf =0..39 CH2Cl2/hexane); mp *171-3 0 C; 1 H NMR (300 MHz, CDCI3): 5 7.45 1 H), 7.42 1 7.39 1 7.30 (in, 1 7.09 (in, 5 4.72 J 7 Hz, 1 3.91 (septet, J 7 H-z, 1 3.83 J 11 Hz, 1 3.78 'J 11 Hz, 1 3.28 (septet, J 7 Hz, 1 1.60 1 1.41 J 6.6 Hz, 3 1.29 (in, 12 H)I FAB-MS calcd for (C28H3 0F 4 0S) 490, found. 490. Anal. Calcd for C28H30F405: C, 68.55; H, 6.16, S, 6.53; F, -15.49. Found: C, 68.67; H, 6.15; 5, 6.56; F, 15.33; [a] 22 +25.6.

0 EXAMPLE 253.

S+-,-ispov--(-rfurmtoyhopey)mt 16(-vrxh).

41 -fluoro-1,1'-bivhenyl r WO 98/04528 WO 9804528PCTIUS97/13248 0 The title compound was prepared from 4-(trifluoromethoxy)benzene thiol and 3 ,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'-fluoro-1,1 '-biphenyl (Example 244, Step according to the procedures described in Example 47, Steps B and C, followed by the procedures described in Example 244, Steps I-K. Rf 0.39 CH2CI2/hexane); mp 124-6'C; 1H NMR (300 ML-z, CDCl3): 8 7.38 1 H), 7.30 (in, 2 7.09 (mn, 6 4.73 I 7 Hz, 1 3.91 (septet, J 7 Hz, 1 3.78 j 11 Hz, 1 3.73 j 11 Hz, 1 3.31 (septet, I 7 H-z, 1 1.60 1 H), 1.41 J 7 Hz, 3 1.28 (mn, 12 FAB-MS calcd for (C28H30F402S) 506, found 506 Anal. Calcd for C28H30F402S: C, 66.39; H, 5.97; S, 6.33; F, 15.00. Found: C, 66.71; H, 6.06; S, 6.22; F, 15.24; [a] 22 +25.8.

EXAMPLE 254

F

OHF

3 ,S-Diisopropyl-2-[F(4-fluorothiOphenayl)-metyl1-6&(1.hydroxethy l)'fluoro- 1,1'-7biphenyl The title. compound was prepar ed from'4-fluorothiolphenol and propyl- 2 -hydroxymethyl-, rboxymethyl4'fluoro1,1'biphnyI (Example 244, Step according 'to the procedures described in Example 47, Steps B and C, followed, by the procedures described in Example 244, Steps Rj 0.35 CH2Cl2/hexane); mp 138-140 0 C; 1H NMR (300 MHz, CDC13): 8 7.37.(s, 1 7.30 (in, 2 7.05 (in, 4 6.90 (in, 2 4.71 1 =7 Hz, 1 3.90 (septet, I 6.6 Hz, 1 3.72 (mn, 2 3.33 (septet, I=6.6 Hz, 1 1.52 1 1.39 6.6 Hz, 3 H), 1.27 (in, 12.H); FAB-MS calcd -for (C28H3OFO2S) 506, found 506 Anal. Calcd for C28H33F02S: C, 74.30; H, 7.35; S, 7.08; F, 4.20. Found: C, 74.06; H, 7.46;'S, 6.87; F, 4.09; [a] 22 =+17.6.

371 L WO 98/04528 PCT/US97/13248 0 EXAMPLE 255

F

HO S O 35-Diisprpl-2-(thiphenmeh 6-ydr methl)-4'-fluoro-1 '-biphenyl A suspension of Wang-resin (100 g, 1.09 mmol/g hydroxylated) was suspended in 1 L of a solution of 4N HCI in dioxane and gently stirred at room temperature for two days. After filtration, the chlorinated resin was washed 6 times with each of the following solvents; dioxane, isopropanol and finally THF. The. resin was then dried at 60°C overnight. From this resin, 2.5 g (2.2 mmol based on the chlorine content detected by eleinental analysis) was suspended in DMF (25 mL) and stirred at room temperature for 5 minutes, then the DMF was decanted off for the addition of a solution of 3,5-diisopropyl-2-hydroxymethyl-6-carboxymethyl-4'fluoro-1,1'-biphenyl (Example 244, Step D) (1.13 g, 3.3 mmol) in DMF (25 mL), followed by a.solution of sodium hydride (60 in mineral oil,,170 mg, 3.3 mmol) in DMF (12.5 mL). The suspension was stirred at room temperature for two days under an argon atmosphere. The suspension was then filtered and the resulting resin was successively washed 10 times with each of the following solvents; DMF, a mixture THF/water THF and finally with CH2C12.

Theresin residue was then treated with a solution of lithium aluminum hydride (1 0 M irTHF, 15 iL, 15 mmol) and heated at reflux for 2 days. The suspension was filtered and the resulting residue was washed successively 10 times with each of the following solvents; THF, a mixture of THF/water a mixture of THF/water THF and finally with CH2Cl2 The residue was suspended in THF (25 mL) and slowly treated with PBr3 (835 gL, 8.7 mmol) at room temperature. The resin was filtered out and washed 10 times with each of the following solvents; THF, mixture of THF/1N sodium bicarbonate THF/water THF and finally CH2C12, then dried at 60°C overnight which afforded 2.25 g of resin (0.62 mmol/g based on the bromine content detected by elemental analysis).

372 Klr I WO 98/04528 PCT/US97/13248 0 To 25 mg of this intermediate coupled with a resin was added thiophenol (26.4 mg, 0.24 mmol) in dry THF (500 gL) and N-methylmorpholine (26 I.L, 0.24 mmol), then the suspension was refluxed for 8 hours. After filtration, the resin was washed successively 10 times with each of the following solvents; THF, a mixture of THF/water and THF. The resin was then suspended in a mixture of TFA and CH2C12 and stirred at room temperature for one hour. The resin was filtered off and the solvent recovered then evaporated. The residue was dissolved in a mixture of methanol and acetonitrile and one drop of diisopropylethylamine, then stirred for one hour; HPLC:. 12.5 min (Hypersil BDS-C18, 5pmn, 125 x 2 mm/Hewlett Packard, Flow 0.5 mL, 0-13 min 30-90%C, 13-15 min 90%C, Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile). After evaporation of the solvent, the remaining residue was transferred in a microtiterplate for testing.

The compounds identified in the following Table as Examples 256-288 were prepared analogously to the compound of Example 255.

Table of Exemplary Compounds 255-288 HPLC Est.'d Purity Example R R.T. (method) 255 H 12.5 60-70 256 4-tBu 14.9 257 4-OMe 12.2 60-70 258 4-Me 13.2 50-60 259 4-ipr 14.4 50-60 260 4-F 12.5 261 4-Et 15.1 262 4-CF3 13.4 70-80 373 J~nh~;Tr:r' ;~~mi~i ~c r.vi, I, WO 98/04528 WO 9804528PCTIUS97/13248 HPLC Est.'d Purity Example R R.T. (method)

M%

263 4-Br 13.9Q() 264 3-Me 13.2 265 3-F 13.0(I-) 70-80 266 3-Cl 13.5 267 3-CF3 13.4 268 2-Me 13.2 269 2-F 12.4 60-70 270 2-Cl 12.9 50-60 271 2,3-Me ND.

ND

272 2 ,3-Cl 6.8 (111) 50-60 273 2,4-Me 13.9 50-60 274 2,4-Cl 14:2 60-70 275 2,4-F 12.6Q() 60-70 276 2-Me4-Cl 14.2 277 -F 2-CI-4-F 13.3-(I-)809 /I 0 279 280 281 282 283 284 285 286 287' 288 2,6-Cl 3,4-Me 3,4-Cl 14.0 (1) 13.7 (1I) 60-70 C x (:160 15.0 (1) 14.3(I) 3-CI-4-F 13.5 3,5-Me 13.9 3,5-CF3 14.4 3,5-Cl11 14.8(I) 2,3,5,6-T-4-Me 14.0 80-90 2,3,,6-F4-C.14.0 60-70 Zrafa.,O-r 12.9--(1) 60-70

-I

60-70 I

I

HPLC: The Retention times for the compounds shown in the above table of exemplary compounds 255-290 were measured in minutes according to one of the three methods described below: MI Hypersil. BDS42C18,Spn, 125 x 2 mmr/I-ewlett P-ackard,' Flow 0.5 mL, 0-13 min 30-90%C, 13-15 min 90% C, Solvent A: Water/0.1%/ TFA; Solvent B: -Acetonitrile.

374 WO 98/04528 PCT/US97/13248 0 (II) Hypersil BDS-C18, 5pm, 125 x 2 mm/Hewlett Packard, Flow 0.5 mL, 0- 13 min 30-90%C, 13-25 min 90% C, Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile.

(III) NPS ODS-1, 1.5mm, 33 x 4.6 mm/Micra, Flow 1.0 mL, 0-8 min 15-70% C, Solvent A: Water/0.1% TFA; Solvent B: Acetonitrile.

The estimated purity numbers were determined by comparison of peak areas, not by reference to standards.

The pharmaceutical utility of compounds of this invention is indicated by the following assay for glucagon receptor activity.

The affinity for the glucagon receptor of compounds of the present invention is determined by the glucagon receptor binding assay. Membranes were prepared from Chinese Hamster Ovary cells expressing the glucagon receptor (CHO-HGR) by scraping the cells into hypotonic lysis buffer (10 mM Tris, pH 7.4, 2 mM EDTA, 5 mM MgC2 and 1 mM PMSF) and subjecting the material to Polytron homogenization. Nuclei were removed by a 15-min 800 x g centrifugation step conducted at 4 0 C. Membranes containing the receptor were collected by centrifugation at 15,000 x g for 15 min at 4 0 C. The membranes were washed once in lysis buffer-and suspended in 0.25 M sucrose, 10 mM Tris, 5 mM EDTA, pH 7.4.

The membranes were used in ligand binding studies as reported (Yoo-Warren, H., Willse, Hancock, Hull, McCaleb, and Livingston, J. Regulation of Rat Glucagon Receptor Expression. Biochem. Biophysical Res. Commun. 1994, 205, 347-353). In brief, 10 ug of membrane protein was incubated in 130 gl of binding buffer that consisted of 20 mM Tris, pH 7.4, l1mM EDTA, 1 mg/ml BSA, and 1 mg/mlbacitracin. The membrane suspension was placed in each well of a 96-well filtration plate (glass fiber type C, Millipore). Twenty pl of test compound was added to each well to give final concentrations ranging from 2 nM to 20 pM.

Following the addition of test compound, '50 pl of 1 2 5 I-glucagon (9 fmol) (NEN) was added to each well. Control wells contained membraies, 0.5% DMSO (solvent for test compounds), radiolabeled glucagon. without and with excess native glucagon (1 pM) to establish nonspecific binding. The plates were incubated for min at room temperature, and then filtered on a Millipore vacuum apparatus.

Following a wash step with ice-cold PBS/0.1% BSA, the filters were punched into test tubes, and the membrane bound radioactivity was determined. An IC50 value (the concentration of test compound needed to reduce membrane binding of radiolabelled glucagon by 50%) was calculated for each compound. If 20 gM 375 WO 98/04528 WO 9804528PCT/US97/13248 o compound did not reduce glucagon binding by 50%, the reduction at 20 jiM was reported in place of an IC50 value. The binding characteristics for compounds -of this invention are shown in Table I(C).

Table I(C) Example IC.50 Inhibition (Wi) (20 jiM) 1 0.6 2 2.73 3 1.52 4 ~1.98' 12.42 6 34.23 42.14 8 17.M 11 8 12 1.7 13 3 14 1.4' 1.7 16 0.85.

17' 0.6 18 0.75 19 0.7 1.3 21 0.8 2211 -23" 0.39 C b ,Z4-1qf U. 11) 0.41 26 .28.

1 WO 98/04528 WO 9804528PCTIUS97/13248 Example 1C50 Inhibition (RM) (20 pM) 29 1 0.9 31 2.6 32 1.1 33 1.8 34 0.6 0.7 36 1.8 37 0.75 38 0.6 39 1.3 0.75 41 0.6 42 0.7 43 1.8 44 1.1 46 9 47 48 1.8 49 1.1 0.9 51 16 52 53 4.9 54 1.8 15.66 -56 1.9 57 58 591 1.6 1377 WO 98/04528 PCT[US97/13248 Exml CSO Inhibition p (pRM) (20 gM) 61 3.4 62 1.1 63 1.7

L

64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 83 84 86 89 91 92 I

T

1.1 0.75 1 13 12 17.46 27.08 34.16 6 1.9 0.65- 1.9 1.1 1.9 5.18 38.76 24.75 36.03 29.14 14.15 11.59 4*S* C 000.' WO 98/04528 WO 9804528PCT/2US97/13248 Example 1C.50 Inhibition (Wi) (20 uiM) 93 28.33 94 38.54 26.53 96 27.84 97 29.25 98 14 99 43.18 100 39.61 101 0.22 102 0.11 103 1.9 104 0.25 105 0.3 106 0.15 107" 3 108 0.24 109 0.12 110 2 112 4.17 113 0.6.

114 38.49 115 21.12 116 V 1703 117 45.14 118 13 119 30.2 120 37.01 121 26.19 122 7.54 123 49.22 124 12-- 379 WO 98/04528 WO 9804528PCTIUS97/13248 Example 1CS0 Inhibition (Wi) (20 JiM) 1.25 31.62 126 35..29 127 45.53 128 3 129 130 1 131 372 132 42.48 133- 35.46 134 34.41 135 4.64 136 2.37 137 1 138 -9 139 -17 140- 46.28 141 34.05 142 33.11 143 0.9 144* 0.8 145 41.44 146 48.78 148 7.78 149' 39.03 150 151' 10.5 152 25.35 153 154 20.71 155 25.25 156 26.05 i lu/ 32.6 380 WO 98/04528 WO 9804528PCT/US97/13248 Example IC50 Inhibition (jiM) (20 AiM) 158 1.8 159 1.1 160 21.03 161 23.99 162 13.88 163 164 -D1 0.045 164 -D2 0.1 165 -D1 0.04 165 -D2' 1.1 166 0.19 167 -D1 0.03 167 -D2, 2.2 169 37.06 '170 45.45 171 48.37 173 27.4 174'- T 33,38 175' 40.8 176' 11~83 177 19 -178 25.98 179 26..79 180 38.21 181 45.96 182 49.07 183 13.23 184 28.93 185 41.22 186 187 12 188 10.5 WO 98/04528 PCT/US97/13248 Example 189 190 191 192 1f9 3 194 195 196 197 198 199' 200 201 202 203' 204 205 206 207 208 -216-- 211 212 21 3 214 215 217 218 219 220 221 222 IC50 I Inhibiti-on (jiM) (20 jM 12 0.3 0.13 0.13 0.086 1 12 7 17 9 63 1.8 18 19 18 19 14' 7 19 8 1.3 1.3 0.11 40.32 44.57 43;97 5.11

C

7 -77 7 -77 777 7 WO 98/04528 WO 9804528PCT/US97/13248

C)

Exml C50 Inhibition pWji) (20 jiM) 223 0.11 224 0.11 225 7 226 3 227 1.3 228 2 229 0.8 .230 0.9 231 232 1.2 233 0.6 234 8 235 3.1 236 4 237 1.2 238 0.01 239 -rac 0.08 239 -El 239- E2 0.05 240 0.016 -241 0.11 -242 0.005 243 0.086 244 0.18 245 0.3 246 0.011 247 0.006 248 0.31 249 0.13 250 0.2 251 0.4 252 0.18 383 WO 98/04528 PCT/JS97/13248 Example 253 254 255 256 257 258 259 260 261 262- -263- 264 265 '266 267 268' 269 270 271' '272 274 1CS 0 Wji) 0.18 0.11 3 7 7.3 7 6 5.4 1.7 3.4 3 2 1.7 4.1 3.4 12 2.6 12 Iniition (20 jiM) 275 J~ 3 1 276 277 278 279- 280 281 282 283 '284' 2 5.4 1.7 12 7 WO 98/04528 WO 9804528PCT/US97/13248 Example 1C50 Inhibition (ttM) (20 jiM) 285 9 286 18 287 288 2 0 Preferred phenyl. pyridine compounds of general formula (IC) and more particularly of general formula 1B are shown in the following list: 2 ,6-Diisopropyl-3-hydroxymethyl-4-phenyl-5-ethylpyridine; C) 2 ,6-Diisopropyl-3-hydroxymethyl-4-(4-flu'orophenyl)-5-.ethylpyridine; 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-ethyllpyridine; 2 6 -Diisopropyl-3-hydroxymethyl-4-(4- 2 6 -Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphenyl)..s.ethylpydi e; 2 6 -Diisop ropyh3-hydroxymethyi4(2-hydro xy-4fluorophenyl);- 2,6-Diisopropyl-3-hydroxymethyl-4-phenyl5-.propylpyridine; 2 6 -Diisopropyl-3-hydroxymethyl4-.(42fluoropheinyl).s..propylp'yndine; 2 6 -Diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5-propylpyridine; 2 6 -Diis poyl-3-hydroxymhtyl--(4-iethylphnyl)5-propylpyridine; 2 ,&Diisopropyl-3-hydroxymefiyl-4-phenyl-l--butylorridine; 2 6 -Diiso "rop y-3.-hydroxyml'ethylA4-(4-fluoropheflyl)-5-butylpyrndine; 2 6 -Diisopropyl-3-hydroxymethyl-4-(4chlorophenyl)s..b'utylpy'ndine; 2,-ispoy--~r~yrehl4(-~'.hlpe-"1)5btlyi~e 2 6 -Diisopropyl-3-hydroxymethyl-4-(2-hydroxyphen'yl)-5-butyl-pyridine; 2 6 -Diisopropyl-3-hydroxymethyi-4-(2-hydro'xy.4fluorophenyl)5butylpyridine; 2 6 -Diisopropyl-3-hydroxymethyl-4-phenylv.-pentylpyridine; 2,-ispoy--yrxmty--4furohnl--etlyiie 2 6 -Diisopropyl3-hydroxymethyl4(-doropheyl)...pentlpyr idine; 2 6 -Diopropyl-3-hydroxymethylA4-(2hydroxyphenyl)--5pentl-pyridine; 385 WO 98/04528 PCTr1US97/13248 0 2 6 DiisopropyI3-hydroxymet--hy...4(2...hydrophyl)ophentl ylid 2 6 -Diisopropy1-3hydroxyrnethylA..(4-.fluorophenyl),5-hexq,1pyridin 2 6 -Diisopropy1-3hydroxymethyI.4-(4choropheny)5hexyyidin 2 6 -Diisopropyl-3-hydroxymethyl..4.(4.methypheny)5hexylpyridin 2 6 -Diisopropyl3hydroxymethy1A.(2hydrox Y4-fluorophey) 5 hexlpyidie pyridine; 2 t 6 §-Diisopropy3[(tollhio~methyl]-meffiy1]4(4hnyro-5henI)5mhflpyridine; 2,-ispoy--(-oyti~ehl--4mtypey)5hdoyehl pyridine; 2 6 -Diisopropy-3[(plytho~myl]io(mehy] drox pyridine; 2,-ispoy-3[ptllhom~hl--2hdoy4furpey)5 hydroxymethyl-pyridine; 2 6 -Diisopropyl3[((4fluoropheny)thio)meffyl 1]pheny5hydroxyethl 0,* pyridine; 26tispo~l3[(-.furpe~lti~ehl--4furpey)5 hydroxymethyl.pyridine; .26Diorpl3[(-lurpey~iOmty]4(-hoohny)5 hydroxymethylpyridine; 2,6 -Diisoproy -(4furpe~y~honttyl4-4mt~lhry)5 :hydroxymethyl..pyridine; hydroxyrnethylipyridine; 2,-ispoy--(4floohnlti ity]--2hdoy4-loohiny)hydroxymethyl-pyridine; 2 6 2,-ispoy--lhdoyty)4(-loohxy)5ehlyi~e 2,-ispoy--lhdoy~hl-.(-hoohnl--typrdn; 2,-ispoy--lhdoyty)4(-ehlhnl--~hlyiie 386 WO 98/04528 WO 9804528PCT/US97/13248 0 2,-ispoy--lhdoyty)4(-yrxpey)5ehlyiie 2,-ispoy--lhdoyty)4(-~doy4furpey)5ehlyiie 2 6 -Diisopropyl- 3 2 6 -Diisopropyl- 3 -(l-hydroxyethyl)-4(4fluorophenyl)-5propylpyridine; 2 ,6-Diisopropyl- 3 -(l-hydroxyethy)4-4-chlorophenyly..5-propylpyidile; 2 6 -Diisopropyl- 3 -(l-hydroxyethy)-4-(4-methylphenyl)-5-propylpyridine; 2 6 -Diisopropyl-3-(l-hydroxyethyl)A4-(2-hydroxyphenyl)-5propylpyridine; 2 6 -Diisopropyl-3-(l-hydroxyethy1)-4(2hydroxy4fluorophenyl)5 propylpyridmne; 2 6 -Diisopropyl-3-(l-hydroxyethy)-4-pheny..5butylpyridine;

C..

2 6 -Diisopropyl- 3 -(l-hydroxyethy)-4-(4-methylpheny)5buirlpyridine;- 2,-ispoy--lhdoyty)4(-yrxpey)5btlyiie 2,-ispoy--lhdoyty)4(-yrx--l ohnl--uypn ie 2,-ispoy--lhdoyty)4(-loohnl--etlyiie 2,-ispoy--Ihdoyty)4-4clpohnl--etlyiie 2,-ispoy--lhdoyty)4(4mtype~l;5p~tlyiie 2,-ispoy--lhdoyty)4-2hdoyhnl--etlyiie 2,-ispoy--lhdoyty)4(-yrx--lo-p~y)5getlyiie 2 6 -Diisopropyl!3-(1-hydroxyethy)A4-pheyl.5.hexylpyridine.; 2,-ispoy-.(-yrxehl-4(-loohnl--elpidie 2,-ispoy--lhdoyty)-4(-hoohnl--ixlyiie Col 2 6 -Diisopropyi-3-(i-hydroxyethy)-4-(4-methylphenyl)5.hexylpyridine; 2,-ispoy--lhdoyty)4(-yrxpey)5hxlyiie 2,-ispoy--lhdoyty)4(-yrx--loohnl--~xlyiie 2,-ispoy--(-oyti~ehl-4peilS(-yrxehl-prdn- 2,-ispoy,3[*-oyti ehl-4(-looh-nl pyridine; 2,-ispoy--(-oyti~ehl--4clrpey),-(-yrxrty) pyridine; 2 6 -Diisopropyl- 3 -[(-tolylffiio)methyl1].-(4.meth.ylphenyl)-5(l4hydroxyeiyl)pyridine; 387 WO 98/04528 PTU9/34 PCTIUS97/13248 o 2 6 -Diisopropyl-3-[(ptolythio)methy4(2hydroxyphenyl).5..(lhydroxethy)pyridine; 2 6 -Diisopropyl-3-[(p-tolylthio)methy4(2.hydroxy4fluorophnyl) 5 (l hydroxyethyl)-pyridine; pyridine.' 2 6 -Diisopropyl- 3 -[((4-fluorophenyl)thio)methyl]-4(4-.fluorophenyl).5-(l.

hydroxyethyl)-pyridine; 2 6 -Diisopropyl-3-[((4fluoropheny)thio)methy4(4chlorophenyl)5(lhydroxyethyl)-pyridine; 2 6 -Diisopropyl-3-[((4.;fluorophenyl)thio)methyl]..4(4-meffiyphenyl)5(lhydrox yethyl)-pyridine; 2,-ispoy--[(-loohnlti~ehl--2hdoyhnl--l hydroxyethyl1),-pyridine; 2,-ispoy--(4furpey~ho~~hl--2hdoy4furpe')5 (l-hydroxyethyl)-pyridne.

Preferred biphenyl compounds of general formnula (IC) and more particularly of general formula 1D are shown in the following list: 3 5 -Diisopropy1-2hydroxymethyl-6-thyl.1,1 -biphenyl;' 3,-i -spoyl2hdoyehl6ehl-clr1,'-biphenyl; 5Disp '-biphenyl;l6-thlL."-hdox-11-bpen 3 1 5 Diisopropyl-2hydroxymeffyl.6propyl41!.mpeh1Ibihn 3

I

5 -Diisopropyl-2-hydroxymethyl..&butyl..1..bipheny; 3,-ispoy--yrxmty-6btl4-loo11-ihnl 388 WO 98/04528 WO 9804528PC'rIUS97I13248 o 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-chloro-1,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-butyl-4'-methyl-1 ,I'-biphenyl; 3 ,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-1,1 '-biphenyl; 3 ,5-Diisopropyl-2-hydroxymethyl-6-butyl-2'-hydroxy-4'-fluoro-1,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-1,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-4'-fluoro-1,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl1-6-pentyl-4'-chloro-1,1 '-biphenyl; 3 5 -Diisopropyl-2-hydroxymethyl- 6-pentyl-4'-methyl-1,1 '-biphenyl; 3,5-Diisopropyl-2-hydroxymethyl-6-pentyl-2'-hydroxy-1,1 '-biphenyl; 3 5 -Diisopropyl-2-hydroxymethy-6-pentyI-2'-hydroxy-A'-fluoro.4,1'biphenyl; 3 ,S-Diisopropyl-2-hydroxymethyl-6-hexy1-1,1'-bi-pheny; 3 ,-Disopropy-2-hydroxymethy-6-hexyA'fluoro1,1'bipheny; 3,5-Diisopropyl-2-hydroxymethyl-6-hexyl-4'-chloro.1,1'-biphenyl; 3 5 -Diisopropyl-2-hydroxymethy-6-hexy..4'-methy11'.bipheny; 3 ,S-Diisopropy1-2-hydroxymethy-6-hexy-2'-hydroxy-1,1'.bipheny; 3 5 -Diisopropyl-2-hydroxymethyl-6hexy2'hydrox.y. 4'tfluoro-l.11Ibipheny; 3 5 -Diisopropy-2-(p-toythio)methyIl.&hydroxymethy..1,1'.bipheny; 3 ,S-Diisopropy-2-[Ip-tolyltho)m'fethyJ-6hydroxymethyAI..-fluoro11'.bipheny; 3 ,-DiisopropyI-2-[(p-tolythio)methyl]...hydroxymethyl1'choro-11'.bipheny; 3 ,-Diisopropyl-2-[(p-tolylthio)methyl]J(6-hydroxymethylA'-metiyl-,1'.bipheny; 3 ,S-Diisopropyl-2-[(p-toly1Uhio)methyl].6.hydroxymethiyl.2'hydro,1'..biphenyl; 3 ,-Diisopropyl-2-[(p-tolylthio)methyI6hydroxymetyl.2'-hydroy4'.fluoro-1,1 biphenyl;: 3 5 -piisopropyl-2-[((4-fluorophenyl)thio)methy1]..6hydroxymethy1-1,1'-bipheny; 3 5 -Diisopropyl-2-[(4-fluoropheny)t1io)methyJhydroyimethyl14'-fluoro 1,1'biphenyl; 3 5 -Diisopropyl-2-[((4-fluoropheny)thio)nethy]...&hydroxymethy4'choro.1,1 biphenyl; 3 5 -Diisopropyl-2-[((4-fluoropheny)tio)nethy1..&hydroxyetyl'-methyl-l.,1 biphenyl; 3 ,S-Diisopropyl-2-[((4fluorophenyl)thio)methyl]J6hydroxymethyl2'-hydroxy.1,1 biphenyl;- 3 ,-Diisopropy1-2-((4-fluoropheny1)thio)methy].6hydroxymeiyl..2'-.hydroxy4'.

fluoro-1,1'-biphenyl; 389 WO 98/04528 WO 9804528PCTIUS97/13248 o 3 5 -Diisopropyl-2-(-hydroxyethy)6effiylI41'4,ipheny; 3 5 -Diisopropyl-2-(-hydroxyehy)6ethl-y4'-fluoro-l1'bipheny; 3 5 -Diisopropyl-2-(1-hydroxyethyl).6-ethyl.4'-chloro.1,1'-biphenyl; 3 5 -Diisopropyl-2-(l-hydroxyethy1)&.-ethy1-.4'-methyl11,1 '-biphenyl; 3 5 -Diisopropy-2-(-hydroxyethy)6ethy1.2'hydroxy-11 '-biphenyl; 3,5-Diisopropyl-2-( l-hydroxyethyl)-6-ethyI-2'-hydroxy.4'fluoro-1,1'-biphenyl; 3 5 -Diisopropyl-2-(l-hydroxyethyl)&6propyl.1,1'.bipheny; 3 5 -Diisopropyl-2-(-hydroxyethyl)propyl.4'.fluoroll 1'-biphenyl; 3 ,S-Diisopropyl-2-(l-hydroxyethyl)-6-propylA'-horo11..bipheny; 3 5 -Diisopropyl-2-(l-hydroxyethyl)-propyl4'-methy1,1..bipheny; 3 5 -Diisopropyl-2-(l-hydroxyethyl).6-propyl2'-hydroxy.1,1'-biphenyl; 3 5 -Diisopropy12-(.hydroxyeth6poyl1)6...proy--hydroyIf1,'bihnl; Disprpl '-biphenyl;-&utl1,'-ipenl 3,-ispoy--lhdoyehl -uy-'fur-,'-biphenyl; 3,-Dio'-biphenyl;ytyl-pL-ny-11-bpenl 3,5Diisopropyl-2-(l-hydroxyefiy).6..heny..1Ij'jhdroy1,1 ih 3 /S-Diisopropy1-2(1hydroxyethyl)..&hentyl.42..fluroxy-'-ihl;ur-,'-ihnl 3 tS, Diisopropy2(hydroxyethy)hel,1Aiphenyll i 3,-i-biphenyl;roythl--hxl-'fuoo1,'bphnl ispopl2(-ydoyty)-hxl4-clr ,'-biphenyl; 3,-ispoy-2( mrxehy)6 xl4-mty-,'petyl11'bphnl 3,-Disprpy--(-h drxyth l-6heyl2'hy rxy1,'390enl WO 98/04528 WO 9804528PCTIUS97/13248 o 3 5 -Diisopropyl-2-[(p-toythio)methyl]6(hydroxyethy)2'hydrox,1biphenyl; 3,-ispoy--(-oyti~ehl-6(-yrxehl-'hdoy4-loo 1Y1-biphenyl; 3 5 -Diisopropyl-2-[((4-fluorophenyl)thio)methyll&(1..-hydroxyethyl..1,1 '-biphenyl; 3,-ispoy--(4furohnlti~ehl16( hyrxehl-'fur-'biphenyl; 3 5 -Diisopropyl- 2 -[((4fluorophenyl)thio)methy1I(1.hydroxyethyl)AI-chloroll biphenyl; 3,-ispoy--(4furp(nlti~ethl--lhd(.) hl-..mty-,' biphenyl;- 3,5-Diisopobpyl.2-[((4-fluorophenyl)thio)methyl1](i(hydroyehy)l.hyrx 11 '-biphenyl; 3 ,Ir-Diisopropyl-2[((4fuorpheyl)io)methylJ6-(hydroxethyl..2hydroxyP...

fluoro-1,1 '-biphenyl.

Other'embodiments of the inv~entioni will b eapparent to the skilled in the art 'from: a consideration- O6f" this' sciica on or practice of the invention disclosed herein. It is intended that the specification and,:examples be considered as 206 ke mplary only, with the true scope and spirit of the invention being indicated by the following claims.

The reference to any prior art in this specification is not, ad should not be take as, I an acknowledgement or any form of s .uggestion that the prior art formns part of the common general knowledge in Australia.

391 a'~<aSSSc st'

Claims (27)

1. Substituted pyridines of the general formula (IA), (IA) in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight- chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NRtR 2 wherein R 1 and R 2 are identical or different and denote, hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, D stands for straight-chain or branched alkyl with up-to 8 carbon atoms, •whih is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stands'for cycloalkyl with 3 to 8 carbon atoms, or E has the above-mentioned meaning and L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or 392 K 1 90- y WO 98/04528 PCT/US97/13248 differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR 3 R 4 wherein R 3 and R 4 are identical or different and have the meaning given above for R 1 and R 2 E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight- chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group ofthe formula -NR 5 R 6 wherein R 5 and R 6 re identical, or different and have the meaning given above for R 1 and R 2 and L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, T stands for a radical,of the formula R 9 R' 0 R8~iL wherein 393 4=i~ -s;i -srrir 4wn; ~li ilii~- WO 98/04528 PCT/US97/13248 0 R 7 and R 8 are identical or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5- to 7-member aromatic, optionally benzo- condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or 0, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula NR 1 1 R 12 wherein R 11 and R 1 2 are identical or different and have the meaning given above for R 1 and R 2 X denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R 9 denotes hydrogen, and R 10 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula NR1 3 R 1 4 wherein R 13 and R 14 are identical or different and have the meaning given above for R1 and R 2 394 ;v-v-s WO 98/04528 PCT/US97/13248 0 or R 9 and R 10 form a carbonyl group together with the carbon atom, and the salts thereof.

2. Substituted pyridines of the formula according to claim 1, in which A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoronethoxy, or by straight- chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR 1 R 2 C wherein R 1 and R 2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which :is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cydoheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy 395 Ez38r~~.:W o- y g WO 98/04528 PCT/US97/13248 0 with up to 6 carbon atoms each, or by a group of the formula -NR 3 R 4 wherein R 3 and R 4 are identical or different and have the meaning given above for R 1 and R 2 or E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight- C chain or branched alkyl, acyl, or alkoxy with up to 6 carbon. atoms each, or by a group of the formula -NR 5 R 6 wherein R 5 and R 6 are identical or different and have the meaning given above for R 1 and R 2 and L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R 9 R 1 i R8 or wherein 396 ri~ ~i i~ Eth*i~ ~ii vr~ ni WO 98/04528 PCT/US97/13248 0 R 7 and R 8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl with up to 5 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn by substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, and/or the rings are optionally substituted by a group of the formula -NR11 R 12, wherein R 1 1 and R 1 2 are identical or different and have the meaning given above for R 1 and R 2 X denotes a straight or' bianched alkyl chain or alkenyl chain with 2 to 8 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R 9 denotes hydrogen, and R 1 0 denotes hydrogen, fluorine, chlorine,' bromine, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or brancled alkoxy with up to 4 carbon atoms, or a radical-of the formula -NR 1 3 R 1 4 wherein R 1 3 and R 14 are identical or different and have the meaning given above for R 1 and R 2 397 WO 98/04528 PCT/US97/13248 0 or R 9 and R 10 form a carbonyl group together with the carbon atom, and the salts thereof.

3. Substituted pyridines of the formula according to claim 1, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or E has the above-mentioned meaning and L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight- chain or branched alkyl or alkoxy with up to 5 carbon atoms each, or E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or 398 IE5i~ii~i YICC:~7l~i. ~A*ii:.i ~ii~ jy7* i~lt~ d$ *ili~~ ~CLi-i~ i I ~2~liJ kv WO 98/04528 PCT/US97/13248 0 stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, and L in this case stands for straight-chain or branched alkoxy with up to carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, T stands for a radical of the formula R 9 R 10 SR7-X- R 8 V or wherein R 7 and R 8 are identical or different and denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,opr adamantyl, or denote phenyl, pyridyl, quinolyl, indolyl, naphthyl, benzothiazolyl, or benzoxazolyl, which are optionally substituted up to 2 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, hydroxy, carboxyl, by straight-chain or branched 25 alkyl, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy, X denotes a straight or branched alkyl chain with 2 to 6 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, R 9 denotes hydrogen, 399 WO 98/04528 PCT/US97/13248 0 and R 1 0 denotes hydrogen, fluorine, chlorine, bromine, azido, amino, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 3 carbon atoms, or R 9 and R 10 form a carbonyl group together with the carbon atom, and the salts thereof.

4. Substituted pyridines of the formula according to claim 1, in which A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl.

5. Substituted pyridines according to claims 1 through 4 for therapeutic use.

6. Process for the production of substituted pyridines according to claims 1 through 4, characterized by the fact that compounds of the general formula (II) or (II) A A OHC R 15 T CHO i l ll (111) L N E L N E in which A, E, L, and T have the above-mentioned meanings, and 400 WO 98/04528 PCT/US97/13248 0 R15 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, or, in the case of compounds with the general formula (III), direct reductions are carried out, optionally via several steps.

7. Pharmaceutical product containing the substituted pyridines according to claims 1 through 4 and, if appropriate, a pharmacologically tolerable formulation adjuvant. C 8. Pharmaceutical product according to claim 7 for the inhibition of cholesterol ester transfer proteins.

9. Use of the substituted pyridines according to claims 1 through 4 for the production of pharmaceutical products.

10. Use of substituted pyridines according to claims 1 through 4 for the production of cholesterol ester transfer protein inhibitors.

11. 3 -heteroalkyl-aryl-substituted pyridines of general formula (IB) A -o D CH 2 OH S' -(IB) L N T in which A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NR 2 R 3 and/or -WR 4 wherein 401 ~I WO 98/04528 PCT/US97/13248 0 R 2 and R 3 are the same or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, W denotes an oxygen or sulfur atom, R 4 denotes aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula wherein R 5 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms or phenyl, 'R 1 stands for cycloalkyl with 3 to 6 carbon atoms, or S stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzo-condensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 heteroatoms from the series S, N, and/or 0, in which the rings, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member 402 WO 98/04528 PCT/US97/13248 heterocyclic compound with up to 3 heteroatoms from the series S, N, and/or 0, and/or are substituted by a group of the formula -OR 6 -SR 7 -SO2R 8 or -NR 9 wherein R 6 R 7 and R 8 are identical or different and denote aryl with 6 to 10 carbon atoms, which in turn is substituted up to 2 times in an identical manner or differently by phenyl or halogen or by straight-chain or branched alkyl with up to 4 carbon atoms, R 9 and R 10 are identical or different and have the above-indicated meaning of R 2 and R 3 L and T are identical or different and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, -or L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heteroatoms from theseries S, N and/or 0, with binding in the case of a nitrogen atom also being possible via this atom, with the rings optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, and the salts thereof.

12. 3-heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which 403 WO 98/04528 PCT/US97/13248 0 A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula -NR 2 R 3 and/or by a group of the formula -W-R 4 wherein R 2 and R 3 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 4 carbon atoms, W denotes an oxygen or sulfur atom, R 4 denotes phenyl or benzyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 6 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula NR 5 wherein R 5 denotes hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms or phenyl, R 1 stands for cyclopropyl, cyclopentyl, or cydohexyl, or tetrahydropyrimidyl or stands for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrizinyl, pyrrolidinyl, tetrahydropyrimidyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or pyrine-yl, 404 WO 98/04528 PCT/US97/13248 0 with the rings, also via the N function in the case of nitrogen-containing rings, being optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine,trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl, and/or by a group of the formula -OR 6 -SR 7 or -S0 2 R 8 wherein R 6 R 7 and R 8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or by straight-chain or branched alkyl with up to 4 carbon atoms, (C L and T are identical or different and stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 7 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, or phenyl, which in turn can be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, trifluoromethyl,,trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or for naphthyl, phenyl, pyridyl, or furyl, which optionally can be substituted up to 3 times in an identical manner or i 30 differently by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, and the salts thereof.

13. 3-heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which A stands for phenyl, which is'optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, hydroxy, trifluoromethyl, trifluoromethoxy, 'or by straight-chain or branched 405 i WO 98/04528 PCT/US97/13248 0 alkyl, acyl, or alkoxy with up to 4 carbon atoms each or by benzyloxy, which in turn can be substituted by fluorine or chlorine. D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 3 carbon atoms, or E stands for a bond, V stands for an oxygen or sulfur atom or for a group of the formula wherein R 5 denotes hydrogen or straight-chain or branched alkyl with up to 3 carbon atoms, R 1 stands for cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyrinidyl, phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, tetrahydropyrimidyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl, pyrazolopyrimidyl, or purine-yl, with the rings, also via the N-function in the case of nitrogen-containing rings, optionally being substituted up to 3 times in an identical manner or differently by fluorine, chlorine, Strifluoromethyl, .hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 3 carbon atoms each, triazolyl, tetrazolyl, C benzoxathiazolyl, or phenyl, and/or substituted by a group of the formula -OR 6 -SR 7 or -S0 2 R 8 wherein R 6 R 7 and R 8 are identical or different and denote phenyl, which in turn is substituted up to 2 times in an identical manner or differently by phenyl, fluorine, chlorine, or is substituted by straight-chain or branched alkyl with up to 3 carbon atoms, L and T are identical or different and 406 WO 98/04528 PCT/JUS97/13248 0 stand for trifluoromethyl, pyrrolidinyl, or for straight-chain or branched alkyl with up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, which in turn may be substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 4 carbon atoms each, or L and/or T stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for naphthyl, phenyl, or furyl, which are optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 3 carbon atoms each, 0 and the salts thereof.

14. 3 -heteroalkyl-aryl-substituted pyridines of the formula according to Claim 11, in which A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently byfluforine, chlorine, trifluoromethyl, methoxy, methyl, orby fluorine- orchlorine-substituted benzyloxy. 3 -heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14 for therapeutic treatment.

16. Process for the production of 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14, characterized in that in the case of V O compounds of general formula (II) S A HQ-D, R 1 T (II) L N T in which A, D, L, and T have the indicated meanirig, 407 WO 98/04528 PCT/US97/13248 0 and R 1 1 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms or for the group of the formula CH 3 CH 3 I I 1 1 CH 3 OH 3 are reacted with compounds of general formula (III) 10 R 1 -E-Z (III) in which R 1 and E have the indicated meaning and Z stands for halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of bases and/or auxiliary agents, and reductive separation is then carried out, depending on the meaning of the group.Rll, compounds of general formula are next converted by reactions with compounds of general formula (IV) O R 12- R12- S- CI (IV) I I inwhich R 12 stands for straight-chain alkyl with up to 4 carbon atoms, into compounds of general formula (V) 408 WO 98/04528 PCT/US97/13248 O A 12 I OD, TR11 R 12 -S-OD I- (V) 0 O L N T in which A, D, L, T, R 1 1 and R 12 have the indicated meaning, and these are then reacted with compounds of general formula (VI) R 1 -E-V-H (VI) in which R 1 E, and V have the indicated meaning, anr dreductiv;e separation is carried out, and optionally, the groups listed tuider substituents A, L, T, and R 1 are introduced or varied according to customary methods.

17. Pharmaceutical product containing. 3-heteroalkyl-aryl-substituted pyridines .according to Claims 11 through 14, as well as a pharmacologically safe formulation auxiliary.

18. Pharmaceutical product according to Claim 17 for the treatment of hyperlipoproteinemia.

19. Use of 3-heteroalkyl-aryl-substituted pyridines according to Claims 11 through 14 for the production of pharmaceutical products. Use according to Claim 19 for the production of pharmaceutical products for the treatment of hyperlipoproteinemia.

21. A compound having glucagon receptor antagonistic activity and the structural formula 1A 409 P, 9 11 n S I I F I WO 98/04528 PCT/US97/13248 Ar' Rla N R Ib wherein Rla and Rib independently represent trifluoromethyl, (Cl-Cio)-alkyl, substituted (Cl-Clo)-alkyl, (C2-Clo)-alkenyl, substituted (C2-C10)-alkenyl, (C2-ClO)-alkynyl, substituted (C2-ClO)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (C1-C6)-alkanoyl; R2represents (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 alkenyl, substituted (C2-Clo)-alkenyl, (C2-Cl 0 )-alkynyl, substituted (C 2 Cl 0 )-alkynyl, (C3-C6)-cycloalky(cC)Oalkyl, or substituted (3C) cycloalkyl-(Cl-C 6 )-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted cycloalkyl R 2 groups being independently from 1 to 3 of halogen, phenyl, substituted phenyl, i 1 3-dioxolan-2-yl, -C(O)NR 4 R5, or -S(O)mR 7 wherein mn is 0, or 2; R 4 and R 5 independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, ,(C3-C7)-cycloalkyl, (C3-C7)-cycloakyl(ClC 6 )-alkyl, phenyl, substituted phenyl, phenyl-(Cl-c6).alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl1, naphthyl-(C-C6)-all, or substituted naphthyl (Cl-CO)alkyl; R 4 and R 5 optionally may be: joined together to form (CH2)rA(CZH2)s- wherein r and s are independently 1, 2, or 3; and wherein A represents 0, S(O)n, CHR6, or NR6; wherein n is0, 1,'or 2;and R6 represents'hydrogen, (Cl-C6)-alkyl, piperidin-1-yl, 7 phenyl, or pheny-(C1-C6)-alkyl; R 7 represents (C-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cjj- C6)-alkyl, substituted phenyl-(Cl-C).alkyl, pyridyl, substituted pyridyl, pyridyl- -(CI-C6)741 .kyl, substituted, pyridyl-(Cl-C6)..alkyl,* naphthyl, substituted naphthyl, naphthyl-(Ci-C6).alkyl, or substituted naphthyl-(Cjj- C6)-alkyl; R 2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached; 410 WO 98/04528 WO 9804528PCT/US97/13248 0 R 3 represents hydroxy, trifluoroacetyl, (Cl-C 6 )-alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R 3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar' represents an optionally mono-, di-, or tni-substituted heteroaromatic ring selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imiddazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are independently from 1- to 3 of halogen, (Cl-C 6 )-alkyl, substituted (C 1 C 6 )-alkyl, (C 2 -C 6 )-alkenyl, substituted (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, substituted (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, nitro, trffluoromethyl,,-OR 4 -C(O)R 4 -OC(O)R 4 -C02R 4 -NRWR, -C(O)NR 4 or -S(O)mR 7 wherein mn is 0, 1, or 2; and c pharmaceutically acceptable salts thereof.

22. A compound of claim 21, where in ristpctural formula 1A, Ria and 'jab independently 'roepre~ent trifluoromethyli (Cl-Clo)-alkyl, substituted (Ci-Ci)-alkyl, (C2-Ci1o)-alken~yl, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)-cycloalkenyl; R,represents. (Cl-Cl 0 )-atkyl,,substituted (CI-:C 10 )-alkyl, (C 2 -Cl 0 alkenyl or substituted, (C 2 -Cl 0 )-alkenyl, wiher ein the substituents on. said substituted a1ladsusiue plkeylg p ae independently from 1 to 3of halogen, phen yl, su1; tituteid phenyl, -C(q))tlR 4 4 5 ,,or -S(OPR wherein r mis,0,.1, r2 R 4 and R 5 independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C1-C6)- Calkyl, substituted phenyl-(C1-C6)-alkl naphthyl, substituted naphthyl, 1iphthiyl-(C-C)-'lky1, or substi titd nphthyl-(Cl-C6)-alkyl; k 6 represents hydrgn (Cl-C6)-a ky, phentyl, or P-henyl-(Cl-C6)- alkyl; R 7 represents (C-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl- C6)-lky, sbsttutd peny-(C-C6)-alkyl, pyriay1, substituted pyridyl, pyridy-(C1-C6)-alkyl, or substituted pyridyl-(C1'C6)_alkyl; R 2 optionally may be joined to Rib to form an alkylene bridge containin"g from 3 to 4 carbon atoms, between the ring carbon atoms to which- R 2 and 'Rib are attached; 411 WO 98/04528 PCT(US97/13248 0 R3 represents (C 1 -C 6 alkanoyl, substituted (C 1 -C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups;-and Ar' is selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, -OR 4 or OC(O)R 4 where R 4 is hydrogen, (C1-C 6 alkyl, phenyl (C1-C 6 alkyl or substituted phenyl (C1-C6) alkyl.

23. A compound of claim 21, wherein in structural formula 1A, r R 1 a and Rib independently represent (C1-C6)-alkyl or (C2-C6)- alkenyl; R 2 represents (C 1 -C 1 0 )-alkyl, substituted (C1-C10) alkyl, (C 2 -C 10 alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents- on said substituted'alkyl and'substituted alkenyl groups are independently from 1 to 3 of halogen or IS(O)iiR 7 wherq;' m"O, R 7 represents (C1 C6)-alkyl, phenyl, substituted phenyl, phenyl (C1- C6)-alkyl or substituted phenyl (C1-C6)-alkyl; R 3 represents substituted (C 1 -C")-alkyl or substituted (C 3 -C 6 alkenyl, wherein the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the grdup consistiAg of pyridyls, furanyls and thiophenyls,and the optional'substitutents are iidependently from 1 to 3 of halogen; (C 1 -C 6 )-alkyl, (C-C 6 )-alkenyl, -OR 4 or -OC(O)R 4 where R 4 is hydrogen or (C1-C6) alkyl.

24.. A' pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 21, and a pharmaceutically atcceptable carrier.

25. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 21.

26. The method of claim 25, wherein the subject is human, the glucagon- mediated condition is diabetes, and the treatment results in lowering of blood glucose. 412 WO 98/04528 PTU9/34 PCT/US97/13248 0

27. A compound having glucagon receptor antagonistic activity and the structural formula 1B Ar" Ra N Rilb 1B wherein R 1 a and Rib independently represent trifluoromethyl, (Cl-Clo)-alkyl, substituted (Cl-Clo)-alkyl, (C2-ClO)-alkenyl, substituted (C2-C10)-alkenyl, (C2-Clo)-alkynyl, substituted (C2-ClO)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Cl-C6)-alkanoyl; R2represents (C 1 -Cl 0 )-alkyl, substituted (Cl-C, 10 )-alkyl, (C 2 -Cl 0 alkenyl, substituted (C 2 -Cl 0 )-alkenyl, (C 2 -Cj 0 )-alkynyl, substituted (C 2 Cl 0 )-alkynyl, (C 3 -C 6 )-cycloalkyl-(Cl-C 6 )-alkyl, or substituted (C 3 -C 6 cycloalkyl-(Cl-C 6 )-alkyl; the., substitutents on said substituted alkyl, substituted alkenyl, substituted ailkynyl, 'znd substituted cycloalkyl R 2 groups being independently from 1 to 3, of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C (O)NR 4 R 5 or -S(O)mR 7 wherein m is 0, 1, or 2; R 4 and R 5 independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- ,alkenyl, (C3- 7)7cycloalkyl,, (C3-C7)cycloalkyl-(C 1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, 'substu~ted naphthyl, naphthy-(C -C6)-alcyl, or substituted naphthyl-(Cl-C6)-alkyl; R 4 and R 5 optionally, may be,, joined together to form. (CH2)rACH2)s- wherein. r and s arejndependently 2, or 3; and wherein A represents 0, S(O)n, CHR6,, or.NR 6 wherein ~n is 0, 1, or 2; and. R 6 represents hydrogen, (C-C6)-alkyj, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkYl; R 7 represents (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl- C6)-alkyl, substituted phenyl-(Cl-C 6)-alkyl, pyridyl,:substituted pyridyl, pyridyl-(Cl-C6)-alkyl, substituted pyridyl-(Cj-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(CI-C6)-a~kyl, or substituted naphthyl-(Ci- C6)-alkyl; 413 WO 98/04528 PCT/US97/13248 0 R 2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached; R3represents hydroxy, trifluoroacetyl, (Cl-C 6 )-alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R 3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; and Ar" represents an optionally mono-, di-, or tni-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (Cl-C 6 )-alkyl, substituted (Cl-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, substituted (C 2 -C 6 -alkenyl, (C 2 C 6 )-alkynyl, substituted (C2-C 6 )-alkynyl, (C3-C 7 )-cycloalkyl, cyano, nitro, trifluoromethyl, -OR 4 -C(O)R 4 -OC(O)R 4 -C02R 4 -NR 4 R 5 -C(O)NR 4 R 5 or -S(O)mR 7 wherein m is 0, 1, or 2; and '0 pharmaceutically acceptable salts thereof.

28. A compound of claim 27, wherein. structural formula 1B, Rla and Rib indep~ndently represent trifluoromethyl, (Cl-Clo)-alkyl, substituted (Cl-Clo)-alkyl, (C2-C 1o)-alkeny1, substituted (C2-C10)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7Y-;cy cloalkenyl; R2represents: (Cl-C 0 )-alkyl, substituted (Cl-Cl 0 )-alIkyl, (C 2 -C 1 alkenyl or substituted (C -Clo)-alkenyl,. -wherein the substituents on said substituted alkyl. and substituted alkenyl groups, are independently from 1 to 3of halogen, phenyl, substituted phenyl, -C(O)NR 4 R 5 orSOm 7 wherein m is ,1,or 2; R 4 and R 5 independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, substituted phenyl, phenyl-(C C alkyl, substituted phenyl-(Cl-CO)-Alkyl., naphthyl, substituted naphthyl, naphthyl-(Cl-C 6 ).alkyl, or substituted naphthyl-(Ci-C6).alkyl; R6 represents hydrogen, (C-C6)-alkyl, phenyl, or phenyl-(Cl-C6)- alkyl; R 7 represents (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-7(Cl- C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl, pyridyl, substituted pyridyl, pyridyl-(Cl-C6)-alkyl, or'substituted pyridyl-(C1-C6)_alkyl; R 2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached; 414 WO 98/04528 WO 9804528PCTIUS97/13248 0 R 3 represents (Cl-C 6 alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (Cl-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, -OR 4 or -OC(O)R 4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl (C1-C6) alkyl or substituted phenyl (C1-C6) alkyl.

29. A compound of claim 27, wherein in structural formula 1B, Ria and Rib independently represent (C1-C6)-alkyl or (C2-C6)- alkenyl; R2represents (Cj-Cj 0 )-alkyl, substituted (Cl-Ci. 1) alkyl, (C 2 -Cl 0 alkenyl, or substituted (C 2 -C 10 alkenyl, wherein the substituents, on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)mjR 7 "wherein m=0; R 7 represents. (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (Ci- C6)-alkyl or substitutedphenyl (C1-C6)-alkyl; R 3 represents substituted (Cl-C 6 )-alkyl or substituted (3C) alkenyl, wherein the substitutents are- 1 or 2 hydroxyl groups; and .Ar" represents a phenyl ring,, and- the -optional substitutents are independently from 1, to 3..of jialogen,, (C 1 7C 6 )-alkyl,. (C 2 -C 6 )-aknl O 4 or -OC(O)R 4 where R 4 is. hydrogen or (Cl-C6) alky. A compound of claim 27, selected from the following group of compounds: 25 2 6 Diisopropyl-3-hydroxymethyl-4phenyl-5-.ethylpyridine; 2 6 -Diisopropyl- 3 -hydroxymethyl-4(4florophenyl)s.--efiylpyxidine; 2 6 -Diisdpropyl3hydroxymethyl4(2hydroxy-4fluorophenyl)... ethylpyridine; 2 6 -Diisopropyl- 3 -hydroxymethyl-4-(4-.fluorophenyl)s..propylpyridine; 2 6 -Diisopropyl-3-hydroxymethylA..(4..chlorophenyl)..5.propyprdine; 415 WO 98/04528 PCT11JS97/13248 0 2,-ispoy--yrx mty--(-ehlhnl--rplyiie 2 6 -Diisopropy1-3hydroxymethy42hydroxheny)5propylyidin 2,-ispoy--yrxmty--2hdoy4furpey)5 propylpyridine; 2,-ispoy--yrxmty--hn 2,-ispoy--yrxmty--4furpey)5btlyiie 2,-ispoy--yrxmty--4clrpey)5btlyiie 2 6 -Diisopropyl3hydroxyrefy4(4methypheny)5buylpyidin pyfidine; 2,-ispoy--yrxmtyl4pey--etlyiie 2 6 -Diisopropy1-3hydroxymethy1...(4fluoropheny)5pentyIpyridine; 2,-ispoy--yrxmty--(-hoohnl--etlyiie 2,-ispoy--yrxmty--4mtypey)5pny-yiie pyridine; 2 6 -Diisopropy-3hydroxyney-(4fluorophenyl)-5hexlpidine 2 6 Diisoprbpyl3hydroxymeth14.(4chorophenyl)S5he lpyidie 2,-ispoy--yrxmty- 4mty'hnl 2 6 Diisopropy 4 hydro oetym4(2hydroxyfur' y pyridine;. 2 6 Disopropy3[(ptohomyll-4-phenyffiy1J4Pheny15hyffiine 2,n.Diorpl3[ pyridine; .26 ~iorpl3[ptllhomohll4(-hlrpe'')5hdoyehl pyridine; 2,-ispoy--(-oyti~rehl--4mtypey)5 hydroxymethyl-pyridine; 2,Diorpl3[p-oyti 1hl-4(-yrxpey)-5 hydroxymethyl-py'ridine; 416 tAt a- a~r- WO 98/04528 WO 9804528PCTIUS97/13248 0 2,-ispoy--(-oyti~ehl--2hdoy4furpey)5 hydroxymethyl-pyridine; 2 6 -Diisopropyl-3-[((4-fluorophenyl)thio)methyl]A4phenyls... hydroxymethyl-pyridmne; 2 6 -Diisopropyl-3-[((4-fluoropheny)thio)methylI4-(4-fluorophenyl)-5- hydroxymethyl-pyridine; 2 6 -Diisopropyl-3-[((4-fluorophenyl)thio)methyll4-(4-chorophenyl)-5 hydroxymethyl-pyridine; 2 6 -Diisopropyl-3-[((4-fluoropheny1)thio)methyll-4-.(4-mefiylphenyl)-5 hydroxymethyl-pyridine; 2 6 -Diisopropyl-3[(( 4 -fluoropheny)thio)methy4(2hydr'oxyphenyl)-5 hydroxymethyl-pyridine; 2 ,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl]-4%-(2hydrox-4- fluoropheny1)-5-hydroxymethy1-pyridine; .26Dispoy--r1-idoyehl--hnl5ehlyiie 2 6 -Diisopropyl-3-(l-hydroxyethyl)-4(4fluoropheny)-i5-thylpyridine; 2 6 -Diisopropyl- 3 -(l-hydroxyethy)-4-(4-methylpheny).&euthylpyridine; 2 ,6QDiisopropyl-3-(l-hydroxyethy)4(2-hydroxyhny).5 -thylpyridine; 2 6 -Diisopropyl-3-(1-hydroxyethyl)-4(2.hydroxyA!fluoropheny)5. ethylpyridine;- 2 6 -Diis opropyl-3-(l-hydroxyethy)-4-(4-chlorophenyl)...sj.propylpyridine; 2 6 -Diisopropyl-3-(-hydroxyethy)(2.hdrox 2 t 6 Diispropyl-3(l-hydroxyethy4-(hdr~yfluoopheny)s.. propylpyridine; 2 ,6-Diisopropyl.-(l-hydroxyethy)-4phenyls'-5-utylpyridirA6-; 2 ,-Diisopropyl-3-(-hydroxyetyl)4(4fluorophenyl.)5..btllpyridine; 301 1 3026Diorpl3(-h~rxehl-4(-ho -hnl--itlyiie 2,-ispoyr-lhdoyty)4(4mthlhnl,57ftlyiie 417 WO 98/04528 PCT/US97/13248 0 2 6 -Diisopropy-3(hydroxyethy).4-(2hydroxy4fluorophenyl)S5 butylpyridine; 2 6 -Diisopropy1-3(-hydroxyethy)A.(4choropheny)5pentyyidin 2,-ispoy--(-yrxehl pentylpyridine; 2 6 -Diisopropyl-3(l-hydroxyeffiyl)A.(4.fluorophenyl)5hexy 1rdie 2 6 Diisopropy3(hydroxyethyy.4(2hydro-4flurhny)- 1.1hexylpyridine; 2 6 -Diisopropyl3[(ptoythio)methy4-phey(1hydythl)- pyridmne;, 2 6 Diisopropy3toythio)methy](4flurh.)- -(l hydroxyethyl)-pyridihe; 2,-ispoy--(-oyti~ehl- (-hoohnl--l hydroxcyethyl)-pyridine! Z,6-Diisoproy-- (-oyti~ehl---4mtypey) -I hydroxyethyly..pyridine;. 2 ,6-Diisoprpyl3[p-tolythio)meffy-4(2hydroxyphe4florophlyls hydroxyety1,)Tpyridiine; hydroxyethyl)-pyridine; 2 6 Diisopropy3((4fluorophenyli)rithl]-mehyl]A(Ifhl hydroxyethyl)-pyridine;

3026-ispoy--(4furpey~homty]4(-loohnl--l hydroxyethyl):-pyridine; 418 WO 98/04528 WO 9804528PCTIUS97/13248 0 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl-4-(4-methylphenyl)-5-(l- hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyll-4-(2-hydroxyphenyl)-5-(1. hydroxyethyl)-pyridine; 2,6-Diisopropyl-3-[((4-fluorophenyl)thio)methyl-4-(2-hydroxy-4- fluorophenyl)-5-(1-hydroxyethyl)-pyridine. 31. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 27, and a pharmaceutically acceptable carrier. 32. A method Ifor treating a glucagon-m ediated condition which comprises administering to0 a subject an effective amount of a compound of claim 27. 33. The method of claim 32, wherein the subject is human, the glucagon- mediated condition is diabetes, and the treatment results in lowering of blood glucose.. 34. A compound, having glucagon receptor antagonistic activity and the structural formula 1C Ar' R 3 R RR8 1iC. wherein R 8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Cl-Clo)-alkyl, substituted (CI-Clo)-alkyl, (Cl-C6)- alkoxy, (C3-C7)-cycloalkyl, phenyl-(Cl-C3)-al1koxy, (Cl-C6)-alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy foml or -NR1, R 4 and- R 5 indep endently represeit hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, '(C3-C7)-cycloalkyl-(C'1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, napnthyl, substituted naphthyl, naphthyl-(C 1-C6')-alkyl, *or substituted naphthyl-(C1-C6)-alkyl; 419 WO 98/04528 PCT/US97/13248 0 R 4 and R 5 optionally may be joined together to form (CH2)rA(CH2)s- wherein r and s are independently 1, 2, or 3, and wherein A represents 0, S(O)n, CHR6, or NR6; wherein n is 0, 1, or 2; and R6 represents hydrogen, (C1-C6)-alkyl, piperidin-1-yl, phenyl, or phenyl-(Cl-C6)-alkyl; Rla and Rib independently represent trifluoromethyl, (Cl-Clo)-alkyl, substituted (Cl-Cio)-alkyl, (C2-Clo)-alkenyl, substituted (C2-C1o)-alkenyl, (C2-Clo)-alkynyl, substituted (C2-Cl 0)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkenyl, or (Cl-C6)-alkanoyl; R2represents (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 alkenyl, substituted (C2-ClQ)-alkenyl, (C2-Cl 0 )-alkynyl, substituted (C 2 Cl 0 )-alkynyl, (C3-C6)-cycloalkyl-(Cl-C 6 ).alkyl, or substituted (C 3 -C 6 cycloalkyl-(Cl-C 6 )-alkyl; the substitutents on said substituted alkyl, substituted alkenyl, substit~t~d alkynyl, and substituted cycloalk yl R 2 groups being independently fromri 1 to 3 of halogen, phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(O)NR 4 R 5 or -S(O)mR 7 *wherein m is 0, 1, or 2; R 7 represents (Cl-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl- C6)-alkyl, substituted phenyl-(Cl-C6)-alkyl,; pykdyl, substituted pyridyl, pyridyl-(Cl-C6)-alkyl, substituted pyridy-(Cl-C -alkl nathl substituted naphthyl, naphthyl-(Cl-C!6)-.akyl, or substituted naphthyl-(Cl- C6)-alkyl; R 2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 5 carbon atoms,.between the, ring carbon atoms to which R 2 and Rib are attached; Rrepresents hydroxy, trifluoroacetyl, (Cl-C 6 )-alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl; the substitutents on said substituted alkyl and substituted alkenyl R 3 groups, being.. from 1 to 3 hydroxyl or trifluoromethyl groups; Ar' represents, .an optionally mono-, or tri-substituted heteroaromatic Ting selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, tniazolyls, tetrazolyls, oxazolyls, isoxazolyls, thiazolyls and isothiazolyls, wherein the substitutents are indeperidently'from 1 to 3 of halogen, (Cl-C 6 )-alkyl,,substituted (Cl- C 6 )-alkyl, (C 2 -C 6 )-alkenyl, substituted (C 2 -C 6 )-alkenyl, J(C 2 -C 6 )-alkynyl, substituted (C2-C 6 )-alkynyl, (C3-C 7 )-cycloalkyl, cyano, nitro, 420 WO 98/04528 WO 9804528PCTIUS97/13248 0 trifluoromethyl, -OR 4 -C(O)R 4 -OC(O)R 4 -C02R 4 -NR 4 R 5 -C(O)NR 4 R 5 or -S(O)mR 7 wherein m is 0, 1, or 2 and pharmaceutically acceptable salts thereof. A compound of claim 34, wherein in structural formula 1C, R 8 represents hydrogen, halogen, trifluoromethyl or (Ci-Clo) alkyl; R 1 a and Rib independently represent trifluoromethyl, (Cl-Cio)-alkyl, substituted (Cl-Cio)-alkyl, (C2-Ci0)-alkenyl, substituted (C2-Cl o)-alkenyl, (C3-C7)-cycloalkyl, or (C3-C7)cycloalkenyl; R2represents (Cl-Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 alkenyl or substituted (C 2 -Cl 0 )-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen, phenyl, substituted phenyl, -C(O)NR 4 R5, or -S(O)mR 7 wherein Q~ mis 0,1,or 2; R 4 and R 5 indepe ndently represenit hydr -ogen, (C-C6)-alkyl, (C3-C6)- alkenyl, (C3-C7)-cycloalkyl, phenyl, suibstituted phenyl, phenyl-(CI-C6)- alkyl, substituted phenyl-(Cl-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(Cl-C6)-alkyl, or substituted na~hthyl-(C1-C6)-alkyl; R6 represents hydrogen, (Cl-C6)-alkyl, phenyl,'or phenyl-(Cl-C6)- alkyl; R 7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Cl- .C6)-alkyl, substituted phenyl-(Ci-C 6)-alkyll, pyridyl, substituted pyridyl, .pyridyl-(C1-C6)-alkyl, or substituted pyrid-Yl-(C1-C6)_alkyl; R 2 optionally may be joined to Rib to form an alkylene bridge containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached; C7 I R 3 rippresents (Cl-C 6 alkanoyl, substituted (Cl'C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and Ar' is -selected from the group consisting of pyridyls, furanyls, thiophenyls, pyrazolyls, triazolyls, oxazolyls and thiazolyls, and the optional substitutents on Ar' are independently from 1 to 3 of halogen, (Cl-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, -OR 4 or OC(O)R 4 where R 4 is hydrogen, (Cl-C6) alkyl, phenyl (Ci-C6) alkyl or substituted phenyl (Ci-C6) alkyl. 421 WO 98/04528 PCT/US97/13248 0 36. A compound of claim 34, wherein in structural formula 1C, R8 represents hydrogen; R la and Rib independently represent (C1-C6)-alkyl or (C2-C6)- alkenyl; R 2 represents (C 1 -C 10 )-alkyl, substituted (C1-C10) alkyl, (C 2 -C 10 alkenyl, or substituted (C2-C10)-alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are independently from 1 to 3 of halogen or -S(O)mR 7 wherein m=0, R 7 represents (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl (C1- C6)-alkyl or substituted phenyl (C1-C6)-alkyl; R 3 represents substituted (C 1 -C 6 )-alkyl or substituted (C3-C)- alkenyl; where the substitutents are 1 or 2 hydroxyl groups; and Ar' is selected from the group consisting of pyridyls, furanyls and thiophenyls, and the optional substitutents are independently from 1 to 3 of halogen, (C 1 -C 6 )-alkyl, (C2-C 6 )-alkenyl, -OR 4 or -OC(O)R 4 where R 4 is hydrogen or (C1-C6),alkyl. 37. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 34, and a pharmaceutically acceptable carrier. 38. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 34. 39. The method of claim 38, wherein the subject is -human, the glucagon- mediated condition is diabetes, and the treatment- results in lowering of ,blood glucose. A compound having glucagon receptor antagonistic activity and the structural formula 1D Ar" R 3 R2 R 1 a R Rib R 8 1D wherein 422 L 1 a -^a -u*rEr riu rrr~7ln7-l:*;;na:i:~ Frrr m:c-)jri pi ar WO 98/04528 WO 9804528PCTIUS97/13248 0 R 8 represents hydrogen, halogen, trifluoromethyl, phenyl, substituted phenyl, (Ci-Ci0)-alkyl, substituted (Cl-Clo)-alkyl, (Cl-C6)- alkoxy, (C3-C7).cycloalkyl, phenyl-(C1-C3)-alkoxy, (Cl-C6)-alkanoyloxy, (Cl-C6)-alkoxycarbonyl, carboxy, formyl, or NR 4 R 4 and R 5 independently represent hydrogen, (Cl-C6)-alkyl, (C3-C6)- alkenyl, (IC3-C7)-cycloalkyl, (C3..C7).cycloalkylz(C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(C1-C6)-alkyl, substituted phenyl-(C1-C6)-alkyl, naphthyl, substituted naphthyl, naphthyl-(C-C6)-alkyl, or substituted naphthyl-(Cl-C6)-alkyl; R 4 and R- 5 optionally may -be joined together to form- (CH2)rA(CH2)s- wherein r -and s are independently 1,2, -or 3, and wherein 4A represents 0, S(O)n CR6, or:NR 6 wherein n is 0,1,or 2;and, R6, represents hydrogen,. (C1-C6)-alkyl,. piperidin-1-yl, ~phenyl,.or pheny-(C1-C6-alkyl;T Rla and Rlbindeednl represent, trifluoroinethyl, (Cl-Cio)-alkyl, substitute4I (Ci-Clo)-alkyl, (C2-ClO)-alkenyl, -substituted (C-2-Clo)-alkenyl,, (C2-Clo)-alkyyl, substituted (C2;Cio)-alkynyi, (C-7gylakyl,(37 cycloalken~yl, or ,(C;1-C6)-alkanoyl; R'represents (Cl-Cl 0 )-alkyl, substituted (Cl-C 1 0 )-alyl, (C 2 -C 10 alkenyl, substituted (C -Cl 0 )-aIkeyL, ((q2-(I1 1 ))-alkynyl,, substituted (C 2 C, 0)r-kypyl, (C3- 6 -coa.kyl- or, substitoted (C 3 -C 6 cydoalkyl-(C 1 -C alkyl; substitutents on said substituted alkyl, substituted alkenyl, substituted ialkyny'~iparid substituted deycloalkyl R 2 .groups, being independently, from, 1 to 3- of .halogeh,; phenyl, substituted phenyl, 1,3-dioxolan-2-yl, -C(0)NR 4 R 5 or -S(0)mR 7 wherein m is 0, 1, or 2; R 7 .Tre rsnts (C1-C6)-alkyl, phenyl, substituted phenyl, phenyl-(Ci- ,C6-alylsubstituted pheny1-(C1-C6),-alkyl, .pyridyl, substituted pyridyl, pyridyl-(Ci-C6)-alkyi, substituted pyridyl-C..Cq).-1y naphthyL, substituted naphthyL naphthyl-(Cl-CO).Alkyl, or sjubitituted phyl(- C6)-alkyl; R 2 optionally may be joined, lo Rib: to form an alkylene bridge containing from 3 to 5 carbon atoms, between the ring carbon atoms to which R 2 .an~d Rib are attached; R 3 represents hydroxy, trifluoroacetyl. (C 1 -C 6 )-alkanoyl, substituted (C 1 -C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl; the substitutents on said 423 WO 98/04528 WO 9804528PCTIUS97/13248 0 substituted alkyl and substituted alkenyl R 3 groups being from 1 to 3 hydroxyl or trifluoromethyl groups; Ar" represents an optionally mono-, di-, or tni-substituted aromatic ring selected from the group consisting of phenyls and naphthyls, wherein the substitutents are independently from 1 to 3 of halogen, (Cl-C 6 )-alkyl, substituted (Cl-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, substituted (C 2 -C 6 )-alkenyl, (C 2 C 6 )-alkynyl, substituted (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, nitro, trifluoromethyl, -OR 4 -C(O)R 4 -OC(O)R 4 -C02R 4 -NR 4 R 5 -C(O)NR 4 R 5 or -S(O)mR 7 wherein m is 1, or 2; and pharmaceutically acceptable salts thereof. 41. A compound of claim 40, wherein in structural formula 1D, R 8 represents hydrogen, halogen, trifluoromethyl or (Cl-C10) alkyl; Rla and Rib independently represent trifluoromethyl, (Ci-Cio)-alkyl, subtitted(CiClo-alyl,(C2Clo-alkenyl, substituted (C2-Clo)-alkenyl, (C3-C7)-cyCdo4lk-y1, or (C3-C7)-cycloalkenyl; repres-ents-(C 1 -Cl 0 )-alkyl, substituted (Cl-Cl 0 )-alkyl, (C 2 -Cl 0 alkenyl ork sdbstituted (C 2 -C 1 6)-alkenyl, wherein th4 substituents on said su'ibstituted alynd substituted g~knlroups are independently from 1 to of halogen, phenyl, substituted phenyl, -C(O)NR 4 R 5 o -S(b)mnR 7 wherein MisQ,1,or2 R 4 andO -~independently represent hydrgn (-C)alkyl, (C3-C6)- a'lkenyl, (C3-C )-cycloalkyl, phenyl, substituted' phenyl, phenyl-(Cl-C6)- alkl, ubsitued heyl-(i- -alkyl, niaphithyl, substituted naphthyl, naphthy-(Cj-C6)-alkyl or substituted naphthyl-(CILC)-alkyl; R6 represents hydrogen, (Ci-C6)-alkyl, pheityl, or phenyl-(Cl-C6)- .alkvl:-. C .R 7 represents (C1-C6)-alkyl, phenyl' substituted phenyl, phenyl-(Cl- C6)-alkyl, substituted phenyl-(Cl-C-6)-alkyl, pyridyl,. substituted pyridyl, pyridy1-(Cl-C6)-alkyl) or suibstituted pyridyl-(C.C6y.AlkyI, R 2 optionally may be joined to Rib to" forma lyeebig containing from 3 to 4 carbon atoms, between the ring carbon atoms to which R 2 and Rib are attached; R 3 represents (Cl-CO) alkanoyl, substituted (Cl-C 6 )-alkyl, or substituted (C 3 -C 6 )-alkenyl, wherein the substitutents are from 1 to 3 hydroxyl groups; and 424 WO 98/04528 WO 9804528PCT/US97/13248 0 Ar" represents a phenyl ring, and the optional substitutents on Ar" are independently from 1 to 3 of halogen, (Cl-C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, cyano, -OR 4 or -OC(O)R 4 where R 4 is hydrogen, (C1-C6) alkyl, phenyl (Cl-C6) alkyl or substituted phenyl (C1-C6) alkyl. 42. A compound of claim 40, wherein in structural formula 1D, R 8 represents hydrogen; Rla and Rib independently represent (Cl-C6)-alkyl or (C2-C6)- alkenyl; R 2 represents (Cl-Cl 0 )-alkyl, substituted (Cl-C1O) alkyl, (C 2 -Cl 0 alkenyl, or substituted (C2-C1O) alkenyl, wherein the substituents on said substituted alkyl and substituted alkenyl groups are .independently from 1 to 3 of halogen or -S(O)mR 7 wherein m=0;-I R 7 represents. (C1-C6)-alkyl, phenyl,.substituted phenyl, phenyl (Ci- C6)-alkyl or substituted phenyl (C-6)-alkyl; R 3 represents substituted (Cl-C 6 )-alkyl or substituted (C 3 -C 6 alkenyl; where. the. substitutents are. 1 or 2 hydroxyl: groups; and Ar" represents a phenyl, ring, and the, optional substitutents are independently .from i.t .o 3 of halogen, (Cl-C 6 )-alkylI (C 2 -C 6 )-alkenyl, -OR 4 or -OC(O)R 4 where R 4 is hydrogen or (Ci-C6). alkyl. 43. A compound of claim 40, selected from the following group of compounds: 3 ,S-Diisopropyl-2-hydroxynetl-.6-ethyl-l,i'-biphenyl; 3,5-Diisopropyl-2-hydroxymethyi-6-.ethyli4'-fluoro-i,i '-biphenyl; 3,5-Diisopropy1-2-h ydroxymethyl-6-ethylA4'-hlo~o..,i '-biphenyl; 3 ,S-Diisopropyl-2-hydroxymethyl-6-ethylA'-methyl..1'biphenyl; 3 ,S-Diisopropyl- 2 -hydroxymethyl-6-.hvl1:2'-hydroxy..'-biphenyl; 3 ,S-Diisopropyl- 2 -hydroxymethyl-6-ethyl-2'-hydrocy4'-fluoro4,i'-biphenyl; 3,-ispoy--yrxmty-7rpl11-ihnl 3 ,S-Diisopropyl- 2 -hydroxymethyl-6-propyl..4'-fluoro-i,i'.biphenyl; 3 5 -Diisopropyl- 2 -hydroxymethyl6propyl4'-chloro-11'biphenyl; 3 ,S-Diisopropyl- 2 -hydroxymethyl-6-.propyl4'-methyl..i,1'4,iphenyl; 3 ,S-Diisopropyl- 2 -hydroxymethy-6-propyIl-2'hyclroxcy-i,i'biphenYl; 425 WO 98/04528 PCT/US97/13248 0 3 ,S-Diisopropy12hydroxymethy6propy2hydroxyA'fluoro1,1'- biphenyl; 3 5 -Diisopropyl-2-hydroxymethyl..6.butylll 1'-biphenyl; 3 ,S-Diisopropyl-2-hydroxymefiyl..6-buty1..4'-.fluoro..ll '-biphenyl; 3 ,5-Diisopropy-2-hydroxymethy..6-.butylA1..chloro-1,1'-biphenyl; 3,-ispoy--hdoyehl6buy 'mty-,'-biphenyl; 3 ,-Diisopropyl-2hydroxymethy-6butl2I-hydroxy1,1'-biphenyl; biphenyl; 3 ,S-Diisopropy1-2-hydroxymethy..6.pentyl1,1 '-biphenyl; 3,-ispoy--yrxmthl6pny 'fur-,'-biphenyl; 3 ,S-DiisopropyI-2-hydroxymethyl...&penylAI-choro.lll'-biphenyl; 3,-ispoy--hdoyehl6pntl2-yr -,'-biphenyl;( biphenyl; 3 ,5-Diisoproky1-2-hydroxymethyl-6-hxyl1..1I..bipheny; 3, Diorpl2i-yixmty -ekl4-l~r-,'-biphenyl; 3,5-b i is p oyhenyox m tyl;h xl-'h d ox h n l biphenyl; b3 5 ipenyl;[ p to y t io m t y l- y ro y e h 'bi h n biphenyl; iorok--(-tllhomthl--yroyehl4 clr-,'- bipheyl; fluoro-1,i -biphenyl; 426 WO 98/04528 PCT/US97/13248 0 3,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl-6-hydroxymefiyl1,1'- biphenyl; 3,5-DiisopropyI-2-[((4-fluorophenyl)thio)methy1]-6-hydroxymethyl4'- fluoro-1,1 '-biphenyl; 3 5 -Diisopropyl-2-[((4-fluorophenyl)thio)methyl..6hydroxymethyl-4'- chloro-1,1 '-biphenyl; 3 5 -Diisopropyl-2-[((4-fluorophenyl)thio)meth-yl]-6..hydroxymethyl-4'. methyl- 1,1'-biphenyl; 3 ,S-Diisopropyl-2-[((4-fluorophenyl)thio)methy]-6-hydroxymethyl..2'- hydroxy-1,1 '-biphenyl; 3 5 -iisopropyl-2-((4-fluorophenyl)ffio)methyl-6hydroxymethyl.2'. hydroxy-4'-fluioro-1,1'-biphenyl; 3 5 -Diisopropyl-2-(l-hydroxyethyl)-6..ethyl..1,1'-biphenyl, 3 ,S-Diisopropyl-2-(l-hydroxyethy)-6-.ethy1-4'..nuoro.1,1'.biphenyl; 3 ,S-Diisopropyl-2-.(1-hydroxcyethy)-&.ethylA'-chio1,1 'biphenyl; 3 ,S-Diisopropyl-2-(-hydroxyethy)6ethylA'metyl..1,1'..biphenyl; 3 ,iS-Diisopropylh2-(l-hydtxyethyl)-6--thyl12'-.hydro,' 11'.biphenyl; 3 ,5-Diisopropyl-2-(l-hydroxyethyl)-6-effy12'-hydroxy-A'-fluoro.1,1'- biphenyl; 3 ,-DiisopropyI-2-(l-hydroxyethy).&propy11'-biphenyl; 3 ,5-Disopropyl-2(l-hydroxcyethyl).;&propyl14'.fluc6-1,1'bipheny; 3 ,S-Diisopropyl-2-(1-hydroxyethy)&6propylA'chloro1;...--bipheny; 3 ,.-Diisopropy1-r2-(-hydrxethy)&propylA'-methyl-l.1;'-bipheny; 3 ,S-Diisopropy1-2-(l-hydroxyethy)-6-propyl-2'-hydroxy1,1 '-biphenyl; 3,-ispoy--lhdrxehl -rpl2-hdo biphenyl; 3 ,S-Diisopropyl-2-(l-hydroxyethy)46..buty1..1,1'.bipheny; 3 iS-Diisopropyl-2-(l-hydroxyethy)6butylA'..fltor-1,1'-bipheny; 3,-ispoy-7--yrxehl)6btl4-hoo11-ihnl 3,-ispoy--lhdoyty)6btl4-ehl11-ihnl 3, ispoy--lryrxehl-6btl2-yr)r11-ihnl 3 ,S-Diisopropyl1-2-(l-hydroxyethyl)6butyl1;2'-hydroxy-A'-fluoro-1,1 biphenyl;. 3 ,S-Diisopropyl- 2 -(l-hydroxyethyly.&pentyll1,1'.biphenyl; 427 WO 98/04528 PCT/US97/13248 0 3,-ispoy--l-yrxehl -eny-'fur-,'-biphenyl; 3 ,S-Diisopropyl-2(1hydroxyeffiyl)-6penty..4'-chloro..ll '-biphenyl; 3 ,S-Diisopropylb2-(lhydroxyethy)6penty..4'-.methyl..ll '-biphenyl; 3,-ispoy--lhdoythl -etl2-yrx-,'-biphenyl; biphenyl; 3,-ispoy--l-yrxehl -exl2-yrx-,'-biphenyl; 3 ,5-Diisopropyl-2(-hydroxyet1y)6..hexy1.2I.hydrox-.flur1,' biphenyl; C biphenyl; biphenyl;, ispoy--[ptllhomtyl--lhdoytyl-"mty-,' biphenyl; flurohenybpheyl 3 5 -Diisopropy2[((4fuo rny~opehyl-6-methydrox(lh l)- biphenyl; fluoro-1,1'-biphenyl; chloro-1,1'-biphenyl; 3 ,5Diisopropy2((4..fluoroph ny1)i~mthylo--mthydroxyhfl)-4 methyl-1,1 -biphenyl; 3,-ispoy--(4furpey~ti~ehl--i-yrxehl-' hydroxy-l,1 '-biphenyl; 428 O WO 98/04528 PCT/US97/13248 0 3 ,5-Diisopropyl-2-[((4-fluorophenyl)thio)methyl]-6-(l-hydroxyethyl)-2- hydroxy-4'-fluoro-1,1'-biphenyl. 44. A pharmaceutical composition for use in treating a glucagon-mediated condition, which comprises: a compound of claim 40, and a pharmaceutically acceptable carrier. A method for treating a glucagon-mediated condition which comprises administering to a subject an effective amount of a compound of claim 46. The method of claim 45, wherein the subject is human, the glucagon- mediated condition is diabetes, and the treatment results in lowering of blood glucose. 47. A compound of claim 21, 27, 34, or 40 wherein the substituent shown-as R 3 is a hydroxyethyl group having the following stereochemistry HO H H 3 C (Remainder of molecule) DATED this 30th day of October, 2001 BAYER CORPORATION AND BAYER AKTIENGESELLSCHAFT By their Patent Attorneys DAVIES COLLISON CAVE 429