WO2002089848A2

WO2002089848A2 - Use of an ampa receptor potentiator for the manufacture of a medicament for the treatment of type 2 diabetes

Info

Publication number: WO2002089848A2
Application number: PCT/US2002/011847
Authority: WO
Inventors: Emanuele Sher
Original assignee: Eli Lilly And Company
Priority date: 2001-05-04
Filing date: 2002-04-22
Publication date: 2002-11-14
Also published as: EP1390072A2; JP2004530680A; WO2002089848A3; CA2446161A1; AU2002307327A1

Abstract

The present invention provides a method for treating diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.

Description

USE OF AN AMPA RECEPTOF POTENTIATOR FOR THE MANUFACTURE OF A MEDICAMENT FOR THE

TREATMENT OF TYPE 2 DIABETES

There are approximately 15.7 million people in the United States who suffer from diabetes which is the seventh leading cause of death in the United States. Diabetes is a chronic disease in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar, starches and other food into energy needed for daily life. In addition, many people do not become aware that they have diabetes until they develop one of its debilitating or life-threatening complications such as blindness, kidney disease, heart disease, stroke, and nerve disease which often results in lower limb amputations.

There are two major types of diabetes, type 1 and type 2. Type 1 diabetes is an auto-immune disease in which the body does not produce any insulin, most often occurring in children and young adults. People suffering from type 1 diabetes must take daily insulin injections to stay alive. Type 1 diabetes accounts for approximately 5-10 percent of diabetes cases.

Type 2 diabetes is a metabolic disorder resulting from the body's inability to make enough insulin, or to properly use insulin. It is the most common form of the disease and accounts for approximately 90-95 percent of diabetes cases. In addition, gestational diabetes is a disease that develops in approximately 2 -5 percent of all pregnancies but disappears when the pregnancy is over. It is believed that women who have had gestational diabetes are at increased risk for developing type 2 diabetes later in life. There are also other specific types of diabetes which result from certain genetic syndromes, surgery, drugs, malnutrition, infections, and other illnesses. Effective and convenient treatment of diabetes continues to be a target of active research in the pharmaceutical industry.

L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The receptors that respond to L-glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21 , 165 (1981); Monaghan, Bridges, and Cotman,

Ann. Rev. Pharmacol. Toxicol, 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11 , 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception. Excitatory amino acid receptors are classified into two general types, ionotropic and metabotropic. The receptors that are directly coupled to the opening of cation channels in the cell membrane of neurons are termed "ionotropic". The ionotropic receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists Λ/-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). It has been disclosed by G. Bertrand, et al., Br. J. Pharmacol, 106. 354-

359 (1992) that L-glutamate stimulates insulin secretion in rat pancreas, by acting on an excitatory amino acid receptor of the AMPA subtype similar to that described in the central nervous system. In addition, T. Gonoi, et al., J. Bio. Chem., 269(25), 16989-16992 (1994), showed that AMPA/kainate and NMDA receptors with electrophysiological and pharmacological properties similar to those found in the CNS are naturally expressed in MIN6 cells and that they mediate insulin secretion.

Furthermore, results disclosed by N. Inagaki, et al., FASEB, 9, 686-691 (1995) indicate that ionotropic glutamate receptors may participate in the regulation of insulin secretion in normal pancreatic islets. G. Bertrand, et al., Am. J. Physiol., 269, E551-556 (1995) concluded that, in rats, glutamate is able to stimulate in vivo at micromolar plasma levels insulin secretion and that these effects appear to be mediated by an excitatory amino acid receptor of the AMPA subtype. By combining immmunolocalisation studies in rat islet sections, western blotting, and electrophysiology, CD. Weaver, et al., J. Biol. Chem., 271(22), 12977-12984 (1996) concluded that AMPA receptor subunits (Glur 2 and 3 in particular) are expressed in both α, β and PP cells. On the other hand, kainate receptors (GluR 6 and 7 in particular) were found mainly in α cells.

CD. Weaver, et al., Mol. Pharm., 54, 639-646 (1998) later confirmed in a new pancreatic β cell line (GK-P3) that AMPA receptor activation results in depolarization and consequent increase in intracellular calcium. In addition, Weaver, et al. highlighted the ability of AMPA potentiators such as cyclothiazide, to amplify these signals and suggested that block of GluR desensitisation by compounds such as diazoxide, may underlie some of the therapeutic benefits of this class of drugs.

U.S. Patent No. 5,459,138, Pirotte et al., disclose compounds that selectively facilitate the activation of the AMPA receptor. Pirotte, et al. further state that these compounds have proved to be advantageous in the treatment of diabetic-type pathologies, related to dysfunctioning of insulin secretion which was described by G. Bertrand, et al., Br. J. Pharmacol., 106, 354-359 (1992) as regulated by AMPA receptors The present invention provides a method of treating diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.

In addition, the present invention provides a method of treating type 2 diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.

According to another aspect, the present invention provides the use of a suitable AMPA receptor potentiator, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating type 2 diabetes.

In addition, the present invention provides the use of a suitable AMPA receptor potentiator or a pharmaceutically acceptable salt thereof for treating type 2 diabetes.

The present invention further provides an article of manufacture comprising packaging material and a suitable AMPA receptor potentiator contained within said packaging material, wherein said packaging material comprises a label which indicates that said suitable AMPA receptor potentiator can be used for treating type 2 diabetes.

As used herein the term "diabetes" refers to and includes type I diabetes, type 2 diabetes, and gestational diabetes.

As used herein the term "type I diabetes" refers to insulin dependent diabetes.

As used herein the term "type 2 diabetes" refers to non-insulin dependent diabetes. As used herein the term "(1-10C)alkyl" includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

As used herein the term "(2-10C)alkenyl" includes (3-10C)alkenyl, (2- 8C)alkenyl, (2-6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl and prop-2-enyl.

As used herein the term "(2-10C)alkynyl" includes (3-10C)alkynyl, (2- 8C)alkynyl, (2-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.

As used herein the term "Cι-C₆ alkoxy" refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical Ci-Cβ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term Ci-Cβ alkoxy includes within its definition the term C₁-C₄ alkoxy.

As used herein the term "(3-8C)cycloalkyl", as such or in the term (3- 8C)cycloalkyloxy, includes monocyclic and polycyclic groups. Particular values are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2]octane. The term includes (3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein the terms "integer of from 1 to 4" or "integer of from 1 to 3" includes the integers 1 , 2, 3, and 4, or the integers 1 , 2, and 3, respectively.

As used herein the term "(5-8C)cycloalkyl" includes cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the term "hydroxy(3-8C)cycloalkyl" includes hydroxy- cyclopentyl, such as 3-hydroxycyclopentyl. As used herein the term "oxo(3-8C)cycloalkyl" includes oxocyclopentyl, such as 3-oxocyclopentyl.

As used herein the terms "halogen", "Hal" or "halide" include fluorine, chlorine, bromine and iodine unless otherwise specified.

As used herein the term "halo(1-10C)alkyl" includes fluoro(1-10C)alkyl, such as trifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such as chloromethyl.

As used herein the term "cyano(2-10C)alkenyl" includes 2-cyanoethenyl. As used herein the term "(2-4C)alkylene" includes ethylene, propylene and butylene. A preferred value is ethylene.

The term thienyl includes thien-2-yl and thien-3-yl. The term furyl includes fur-2-yl and fur-3-yl. The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.

The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl. The term oxadiazolyl includes [1 ,2,4]oxadiazol-3-yl and [1 ,2,4]oxadiazol-5- yl.

The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.

The term thiadiazolyl includes [1 ,2,4]thiadiazol-3-yl, and [1 ,2,4]thiadiazol- 5-yl.

The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol- 5-yl. The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-

5-yl.

The term triazolyl includes [1 ,2,4]triazol-3-yl and [1 ,2,4]triazol-5-yl. The term tetrazolyl includes tetrazol-5-yl. The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl. The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.

The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.

The term benzofuryl includes benzofur-2-yl and benzofur-3-yl. The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.

The term benzimidazolyl includes benzimidazol-2-yl. The term benzoxazolyl includes benzoxazol-2-yl. The term benzothiazolyl includes benzothiazol-2-yl. The term indolyl includes indol-2-yl and indol-3-yl. The term quinolyl includes quinol-2-yl.

The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term (1- 4C)alkoxycarbonyIdihydrothiazolyl includes 4-methoxycarbonyl-4, 5- dihydrothiazol-2-yl. As used herein the term "-(1-4C)alkyl(3-8C)cycloalkyl" includes the following:

As used herein the term "-(1-4C)alkylaromatic" includes the following:

The present invention includes the pharmaceutically acceptable salts of the compounds used herein. The compounds used in this invention can possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds used herein which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66. 2-19 (1977), which are known to the skilled artisan. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1 ,4-dioate, butyne-1 ,4-dicarboxylate, hexyne-1 ,4-dicarboxylate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p- toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate, citrate, lactate, α-hydroxybutyrate, glycolate, tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-napththalenesulfonate, 1 ,5- naphthalenedisulfonate, mandelate, tartarate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.

As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation:

ee = E¹ - E² X 100

wherein E¹ is the amount of the first enantiomer and E² is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers. Racemates, and Resolutions". John Wiley and Sons, Inc., 1981 , and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds". (Wiley- Interscience 1994), and European Patent Application No. EP-A-838448, published April 29, 1998. Examples of resolutions include recrystallization techniques or chiral chromatography. Some of the compounds used in the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.

The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice",

(J.H. Fletcher, et al., eds., 1974) at pages 103-120.

As used herein the term "potentiating glutamate receptor function" refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.

As used herein the term "suitable AMPA receptor potentiator" refers to a compound which inhibits the rapid desensitization or deactivation of AMPA receptors to glutamate and augments insulin secretion. A preferred suitable AMPA receptor potentiator augments insulin secretion only during high glucose levels.

Examples of AMPA receptor potentiators include the following as described in Sections A through E. It is understood that suitable AMPA receptor potentiators fall within the scope of the compounds described in Sections A through E.

Section A

A compound of formula I

R^x -L- HSθ₂R² I in which

R^"! represents an unsubstituted or substituted aromatic or heteroaromatic group;

R² represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1- 6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R3R4|\J in which R^ and R4 each independently represents (1- 4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and

L represents a (2-4C)alkylene chain which is unsubstituted or substituted by one or two substituents selected independently from (1-6C)alkyl, aryl(1- 6C)alkyl,

(2-6C)alkenyl, aryl(2-6C)alkenyl and aryl, or by two substituents which, together with the carbon atom or carbon atoms to which they are attached form a (3- 8C)carbocyclic ring; or a pharmaceutically acceptable salt thereof as disclosed in Intemational Patent Application WO 98/33496 published August 6, 1998 including the preferred and specific compounds disclosed therein. The disclosure of International Patent Application WO 98/33496 published August 6, 1998 is hereby incorporated by reference.

As used herein with regard to formula I, the term "aromatic group" means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2-naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyI, and the like. Phenyl is the preferred aromatic group.

The term "heteroaromatic group" in formula I includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, and quinolyl.

The term "substituted" as used in the term "substituted aromatic or heteroaromatic group" herein for formula I signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula II from functioning as a potentiator of glutamate receptor function. It is understood that when R¹ in formula I represents an unsubstituted or substituted (5-8C)cycloalkyl group, mixtures of cis and trans isomers may result which can be separated into the individual cis and trans isomers by one of ordinary skill in the art, using standard techniques and procedures such as reverse phase or normal phase high performance liquid chromatography or flash chromatography, with a suitable stationary phase and a suitable eluent. Examples of suitable stationary phases are silica gel, alumina, and the like. Examples of suitable eluents are ethyl acetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and the like. Such individual cis and trans isomers are included within the scope of the present invention. Examples of substituents which may be present in a substituted aromatic, heteroaromatic group or (5-8C)cycloalkyl group in formula I include halogen; nitro; cyano; hydroxyimino; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3- 8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;

(CH2)yX^'' R® in which y is 0 or an integer of from 1 to 4, χ1 represents O, S, NR10, CO, COO, OCO, CONR1¹ , NR ²CO, NR COCOO, OCONR13, R9 represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰> R^ . R^² and R^³ each independently represents hydrogen or (1-10C)alkyl, or R⁹ and R^°> R^ > R¹² or

R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl; fury!; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl; (1 -4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R14_ (L^a)_n-X²-(L^b)m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or

CH=CH, L^a and L^D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R^4 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2- thiazinyl); halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH2)_ZX³R¹⁵ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH),

COO, OCO, CONR17, NR¹⁸CO, NHSO2, SO2NH, NHSO2NRI 7 OCONR¹⁹ or

NR ⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R16 R17, R18 _and R^9 each independently represents hydrogen or (1-10C)alkyl, or R^S and R16, R17_J R18 _or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

In the compounds of formula I, L preferably represents a group of formula R⁸ _R6

I I

- C — C — I I

R⁵ R⁷ in which two of Rβ, R6, R7 and Rβ represents hydrogen and the remainder represent independently hydrogen, (1-6C)alkyl, aryl(1-6C)alkyl, (2-6C)alkenyl, aryl(2-6C)alkenyl or aryl, or together with the carbon atom or carbon atoms to which they are attached form a (3-8C)carbocyclic ring.

Preferably either one or two of Rβ, Rβ, RJ and Rβ in formual I represents

(1-6C)alkyl, aryl(1-6C)alkyl, (2-6C)alkenyl, aryl(2-6C)alkenyl or aryl, or two of R⁵,

Rβ, R7 and Rβ together with the carbon atom or carbon atoms to which they are attached form a (3-8C)carbocyclic ring; and the remainder of Rβ, Rβ, RJ and Rβ represent hydrogen.

Examples of a (1-6C)alkyl group represented by R5, R6, R7 _anc| R8 j_n formula I are methyl, ethyl and propyl. An example of an aryl(1-C)alkyl group is benzyl. An example of a (2-6C)alkenyl group is prop-2-enyl. An example of a (3- 8C)carbocyclic ring is a cyclopropyl ring. More preferably R^ and R^ represent hydrogen in formula I.

Preferably in formula I, R^ and Rβ each independently represents hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-8C) carbocyclic ring.

More preferably in formula I, Rβ represents methyl or ethyl, or R§ and Rβ together with the carbon atom to which they are attached form a cyclopropyl ring. When Rβ represents methyl or ethyl, R preferably represents hydrogen or methyl.

Especially preferred in formula I are compounds in which Rβ represents methyl and Rβ, Rβ and R7 represent hydrogen. Preferably in formula I, Rβ and R4 each represent methyl.

Examples of values for R² in formula I are methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyI, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino. Preferably R² is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred.

Examples of values in formula I for Rβ are hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

Examples of values in formula I for R15 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO in formula I. z is preferably 0 in formula I.

In formula I, R⁹ is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl. In formula I particular values for the groups (CH2)yX^ R⁹ and

(CH2)zX³R¹⁵ include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl.

In formula I examples of particular values for y are 0 and 1.

Examples of particular values for z are 0, 1 , 2 and 3 in formula I.

L^a and L^D preferably each independently represents CH2 in formula I.

X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH in formula I.

Preferably the group (CH2)yX¹ R⁹ represents CHO; COCH3, OCH3;

OCH(CH3)2; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy in formula I. In formula I preferably the group (CH2)zX³ ^ represents NH2; CH2NH2; (CH2)2NH2; (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2Hδ)2; CH2OH; CH(OH)CH3; CH(OH)CH2CH2; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; NHSO2CH(CH3)2; a group of formula (CH2)2NHSO2R¹⁵ in which R¹⁵ represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3, benzyl, CH2CF3, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, 1-(2-dimethylamino)naphthyl or 2- thienyl; CH(OH)CH2NHSO2CH3; (CH2)3NHSO2CH(CH3)2; COCH2N(OCOC(CH3)2SO2CH3; COCH2NHSO2CH3; (CH2)2NHCOR¹⁵ in which R¹⁵ represents CH3, CH(CH3)2, CH2CH(CH3)2, phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl, CH=CH, CH=CHCN, OCH3 or O(CH2)3CH3-

In formula I examples of particular values for (L^a)n-X -(L.k)_m are a bond, O, NH, S, SO, SO2, CO, CH2, COCH2, COCONH, CH(OH)CH2, CONH, NHCO, NHCONH, CH2O, OCH2, OCH2CONH, CH2NH, NHCH2 and CH2CH2.

In formula I, R14 j_s preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group. Examples of particular values in formula I for R14 are phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4- chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3- difluoro-phenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl, 4- methylphenyl, 4-ethyl phenyl, 3-propylphenyl, 4-t-butylphenyl, 2-prop-2- enylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl)phenyl, 2- trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifIuoromethylphenyl, 2- bromomethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl, 2-formyIphenyl, 3-formylphenyl, 4-formyIphenyI, 2-acetylphenyl, 3- acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl, 2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl, 3-(1- hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 2-(1-hydroxypropyl)phenyl, 4-(1- hydroxypropyl)phenyl, 2-(1 -hydroxy-2,2-dimethyl-propyl)phenyl, 4- trifluoromethoxyphenyl, 2-aminophenyl,4-aminophenyl, 4-N,N- diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3- aminopropyl)phenyl, 4-carboxyphenyl, 4-carbamoylphenyl, 4-N- methylcarbamoylphenyl, 4-N,N-dimethylcarbamoylphenyl, 2- isopropylaminomethylphenyl, 4-t-butoxycarbonylaminomethylphenyl, 4-(2- isopropoxy-carboxamido)ethylphenyl, 4-(2-t-butoxycarboxamido)ethyl-phenyl, 4- isopropylsulfonylaminophenyl, 4-(2-methane-sulfonylamino)ethylphenyl, 4-(2- ethylsulfonylamino)ethyl-phenyl, 4-(3-isopropylsulfonylamino)propylphenyl, 4-(1 - (2-(2-propane)sulfonylamino)propyl)phenyl, 4-(2-propylsulfonyl- amino)ethylphenyl, 4-(2-isopropylsulfonylamino)ethylphenyl, 4-(2- butylsulfonylamino)ethylphenyl, 4-(1 -isopropyl-sulfonylaminomethyl)ethylphenyl, 4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl, 4-(2-(2,2,2-trifluoroethyl)- sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonylamino)-ethylphenyl, 4-(2- (2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl, 4-(2-N,N- dimethylaminosulfonylamino)-ethylphenyl, 4-(2-phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluoro- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(2-trifluoromethyl- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-trifluoro- methylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1 -(5- dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(1 -(2-(2-methoxy- carbonylethanesulfonylamino)ethyl)phenyl, 4-(1 -(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl, 4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl, 4- (N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl, 4-(2-(2- thienylcarboxamido)ethyl)phenyl, thien-2-yl, 5-hydroxy-methylthien-2-yl, 5- formylthien-2-yl, thien-3-yl, 5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2- bromothien-3-yl, fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl, 3-bromoisoxazol-5- yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl, 5-methylisoxazol-3-yl, 5- 5 hydroxymethylisoxazol-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 5-(2- hydroxyethyl)isoxazol-3-yl, 5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl, 5-N- methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl, 3- bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yI, thiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl, 4-carboxythiazol-2-yl, imidazol-1 -yl, 2-sulfhydryl- l o imidazol-1 -yl, [1 ,2,4]triazol-1 -yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-ethyltetrazol- 5-yl, 2-isopropyl-tetrazol-5-yl, 2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl, 5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl, 5- trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl, 6-methylpyridazin-3-yl, 6- methoxypyrazin-3-yl, pyrimidin-5-yl, benzothien-2-yl, benzothiazol-2-yl, and

15 quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R^ are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl) .

In formula I, R^ preferably represents a naphthyl group or a phenyl, furyl, 20 thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-

8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH2)yX R⁹ in which y is 0 or an integer of from 1 to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO,

25 CONR^{1 1} , NR1²C0, NR¹²COCOO, OCONR13, R9 represents hydrogen, (1- 10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolindinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and Rl0> R^ > R^² and R13 each independently represents hydrogen or (1-10C)alkyl, or R⁹ and R^°> R^ . R^² or R¹³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, 30 piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-

4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl, (1-

4C)alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R^4_ (L )_n-X²-(L^b)m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCONH, NHCO, NHCOO, COCONH, OCH2CONH or

CH=CH, L^a and L^D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C)alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)cycloalkyl, 4-(1 ,1- dioxotetrahydro-1 ,2-thiazinyl), halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH2)z*³R^ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO, CONR17, NR¹⁸CO, NHSO2, NHSO2NR17, NHCONH, OCONR1⁹ or NR¹⁹COO, R ⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1-10C)haloalkyl, (1-4C)alkoxy(1-4C)alkyl, (1- 4C)alkylsulfonylamino)(1 -4C)alkyl, (N-(1 -4C)alkoxycarbonyl)(1 - 4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3- 8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1 -4C)alkyl, (1 -

4C)haloalkyl, di(1-4C)alkylamino and (1-4C)alkoxy and R¹6, R¹ , R ⁸ and R1⁹ each independently represents hydrogen or (1-10C)alkyl, or R^ and R16, R¹?,

R18 or R1⁹ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group. More preferably in formula I, R^ represents 2-naphthyl or a group of formula

in which

In formula I, R²^ represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3- 8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1 -10C)alkyl; (CH2)yX¹ R⁹ in which y is 0 or an integer of from 1 to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO,

CONR ¹, NR ²CO, NR ²COCOO, OCONR ³, R⁹ represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10> R1 1 » R1² and R13 each independently represents hydrogen or (1-10C)alkyl, or R⁹ and R10> R^{1 1}. R^² or R^³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl- dihydrothiazolyl; (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group of formula R^^-( ^a)_n~ X²-(l_^b)m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH2CONH or CH=CH, NHCO, L^a and L^b each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R^"14 represents a phenyl or hetero-aromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl); halo(1- 10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH2)zX³R¹⁵ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR16, CO, CH(OH), COO, OCO,

CO R17, NRlScO, NHSO2, NHSO2NR¹⁷, NHCONH, OCONR ⁹ or

NR¹⁹COO, R ⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1- 10C)haloalkyl, (1 -4C)alkoxycarbonyl(1 -4C)alkyl, (1 -4C)alkylsulfonylamino(1 - 4C)alkyl, (N-(1 -4C)alkoxycarbonyl)(1 -4C)alkylsulfonylamino(1 -4C)alkyl, (3- 10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, (1-4C)haloalkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R^"! 6, R1 ^ R18 and R^ each independently represents hydrogen or (1 -

10C)alkyl, or R¹⁵ and R ⁶, R¹⁷, R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

In formula I, R²^ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group.

Examples of particular values in formula I for R²^ are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido, cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido, cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino, piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4- yl, pyrimidin-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2- yl, 4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl, benzothien-2-yl, benzothiazol-2-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-difluorophenyl, 4- chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4- cyanophenyl, 2-methylphenyl, 4-methylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2- thiazinyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoro-methylphenyl, 4-(2- cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyI, 4-formylphenyl, 3-acetyl- phenyl, 4-acetylphenyl, 4-carboxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl, 4-(1- . hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)-phenyl, 4-(3- aminopropyl)phenyl, 4-(2-acetylaminoethyl)-phenyl, 4-t- butoxycarboxylaminoethyl)phenyl, 4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl- aminoethyl)phenyl, 4-(2-ethylsulfonylaminoethyl)phenyl, 4-(2- propylsulfonylaminoethyl)phenyl, 4-(2-butylsulfonyl-aminoethyl)phenyl, 4-(2- isopropylsulfonylaminoethyl)phenyl, 4-(1 -hydroxy-2- methanesulfonylaminoethyl)phenyl, 4-(2- dimethylaminosulfonylaminoethyl)phenyl, 4-(1 -(2-(2- propyl)sulfonylaminopropyl)phenyl, 4-(2-(2,2,2-trifluoro- ethyl)sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonyl-aminoethyl)phenyl, 4-(2- phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(2- trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1 -(5- dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4- carbamoylphenyl, 4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl, 4-(2- (2-methylpropaneamido)ethyl)phenyl, 4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido, 2-fluorobenzamido, 3-fIurobenzamido, 4- fluorobenzamido, 2,4-difluorobenzamido, 3-chlorobenzamido, 4- chlorobenzamido, 4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3- methylbenzamido, 4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido, 4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido, 3- trifluoromethylbenzamido, 4-trifluoromethylbenzamido, 2-fluoro-4-trifluoromethyl- benzamido, 2-methoxybenzamido, 3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido, 4-phenylphenyl-carboxamido, 4-benzylcarboxamido, 4- phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy, 2-fluoro- benzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl, 4-(1-(2-(2- methoxycarbonylethanesulfonylamino)ethyl)phenyl, 4-(1 -(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonylamino)ethyl)phenyl, 4-(2-phenylacetamido)-ethyl)phenyl, 4-(methanesulfonylaminoethanoyl)phenyl, 4- (N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl, 2- thienylcarboxamido, 2-furylcarboxamido, 3-(5-methyl-isoxazolyl)carboxamido, 5- isoxazolylcarboxamido, 2-benzothienylcarboxamido, 4-(5-methyl-3- phenylisoxazolyl)-carboxamido, 4-pyridylcarboxamido, 2-(5-nitrofuryl)- carboxamido, 2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido, 2- thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino, 2- furylmethylamino, 3-furylmethylamino, 3-acetylureido and 2-(2- thienyl)ethylureido.

Examples of particular values in formula I for R ^ are hydrogen and chlorine. R²^ is preferably ortho to R²⁽ .

Examples of particular values in formula I for R1 are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl- phenyl, 4-isobutylphenyl, 4-f-butyl phenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(p^"yrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3- fluoro-phenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl, 4-(4- . formylphenyl)phenyl, 4-(4-methylphenyl)phenyl and 4-(2-methoxyphenyl)phenyl. Section B

A compound of formula II:

formula II

wherein:

A represents SO₂, or CONH;

R^a represents (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or

-(1 -4C)alkylaromatic; R^b represents H, (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or

-(1-4C)alkylaromatic; or

R^a and R^b together with the carbon atoms to which they are attached form a (3-

8C) saturated carbocyclic ring, a (3-8C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (5-8C) carbocyclic ring containing one double bond;

R¹ represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5-

8C)cycloalkyl group;

R² represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or when A represents SO₂, a group of formula R³R⁴N in which R³ and R⁴ each independently represents (1- 4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof as disclosed in International Patent Application WO 00/66546 published November 9, 2000 including the preferred and specific compounds disclosed therein. The disclosure of International Patent Application WO 00/66546 published November 9, 2000 is hereby incorporated by reference. As used herein with regard to formula II, the term "aromatic group" means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2-naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and the like. Phenyl is the preferred aromatic group. 5 The term "heteroaromatic group" in formula II includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one 0 to four atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, and quinolyl. 5 The term "substituted" as used in the term "substituted aromatic or heteroaromatic group" in formula II herein signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula II from functioning as a potentiator of glutamate o receptor function .

It is understood that in formula II, when R¹ represents an unsubstituted or substituted (5-8C)cycloalkyl group, mixtures of cis and trans isomers may result which can be separated into the individual cis and trans isomers by one of ordinary skill in the art, using standard techniques and procedures such as 5 reverse phase or normal phase high performance liquid chromatography or flash chromatography, with a suitable stationary phase and a suitable eluent. Examples of suitable stationary phases are silica gel, alumina, and the like. Examples of suitable eluents are ethyl acetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and the like. Such individual cis and trans isomers o are included within the scope of the present invention.

Examples of substituents which may be present in a substituted aromatic, heteroaromatic group or (5-8C)cycloalkyl group include halogen; nitro; cyano; hydroxyimino; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; ha!o(1-10C)alkyl; (CH2)yX¹ R⁹ in which y is 0 or an integer of from 1 to 4, X¹ represents O, S, NR¹⁰, CO, COO,

OCO, CONR11 , NR¹²CO, NRl²COCOO, OCONRI³, R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10, R11 , R12 _an( R13 _each independently represents hydrogen or (1-10C)alkyl, or R⁹ and R^"10» R1 ^ R^² or R^³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl; (1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R^4- (L^a)n-X²-(L^b)_m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or

CH=CH, l_^a and L^D each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1 -dioxotetrahydro-1 ,2- thiazinyl); halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH2)zX³R¹⁵ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH),

COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO2, SO2NH, NHSO2NR17, OCONR ⁹ or

NR¹⁹COO, R ⁵ represents hydrogen, (MOC)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)aIkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R1⁹ each independently represents hydrogen or (1 -10C)alkyl, or R^ 5 and R^ ⁶, 17₍ R18 _or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group. Preferably substituent A in formula II represents SO₂.

Preferably R^a in formula II is methyl, ethyl, propyl, n-butyl, sec-butyl, pentyl, and hexyl with methyl being most preferred.

Preferably R^D in formula II is hydrogen, methyl, ethyl, propyl, n-butyl, sec- butyl, pentyl, and hexyl, with hydrogen being most preferred.

Preferably R³ and R4 in formula II each represent methyl.

Examples of values for R² in formula II are methyl, ethyl, propyl, 2-propyl, butyl, 2-methyl propyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino. Preferably R² is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred. ,

Examples of values for R⁹ in formula II are hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl. R⁹ is preferably (1-4C)alkyl, (2- 4C)alkenyl, (3-6C)cycloalkyl, pyrrolidinyl, morpholino or tetrahydrofuryl.

Examples of values for R15 jn formula II are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO in formula II. z is preferably 0 in formula II. In formula II particular values for the groups (CH2)yX^'' R⁹ and

(CH2)_ZX³R¹⁵ include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl.

In formula II examples of particular values for y are 0 and 1. ln formula II examples of particular values for z are 0, 1 , 2 and 3.

In formula II L^a and l_^D preferably each independently represents CH2-

In formula II X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH, with a bond, O, and CONH being especially preferred.

In formula II preferably the group (CH2)yX¹ R⁹ represents CHO; COCH3,

OCH3; OCH(CH3)2; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl, t- butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.

Preferably the group (CH2)zX³R^ in formula II represents NH2; CH2NH2; (CH2)2NH2! (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2H5)2! CH2OH; CH(OH)CH3; CH(OH)CH2CH2; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; SO2NH2; NHSO2CH3; NHSO2CH(CH3)2; a group of formula (CH2)2NHSO2R¹⁵ in which

R¹⁵ represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3. benzyl, CH2CF3, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2- fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4- methoxyphenyl, 1-(2-dimethylamino)naphthyl or 2-thienyl; CH(OH)CH2NHSO2CH3; (CH2)3NHSO2CH(CH3)2;

COCH2N(OCOC(CH3)2SO2CH3; COCH2NHSO2CH3; (CH2)2NHCOR¹5 in which R¹⁵ represents CH3, CH(CH3)2, CH2CH(CH3)2, phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl, CH=CH, CH=CHCN, OCH3 or O(CH2)3CH3. Examples of particular values for (L^a)_n-X²-(L^b)m in formula II are a bond,

O, NH, S, SO, SO2, CO, CH2, COCH2, COCONH, CH(OH)CH2, CONH, NHCO, NHCONH, CH2O, OCH2, OCH2CONH, CH2NH, NHCH2 and CH2CH2, with a bond, CONH, and CH2O being especially preferred. R1 jn formula II is preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.

Examples of particular values for R14 j_n formula II are phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4- chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3- difluoro-phenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 4-cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2- methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl, 2- prop-2-enylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl)phenyl, 2- trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- bromomethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl, 3- acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl, 2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl, 3-(1- hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 2-(1-hydroxypropyl)phenyl, 4-(1- hydroxypropyl)phenyl, 2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4- trifluoromethoxyphenyl, 2-aminophenyl,4-aminophenyl, 4-N.N- diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3- aminopropyl)phenyl, 4-carboxyphenyl, 4-carbamoylphenyl, 4-N- methylcarbamoylphenyl, 4-N,N-dimethylcarbamoylphenyl, 2- isopropylaminomethylphenyl, 4-t-butoxycarbonylaminomethylphenyl, 4-(2- isopropoxy-carboxamido)ethylphenyl, 4-(2-t-butoxycarboxamido)ethyl-phenyl, 4- isopropylsulfonylaminophenyl, 4-(2-methane-sulfonylamino)ethylphenyl, 4-(2- ethylsulfonylamino)ethyl-phenyl, 4-(3-isopropylsulfonylamino)propylphenyl, 4-(1 - (2-(2-propane)sulfonylamino)propyl)phenyl, 4-(2-propylsulfonyl- amino)ethylphenyl, 4-(2-isopropylsulfonylamino)ethylphenyl, 4-(2- butylsulfonylamino)ethylphenyl, 4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl, 4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl, 4-(2-(2,2,2-trifluoroethyl)- sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonylamino)-ethylphenyl, 4-(2- (2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl, 4-(2-N,N- dimethylaminosulfonylamino)-ethyIphenyl, 4-(2-phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluoro- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(2-trifluoromethyl- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-trifluoro- methylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1 -(5- dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)pheriyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(1 -(2-(2-methoxy- carbonylethanesulfonylamino)ethyl)phenyl, 4-(1-(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl, 4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl, 4- (N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl, 4-(2-(2- thienylcarboxamido)ethyl)phenyl, thien-2-yl, 5-hydroxy-methylthien-2-yl, 5- formylthien-2-yl, thien-3-yl, 5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2- bromothien-3-yl, fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl, 3-bromoisoxazol-5- yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl, 5-methylisoxazol-3-yl, 5- hydroxymethylisoxazol-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 5-(2- hydroxyethyl)isoxazol-3-yl, 5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl, 5-N- methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl, 3- bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl, 4-carboxythiazol-2-yl, imidazol-1 -yl, 2-sulfhydryl- imidazol-1 -yl, [1 ,2,4]triazol-1 -yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-ethyltetrazol- 5-yl, 2-isopropyl-tetrazol-5-yl, 2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl, 5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl, 5- trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl, 6-methylpyridazin-3-yl, 6- methoxypyrazin-3-yl, pyrimidin-5-yl, benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl. Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R1 in formula II are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

Examples of an unsubstituted or substituted (5-8C)cycloalkyl group represented by R1 are unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.

More preferably in formula II, R^ represents 2-naphthyl or a group of formula

in which

In formula II, R^2< represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3-

CONR11 , NR ²CO, NRl²COCOO, OCONR¹³, R⁹ represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R^0> R^ ■ R^² and R^³ each independently represents hydrogen or (1-10C)alkyl, or R⁹ and R¹⁰> R11 > R^² or R¹³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl- dihydrothiazolyl; (1-4C)alkoxycarbonyIdimethyl-dihydrothiazolyI; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group of formula R^"14_(i_a)_n_

X²-(L^b)m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH2CONH or CH=CH, NHCO, L^a and L^b each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or hetero-aromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl); halo(1-

10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH2)_ZX³R ⁵ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,

CONR¹⁷, NR¹⁸CO, NHSO2, NHSO2NR¹⁷, NHCONH, OCONR¹⁹ or

NR¹ COO, R ⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1- 10C)alkyl, (1 -4C)alkoxycarbonyl(1 -4C)alkyl, (1 -4C)alkylsulfonylamino(1 -4C)alkyl, (N-(1 -4C)alkoxycarbonyl)(1 -4C)alkylsulfonylamino(1 -4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R^ each independently represents hydrogen or (1-10C)alkyl, or R^ and R 6, R17_J R18 _or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

In formula II, R²^ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group.

Examples of particular values for R²^ in formula II are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido, cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido, cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino, piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4- yl, pyrimidin-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2- yl, 4,5-dihydro-4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl, benzothien-2-yI, benzothiazol-2-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-difluorophenyl, 4- chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4- cyanophenyl, 2-methylphenyl, 4-methylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2- thiazinyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoro-methylphenyl, 4-(2- cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 3-acetyl- phenyl, 4-acetylphenyl, 4-carboxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl, 4-(1- hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)-phenyl, 4-(3- aminopropyl)phenyl, 4-(2-acetylaminoethyl)-phenyl, 4-t- butoxycarboxylaminoethyl)phenyl, 4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl- aminoethyl)phenyl, 4-(2-ethylsulfonylaminoethyl)phenyl, 4-(2- propylsulfonylaminoethyl)phenyl, 4-(2-butylsulfonyl-aminoethyl)phenyl, 4-(2- isopropylsulfonylaminoethyl)phenyl, 4-(1-hydroxy-2- methanesulfonylaminoethy phenyl, 4-(2- dimethylaminosulfonylaminoethyl)phenyl, 4-(1 -(2-(2- propyl)sulfonylaminopropyl)phenyl, 4-(2-(2,2,2-trifluoro- ethyl)sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonyl-aminoethyl)phenyl, 4-(2- phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(2- trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- trifluoromethylphenyI)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1 -(5- dimethylamino)napthalenesulfonylamino)ethyI)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyI, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4- carbamoylphenyl, 4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl, 4-(2- (2-methylpropaneamido)ethyl)phenyl, 4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido, 2-fluorobenzamido, 3-flurobenzamido, 4- fluorobenzamido, 2,4-difluorobenzamido, 3-chlorobenzamido, 4- chlorobenzamido, 4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3- methylbenzamido, 4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido, 4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido, 3- trifluoromethylbenzamido, 4-trifluoromethylbenzamido, 2-fluoro-4-trifluoromethyl- benzamido, 2-methoxybenzamido, 3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido, 4-phenylphenyl-carboxamido, 4-benzylcarboxamido, 4- phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy, 2-fluoro- benzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl, 4-(1-(2-(2- methoxycarbonylethanesulfonylamino)ethyl)phenyl, 4-(1 -(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonylamino)ethyl)phenyl, 4-(2-phenylacetamido)-ethyl)phenyl, 4-(methanesulfonylaminoethanoyl)phenyl, 4- (N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl, 2- thienylcarboxamido, 2-furylcarboxamido, 3-(5-methyl-isoxazolyl)carboxamido, 5- isoxazolylcarboxamido, 2-benzothienylcarboxamido, 4-(5-methyl-3- phenylisoxazolyl)-carboxamido, 4-pyridylcarboxamido, 2-(5-nitrofuryl)- carboxamido, 2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido, 2- thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino, 2- furylmethylamino, 3-furylmethylamino, 3-acetylureido and 2-(2- thienyl)ethylureido. Examples of particular values for R²1 in formula II are hydrogen and chlorine. R²^ is preferably ortho to R²⁰.

Examples of particular values for Ri in formula II are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methyIphenyl, 4-isopropyI- phenyl, 4-isobutylphenyl, 4-f-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3- fluoro-phenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl, 4-(4- formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, and 4-(2-methoxyphenyl)phenyl.

Section C

A compound of formula III:

formula

wherein

R¹, R², and R³ each independently represent hydrogen, halogen, CF₃, OCF₃, CN, NO₂, NH₂, (1 -6C)alkyl, (1 -6C)alkoxy, -(CH₂)nNHSO₂R⁵, -(CH₂)_nNHC(=O)R⁵, -

SO₂R⁵, -C(=O)R⁶, -CH=CHCO₂R⁷, heterocycle, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen, CF₃, OCF₃, CN, NO₂, NH₂, (1-6C)alkyl, (1-6C)alkoxy, -

(CH₂)nNHSO₂R⁵, -(CH₂)_nNHC(=O)R⁵, -SO₂R⁵, -C(=O)R⁶, -C(=O)NR¹⁰R¹¹, -SO₂NR¹⁰R¹¹, or -CH=CHCO₂R⁷;

R⁴ represents (1-6C)alkyl, (2-6C)alkenyl, or NR⁸R⁹;

R⁵ represents (1-6C)alkyl, CF₃, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen,

CF₃, CN, NO₂, NH₂₎ (1-6C)alkyl, or (1-6C)alkoxy; R⁶ represents (1 -4C)alkyl or phenyl;

R⁷ represents hydrogen or (1-4C)alkyl;

R⁸ and R⁹ each independently represent hydrogen or

(1-4C)alkyl;

R¹⁰ and R¹¹ each independently represent hydrogen or (1-4C)alkyl; and n is O, 1 , 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

One of ordinary skill in the art can prepare compounds of formula III following, for example, Schemes I through V set forth below. More specifically, the compounds of structures (4) and (6) can be prepared following the procedures set forth in Scheme I below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme I

In Scheme I, step A, the cyclopentene of structure (1) is converted to the borane of structure (2) under standard conditions. For example, cyclopentene (1 ) is dissolved in a suitable organic solvent, such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0°C The solution is treated with about 0.5 equivalents of monochloroborane-methyl sulfide. The reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours. The solvent is removed under vacuum under a nitrogen atmosphere to provide borane (2).

In Scheme I, step B, borane (2) is methylated to provide the methylborane of structure (3). For example borane (2) is dissolved in a suitable organic solvent, such as dry hexanes under an atmosphere of nitrogen. The solution is cooled to about 0°C and treated with about 0.3 equivalents of trimethylaluminum in hexanes. The reaction mixture is allowed to warm to room temperature and stirred for about 1.5 hours. A precipitate results and the supernatant is transferred via cannula to a nitrogen flushed separatory funnel containing saturated aqueous ammonium chloride. The organic phase is then transferred via cannula to a flask containing anhydrous sodium sulfate. The organic solution is then transferred via cannula to a dry, nitrogen flushed flask and the solvent is removed under vacuum in the presence of a nitrogen atmosphere to provide the methylated borane (3).

In Scheme I, step C, the methylated borane (3) is hydrolyzed to the trans- cyclopentylamine of structure (4). For example, methylated borane (3) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and cautiously treated in small portions with a slight excess of hydroxylamine-O- sulfonic acid (referred to herein as "HAS") dissolved in tetrahydrofuran. The reaction is exothermic. After addition is complete, the reaction mixture is stirred for about 24 hours and then filtered. The filtrate is concentrated under vacuum and the residue is treated with concentrated HCI:methanol:water:diethyl ether (30:15:20:60, by volume). The mixture is stirred at room temperature for about 30 minutes. The layers are separated, the organic phase is washed with water and the water wash is combined with the aqueous phase. The aqueous phase is cooled to about 0°C, diethyl ether is added and the aqueous is made basic with sodium hydroxide. The organic phase is separated and the aqueous phase is extracted with diethyl ether and ethyl acetate. The organic phase and organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the cyclopentylamine (4).

In Scheme I, step D, the cyclopentene of structure (1) is nitrated under standard conditions to provide the compound of structure (5). For example, see the procedure disclosed by F.G. Bordwell, et al., J. Org. Chem., 1765. In Scheme I, step E, the nitrated compound of structure (5) is reduced under standard conditions to provide the amine of structure (6). For example, compound (5) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon, the solution is placed under hydrogen at about 413.69 kPa (60 psi). After about 8 to 16 hours, the reaction mixture is filtered and the filtrate is concentrated under vacuum to provide the compound (6).

The compound of structure (6) can be prepared by the alternative procedures set forth in Schemes IA and IB below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme IA

In Scheme IA, step A, the cyclopentanone of structure (7) is converted to the corresponding oxime of structure (8) under conditions well known in the art. For example, cyclopentanone (7) is dissolved in a suitable organic solvent, such as ethanol, treated with about 2 equivalents of aqueous sodium hydroxide and about 1.5 equivalents of hydroxylamine hydrochloride. The reaction mixture is stirred for about 8 to 16 hours at room temperature. It is then diluted with water and the precipitated oxime (8) is collected by filtration and dried under vacuum at about 35°C

In Scheme IA, step B, oxime (8) is hydrogenated under standard conditions to provide the amine of structure (6). For example, oxime (8) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable catalyst, such as palladium on carbon, and placed under hydrogen at about 413.69 kPa (60 psi). The hydrogenation is carried out at about 40°C for about 8 to 16 hours. The reaction mixture is then filtered and the filtrate concentrated under vacuum to provide the amine (8). Scheme IB

In Scheme IB, step A, the epoxide (9) is coupled with the Grignard reagent to provide the alcohol (11 ). For example, Grignard (10) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with a catalytic amount of copper iodide. To this solution is slowly added the epoxide (9) dissolved in tetrahydrofuran. The reaction is exothermic. The reaction is stirred until the temperature reaches room temperature and it is quenched with aqueous ammonium chloride. The quenched reaction is extracted with a suitable organic solvent, such as diethyl ether. The organic extracts are combined, washed with aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide alcohol (11 ).

In Scheme IB, step B, alcohol (11) is converted to the compound of structure (12) under standard conditions well known in the art. For example, about one equivalent of triphenylphosphine is dissolved in a suitable organic solvent, such as tetrahydrofuran. The solution is cooled to about 0°C and a solution of about one equivalent of diisopropyl azodicarboxylate in tetrahydrofuran is added dropwise to the solution with stirring. To this reaction mixture is added about one equivalent of phthalimide followed by addition of about one equivalent of alcohol (11) dissolved in tetrahydrofuran maintaining the temperature between about 5°C and 0°C The reaction is then stirred at about 0°C for about 4 hours, warmed to room temperature, and stirred for 4 to 12 hours. The reaction is then quenched with water and extracted with a suitable organic solvent, such as chloroform. The organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (12).

In Scheme IB, step C, compound (12) is converted to compound (6) in an exchange reaction well known in the art. For example, compound (12) is dissolved in a suitable organic solvent, such as toluene, and an excess of anhydrous hydrazine is added dropwise over about 15 minutes with stirring. The reaction mixture is stirred for about one hour at room temperature and then heated at about 90-95°C for about 6 hours. The reaction mixture is then cooled to room temperature, filtered, the precipitate rinsed with toluene, the filtrates combined, concentrated under vacuum to provide compound (6).

Alternatively, compound (12) is dissolved in 2-aminoethanol and heated at about 80-90°C for about 1 to 2 hours. The reaction is then diluted with diethyl ether, washed with dilute sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to provide compound (6). In Scheme IB, step D, compound (11 ) oxidized to the ketone of structure (7) under standard conditions well known in the art. For example, compound (11) is added dropwise to a suspension of an excess of pyridinium chlorochromate in a suitable organic solvent, such as methylene chloride. The reaction is stirred for about 8 to 48 hours at room temperature. It is then diluted with a diethyl ether, filtered through a pad of silica gel and the filtrate concentrated under vacuum to provide crude compound (7). This material can be purified by standard techniques, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.

In Scheme IB, steps E through H, compound (11 ) is converted to the amine (4) using standard techniques and reactions well known in the art. For example, in step E, compound (11) is subjected to Mitsunobu conditions to provide the cis-benzoate derivative. More specifically, compound (11) is dissolved in a suitable organic solvent, such as THF and combined with about 1.05 equivalents of diethyl azodicarboxylate (referred to herein as "DEAD"), about 1.2 equivalents of benzoic acid and about 1.2 equivalents of triphenylphosphine at about 0°C The reaction is stirred for about 2 hours, allowed to warm to room temperature and then concentrated under vacuum. The crude residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-benzoate derivative.

In Scheme IB, step F, the cis-benzoate is hydrolyzed under standard conditions to provide the cis-alcohol. For example, the cis-benzoate is combined with 5% NaOH/methanol and stirred at room temperature for about 3 hours. The reaction mixture is then concentrated under vacuum, the residue dissolved in a suitable organic solvent, such as diethyl ether, which is washed with water. The organic phase is then dried over potassium carbonate, filtered, and concentrated under vacuum. The residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-alcohol. In Scheme IB, step G, the cis-alcohol is converted to the phthalimide derivative in a manner analogous to the procedure described above in Scheme IB, step B.

In Scheme IB, step H, the phthalimide derivative is converted to the trans- amine (4) in a manner analogous to the procedure described above in Scheme IB, step C

Scheme IC

In Scheme IC, the compound (11) is subjected to an enzymatic resolution to provide the unreacted optically active alcohol (11a) and the optically active acetate (11 b). For example, see the procedure described by Seemayer and Schneider, Reel. Trav. Chim. Pays-Bas, 110, 171-174 (1991), "Enzymatic Hydrolysis and Esterification. Routes to Optically Pure Cyclopentanols". More specifically, the alcohol (11) is dissolved in a suitable organic solvent, such as tert-butyl methyl ether and combined with a suitable enzyme, such as Candida antartctica B lipase. With stirring, about 0.5 to about 0.6 equivalents of vinyl acetate is added and the reaction is stirred at room temperature for about 2 to 4 hours. The reaction mixture is then filtered and the filtrated is concentrated under vacuum to provide a mixture of the optically active alcohol (11a) and optically active acetate (11b). These compounds are then readily separated from each other using standard techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.

The compounds of formulas III, Ilia, Ilia', Ilia", and lllb can be prepared following the procedures set forth in Schemes II and IIA below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. Scheme II

Y represents Br or I.

In Scheme II, step A, compound (4) or (6) is sulfonylated with sulfonyl chloride (13) under conditions well known in the art to provide the sulfonamide of formula (Ilia). For example, compound (4) or (6) is dissolved in a suitable organic solvent, such as methylene chloride and cooled to about 0°C under an atmosphere of nitrogen. About 1.1 equivalents of 1 ,8-diazabicyclo[5.4.0]undec-

7-ene (DBU) are added followed by dropwise addition of about 1.1 equivalents of a sulfonyl chloride (13). The reaction mixture is then allowed to warm to room temperature and stirred for about 8 to 24 hours. Additional small amounts of

DBU and sulfonyl chloride (9) may optionally be added in equivalent amounts as necessary in order to drive the reaction to completion. The reaction may be stirred for an additional 8 to 48 hours after additional amounts of DBU and sulfonyl chloride (13) are added. The reaction mixture is then diluted with a suitable organic solvent, such as methylene chloride and washed with 1 N HCI.

The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula III. This crude material can be purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride/ethyl acetate.

In Scheme II, step B, the compound of formula III wherein R¹, R² and R³ represent hydrogen, can be converted to the compound of formula Ilia wherein Y represents iodine. For example, compound of formula III is dissolved in a suitable solvent, such as glacial acetic acid. To this solution is added concentrated sulfuric acid followed by about 0.5 equivalents of iodine and about 0.4 equivalents of diiodine pentoxide. The reaction mixture is protected from light and heated at about 90°C for about 22 hours. The reaction mixture is then treated slowly with 10% aqueous sodium bisulfite, cooled to 0°C for about one hour and the precipitate collected by filtration. The precipitate is dissolved in a suitable organic solvent, such as warm diethyl ether and then washed with water, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the iodo compound of formula Ilia. Alternatively, one of R¹, R² or R³ may represent Br in Scheme II, step A.

In Scheme II, step C, the compounds of formula Ilia, wherein Y represents Br or I, may be converted into compounds of formula 1Mb under conditions well known in the art, such as by reaction with an appropriate boronic acid (14) or boronic ester (14a) wherein R¹⁰, R¹¹ and R¹² each individually represent hydrogen, halogen, CF₃, CN, NO₂, NH₂, (1-6C)alkyl, (1-6C)alkoxy, - (CH₂)_nNHSO₂R⁵, -(CH₂)_nNHC(=O)R⁵, or -SO₂R⁵. See for example, International Publication Number WO 98/33496, published August 6, 1998, the disclosure of which is hereby incorporated by reference. In addition, see Suzuki, A., Journal of Organometallic Chemistry, 576, 147-168 (1999), and Miyaura and Suzuki,

Chemical Reviews, 95, 2457-2483 (1995) for examples of Suzuki-type coupling reactions and conditions. More specifically, the reaction is conveniently performed in the presence of a tetrakis (triarylphosphine)palladium(O) catalyst, such as tetrakis (triphenylphosphine)palladium(O) and a base such as potassium carbonate. Suitable solvents for the reaction include aromatic hydrocarbons, such as toluene. The temperature at which the reaction is conducted is conveniently in the range of from 0 to 150°C, preferably 75 to 120°C. Alternatively, the coupling reaction may be carried out using palladium diacetate with a suitable organic solvent, such as n-propanol or acetone. See for example, Organic Synthesis 1998. 75, 61 ; Goodson, F. E.; Wallow, T. I.; Novak, B. M. and Organic Synthesis 1998. 75, 53; Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. wherein analogous coupling conditions are employed. More specifically, for example, a compound of formula Ilia and about 1.2 equivalents of boronic acid (14) or boronic ester (14a) are dissolved in a suitable organic solvent, such as n-propanol. About 1.2 equivalents of potassium carbonate in water is added, followed by a catalytic amount of palladium acetate. The reaction mixture is heated at reflux for about 4 hours, filtered and the solid rinsed with ethyl acetate. The filtrates are combined, diluted with additional ethyl acetate, and washed with saturated sodium bicarbonate and brine. The organic phase is then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula 1Mb. This crude material can then be purified by techniques well known in the art, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride/ethyl acetate or reverse phase chromatography on a C18 column with a suitable eluent, such as aqueous acetonitrile. Alternatively, compounds of formula Ilia'

formula Ilia' wherein Q represents a bromo or triflate group may be coupled to boronic acid (14) in a manner analogous to the procedures set forth above in Scheme II, step C

The boronic acid (14) used as a starting material may be prepared by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature. For example, 2-fluoro- benzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about -78°C to afford 2-fluorophenyl lithium, and then reacting this organolithium compound with triisopropyl borate. This is followed by hydrolysis with aqueous HCI.

Scheme IIA

formula Ilia"

(14b)

Alternatively, compounds of formula 1Mb can be prepared under Suzuki-type reaction conditions as appreciated by one of ordinary skill in the art, from a compound of formula Ilia" and a compound of structure (14b). For example, the compound of formula Ilia" is dissolved in a suitable organic solvent, such as DMSO and treated with about 3 equivalents of potassium acetate. The reaction mixture is degassed and treated with about 1.1 equivalents of bis(pinacolato)diboron followed by addition of a catalytic amount of a suitable palladium catalyst, such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1. The reaction mixture is then heated at about 80°C under nitrogen with stirring for about 1 to about 4 hours. The reaction mixture is then cooled to room temperature and about one equivalent of the compound (14b) is added followed by addition of about 3 equivalents of sodium carbonate, water, and a catalytic amount of a suitable palladium catalyst, such as [1 ,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1 :1. The reaction mixture is then heat at about 105°C for about 10 to about 20 hours. It is then allowed to cool and is diluted with a suitable organic solvent, such as methylene chloride. The mixture is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude compound formula lllb. This crude material can then be purified by techniques well known in the art, such as chromatography on silica gel with a suitable eluent, such as 1% methanol/methylene chloride to provide the purified compound of formula lllb. The compounds of formulas lllc and Hid can be prepared following the procedures set forth in Scheme III below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme

In Scheme III, step A compound of formula 1Mb' wherein R¹⁰ and R¹² each independently represent hydrogen, halogen, CF₃, (1-6C)alkyl, or (1-6C)alkoxy and m is 0, 1 , 2, or 3, is reduced under conditions well known in the art to provide the amine of formula lllc. For example, compound of formula lb' is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and treated with a suitable reducing agent, such as borane dimethyl sulfide. The reaction is heated at reflux for about 4 hours and then concentrated under vacuum. The residue is treated with diethyl ether:concentrated HCI:water:methanol (6:3:2:1 )and stirred for about 30 minutes. The aqueous layer is then separated and the organic layer washed with water. The aqueous phases are combined, cooled to about 0°C, made basic with a suitable base, such as sodium hydroxide, and extracted with a suitable organic solvent, such as diethyl ether or ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula lllc.

In Scheme III, step B, the amine of formula lllc is converted to the amide of formula Hid under standard coupling conditions as is well known in the art of peptide chemistry. For example, the amine of formula lllc is dissolved in a suitable organic solvent, such as dry methylene chloride. A slight excess of a suitable organic base, such as triethylamine is added followed by addition of about one equivalent of acetyl chloride. The reaction is stirred at room temperature for about 8 to 72 hours and then concentrated under vacuum to provide the crude amide of formula Hid. This crude material is then purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride:methanol.

In Scheme III, step C, the amine of formula lllc is readily converted to the sulfonamide of formula Hie under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A. The compounds of formulas lllg, lllh, lllj and lllk can be prepared following the procedures set forth in Scheme IV below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme IV

In Scheme IV, step A, the compound of formula lllf, wherein R¹ and R³ each independently represent hydrogen, halogen, CF₃, (1-6C)alkyl, or (1- 6C)alkoxy, is nitrated under standard conditions to provide the nitro compound of formula lllg. For example, compound of formula lllf is dissolved in a suitable acid, such as trifluoroacetic acid and an excess of sodium nitrate is added. The reaction mixture is stirred for about 5 hours at room temperature. It is then diluted with a suitable organic solvent, such as methylene chloride, washed with water, dilute sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude nitro compound of formula lllg. The crude material can then be purified using standard techniques such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride:ethyl acetate. ln Scheme IV, step B, the compound of formula lllg is reduced to the amine of formula lllh under conditions well known in the art. For example, the compound of formula lllg is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon and placed under hydrogen at about 413.69 kPa (60 psi). The reaction mixture is hydrogenated at room temperature for about 4 to 12 hours, filtered, and concentrated under vacuum to provide the amine of formula lllh.

In Scheme IV, step C the amine of formula lllh is converted to the amide of formula lllj under standard coupling conditions as is well known in the art of peptide chemistry in a manner analogous to the procedure previously described in Scheme III, step B.

In Scheme IV, step D the amine of formula lllh is converted to the sulfonamide of formula lllk under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A.

The compounds of formulas lllm, llln, lllp and lllq can be prepared following the procedures set forth in Scheme V below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme V

In Scheme V, step A, the compound of formula Ilia' is converted to the compound of formula lllm under standard conditions. For example, compound of formula Ilia' is dissolved in a suitable organic solvent, such as DMF. It is then treated with an excess of ethyl acrylate and an excess of a suitable organic base, such as triethylamine followed by a catalytic amount of palladium acetate and triphenylphosphine. The reaction is then heated at about 80°C under nitrogen for about 8 to 16 hours. The reaction is then allowed to cool and diluted with 75 mL of 10% aqueous sodium bisulfate. The quenched reaction mixture is then extracted with a suitable organic solvent, such as methylene chloride, the organic extracts dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the compound of formula lllm. The crude product can be purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.

In Scheme V, step B, the compound of formula lllm is reduced under conditions well known in the art to provide the compound of formula llln. For example, the compound of formula lllm is placed in a Parr bottle and dissolved in a suitable organic solvent, such as ethyl acetate. It is treated with a catalytic amount of 10% palladium on carbon and the mixture is placed under hydrogen at about 275.80 kPa (40 psi) to about 413.69 kPa (60 psi) for about 4 to 16 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum to provide the compound of formula llln. This material can be further purified, if necessary, for example by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.

In Scheme V, step C, the compound of formula llln is hydrolyzed to the acid of formula lllp under standard conditions. For example, the compound of formula llln is dissolved in a suitable organic solvent, such as methanol with water added. The solution is treated with a suitable base, such as sodium hydroxide and the reaction is allowed to stir for about one to two days. The reaction mixture is then washed with a suitable organic solvent, such as ethyl acetate. The aqueous is cooled with an ice-water bath and made acidic with concentrated HCI. The acidified aqueous is then extracted with ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the acid of formula lllp. In Scheme V, step D, the acid of formula lllp is converted to the carbamate of formula II Iq under standard conditions. For example, the acid of formula lllp is dissolved in a suitable organic solvent, such as benzene and is treated with one equivalent of diphenylphosphoryl azide and one equivalent of triethylamine under nitrogen. The reaction is heated at reflux for about 4 hours, cooled to room temperature and stirred for about 8 to 16 hours. An equivalent of a suitable alcohol, such as methanol or benzyl alcohol is then added to the reaction, and the reaction is heated at reflux for about 8 hours. The reaction is then cooled to room temperature and stirred for about 8 to 16 hours. The reaction is then concentrated under vacuum and the residue purified by flash or radial chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.

In Scheme V, step E, the carbamate of formula lllq is deprotected under conditions well known in the art such as those conditions described by T.W. Green "Protective Groups in Organic Synthesis," John Wiley & Sons, 1981 , pages 239-241 , to provide the amine of formula lllr. For example, the carbamate of formula lllq is dissolved in a suitable organic solvent, such as methylene chloride and treated with trifluoroacetic acid. The reaction mixture is allowed to stir at room temperature for about 4 to 16 hours and then the solution is made basic with 2N sodium hydroxide. The reaction mixture is then extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula Ir. This material may be further purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride. Alternatively, the carbamate of formula lllq may be deprotected using hydrogenation conditions well known in the art to provide the amine of formula lllr.

In Scheme V, step F, the amine of formula lllr is converted to the sulfonamide of formula lilt under standard conditions well known in the art, for example, in a manner analogous to the procedure described in Scheme II, step A above. With respect to substituent R⁴ in formula III compounds wherein R⁴ is methyl, ethyl, n-propyl and isopropyl are preferred, with 2-propyl being especially preferred.

With respect to substituent R¹ in formula III, compounds wherein R¹ is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, -NHSO₂CH₃, and (1-6C)alkyl are preferred.

With respect to substituent R² in formula III, compounds wherein R² is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, -NHSO₂CH₃, and (1-6C)alkyl are preferred. With respect to substituent R³ in formula III, compounds wherein R³ is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, -NHSO₂CH₃, and (1-6C)alkyl are preferred.

More specifically, with respect to R¹, R², and R³ in forumla III, compounds wherein R¹ is hydrogen and R² and R³ are fluoro are preferred, and compounds wherein R¹ and R² are hydrogen and R³ is (1-6C)alkyl, amino, nitro, -NHSO₂CH₃, fluoro, chloro, bromo and iodo are especially preferred.

With respect to substituents R¹, R^1', R², R³, and R^3' in formula III, compounds wherein R¹, R¹ , R³, and R³ are hydrogen, and R² is in the para- position and is as listed in table 1 , are preferred:

Table 1

With respect to substituents R¹⁰, R^10', R¹¹, R^11>, R¹², and R^12' in formula II compounds wherein R¹⁰, R¹⁰ , R¹², and R¹² are hydrogen and R¹¹ are - NHC(=O)R⁵, -NHSO₂R⁵, -CH₂NHSO₂R⁵, -CH₂CH₂NHSO₂R⁵ are preferred.

With respect to substituent R⁵ in formula III, compounds wherein R⁵ are methyl, ethyl, n-propyl, isopropyl, phenyl are preferred, with methyl being most preferred.

With respect to substituent R⁶ in formula III, compounds wherein R⁶ are methyl, ethyl, propyl, isopropyl, tert-butyl or phenyl are preferred.

With respect to substituent R⁷ in formula III, compounds wherein R⁷ are hydrogen, methyl, ethyl or propyl are preferred.

With respect to substituent R⁸ in formula III, compounds wherein R⁸ are hydrogen, methyl, ethyl or propyl are preferred.

With respect to substituent R⁹ in formula III, compounds wherein R⁹ are hydrogen, methyl, ethyl or propyl are preferred.

With respect to n in formula III, compounds wherein n is 0, 1 , or 2 are preferred. Section D

A compound of formula IV:

formula IV

wherein

R¹ represents an unsubstituted or substituted aromatic group, or an unsubstituted or substituted heteroaromatic group;

R² represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl,

(2-6C)alkenyl, phenyl which is unsubstituted or substituted by halogen, (1- 4C)alkyl or (1 -4C)alkoxy, or a group of formula R³R⁴N in which R³ and R⁴ each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group;

R⁵ represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl; and R⁶ represents hydrogen, (1-6C)alkyl; (2-6C)alkenyl; or aryl; or a pharmaceutically acceptable salt thereof but excluding the compound

[(methylethyl)sulfonyl]{2-[4-(3-(2-thienyl)phenyl)phenoxy]propyl}amine.

The compounds of formula IV can be prepared as set forth in the following Schemes VI through VIII . The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme VI

Step B

(19) (18)

Step D

formula IV In Scheme VI, step A the compound of structure (15) is O-alkylated with the compound of structure (16). For example, at room temperature, compound (15) is dissolved in a suitable organic solvent, such as N,N-dimethylformamide and added to about 1.0 to about 1.1 equivalents of a suitable base, such as sodium hydride in N,N-dimethylformamide. The reaction mixture is stirred for about 30 minutes to about 2 hours and about one equivalent of compound (16), wherein Hal represents Br or CI and R represents H or (1-10C)alkyl, dissolved in N,N-dimethylformamide is added dropwise to the reaction mixture. This is followed by addition of about 1.2 equivalents of sodium iodide. The reaction mixture is then heated at reflux for about 2 to 6 hours and then allowed to cool to room temperature. The ether (17) is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography. For example, the cooled reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate. The organic extracts are combined, washed with water, dried over potassium carbonate, filtered, and concentrated under vacuum to provide the crude ether (17). This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified ether (17). In Scheme VI, step B, ether (17) is converted to the amide of structure

(18) under standard conditions. For example, ether (17) is combined with an excess of ammonia (2M solution of ammonia in methanol for example) in a suitable organic solvent, such as tetrahydrofuran and the reaction mixture is stirred for about 24 to about 48 hours at room temperature. The reaction mixture is then concentrated under vacuum to provide the amide (18).

In Scheme VI, step C, the amide (18) is reduced under conditions well known in the art to provide the amine of structure (19). For example, see Jerry March, "Advanced Organic Chemistry," second edition, McGraw-Hill Book Company, 1977, page 1122. More specifically, for example, amide (18) is dissolved in a suitable organic solvent, such as tetrahyrofuran and treated with about 1 equivalent of a suitable reducing agent, such as borane-methyl sulfide complex. The reaction mixture is then heated at reflux for about 8 to 16 hours under a nitrogen atmosphere and then cooled to room temperature. The reaction is then quenched by addition of a tetrahydrofuran/methanol (1 :1) mixture until foaming ceases. Then 5N aqueous sodium hydroxide is added and the reaction is heated at reflux for about 5 hours. The reaction is then allowed to cool and is extracted with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude amine (19). This material can be converted to its corresponding HCI salt by dissolving the amine (19) in a suitable organic solvent, such as diethyl ether and treating with excess anhydrous HCI gas. The mixture is allowed to stir for about 1 to 6 hours and the resulting precipitate is collected by filtration to provide the amine (19) hydrochloride salt. Alternatively, the mixture can be concentrated under vacuum to provide amine (19) hydrochloride salt.

In Scheme VI, step D the amine (19) is sulfonylated under conditions well known in the art with a sulfonyl chloride of formula CISO₂R² to provide the compound of formula IV. For example, the amine (19) is dissolved in a suitable organic solvent, such as methylene chloride and treated with an excess of a suitable organic base, such as triethylamine under an atmosphere of nitrogen. The solution is cooled to about 0°C and treated slowly with about 1.0 to 1.2 equivalents of a sulfonyl chloride of formula CISO2R², and the reaction mixture is then allowed to warm to room temperature and stirred for about 8 to 16 hours. The compound of formula IV is then isolated and purified by techniques well known in the art. For example, the reaction mixture is quenched with water and the organic phase is separated from the aqueous layer. The organic phase is then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula IV. This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified compound of formula IV.

The compounds of formula IV in which R¹ represents a 4-bromophenyl group may be converted into other compounds of formula I in which R¹ represents a 4-substituted alkyl- or cycloalkylphenyl group, such as 4- cyclopentylphenyl by treatment of the corresponding bromide with an appropriate alkyl- or cycloalkyl Grignard reagent, such as cyclopentyl-magnesium bromide, in the presence of a palladium(ll) catalyst, such as [1 ,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(ll)(PdCl2(dppf)), in an aprotic solvent, such as diethyl ether at temperatures ranging from -78 °C to 25 °C

Alternatively, the compounds of formula IV in which R¹ represents a 4- bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or 4-(tri-n- butylstannyl)phenyl group by treatment of the corresponding bromide with a palladium(O) catalyst, such as tetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, where the alkyl group is methyl or n-butyl, in an aprotic solvent such as toluene in the presence of a tertiary amine base such as triethylamine, at temperatures ranging from 80 to 140°C, preferably from 90 to 110°C. The compounds of formula IV in which R¹ represents a 4-(tri-π- butylstannyl)phenyl group may then be reacted with an aryl- or heteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, or an aryl- or heteroaryliodide, or an aryl- or heteroaryltriflate, in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0), or a palladium(ll) catalyst, such as bis(triphenylphosphine)-palladium(ll) dichloride, in an aprotic solvent, such as dioxane, at temperatures ranging from 80 to 140°C, preferably from 90 to 110°C, to afford the corresponding 4-(aryl)phenyl or 4- (heteroaryl)phenyl substituted compound.

The compounds of formula IV in which R¹ represents a 4-bromophenyl group may be converted into a 4-substituted carboxyaldehydephenyl(formylphenyl) group by reaction of the corresponding bromide with the carbon monoxide gas which is bubbled into the reaction under atmospheric pressure in the presence of a palladium(ll) catalyst, such as bis(triphenyl-phosphine)palladium(ll) dichloride and sodium formate in an aprotic solvent, such as dimethylformamide at temperatures ranging from 70 to 110°C, preferably at 90 °C

The compounds of formula IV in which R¹ represents a 4-hydroxyphenyl group may be converted into other compounds of formula I in which R¹ represents an alkoxy group by treatment of the corresponding hydroxyphenyl group with an appropriate alkyl halide such as benzyl bromide in the presence of sodium hydride in an aprotic solvent such as dimethylformamide at temperatures ranging from 25 to 100°C, preferably from 50 to 90°C More specifically, the compounds of formulas IVa and IVb can be prepared as set forth in Scheme VII. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme VII

Step B

Step D

In Scheme VII, step A the compound of structure (15a) is O-alkylated with the compound of structure (16) to provide the ether of structure (17a) in a manner analogous to the procedure set forth above in Scheme VI, step A.

In Scheme VII, step B, ether (17a) is converted to the amide of structure (18a) in a manner analogous to the procedure set forth above in Scheme VI, step B. In Scheme VII, step C, the amide (18a) is reduced in a manner analogous to the procedure described in Scheme VI, step C above, to provide the amine of structure (19a).

In Scheme VII, step D the amine (19a) is sulfonylated with a sulfonyl chloride of formula CISO₂R² to provide the compound of formula IVa in a manner analogous to the procedure set forth in Scheme VI, step D above.

In Scheme VII, step E, the compound of formula IVa is coupled with the boronic acid of structure (20), wherein R^1a and R^1b each independently represent hydrogen, halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3- 8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl); halo(1-10C)alkyl; cyano(2-

10C)alkenyl; phenyl; thienyl; (CH2)z ³R^⁵ in which z is 0 or an integer of from 1 to 4, χ3 represents O, S, NR¹^, CO, CH(OH), COO, OCO, CONR17 NRI ^CO, NHSO2, NHSO2NR¹⁷, NHCONH, OCONR¹⁹ or NRl⁹COO, R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1- 4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyI, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R¹6, R1 ?, R18 and R¹⁹ each independently represents hydrogen or (1 -10C)alkyl, or R1⁵ and R1⁶, R17_J R18 _or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; under conditions well known in the art to provide the biphenyl compound of formula IVb. For example, see International Patent Application Publication: WO 98/33496 published August 6, 1998. More specifically, for example, the compound of formula IVa is combined with about 1.0 to about 1.2 equivalents of a boronic acid (20), a catalytic amount of tetrakis(triphenylphosphine)palladium(0), and an excess of a suitable base, such as aqueous sodium carbonate, in a suitable organic solvent, such as 1 ,4-dioxane under an atmosphere of nitrogen. The reaction mixture is heated at reflux for about 8 to about 16 hours. After cooling, the reaction is then quenched with water and the compound of formula IVb is isolated and purified by techniques well known in the art, such as extraction techniques and silica gel chromatography respectively. For example, the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb. This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1) to provide the purified compound of formula IVb. Alternatively, in Scheme VII, step E, the compound of formula IVa is combined with about 1.1 to about 1.2 equivalents of a boronic acid (20), a catalytic amount of dichlorobis(triphenylphosphine)palladium (II), and an excess of a suitable base, such as aqueous sodium carbonate, in a suitable organic solvent, such as 1 ,2-dimethoxyethane under an atmosphere of nitrogen. The reaction mixture is heated at reflux for about 8 to about 16 hours. After cooling, the reaction is then quenched with water and the compound of formula IVb is isolated and purified by techniques well known in the art, such as extraction techniques and silica gel chromatography respectively. For example, the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula IVb. This crude material is then purified by silica gel chromatography with a suitable eluent, such as hexane/ethyl acetate (1 :1 ) to provide the purified compound of formula IVb.

Alternatively, the coupling reaction may be carried out using palladium diacetate with a suitable organic solvent, such as n-propanol or acetone. See for example, Organic Synthesis 1998, 75, 61 ; Goodson, F. E.; Wallow, T. I.; Novak, B. M. and Organic Synthesis 1998, 75, 53; Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. wherein analogous coupling conditions are employed.

The boronic acid (20) may be prepared, for example, by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature. For example, 2-fluorobenzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about -

78°C to afford 2-fluorophenyl lithium, and then reacting this organolithium compound with triisopropyl borate. This is followed by hydrolysis with aqueous HCI. The compounds of formulas IVc, IVd, and IVe can be prepared as set forth in Scheme VIII. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme VIII

Step C Step B

In Scheme VIII, step A, the compound of formula IVb' wherein z is 0 or an integer 1 , 2, 3 or 4, is reduced to the amine of formula IVc under conditions well known in the art. For example, see Jerry March, "Advanced Organic Chemistry," second edition, McGraw-Hill Book Company, 1977, page 835. More specifically, for example, compounds of formula IVb' are dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with an excess of a suitable reducing agent, such as borane-methyl sulfide complex. The reaction mixture is then heated at reflux for about 8 to 16 hours, and then allowed to cool to room temperature. The reaction is treated with a mixture of tetrahydrofuran/methanol (1 :1 ) until foaming ceases. The reaction is then treated with 5N aqueous sodium hydroxide and heated at reflux for about 3 to 6 hours. The reaction is then cooled to room temperature and extracted with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, dried over potassium carbonate, filtered, and concentrated under vacuum to provide the crude amine of formula IVc. The crude material is then purified by techniques well known in the art, such as silica gel chromatography or formation of the corresponding HCI salt and subsequent crystallization. For example, the crude amine of formula lc is dissolved in a suitable organic solvent, sucha s diethyl ether and treated with excess anhydrous HCI gas. The mixture is allowed to stir for about 1 to 3 hours and the resulting precipitate is collected by filtration. The precipitate is washed with cold diethyl ether and dried under vacuum to provide the purified amine HCI salt of formula IVc.

In Scheme VIII, step B the amine of formula IVc is sulfonylated under standared conditions with a sulfonyl chloride of formula CISO₂R¹⁵, wherein R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1- 4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, to provide the compound of formula IVd. For example, the amine of formula IVc is dissolved in a suitable organic solvent, such as methylene chloride under an atmosphere of nitrogen, and treated with an excess of a suitable organic base, such as triethylamine. The solution is cooled to about 0°C and treated with about 1.1 to about 1.5 equivalents of a sulfonyl chloride of formula CISO₂R¹⁵. After addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours. The reaction is then quenched with water, the organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula Id. This crude material is purified by silica gel chromatography with a suitable eluent, such as ethyl acetate/hexane (1 :1 ) to provide the purified compound of formula IVd.

In Scheme VIII, step C the amine of formula IVc is converted to the amide of formula IVe under conditions well known in the art. For example, amide formation can be carried out using standard peptide coupling procedures well known in the art, such as the azide method, the mixed carbonic acid anhydride (isobutyl chloroformate) method, or the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method. Some of these methods, such as the carbodiimide method, can be enhanced by adding 1- hydroxybenzotriazole. More specifically, for example, the amine of formula lc is dissolved in a suitable organic solvent, such as methylene chloride under an atmosphere of nitrogen, and treated with an excess of a suitable organic base, 5 such as triethylamine. The solution is cooled to about 0°C and treated with about 1.1 to about 1.5 equivalents of an acid chloride of formula CICOR¹⁵. After addition, the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours. The reaction is then quenched with water and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide 0 the crude amide of formula IVe. This crude material is purified by silica gel chromatography with a suitable eluent, such as ethyl acetate/hexane (1:1) to provide the purified compound of formula IVe.

Examples of values for R2 in formula IV are methyl, ethyl, propyl, 2-propyl, 5 butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino. Preferably R2 is ethyl, 2-propyl or dimethylamino with 2-propyl being most preferred.

Examples of values for R⁹ in formula IV are hydrogen, methyl, ethyl, 0 propyl, isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Examples of values for R15 j_n formula IV are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl, 2- 5 methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 3- fluorophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO in formula IV. z is preferably 0 in formula IV. o Particular values for the groups (CH2)yX¹ R⁹ and (CH2)zX³R¹⁵ in formula

IV include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy, including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy, including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl, such as formyl and ethanoyl. Examples of particular values in formula IV for y are 0 and 1.

Examples of particular values in formula IV for z are 0, 1 , 2 and 3.

In formula IV, L^a and lβ preferably each independently represents CH2-

In formula IV, X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH or OCH2CONH, with a bond, O, and CONH being especially preferred. In formula IV, preferably the group (CH2)yX¹ R⁹ represents CHO; COCH3,

OCH3; OCH(CH3)2; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl, t- butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropyl or cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy. In formula IV, preferably the group (CH2)zX³R^ ⁵ represents NH2;

CH2NH2; (CH2)2NH2; (CH2)3NH2; CONH2; CONHCH3; CON(CH3)2; N(C2H5)2; CH2OH; CH(OH)CH3; CH(OH)CH2CH2; CHO; COCH3; COOH; COOCH3; CH2NHCOOC(CH3)3; (CH2)2NHCOOC(CH3)3; SO2NH2; NHSO2CH3; NHSO2CH(CH3)2. OCH(CH₃)CH₂NHSO2CH(CH3)2, N(COCH₃)₂; a group of formula (CH2)2NHSO2R¹⁵ in which R¹⁵ represents CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH3)3CH3, benzyl, CH2CF3, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl, 2-fluorophenyl, 4-fluorophenyl, 2- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 1-(2- dimethylamino)naphthyl or 2-thienyl; CH(OH)CH2NHSO2CH3; (CH2)3NHSθ2CH(CH3)2; COCH2N(OCOC(CH3)2Sθ2CH3;

COCH2NHSO2CH3; (CH2)2NHCOR¹⁵ in^' which R¹⁵ represents CH3, CH(CH3)2, CH2CH(CH3)2, phenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 2- methoxyphenyl, 4-methoxyphenyl, 2-thienyl, CH=CH, CH=CHCN, OCH3 or 0(CH2)3CH₃. Examples of particular values in formula IV for (L^a)_n-X²-( b)_m are a bond, O, NH, S, SO, SO2, CO, CH2, COCH2, COCONH, CH(OH)CH2, CONH, NHCO, NHCONH, CH2O, OCH2, OCH2CONH, CH2NH, NHCH2 and CH2CH2, with a bond, CONH, and CH2O being especially preferred. In formula IV, R^4 js preferably an unsubstituted or substituted phenyl, naphthyl, furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidyl benzothienyl or benzothiazolyl group.

Examples of particular values for R14 are phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl, 4-chlorophenyl, 2- bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4- cyanophenyl, 3-nitrophenyl, 4-hydroxyiminophenyl, 2-methylphenyl, 4- methylphenyl, 4-ethylphenyl, 3-propylphenyl, 4-t-butylphenyl, 2-prop-2- enylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl)phenyl, 2- trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- bromomethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetyl phenyl, 3- acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl, 2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl, 3-(1- hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 2-(1-hydroxypropyl)phenyl, 4-(1- hydroxypropyl)phenyl, 2-(1 -hydroxy-2,2-dimethyl-propyl)phenyl, 4- trifluoromethoxyphenyl, 2-aminophenyI,4-aminophenyl, 4-N.N- diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3- aminopropyl)phenyl, 4-carboxyphenyl, 4-carbamoylphenyl, 4-N- methylcarbamoylphenyl, 4-N,N-dimethylcarbamoylphenyl, 2- isopropylaminomethylphenyl, 4-t-butoxycarbonylaminomethylphenyl, 4-(2- isopropoxy-carboxamido)ethylphenyl, 4-(2-t-butoxycarboxamido)ethyl-phenyl, 4- isopropylsulfonylaminophenyl, 4-(2-methane-sulfonylamino)ethylphenyl, 4-(2- ethylsulfonylamino)ethyl-phenyl, 4-(3-isopropylsulfonyIamino)propylphenyl, 4-(1- (2-(2-propane)sulfonylamino)propyI)phenyl, 4-(2-propylsulfonyl- amino)ethylphenyl, 4-(2-isopropylsulfonylamino)ethylphenyl, 4-(2- butylsulfonylamino)ethylphenyl, 4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl, 4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl, 4-(2-(2,2,2-trifluoroethyl)- sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonylamino)-ethylphenyl, 4-(2- (2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl, 4-(2-N,N- dimethylaminosulfonylamino)-ethylphenyl, 4-(2-phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluoro- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(2-trifluoromethyl- phenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-trifluoro- methylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1-(5- dimethylamino)napthalenesulfonylamino)ethyl)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(1-(2-(2-methoxy- carbonylethanesulfonylamino)ethyl)phenyl, 4-(1 -(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl, 4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl, 4- (N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl, 4-(2-(2- thienylcarboxamido)ethyl)phenyl, thien-2-yl, 5-hydroxy-methylthien-2-yl, 5- formylthien-2-yl, thien-3-yl, 5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2- bromothien-3-yl, fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl, 3-bromoisoxazol-5- yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl, 5-methylisoxazol-3-yl, 5- hydroxymethylisoxazol-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 5-(2- hydroxyethyl)isoxazol-3-yl, 5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl, 5-N- methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl, 3- bromo[1 ,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl, 4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl, 4-carboxythiazol-2-yl, imidazol-1 -yl, 2-sulfhydryl- imidazol-1-yl, [1 ,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 2-ethyltetrazol- 5-yl, 2-isopropyl-tetrazol-5-yl, 2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl, 5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl, 5- trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl, 6-methylpyridazin-3-yl, 6- methoxypyrazin-3-yl, pyrimidin-5-yl, benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromatic group represented by R^ in formula IV are unsubstituted or substituted phenyl, furyl, thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

Examples of an unsubstituted or substituted (5-8C)cycloalkyl group represented by R^ in formula IV are unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclohexyl being preferred.

More preferably in formula IV, R^ represents 2-naphthyl or a group of formula

in which in formula IV, R²⁰ represents halogen; nitro; cyano; hydroxyimino; (1- 10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl; hydroxy(3-

8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH2)yX¹ R⁹ in which y is 0 or an integer of from 1 to 4, X¹ represents O, S, NR¹⁰, CO, COO, OCO,

CONR11 , NR ²CO, NRl²COCOO, OCONR13, R9 represents hydrogen, (1- 10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R10> R^ > R^"^² and R13 each independently represents hydrogen or (1 -10C)alkyl, or R⁹ and R¹ °> R^{1 1}. R¹² or R¹³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1- 4C)alkyIpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl- dihydrothiazolyl; (1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group of formula Rl4-(i_a)_n- X²-(L^b)_m in which X² represents a bond, O, NH, S, SO, SO2, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH2CONH or CH=CH, NHCO, L^a and Lb each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or hetero-aromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1 ,1-dioxotetrahydro-1 ,2-thiazinyl); halo(1- 10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH2)zX³R¹⁵ in which z is 0 or an integer of from 1 to 4, X³ represents O, S, NR16, CO, CH(OH), COO, OCO,

CONR¹⁷, NR ⁸CO, NHSO2_. NHSO2NR¹⁷, NHCONH, OCONRI⁹, N(CO(1-

4C)alkyl)CO, or NR¹⁹COO, R15 represents hydrogen, (1-10C)alkyl, phenyl(1- 4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1- 4C)alkylsulfonylamino(1-4C)alkyl, (1-4C)alkylaminosulfonyl(1-4C)alkyl, (N-(1- 4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3- 10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R ⁷, R ⁸ and R1⁹ each independently represents hydrogen or (1 -10C)alkyl, or R^ 5 and R16, R17_] R18 _or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

In formula IV, R ^ represents a hydrogen atom, a halogen atom, a (1- 4C)alkyl group or a (1-4C)alkoxy group. Examples of particular values for R²^ in formula IV are fluorine, chlorine, bromine, cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl, 2- methylpropyl, 1 ,1-dimethylethyl, cyclopentyl, cyclohexyl, 3-hydroxycyclopentyl, 3- oxocyclopentyl, methoxy, ethoxy, propoxy, 2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido, 1 -butanoylamido, t-butylcarboxamido, acryloylamido, 2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy, morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido, cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido, cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino, piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4- yl, pyrimidin-5-yl, 4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2- yl , 4 ,5-d ihyd ro-4-methoxy-carbonyl-5 , 5-d imethylth iazol-2-yl , benzoth ien-2-yl , benzothiazol-2-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2,3-difluorophenyl, 4- chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-nitrophenyl, 4- cyanophenyl, 2-methylphenyl, 4-methylphenyl, 4-(4-(1 ,1-dioxotetrahydro-1 ,2- thiazinyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoro-methylphenyl, 4-(2- cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 3-acetyl- phenyl, 4-acetylphenyl, 4-carboxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2- hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl, 4-(1- hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl, 4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl, 4-(2-aminoethyl)-phenyl, 4-(3- aminopropyl)phenyl, 4-(2-acetylaminoethyl)-phenyl, 4-t- butoxycarboxylaminoethyl)phenyl, 4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino, 4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonyl- aminoethyl)phenyl, 4-(2-ethylsulfonylaminoethyl)phenyl, 4-(2- propylsulfonylaminoethyl)phenyl, 4-(2-butylsulfonyl-aminoethyl)phenyl, 4-(2- isopropylsulfonylaminoethyl)phenyl, 4-(1 -hydroxy-2- methanesulfonylaminoethyl)phenyl, 4-(2- dimethylaminosulfonylaminoethyl)phenyl, 4-(1 -(2-(2- propyl)sulfonylaminopropyl)phenyl, 4-(2-(2,2,2-trifluoro- ethyl)sulfonylaminoethyl)phenyl, 4-(2-cyclohexylsulfonyl-aminoethyl)phenyl, 4-(2- phenylsulfonylaminoethyl)phenyl, 4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl, 4-(2-(2- trifluoromethylphenyl)sulfonylaminoethyI)phenyl, 4-(2-(4- trifluoromethylphenyl)sulfonylaminoethyl)phenyl, 4-(2-(4- methoxyphenyl)sulfonylaminoethyl)phenyl, 4-(2-(1-(5- dimethylamino)napthalenesulfonyIamino)ethyl)phenyl, 4-(2-(2- thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl, 4-(2-(4- fluorobenzamido)ethyl)phenyl, 4-(2-(3-methoxybenzamido)ethyl)phenyl, 4-(2-(3- fluorobenzamido)-ethyl)phenyl, 4-(2-(4-methoxybenzamido)ethyl)phenyl, 4-(2-(2- methoxybenzamido)ethyl)phenyl, 4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4- carbamoylphenyl, 4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl, 4-(2- (2-methylpropaneamido)ethyl)phenyl, 4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido, 2-fluorobenzamido, 3-flurobenzamido, 4- fluorobenzamido, 2,4-difluorobenzamido, 3-chlorobenzamido, 4- chlorobenzamido, 4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3- methylbenzamido, 4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido, 4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido, 3-. trifluoromethylbenzamido, 4-trifluoromethylbenzamido, 2-fluoro-4-trifluoromethyl- benzamido, 2-methoxybenzamido, 3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido, 4-phenylphenyl-carboxamido, 4-benzylcarboxamido, 4- phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy, 2-fluoro- benzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl, 4-(1-(2-(2- methoxycarbonyIethanesulfonylamino)ethyl)phenyl, 4-(1-(2-(10- camphorsulfonylamino)ethyl)phenyl, 4-(1-(2-(benzylsulfonylamino)ethyl)phenyl, 4-(2-phenylacetamido)-ethyl)phenyl, 4-(methanesulfonylaminoethanoyl)phenyl, 4- (N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl, 2- thienylcarboxamido, 2-furylcarboxamido, 3-(5-methyl-isoxazolyl)carboxamido, 5- isoxazolylcarboxamido, 2-benzothienylcarboxamido, 4-(5-methyl-3- phenylisoxazolyl)-carboxamido, 4-pyridylcarboxamido, 2-(5-nitrofuryl)- carboxamido, 2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido, 2- thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino, 2- furylmethylamino, 3-furylmethylamino, 3-acetylureido and 2-(2- thienyl)ethylureido.

Examples of particular values for R²^ in formula IV are hydrogen and chlorine. R²^ is preferably ortho to R²⁰.

Examples of particular values for Ri in formula IV are 2-naphthyl, 4- bromophenyl, 4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl- phenyl, 4-isobutyIphenyl, 4-f-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4- hydroxymethylphenyl)-phenyl, 4-(2-furyl)phenyI, 4-(3-furyl)phenyl, 4-(2-thienyl)- phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-l-yl)phenyl, 3- chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3- fluoro-phenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl, 4-(4- formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, and 4-(2-methoxyphenyl)phenyl. It is understood that compounds of the formulas IVf, IVg, and IVh:

wherein z is 0, or an integer 1 , 2, 3 or 4;

R^15a represents (1-6C)alkyl, fluoro(1-4C)alkyl, or phenyl which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, and (1- 4C)alkoxy; and R^1a and R^1b each independently represent hydrogen, halogen; nitro; cyano; (1- 10C)alkyl; halo(1-10C)alkyl; phenyl; thienyl; (CH2)zX³R^15b in which z is 0 or an integer 1 , 2, 3, or 4, X³ represents O, S, NR¹⁶, CO, COO, OCO, R^15b represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (3- 10C)alkenyl, or phenyl which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy; and

R^6 represents hydrogen or (1-10C)alkyl; or a pharmaceutically acceptable salt thereof; are included within the scope of the present invention and are particularly preferred.

Preferably, in formula IVf, R^1a is hydrogen and R^1b is methyl, methoxy, fluoro, chloro, cyano, NH₂, -CH₂NH₂, -CH2CH2NH2, 2-thienyl, 3-thienyl, -CHO, trifluoromethyl, -CH₂CN, -CO2CH3, or -CO₂CH₂CH₃; or R^1a and R ^b are both hydrogen, fluoro, or chloro.

Preferably, in formulas IVg and Ih, R^15a respresents methyl, ethyl, isopropyl, or trifluoromethyl.

Preferably, in formulas IVg and IVh, z represents 0, 1 or 2.

Preferably R⁵ in formula IV represents hydrogen or methyl.

Preferably R⁶ in formula IV represents hydrogen or methyl.

It is especially preferred in formula IV that R⁵ is hydrogen and R⁶ is methyl.

Section E

A compound of formula V:

formula V

wherein

R¹ represents (1-6C)alkyl, (2-6C)alkenyl, or NR⁷R⁸;

R² and R³ each independently represent hydrogen, F, (1-4C)alkyl, or

-OR⁹;

R^4a and R^4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,

Br, CI, or F; and

Q is selected from the following:

wherein

R⁵ represents hydrogen or (1-6C)alkyl;

Y represents CH₂CH₂, CR¹⁰R¹¹, NR⁶, S, or O;

Z represents O, S, or NH; and

R⁶ represents hydrogen or (1-6C)alkyl;

R⁷ and R⁸ each independently represent hydrogen or (1-4C)alkyl;

R⁹ represents hydrogen or (1-4C)alkyl; and

R¹⁰ and R¹¹ each independently represent hydrogen or (1-4C)alkyl; or a pharmaceutically acceptable salt thereof.

The compounds of formula V can be prepared by one of ordinary skill in the art following, for example, the various procedures set forth in the Schemes below. The reagents and starting materials are readily available to one of ordinary skill in the art, for example, see International Patent Application Publications: WO 98/33496 published August 6, 1998, and WO 00/06148 and WO 00/06158, both published February 10, 2000. All substituents, unless otherwise specified are as previously defined.

Scheme IX

(21) (22) (23)

Step B' Step B

formula Va

In Scheme IX, step A the compound of structure (21) is combined with the compound of structure (22) under conditions well known in the art to provide the compound of structure (23). More specifically, for example, the compound (21 ) is dissolved in a suitable organic solvent. Examples of suitable organic solvents include methylene chloride, tetrahydrofuran, and the like. The solution is treated with a slight excess of a suitable base, and then cooled to about -78°C to about 0°C. Examples of suitable bases include triethylamine, pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU),and the like. To the stirring solution is added one equivalent of compound (22). The term "Lg" as used herein refers to a suitable leaving group. Examples of suitable leaving groups include, CI, Br, and the like. CI is the preferred leaving group. The reaction mixture is stirred at about 0°C to about 50°C for about 0.5 hours to about 16 hours. The compound (23) is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography. For example, the mixture is washed with 10% sodium bisulfate, the layers separated and the aqueous extracted with several times with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is then purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane to provide the compound (23).

In Scheme IX, step B the compound of structure (23) is fluorinated under conditions well known in the art to provide the compound of formula la. For example, compound (23) is dissolved in a suitable organic solvent, such as methylene chloride and the solution is cooled to about -78°C under an inert atmosphere, such as nitrogen. To this solution is added slowly, about one equivalent of diethylaminosulfur trifluoride (DAST) dissolved in a suitable organic solvent, such as methylene chloride with stirring. The reaction is then allowed to warm to room temperature (about 22°C) and the compound of formula la is then isolated and purified using techniques and procedures well known in the art, such as extraction techniques and chromatography. For example, the reaction is diluted with water and methylene chloride. The layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula la. This crude material can then be purified by standard techniques, such as recrystallization from a suitable eluent, or chromatography on silica gel, with a suitable eluent, such as hexane/ethyl acetate to provide purified compound of formula Va. Alternatively, in Scheme IX, step B' the compound (21 ) is fluorinated in a manner analogous to the procedure described in step B above with DAST to provide the compound of structure (24). In Scheme I, step A' compound (24) is converted to the compound of formula Va in a manner analogous to the procedure described in step A above. The compounds of formula Va can be prepared following the procedure described in Scheme X. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. Scheme X

(25) (27)

Step B' Step B

(28) formula Va

In Scheme X, step A the compound of structure (25) is coupled with compound of structure (26) under standard Suzuki coupling conditions to provide compound of structure (27). See Suzuki, A., Journal of Organometallic

Chemistry, 576, 147-168 (1999), and Miyaura and Suzuki, Chemical Reviews, 95, 2457-2483 (1995) for examples of Suzuki-type coupling reactions and conditions. For example, compound (25) is combined with about 1.5 equivalents of compound (26), about 1.5 equivalents of potassium carbonate, and about 0.06 equivalents of tetrakis(triphenyl phosphine)palladium(O) in a suitable solvent or solvent mixture, such as dioxane/water (3:1 ). The mixture is then heated at about 100°C for about 18 hours. The reaction is then cooled and compound (27) is isolated and purified using standard techniques and procedures, such as extraction techniques and chromatography. For example, the reaction mixture is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material is then purified by chromatography on silica gel with a suitable eluent, such as hexane/ethyl acetate to provide purified compound (25). In Scheme II, step B, compound (27) is fluorinated under standard conditions to provide the compound of formula la. For example, compound (27) is dissolved in a suitable organic solvent, such as methylene chloride is added to about one equivalent of DAST at about -78°C with stirring under an atmosphere of nitrogen. The reaction is allowed to warm to room temperature and the compound of formula Va is isolated and purified using standard techniques, such as extraction techniques and chromatography. For example, the reaction mixture is diluted with water and a suitable organic solvent, such as methylene chloride. The layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material is then purified by chromatography on silica gel with a suitable eluent, such as hexane/ethyl acetate to provide the purified compound of formula la. Alternatively, in Scheme X, step B' the compound (25) is fluorinated to provide the compound (28) in a manner analogous to the procedure described above in step B.

In addition, in Scheme X, step A' the compound (28) is converted to the compound of formula Va in a manner analogous to the procedure described above in step A.

Compounds of formula Vb can be prepared as shown in Scheme XI. Reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified, are previously defined.

Scheme XI

(21 ) (29)

Step B' Step B

(24) formula Vb

In Scheme XI, step A, the compound of structure (21) is combined with a compound of formula CISO₂NR⁷R⁸ under standard conditions to provide the compound of structure (29). For example, compound (21 ) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with about one equivalent of a suitable base, such as DBU at about 0°C. The solution is then treated with about one equivalent of a compound of formula CISO₂NR⁷R⁸. The reaction is then allowed to warm to room temperature and stirred for about 4 to 16 hours. The reaction is then concentrated under vacuum to provide the crude product (29) which can then be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.

In Scheme XI, step B, compound (29) is converted to the compound of formula Vb in a manner analogous to the procedure set forth in Scheme IX, step B.

Alternatively, in Scheme XI, step B' the compound (21) is fluorinated in a manner analogous to the procedure described in Scheme IX, step B with DAST to provide the compound of structure (24). In Scheme XI, step A compound (24) is converted to the compound of formula Vb in a manner analogous to the procedure described above in step A. The compounds of structure (25) can be prepared following the procedure described in Scheme XII. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

Scheme XII

(30) (31)

Step B

(25) (32)

TMS represents trimethylsilyl

In Scheme XII, step A the compound of structure (30) is converted to the compound of structure (31) under standard conditions. For example, see Greenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). For example, compound (30) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran, containing excess 18-crown-6, and excess potassium cyanide. To this mixture at room temperature is added dropwise about 1.2 equivalents of cyanotrimethylsilane. The reaction mixture is allowed to stir for about 1 to 4 hours to provide compound (31). Compound (31) is then carried on directly to step B without isolation.

Alternatively, in Scheme XII, step A, for example, compound (30) is combined with a catalytic amount of zinc iodide followed by slow addition of excess trimethylsilyl cyanide with the generation of heat. The resulting solution is stirred at room temperature under nitrogen for about 8 to 16 hours. The mixture is then diluted with a suitable organic solvent, such as chloroform, washed with saturated sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (31 ).

In Scheme XII, step B compound (31) is converted to compound of structure (32). For example, compound (31) prepared above, still in solution, is treated with a solution of about 1.4 equivalents of borane in dimethylsulfide. The reaction mixture is then heated to reflux for about 16 hours and then cooled to room temperature. The reaction mixture is then cautiously treated with anhydrous HCI in methanol and allowed to stir for about one hour. The product (32) is then isolated and purified using standard techniques and procedures. For example, the solvent is removed under vacuum and the residue triturated with a suitable organic solvent, such at methy t-butyl ether and the solid is collected by filtration. The solid is then suspended in methylene chloride/tetrahydrofuran mixture (1 :2.4) and treated with 1 N NaOH until about pH 12.3 is reached. The phases are separated and the organic phase is rinsed with brine. The organic phase is then concentrated under vacuum and the residue triturated with diethyl ether to provide the purified compound (32).

In Scheme XII, step C, compound (32) is then sulfonylated to provide compound (25) in a manner analogous to the procedure described in Scheme IX, step A. With respect to R¹, compounds of formula V wherein R¹ is methyl, ethyl, isopropyl or N(CH₃)₂ are preferred with 2-propyl being most preferred.

With respect to R², compounds of formula V wherein R² is hydrogen, methyl or ethyl are preferred, with hydrogen or methyl being most preferred.

With respect to R³, compounds of formula V wherein R³ is hydrogen, methyl or ethyl are preferred, with hydrogen or methyl being most preferred.

In addition, in compounds of formula V, when R² is methyl, it is most preferred that R³ is hydrogen, and when R² is hydrogen, it is most preferred that R³ is methyl.

With respect to R^4a and R^4b, compounds of formula V wherein R^4a and R^4b are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, Br, CI or F are preferred, with hydrogen, methyl, methoxy and F being most preferred, and hydrogen be most especially preferred. With respect to R⁵, compounds of formula V wherein R⁵ is hydrogen or methyl are preferred, with hydrogen being most preferred.

With respect to R⁶, compounds of formula V wherein R⁶ is hydrogen or methyl are preferred. With respect to R⁷ and R⁸, compounds of formula V wherein R⁷ and R⁸ are each independently hydrogen, methyl, or ethyl are preferred, with methyl being most preferred.

With respect to R⁹, compounds of formula V wherein R⁹ is hydrogen, methyl, or ethyl are preferred, with methyl being most preferred. With respect to R¹⁰ and R¹¹ compounds of formula V wherein R¹⁰ is hydrogen or methyl are preferred, and R¹¹ is hydrogen or methyl are preferred. It is most preferred that R¹⁰ and R¹¹ each represent hydrogen.

With respect to Y and Z, compounds of formula V wherein Y is N when Z is O, Y is CH₂ when Z is O and Y is CH2CH2 when Z is O are preferred. The following examples are illustrative only and represent typical syntheses of compounds described above. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: "eq" refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μl_" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "kPa" refers to kilopascals; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "R_f" refers to retention factor; "DEAD" refers to diethyl azodicarboxylate; "R_t" refers to retention time; "δ'Yefers to part per million down- field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N- dimethylformamide; "DMSO" refers to methyl sulfoxide; "LDA" refers to lithium diisopropylamide; "EtOAc" refers to ethyl acetate; "aq" refers to aqueous; "iPrOAc" refers to isopropyl acetate; "methyl DAST" refers to dimethylaminosulfur trifluoride, "DAST" refers to diethylaminosulfur trifluoride, "DBU" refers to 1 ,8- diazabicyclo[5.4.0]undec-7-ene; as used herein "Pd(dppf)₂CI₂ catalyst" refers to ([1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with CH₂CI₂; as used herein the terms "Me", "Et", "Pr", "iPr", and "Bu" refer to methyl, ethyl, propyl, isopropyl, and butyl respectively, and "RT" refers to room temperature.

Example 1

Preparation of N-2-(4-N-(3,5-Difluorobenzamido)phenyl)propyl-2- propanesulfonamide.

The title compound is prepared in a manner analogous to the procedure described at Example 196 in International Patent Application Publication WO 98/33496 published August 6, 1998 from 3,5-difluorobenzoyl chloride.

Alternatively, the title compound can be prepared in a manner analogous to the procedures described generally in Schemes I and II, and more specifically as described in examples 2 and 3 below without employing the resolution steps as would be appreciated by one of ordinary skill in the art.

More specifically, into a 500 mL 3-neck flask fitted with a stirrer and thermometer, 3,5-difluorobenzoyl chloride (1.13 g) was added dropwise to a stirred solution of [2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (1.50 g) and triethylamine (625 mg) in methylene chloride (200 mL) at room temperature and under a nitrogen atmosphere. After stirring one hour at this temperature,

TLC showed that the starting aniline had been consumed. The organic layer was washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield the crude material (2.61 g) as a solid. This crude material was purified by recrystallization from hexane/ethyl acetate 1 :1 to yield the title compound (1.64 g, 71 %)) as yellow crystals. M.P. 158°C- 160°C. Ion spray M.S. 397.1 (M* + 1). Calculated for C₁₉H₂₂N₂O₂SF₂-H₂O:

Theory: C 55.03, H 5.83, N 6.76 Found : C 54.63, H 5.84, N 6.61 Example 1a Preparation of N-f4-((1RV1-methyl-2- {r(methylethvπsulfonyllamino}ethyl)phenvn(3.5-difluorophenyl)carboxamide.

Preparation of 2-Phenyl-1-propylamine HCI.

To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64 °C for 3 hours. 1 H NMR analysis of an aliquot showed less than 5% starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to -400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitated solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCI (634.4 g, 76.2%) as a white powder.

1 H NMR analysis of the free base: 1 H NMR (CDCI3, 300 MHz) δ 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1 H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H). Preparation of (2R)-2-phenylpropylamine malate.

To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl- 1-propylamine HCI (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCI salts were filtered. An aliquot of the filtrate was analyzed by gas chromatography to provide ' the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles). A solution of L- malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75 °C. The solution was stirred at 75 °C for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5%) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1- propylamine revealed 83.2% e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison, via chiral HPLC, with commercially available (R)-2-phenyl-1 -propylamine). ¹H NMR (CDCI₃, 300 MHz) δ 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1 H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).

A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2% e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (-79.2 °C) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5 °C) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35 °C to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2% recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenyIpropylamine, revealed 96.7% e.e. enriched in the R-isomer. ¹H NMR (CD₃OD, 300 MHz) 67.32 (m, 10 H), 4.26 (dd, 1 H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1 H, J=9.3, 15.3), 2.38 (dd, 1 H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6).

Preparation of ((2R)-2-phenylpropyl)r(methylethyl)sulfonvπamine.

To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH₂CI₂ (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH₂CI₂ rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109 °C.

The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH₂Cl₂(500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5°C and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH₂CI₂ (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material. The stirred mixture was cooled to 8 °C and 2 N HCI (500 mL) was added dropwise. The organic phase was separated and extracted with water (1 x 500 mL) and saturated NaHCO3 (1 x 500 mL). The organic phase was isolated, dried (Na₂SO ), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230g, 96%) as a pale yellow oil. ¹H NMR (CDCI₃, 300 MHz) δ 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (brt, 1 H, J=5.4), 3.36 (m, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1 H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9).

Preparation of r(2R)-2-(4-aminophenyl)propylir(methylethyl)sulfonyl]amine p- toluenesulfonate.

To a round-bottom flask equipped with stir rod, thermocouple and nitrogen purge at 25 °C, was charged ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (5.00 g, 0.0207 mol), trifluoroacetic acid (15 mL), dichloromethane (1.2 mL) and 0 heptane (8 mL). The mixture was cooled to - 5 °C and 98% fuming nitric acid (1.60 g, 0.0249 mol) was added dropwise. The reaction mixture was stirred at -5 to+5 °C for 3-5 hours and then warmed to 20-25 °C. The reaction was allowed to stir until GC analysis revealed that ((2R)-2- phenylpropyl)[(methylethyl)sulfonyl]amine is less then 1 % (area %). 5 The reaction mixture was then diluted with dichloromethane (20 mL) and diionized water (20 mL), and the mixture was transferred to a suitably sized 3- neck bottom outlet round-bottom flask. The mixture was stirred for 10-15 minutes. The aqueous phase was separated, extracted with dichloromethane (1 x 20 mL), and the organic phases were combined. To the organic phase was o added water (15 mL), 10% NaOH (10 mL), and the pH was adjusted to 6.5-7.5 with saturated sodium carbonate. After 10-15 minintes of stirring, the organic layer was separated and concentrated to an oil under reduced pressure (25-35 °C).

The oil containing the mixture of [(2R)-2-(4- 5 nitrophenyl)propyl][(methylethyl)sulfonyl]amine, [(2R)-2-(3- nitrophenyl)propyl][(methylethyl)sulfonyl]amine, and [(2R)-2-(2- nitrophenyl)propyI][(methylethyl)sulfonyl]amine, was diluted with ethanol and was transferred to a Parr bottle containing 1.25g of 5% Pd on C (rinsed in with 5 L of THF) under nitrogen (total ethanol = 45 mL). The reaction mixture was o hydrogenated for 16-20 hours at 20-25 °C until the GC area % of [(2R)-2-(4- aminophenyl)propyl][(methyIethyl)sulfonyl]amine was greater than 70%. The reaction mixture was filtered through Hyflo followed by an ethanol rinse (25 mL).

The oil was diluted with THF (35 mL) and p-toluenesulfonic acid monohydrate (3.94 g, 0.0207 mol) was added with stirring at 20-25 °C. When the solids completely dissolved, MTBE (22 mL) was added and the slurry was stirred for 1-2 hours. The slurry was filtered and the cake was rinsed three times with a 3:7 (v/v) solution of MBTE and THF. This process afforded [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine p-toluenesulfonate in 53.5 % yields as an off white powder. Chiral analysis of the freebase, [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine, obtained extractively from [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine p-toluenesulfonate, showed % e.e. of 99.5%.

¹H NMR (CD₃OD, 300 MHz) δ 7.70 (d, 2H, J=8.4), 7.43 (d, 2H, J=8.4), 7.33 (d, 2H, J=8.4), 7.23 (d, 2H, J=7.8), 3.22 (m, 2H), 3.08 (quint, 1 H, J=6.9), 2.99 (q, 1 H, J=6.9), 1.29 (d, 3H, J=6.6), 1.23 (d, 3H, J=6.6).

Preparation of r(2R)-2-(4-aminophenyl)propylir(methylethyl)sulfonvnamine.

To a suspension of [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine p-toluenesulfonate (41.2 g,

0.0961 mol) in CH₂CI₂ (300 mL) was added saturated aqueous NaHCO₃ until the pH of the aqueous phase was 6.5. The phases were separated and the organic phase was washed with 5% NaHCO₃ (2 x 100 mL), H₂O (100 mL), and concentrated to provide [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine as an oil. After diluting the oil with diethyl ether (50 mL), crystallization began after 10 min. Caution: Heat of crystallization caused ether to boil. After the exotherm subsided (45 minutes), the suspension was filtered, and the filter cake was washed with diethyl ether (2 x 20 mL), and dried under reduced pressure to afford [(2R)-2-(4- aminophenyl)propyl][(methylethyI)sulfonyl]amine (21.7 g, 88.1 %). ¹H NMR (CDCI₃, 300 MHz) δ 7.00 (d, 2H, J=8.1); 6.66 (d, 2H, J=8.4), 3.83 (m, 1 H), 3.65 (br s, 2H), 3.31 (m, 1 H), 3.09 (m, 2H), 2.85 (m, 1H), 1.30 (d, 3H, J=7.2), 1.26 (d, 3H, J=6.9), 1.24 (d, 3H, J=6.9).

Preparation of N-r4-((1 R)-1-methyl-2-

{r(methylethvπsulfonyllamino)ethyl)phenyll(3.5-difluorophenvπcarboxamide. Method A.

[(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine p- toluenesulfonate (60.0 g, 0.140 mol), suspended in dichloromethane (375 mL), was treated with saturated aqueous NaHCO₃ in an amount sufficient to bring the salt into solution. The organic phase was separated and washed twice with aqueous NaHCO₃. HPLC analysis showed complete removal of p- toluenesulfonate from the organic phase. The organic phase was dried (MgSO₄), filtered, and chilled to -10 °C. 3,5-difluorobenzoyl chloride (27.2 g, 0.154 mol) was added dropwise over 10 min and the mixture was allowed to warm to room temperature with stirring overnight.

After completion of reaction, the mixture was diluted with water (100 mL) and acetone (75 mL). The phases were separated, and the organic phase was washed with 0.1 N HCI (2 x 100 mL), 0.01 N NaOH (3 x 100 mL), and 0.1 N HCI (1 x 100 mL). The organic phase was separated and concentrated to a solid. The solid was resuspended in ethyl acetate and co-evaporated twice with ethyl acetate (2 x 60 mL) to remove traces of dichloromethane. The residue was transferred to a 500 mL flask with ethyl acetate (150 mL) and this mixture was heated to reflux to afford a clear solution. The solution was allowed to cool to room temperature over 5 hours, and the suspension was left to stir slowly overnight. The suspension was cooled to 0 °C and stirred for 1 hour. The product was collected by filtration and was vacuum dried to afford N-[4-((1 R)-1 - methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5- difluorophenyl)carboxamide (43.9g, 79.0%) as a white crystalline solid. ¹H NMR (CDCI₃, 300 MHz) δ 7.80 (s, 1 H), 7.59 (d, 2H, J=8.4), 7.40 (m, 2H), 7.23 (d, 2H, J=8.7), 7.01 (tt, 1 H, J=2.1 , 8.7), 3.87 (dd, 1H, J=5.1 , 7.5), 3.36 (m, 1 H), 3.21 (m, 1 H), 3.09 (m, 1 H), 2.98 (m, 1 H), 1.32 (d, 3H, J=6.6), 1.30 (d, 3H, J=7.2), 1.28 (d, 3H, J=6.6). Preparation of N-I4-((1 R)-1 -methyl-2-

{[(methylethyl)sulfonyl1amino)ethyl)phenvn(3,5-difluorophenyl)carboxamide, Method B. To a 0 °C solution of [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine (21.5 g, 0.0838 mol) and triethylamine (9.75g, 13.4 mL, 0.0964 mol) in CH₂CI₂ (86 mL) was added 3,5- difluorobenzoyl chloride (16.3 g, 0.0922 mol) dropwise over 30 min. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was washed with deionized water (2 x 100 mL) and 0.1 N HCI (2 x 100 mL). The organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K₂CO₃ (100 mL), 0.1 N HCI (100 mL), dried (MgSO₄, 3 g), filtered and co-evaporated with EtOAc to afford an oil. This oil was diluted with diethyl ether (125 mL), which induced crystallization. The solids were collected by filtration, washed with diethyl ether (2 x 20 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (31.8 g, 95.7 %) as a white crystalline powder. An analytical sample was prepared via recrystallization from EtOAc. Thus, a clear solution of N-[4-((1 R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (28 g) was achieved in refluxing EtOAc (90 mL, minimum amount). This solution was allowed to cool over 2 hour to room temperature without stirring. The resulting dense mass was pulvarized with a glass rod and recovered by filtration. The collected solids were reslurried in diethyl ether, filtered and dried under reduced pressure to afford N-[4-((1 R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (22.2 g, 79% recovery) as a white crystalline powder. In addition, the final title compound, N-[4-((1 R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, can be jet milled by one of ordinary skill in the art, for example, with a Model 4 SDM Micronizer by Sturtevant Inc. to provide compound with a mean particle size of about 5.5 microns.

Alternative preparation of N-[4-((1 R)-1-methyl-2- {[(methylethyl)sulfonyl1amino)ethyl)phenyll(3,5-difluorophenyl)carboxamide.

Preparation of (2RV2-(4-nitrophenyl)propanoic acid. S(-)-α-methylbenzylamine.

A 2 liter three necked flask equipped with a mechanical stirrer is charged with racemic 2-(4-nitrophenyl)propionic acid (40.55 grams, 0.208 mol) and ethyl acetate ( 1600.0 mL). To this solution at 30°C was then added S(-)-α- methylbenzylamine ( 13.49 mL, 0.104 mol) all at once. Reaction exothermed to 38°C with massive formation of a white precipitate in less than 15.0 minutes. The reaction mixture was then heated at ethyl acetate reflux for 10.0 minutes and allowed to equilibrate to room temperature with stirring overnight. The precipitate was then filtered to give a semi-dried white product, (2R)-2-(4- nitrophenyl)propanoic acid, S(-)-α-methylbenzylamine ( wet cake = 25.43 grams). Reslurried the wet cake in ethyl acetate (1600.0 mL) at reflux for 10.0 minutes, stirred to room temperature overnight, and filtered the white precipitate, (2R)-2- (4-nitrophenyl)propanoic acid, S(-)-α-methylbenzylamine, ( wet cake = 21.02 grams, ee = 91.4%). Repeated the later again and dried the precipitate at 40°C in a vacuum oven for 24.0 hours, (2R)-2-(4-nitrophenyl)propanoic acid, S(-)-α- methylbenzylamine, (18.02 g, 55%, ee = 95%); ¹H nmr (DMSO, 300 MHz) δ 1.31- 1.32 (d, 3H), 1.37-1.38 (d, 3H), 3.56-3.60 (m, 1 H), 4.18-4.20 (m, 1H), 7.27-7.53 (aromatic, 7H), 8.09-8.12 (aromatic, 2H); ¹³C nmr (DMSO, 300 MHz)) δ 19.91 , 22.93, 48.45, 50.55, 123.71 , 124.15, 127.15, 128.27, 129.06, 129.41 , 129.76, 146.31 , 153.36, 176.24. Preparation of (2Ry-2-(4-nitrophenvQpropanoic acid.

To reaction mixture of (2R)-2-(4-nitrophenyl)propanoic acid, S(-)-α- methylbenzylamine (56.04 g, 0.177 moles) in methylene chloride (400.0 mL) at room temperature was added 1 N HCI (300.0 mL) all at once with stirring for 45.0 minutes. The lower organic layer was then separated, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, (2R)-2-(4-nitrophenyl)propanoic acid, (34.58 g, 100%) as an oil.

Preparation of (2R)-2-(4-nitrophenyl)propan-1-ol.

A 500 ml three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and a continuous nitrogen purge is charged with (2R)-2-(4-nitrophenyl)propanoic acid (8.12 g, 41.6 mmol) and THF (120.0 mL). To this solution was added 10.0M borane dimethylsulfide (10.56 ml, 105.66 mmol) over a period of 30.0 minutes at room temperature. Reaction is quite exothermic with evolution of gas (exotherm can be controlled by the rate of addition of borane solution). The reaction is then refluxed for 5.0 hours, brought to room temperature and then quenched very carefully with saturated potassium carbonate solution (100.0 mL). Foaming observed during the quench can be controlled by the rate of addition of the carbonate solution. After 3.0 hours of stirring, the top organic layer is separated and the aqueous layer back extracted with methylene chloride (130.0 mL). The combined organic layer is then washed with saturated brine (100.0 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50°C to afford (2R)-2-(4-nitrophenyl)propan-1-ol (7.24 g, 96%); 1 H nmr (CDCI3, 300 MHz) δ 1.29 (d, 3H, J= 7.02Hz), 1.69 (b. triplet, OH), 3.05 (m, 1 H), 3.72 (m, 2H), 7.39 (d, 2H), 8.15 (d, 2H); 13C nmr (CDCI3, 300 MHz) δ 17.61 , 25.82, 42.61 , 68.17, 123.92, 128.61 , 146.90, 152.24.

Preparation of 2-r(2R)-2-(4-nitrophenyl)propyπisoindoline-1 ,3-dione.

A 250 mL three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer, and a reflux condenser is charged with (2R)-2-(4-nitrophenyl)propan-1-ol (2.0 g, 11.04 mmol), phthalimide (1.62g, 11.04 mm), triphenylphosphine (4.3 g, 16.59 mmol) and THF (50.0 mL) at room 0 temperature. To this solution was added DEAD (2.6 mL, 16.59 mmol) over a period of 5 minutes (reaction exothermed to reflux by the end of addition). The reaction was then stirred to room temperature overnight for convenience, quenched with water (50.0 mL) and extracted organic with methylene chloride (50.0 mL). The organic layer was then dried with anhydrous magnesium sulfate, 5 filtered, and concentrated under reduced pressure at 50°C to an oil (11.62 g). Plug filtration of the oil over silica gel with 1 :1 ethyl acetate/ hexane (470.0 mL) and subsequent concentration of the fractions containing product afforded a light yellow precipitate. The precipitate was then dried in a house vacuum at 40°C to provide 2-[(2R)-2-(4-nitrophenyl)propyl]isoindoline-1 ,3-dione (3.32 g, 96.9%); ¹H o nmr (CDCI₃, 300 MHz) δ 1.50 (d, 3H, J=6.74Hz), 3.45 (m, 1 H), 3.89-3.95 (m, 2H), 7.5 (d, 2H), 7.67 (m, 2H), 7.68 (m, 2H), 8.10 (d, 2H); ¹³C nmr (CDCI₃, 300 MHz) δ 19.21 , 38.90, 44.45, 123.59, 123.99, 128.50, 131.86, 134.35, 151.13, 168.34.

Preparation of (2R)-2-(4-nitrophenvDpropylamine.

A 250 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and addition funnel is charged with 2- [(2R)-2-(4-nitrophenyl)propyl]isoindoline-1 ,3-dione (25.02 g, 80.6 mmol) and toluene (200.0 mL). To this solution at room temperature was added anhydrous hydrazine (7.08 mL, 226.0 mmol). Reaction exothermed slightly and was stirred for 45 minutes, heated at 90°C-95°C until the disappearance of starting material. A massive precipitate formed by the end of the reaction. Cooled to room temperature and chilled to 0°C before filtration. Concentration of the filtrate afforded (2R)-2-(4-nitrophenyl)propylamine (14.11 g, 97%) as an oil; 1 H nmr (CDCI3, 300 MHz) δ 1.01 (b, 1H), 1.27 (d, 3H, J= 6.4Hz), 2.87 (m, 2H), 7.36 (d, 2H), 8.14 (d, 2H); 13C nmr (CDCI3, 300 MHz) δ 19.03, 43.51 , 49.21 , 123.67, 128.09, 153.04.

Preparation of r(2R)-2-(4-nitrophenyl)propylir(methylethyl)sulfonyl1amine.

A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and an addition funnel is charged with (2R)-2-(4- nitrophenyl)propylamine (11.75 g, 65.21 mmol), methylene chloride (150.0 mL) and triethylamine (18.2 mL, 130.4 mmol). To this solution at 0°C was added isopropylsulfonyl chloride (8.92 mL, 63.9 mmol) over a period of 20 minutes. Reaction was then stirred to room temperature overnight, then quenched with 1N HCI (150.0 mL). The lower organic layer is separated and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (14.11 g, 97%) as an oil; 1 H nmr (CDCI3, 300 MHz) δ 1.26 (d, 3H,J= 6.7Hz), 1.31 (d, 6H), 3.06 (m, 1 H), 3.30 (m, 1 H), 4.25 (broad triplet, 1 H), 7.38 (d, 2H), 8.10 (2H); 13C nmr (CDCI3, 300 MHz) δ 16.75, 18.95, 41.29, 50.15, 53.85, 124.22, 128.52, 151.26. Preparation of r(2R)-2-(4-nitrophenyl)propynr(methylethyl)sulfonyl1amine.

A 500 mL parr bottle is charged with [(2R)-2-(4- nitrophenyl)propyl][(methylethyl)sulfonyl]amine (14.45 g, 50.60 mmol), 3A EtOH ( 80.0 mL) and 10%P/C (4.0 g). The reaction mixture was then hydrogenated at room temperature and at 55 psi for 6 hours. Filtered reaction mixture over hyflo and washed cake with 3A EtOH (100.0 mL). The filtrate was then concentrated at reduced pressure to provide [(2R)-2-(4- nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.97 g, 100%) as an oil; 1 H nmr (CDCI3, 300 MHz) δ 1.26 (d, 3H,J= 6.7Hz), 1.31 (d, 6H), 2.4 (m, 1 H), 3.0-3.2 (m, 2H), 3.2-3.4 (m, 1 H), 4.0 (b, 1 H), 4.6 (b,2H), 6.61 (d, 2H), 7.0 (d, 2H).

Preparation of N-r4-((1 R)-1-methyl-2- (r(methylethyl)sulfonvnamino)ethyl)phenvn(3.5-difluorophenvπcarboxamide.

A 500mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel and a positive nitrogen was charged with [(2R)-2-(4- nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.02 g, 46.85 mmol) and methylene chloride (200.0 mL). To this solution was added triethylamine (6.53 mL, 46.85 mmol) all once. The solution was stirred for 10 minutes then added dropwise, neat 3,5- difluorobenzoyl chloride (5.9 mL, 46.85 mmol) over a period of 20 minutes. The reaction exothermed to reflux by the end of addition. Stirred to room temperature over the weekend for convenience. Quenched reaction with 1 N HCI (100.0 mL) and separated lower organic layer. Washed the organic layer with 25% brine (70.0 mL) and dried with anhydrous magnesium sulfate. Filtered precipitates and concentrated filtrate to a tan oil (20.0 g). To this oil was added 1 :1 ethyl acetate/hexane (125.0 mL) with stirring. A massive off white precipitate formed. The precipitate was then filtered and the cake washed with 1 :1 ethyl acetate/hexane (50.0 mL). Precipitate was then dried in a house vacuum oven at 40°C to provide N-[4~((1 R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (15.02 g, 80.9%); 1 H NMR (CDCI3, 300 MHz) δ 1.26-1.27 (d, 6H), 1.29-1.30 (d,2H), 2.92 (m,1 H), 3.10 (m, 1 H), 3.20 (1 H), 3.3-3.4 (m, 1 H), 7.0 (triplet, 1 H), 7.20 (d, 2H), 7.40 (d, 2H), 7.60 (m, 2H), 8.19 (s, 1 H); 13C NMR (CDCI3, 300 MHz) δ 17.19, 17.30, 19.75, 41.03, 50.99, 54.15, 107.68, 107.86, 108.08, 111.12, 111.33, 121.81 , 128.59, 136.97, 138.77, 140.51 , 162.62, 162.71 , 164.12, 164.61 , 164.71.

Alternative preparation of IY2R)-2-(4- aminophenyl)propyπr(methylethyl)sulfonvπamine P-toluenesulfonate.

To a mechanically stirred solution of 2-phenyl-1-propylamine amine (50.0 g, 0.370 mol, can be prepared in a manner analogous to the procedure disclosed by A. W. Weston, et al., J. Am. Chem. Soc, 65, 674 (1943)) in 90% ethanol / H₂O (denatured with 0.5% toluene) (450 mL) was added L-malic acid (24.8 g, 0.185 mol) portionwise at room temperature with a 90% ethanol / H₂O rinse (50 mL) to give a clear solution after a mild exotherm. This solution was allowed to cool and a white precipitate appeared after 30 min. The precipitation was allowed to proceed with slow stirring overnight. The resulting slurry was suction filtered (buchner funnel) and rinsed with 100% ethanol (denatured with 0.5% toluene) (2 x 100 mL) to afford, after air-drying, 30 g of (2R)-2-phenylpropylamine malate as a white solid. Chiral chromatographic analysis of the isopropylsulfonamide derivative of the free base indicated 84% ee.

This (2R)-2-phenylpropylamine malate (30 g) was suspended in 90% ethanol / H₂O (300 mL) and heated to 78 °C with slow stirring to afford a clear colorless solution. The solution was allowed to cool slowly to room temperature overnight. Precipitation commenced at 60-65 °C. The solids were filtered and rinsed at room temperature with 100% ethanol (2 x 50 mL) to give (2R)-2- phenylpropylamine malate (24.3 g, 32%) as a white crystalline solid. Chiral chromatographic analysis of the isopropylsulfonamide derivative of the free base indicated 96.5% ee.

Preparation of (2R)-2-phenylpropylamine.

To a stirred suspension of (2R)-2-phenylpropylamine malate (24.3 g, 0.0601 mol, prepared directly above) in CH₂CI₂ (200 mL) was added 1.0 N NaOH dropwise at room temperature. The organic phase was isolated, extracted with brine (1 x 125 mL), dried (Na2SO₄), filtered, and concentrated under reduced pressure to give (2R)-2-phenylpropylamine (19 g) as a clear, colorless oil.

Preparation of ((2R)-2-phenylpropyl)r(methylethv0sulfonvπamine.

To a stirred 2 °C solution of (2R)-2-phenylpropylamine (0.12 mol) and triethylamine (24.3 g, 0.240 mol) in CH₂CI₂ (140 mL) under nitrogen, was added a solution of isopropylsulfonyl chloride (97%) (16.3 g, 0.118 mol) in CH₂CI₂ (20 mL) dropwise while maintaining the reaction temperature below 15 °C. Residual isopropylsulfonyl chloride was rinsed in with CH₂CI₂ (10 mL). This solution was stirred at 0 °C for 1 hour and was then allowed to warm to room temperature overnight.

The reaction mixture was re-cooled to 0 °C before adding 1 N HCI (125 mL) dropwise with stirring. The organic phase was then isolated and washed with saturated aqueous NaHCO₃ (1 x 125 mL) and the organic phase was separated, dried (MgSO ), and filtered. The filtrate was concentrated under reduced pressure to afford ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (25.76 g, 90%) as a yellow oil. Preparation of r(2R)-2-(4-aminophenvπpropylir(methylethvπsulfonyllamine p- toluenesulfonate.

To a room temperature solution of ((2R)-2- phenylpropyl)[(methylethyl)sulfonyl]amine (43.3 g, 0.179 mol) in trifluoroacetic acid (344 mL) was added NaNO₃ (45.7 g, 0.538 mol), and the resulting reaction mixture was stirred for 5 hours. The reaction mixture was diluted with CH₂CI₂ (1

L), and washed with H₂O (2 x 300 mL), and separated. The organic phase was diluted again with H₂O (150 mL), and the heterogeneous mixture was neutralized with solid NaHCO₃ until the aqueous layer was pH 5.7. The organic phase was concentrated to an oil (43 g) that was dissolved in 3A ethanol (250 mL). The solution was then hydrogenated overnight at 50-60 psi over 7 g of 5% palladium on carbon.

¹H NMR analysis of a reaction aliquot indicated complete reduction and 70% para isomer in the regioisomeric mixture. The mixture was filtered through Celite^®, and the filtrate was concentrated to an oil (41 g, 0.160 mol) that was subsequently diluted with THF (125 mL). This THF solution was added to a solution of p-toluenesulfonic acid monohydrate (37 g, 0.195 mol) in a 1 :1 (v/v) THF/diethyl ether solution. Diethyl ether was added to this clear solution until the onset of cloudiness. After about 10 minutes, solids precipitated as a dense unstirrable mass. The mixture was diluted further with diethyl ether (300 mL) and THF (350 mL), and the resulting suspension was filtered. The filter cake was washed with 2:5 (v/v) THF / diethyl ether (3 x 80 mL) and the cake was dried under reduced pressure to afford [(2R)-2-(4- aminophenyl)propyl][(methylethyl)sulfonyl]amine p-toluenesulfonate (41.7 g, 54 %) as a white powder.

Alternative preparation of ((2R)-2-phenylpropy0r(methylethyl)sulfonyl1amine.

Preparation of (2R)-2-phenylpropan-1-ol.

An oven dried 500.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2 mmol) and toluene (75. mL). Reaction solution was then chilled to -60°C with dry ice/acetone bath. To this solution was then added R-styrene oxide dissolved in 100.0 mL of toluene over a period 50.0 minutes (reaction is quite exothermic and can be controlled by the rate of addition of substrate). After stirring at this temperature for 60.0 minutes, reaction was brought to 5 room temperature and stirred for 4.0 hours. Reverse quenched reaction at room temperature into a slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g) ver cautiously over a period of 90.0 minutes (quenching was quite exothermic with evolution gas). Filtered the precipitate formed over hyflo, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropan-1-ol, (11.03 g, 92.6%) as an oil; 1 H 0 nmr (CDCI3, 300 MHz) δ 1.28-1.29 (d, 3H, J = 6.9Hz), 1.5 (b, 1 H), 2.9-3.0 (m, 1 H), 3.69- 3.70 (d, 2H, J = 6.64Hz), 7.24-7.35 (aromatic); 13C nmr (CDCI3, 300 MHz) δ 18.31 , 43.1 69.40, 127.38, 128.20, 129.26144.39.

Preparation of 2-((2R)-2-phenylpropy0isoindoline-1.3-dione 5 An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 o mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50°C by the end of addition went from clear to reddish color). Stirred reaction to room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil 5 was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1 :1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2-((2R)-2- phenylpropyl)isoindoline-1 ,3-dione, (4.27 g, 96%) as an oil which solidified on equilibratin to room temperature; 1 H nmr (CDCI3, 300 MHz) δ 1.3 (d, 3H), 3.3-4.0(m, 1 H), 3.7-3.9 (m 0 2H), 7.1-7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H). Preparation of (2R)-2-phenylpropylamine.

A 500mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1 ,3- dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL,

86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90°C-95°C for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2- phenylpropylamine, (5.58 g, 94.9%) an oil; 1 H nmr (CDCI3, 300 MHz) δ 1.21 (d,3H), 1.40 1.60 (b, 2H), 2.68-2.80 (m, 1 H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H).

Preparation of final title compound.

To a solution of the (2R)-2-phenylpropylamine (1.2g, 8.87mmol) in hexane (16.0m was added triethylamine (2.47 mL, 17.74 mmol) and dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5°C, then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes.

Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with 1 N HCI (20.0 mL) and extracted organic with methylene chloride (25.0 mL).

Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate t provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1%) an oil; 1 H nmr (CDCI3, 300 MHz) δ 1.25 (d,3H, J=6.9Hz), 1.29(d, 3H, J=6.9Hz)

1.30 (d, 3H, J= 7.2Hz), 2.98 (m, 1 H), 3.05 (m, 1 H), 3.22 (m, 1 H), 3.36 (m, 1 H), 3.89 (b,

1 H), 7.23 (m, 2H), 7.34 (m, 2H).

Example 1b

Preparation of N-r4-((1S)-1-methyl-2- •ff(methylethyl)sulfonvnamino>ethyl)phenyl1(3,5-difluorophenyl)carboxamide.

The title compound can be prepared in a manner analogous to the procedure described in example 1a from of (2S)-2-phenylpropylamine. Example 2 Preparation of [(methylethyl)sulfonyll{2-r4-(4-{2- r(methylsulfonyl)aminolethyl)phenyl)phenvnpropyl>amine.

The title compound can be prepared following the procedure disclosed in WO 98/33496 published August 6, 1998, Example 51). More specifically, to a room temperature solution of 0.1 g (0.3 mmol) of N-2-(4-(4-(2- aminoethyl)phenyl)phenyl)propyl 2-propanesulfonamide (prepared following procedure disclosed in WO 98/33496 published August 6, 1998, Example 50) and 0.06 mL (0.4 mmol) of triethylamine in 2 mL of dichloromethane was added 0.03 mL (0.4 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 16 hours. Chromatography (10 g silica gel, 50% ethyl acetate/hexane) of the reaction mixture afforded 0.1 g (94%) of the title compound.

Analysis calculated for C2iH₃oN₂O S2 : Theory %C, 57.51 ; %H, 6.89; %N, 6.39.

Found: %C, 57.90; %H, 6.72; %N, 6.

Example 2a

Preparation of K2R)-2-r4-(4-(2- r(methylsulfonyl)aminolethyl>phenvnphenyllpropyl r(methylethvnsulfonyllamine.

Preparation of 2-Phenyl-1-propylamine HCI.

To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613g, 5.6 mole). The mixture was stirred rapidly and pressurized to 75-78 psi with hydrogen. The mixture was then heated to 50-64 °C for 3 hours. 1H NMR analysis of an aliquot showed less than 5% starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to -400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCI (634.4 g, 76.2%) as a white powder. 1 H NMR analysis of the free base: 1 H NMR (CDCI3, 300 MHz) δ 7.32 (m,

2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1 H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).

Preparation of (2R)-2-phenylpropylamine malate.

To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl- 1-propylamine HCI (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads (75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The mixture was stirred for 1.6 hours, and the resulting milky white NaCI salts were filtered. An aliquot of the filtrate was analyzed by gas chrqmatography to provide the amount of free amine, 2-phenyl-1 -propylamine, (1.85 moles). A solution of L- malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was added dropwise to the yellow filtrate and the solution was heated to 75 °C. The solution was stirred at 75 °C for 30 minutes. The heat was removed and the solution was allowed to cool slowly. The resulting thick precipitate was allowed to stir overnight. The precipitate was filtered and dried under vacuum after rinsing with ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5%) as a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1- propylamine revealed 83.2% e.e. enriched in the R-isomer (configuration was assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine) ¹H NMR (CDCI₃, 300 MHz) δ 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1 H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).

A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2% e.e.) in 1325 mL ethanol and 150 mL deionized water was heated to reflux (-79.2 °C) until the solids went into solution. The homogeneous solution was allowed to slowly cool with stirring overnight. The precipitated white solids were cooled (0-5 °C) and filtered. The collected solids were rinsed with ethanol (150 mL) and dried at 35 °C to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2% recovery) as a white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine, revealed 96.7% e.e. enriched in the R-isomer. ¹H NMR (CD₃OD, 300 MHz) δ 7.32 (m, 10 H), 4.26 (dd, 1 H, J=3.6, 9.9), 3.08 (m, 6H), 2.72 (dd, 1 H, J=9.3, 15.3), 2.38 (dd, 1 H, J=9.3, 15.6), 1.33 (d, 6H, J=6.6).

Preparation of ((2R)-2-phenylpropyl)r(methylethyl)sulfonvnamine.

To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol) in CH₂CI₂ (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The mixture was stirred at room temperature for 1 hour and the organic phase was separated and gravity filtered into a 3.0 L round-bottom flask with a CH₂CI₂ rinse (200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via azeotropic distillation. Accordingly, the clear filtrate was concentrated to 600 mL at atmospheric pressure via distillation through a simple distillation head. Heptane (1000 mL) was added and the solution was concentrated again at atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of distillation. The final pot temperature was 109 °C. The solution was cooled to room temperature under nitrogen with stirring to give a clear, colorless heptane solution (600 mL) of (2R)-2-phenylpropylamine. To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 mol), triethylamine (200 g, 1.98 moles), and CH CI₂(500 mL). The mixture was stirred at room temperature until a clear solution was obtained. This solution was cooled to 5°C and a solution of isopropylsulfonyl chloride (148 g, 1.04 moles) in CH₂CI₂ (250 mL) was added dropwise with stirring over 2 hrs. The mixture was allowed to warm gradually to room temperature over 16 h. GC analysis indicated complete consumption of the (2R)-2-phenylpropylamine starting material.

The stirred mixture was cooled to 8 °C and 2 N HCI (500 mL) was added dropwise. The organic phase was separated and extracted with water (1 x 500 mL) and saturated NaHCO₃ (1 x 500 mL). The organic phase was isolated, dried (Na₂SO ), and gravity filtered. The filtrate was concentrated under reduced pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230g, 96%) as a pale yellow oil. ¹H NMR (CDCI₃, 300 MHz) δ 7.34 (m, 2H), 7.23 (m, 3H), 3.89 (br t, 1 H, J=5.4), 3.36 (m, 1 H), 3.22 (m, 1 H), 3.05 (m, 1 H), 2.98 (m, 1 H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 1.25 (d, 3H, J=6.9).

Preparation of r(2R)-2-(4-iodophenyl)propyl (methylethyl)sulfonvnamine.

A stirred room temperature solution of ((2R)-2- phenylpropyl)[(methylethyl)sulfonyl]amine (37.1 g, 0.154 mol) in glacial acetic acid (185 mL) was treated with concentrated H₂SO₄ (16.0 g, 0.163 mol), added dropwise in a slow stream, followed by a H₂O rinse (37 mL). To this solution (-30 °C) was added H₅IO₆ (8.29 g, 0.0369 mol), followed by iodine (17.9 g, 0.0707 mol). The resulting reaction mixture was heated and allowed to stir for 3 h at 60 °C. After HPLC analysis verified the consumption of starting material, the reaction mixture was cooled to 30° C and a 10% aqueous solution of NaHSO₃ (220 mL) was added dropwise while maintaining the temperature between 25 ° C and 30° C. The mixture crystallized to a solid mass upon cooling to 0-5 °C. The solids were suction filtered and rinsed with H₂O to afford 61.7 g of crude solids that were redissolved into warm MTBE (500 mL). This solution was extracted with H₂O (2 x 200 mL) and saturated NaHCO₃ (1 x 200 mL) and the organic phase was dried (MgS0 ), filtered, and concentrated under reduced pressure to -200 mL. Heptane (100 mL) was added dropwise to the product solution with slow stirring until crystallization commenced. An additional 100 mL of heptane was added and the resulting suspension was allowed to stir slowly overnight at room temperature. The mixture was then cooled (0 °C), filtered, and the collected solids were rinsed with heptane. The solids were then air-dried to afford the intermediate title compound, [(2R)-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (33.7 g, 59.8%) as a white powder. Chiral Chromatography of this lot indicated 100 % e.e. ¹H NMR (CDCI₃, 300 MHz) δ 7.66 (d, 2H, J=8.1), 6.98 (d, 2H, J=8.4), 3.86 (br t, 1 H, J=5.1 ), 3.33 (m, 1 H), 3.18 (m, 1 H), 3.06 (m, 1 H), 2.92 (m, 1 H), 1.30 (d, 3H, J=6.6), 1.27 (d, 6H, J=6.6).

Preparation of (methylsulfonyl)(2-phenylethyl)amine.

To a 10 °C solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH₂CI₂ (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1 N HCI (5 x 20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil. ¹H NMR (CDCI₃, 300 MHz) δ7.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s, 1H), 3.40 (t, 2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H). Preparation of r2-(4-iodophenyl)ethyl1(methylsulfonyl)amine.

To a stirring room temperature solution of (methylsulfonyl)(2- phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95% sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (H₅IO₆, 45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75 °C for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15 °C and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH₂CI₂ (1 L) and extracted with additional water (2 x 200 mL). The organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2%) as a white powder.

¹H NMR (CDCI₃, 300 MHz) δ 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1 H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9).

A room temperature solution of [2-(4- iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol), 4- dimethylaminopyridine (3.8 g, 0.031 mol) and di-fe/f-butyl dicarbonate (162 g, 0.744 mol) in CH₂CI₂ (1 L) was allowed to stir overnight. The reaction mixture was washed with water (2 x 400 mL) and the organic phase was concentrated to about 600 mL and hexanes (400 mL) was added. This combined solution was washed again with water (400 mL) and was concentrated to a solid that was suspended in hexanes (600 mL) and filtered. The collected solids were dried under reduced pressure to afford the intermediate title compound, (tert-butoxy)- N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (241.5 g, 91.5%) as a white solid.

¹H NMR (CDCI₃, 300 MHz) δ 7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8), 3.88 (t, 2H, J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H).

Preparation of (tert-butoxy)-N-(methylsulfonyl)-N-(2-F4-(4.4.5.5-tetramethyl(1.3.2- dioxaborolan-2-yl))phenyllethyl)carboxamide.

To a degassed solution of (tert-butoxy)-N-[2-(4-iodophenyl)ethyl]-N- (methylsulfonyl)carboxamide (128 g, 0.300 mol), triethylamine (91.1 g, 0.900 mol), and 1 ,1'-bis(diphenylphosphino) ferrocenedichloropalladium (ll)-CH₂Cl₂ complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was added pinacolborane (50 g, 0.391 mol) dropwise. The mixture was stirred at 70-74 °C for 8 h and then was cooled to room temperature. The reaction mixture was concentrated to a fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The organic phase was separated and washed with water (2 x 200 mL) and concentrated to a residue that was partially dissolved with heptane (1 L). The heptane soluble fraction was filtered through Celite^® 521 and concentrated to an oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL) and filtered through Celite^® 521. The combined filtrates were concentrated to 95 g of a mixture of a 3:1 molar ratio (¹H NMR, 81.0% by weight) of intermediate title compound, (tert-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1 ,3,2- dioxaborolan-2-yl))phenyl]ethyl}carboxamide, (60.3% potency corrected yield) and protio derivative.

¹H NMR (CDCI₃, 300 MHz) δ 7.75 (d, 2H, J=7.8), 7.23 (d, 2H, J=8.1), 3.87 (t, 2H, J=8.1 ), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s, 9H), 1.33 (s, 6H), 1.27 (s, 6H).

Preparation of (methylsulfonyl)f2-r4-(4.4.5,5-tetramethyl(1 ,3,2-dioxaborolan-2- yl))phenvπethyl}amine.

To a 2 L flask charged with a stirring solution of (tert-butoxy)-N- (methylsulfonyl)-N-{2-[4-(4,4,5,5-tetramethyl(1 ,3,2-dioxaborolan-2- yl))phenyl]ethyl}carboxamide (98.7 g, 0.232 mol) in CH₂CI₂ (500 mL) was added trifluoroacetic acid (82 mL, 121.4 g, 1.06 moles) dropwise from an addition funnel. No exotherm was observed and the reaction solution was allowed to stir at room temperature for 18 h. HPLC analysis indicated 98% completion so the cooled (5 °C) reaction mixture was neutralized by the slow addition of 5N NaOH (175 mL). The pH of the aqueous phase was 10.5. The phases were separated and the aqueous phase was extracted with CH2CI2 (50 mL). The combined CH2CI₂ phases were washed with brine (2 x 100 mL) and water (1 x 100 mL). The CH₂CI₂ phase was diluted with heptane (300 mL) and was concentrated under reduced pressure to afford a suspension that was isolated by filtration. The collected solids were washed with pentane (2 x 100 mL) and dried under vacuum to provide the intermediate title compound, (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1 ,3,2- dioxaborolan-2-yl))phenyl]ethyl}amine, (69.0g, 91.4%) as a white powder. ¹H NMR (CDCI₃, 300 MHz) δ 7.77 (d, 2H, J=8.1 ), 7.22 (d, 2H, J=7.8), 4.26 (br t, 1 H, J=6), 3.40 (q, 2H, J=6.9), 2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s, 12H). Preparation of 4-{2-[(methylsulfonyl)aminolethyl}benzene boronic acid.

(Methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2- yl))phenyl]ethyl}amine (68.0 g, 0.209 mol) was placed into a 2L flask and combined with acetone (600 mL), 1 N ammonium acetate (600 mL), and Nal0₄ (168.1 g, 0.786 mol). This mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove insoluble matter to afford filtrate A. The collected solids were washed with acetone (2 x 100 mL) and this filtrate was combined with filtrate A. The combined filtrates were concentrated under reduced pressure to 600 mL to afford a precipitate that was recovered by filtration. The collected solids were air-dried to give 110g of crude material. This crude material was suspended in water (100 mL) and 5N NaOH was added until the pH was 12.5. The resulting suspension was filtered and the filtrate was treated with decolorizing carbon (Darco 6-60). The mixture was filtered and the filtrate was diluted with 10N H₂SO4 until the pH was 5.0 to precipitate the intermediate title compound. This precipitate was collected by filtration and dried under reduced pressure to provide the intermediate title compound, 4-{2- [(methylsulfonyl)amino]ethyl}benzene boronic acid, (41.9 g, 82.5%) as a white powder. ¹H NMR (acetone-c/e, 300 MHz) δ 7.82 (d, 2H, J=8.4), 7.27 (d, 2H, J=7.8), 7.11 (s, 2H), 6.03 (m, 1 H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s, 3H).

Preparation of final title compound.

An aqueous solution of potassium formate was prepared in the following manner. To 15 mL of water was added KOH (85% flakes, 6.73 g, 0.102 mol), then 98% formic acid (4.70 g, 0.102 mol). Alternatively, one may use commercially available potassium formate. To this solution was then added K₂C0₃ (2.76 g, 0.0210 mol), 4-{2-[(methylsulfonyl)amino]ethyl}benzene boronic acid (4.62 g, 0.190 mol), 1-propanol (100 mL), and [(2R)-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (7.35 g, 0.200 mol). This mixture was deoxygenated via three vacuums-refill cycles. Palladium black (0.0215 g, 0.0002 mol) was added and the mixture was again deoxygenated via three vacuums-refill cycles. The reaction flask was heated in a preheated oil bath at 88 °C and the mixture was stirred overnight. HPLC analysis showed complete consumption of 4-{2-

[(methylsulfonyl)amino]ethyl}benzene boronic acid, and the mixture was diluted with ethyl acetate and filtered through Celite^® to remove palladium. The mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic phase was concentrated and the solid residue was collected and recrystallized from 1 :1 acetone / water to afford the final title compound, {(2R)-2-[4-(4-{2- [(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, (6.2 g, 75%) as a white crystalline powder. ¹H NMR (CDCI₃, 300 MHz) δ 7.54 (dd, 4H, J=1.8, 8.1), 7.29 (dd, 4H, J=1.8, 8.1), 4.27 (t, 1 H, J=6.6), 3.91 (m, 1 H), 3.43 (q, 2H, J=6.6), 3.37 (dd, 1 H, J=5.7, 7.5), 3.26 (m, 1 H), 3.07 (m, 2H), 2.93 (t, 2H, J=6.6), 2.87 (s, 3H), 1.34 (d, 3H, J=7.2), 1.31 (d, 3H, J=6.9), 1.27 (d, 3H, J=6.6).

Additional preparation of {(2R)-2-f4-(4-f2- r(methylsulfonyl)amino1ethyl|phenyl)phenvnpropyl)r(methylethvπsulfonyllamine.

Within a single-neck, 3L round bottom flask equipped with a magnetic stir bar was placed potassium formate (112.8 g, 1.34 moles, 5.1 eq) and water (200 mL) to provide a pH 8 solution. Potassium carbonate (72.7g, 0.526 mol, 2.0 eq), and 4-{2-[(methylsulfonyl)amino]ethyl}benzene boronic acid (60.8 g, 0.250 mol, 0.95 eq) was added to form a stirring suspension as 1-propanol (720 mL) was added. [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (96.6 g, 0.263 mol, 1.0 eq) was added followed by additional 1-propanol (600 mL). The resulting mixture was stirred for 3 minutes while the reaction flask was fitted with a heating mantle and a glycol-cooled reflux condenser. Vacuum (10-20 torr) was slowly applied to the system over 10 minutes. Stirring had stopped due to the additional precipitation of the cooled system; nevertheless, after 30 minutes, the system was returned to atmospheric pressure with nitrogen. With gentle heating, the flask was evacuated and refilled with nitrogen two additional times. Stirring was stopped and palladium black (0.28 g, 0.0026 mol, 0.01 eq) was quickly added to the flask. Stirring was resumed and the system was again evacuated and returned to atmospheric pressure with nitrogen over a 2 minute cycle. This evacuation / nitrogen purge was repeated two more times over a 15 second cycle and the mixture was heated to reflux.

After 16 hours, an aliquot was removed and analyzed by HPLC (275nm detection). Analysis showed 0.07% of achiral dimer, (methylsulfonyl){2-[4-(4-{2- [(methylsulfonyl)amino]ethyl}phenyl)phenyl]ethyl}amine, relative to the desired product, {(2R)-2-[4-(4-{2-

[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine. The reaction mixture was cooled to 50 °C and ethyl acetate (500 mL) was added. The reaction mixture was then cooled to room temperature and the product, {(2R)-2-[4-(4-{2- [(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, began to precipitate. Additional ethyl acetate (1 L) was introduced to redissolve the product and the upper organic phase was decanted and filtered through Celite^® to remove palladium metal. The filter cake was rinsed with 1-propanol. The homogeneous filtrate was concentrated under reduced pressure to remove n-propanol and after removal of 1.5 L of distillate, the product suspension was filtered. The combined filter cakes were dried to afford 109.8g of crude final title compound.

Recrystallization: The crude final title compound (109.8 g) was dissolved in acetone (490 mL). This solution was filtered though a glass filter to retain a minor amount of dark insoluble material. To the slowly stirred filtrate was added water (300 mL) over 15 min. The resulting suspension was stirred for 15 minutes and additional water (20 mL) was introduced over 10 minutes. The suspension was subsequently stirred for 30 minutes at room temperature and was filtered. The cake was washed with 1 :1 acetone / water (600 mL) and was dried at 35 °C overnight. This process afforded 80.3 g (81.1%) of {(2R)-2-[4-(4-{2-

[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine as a white crystalline powder with a mean particle size of about 29 to about 34 microns. HPLC analysis indicated 0.01% achiral dimer, (methylsulfonyl){2-[4-(4- {2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]ethyl}amine, and 0.02% chiral dimer, ((2R)-2-{4-[4-((1 R)-1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}propyl)[(methylethyl)sulfonyl]a mine.

Alternative preparation of K2R)-2-f4-(4-(2- r(methylsulfonyl)amino1ethyl>phenyl)phenvnpropyl)r(methylethyl)sulfonvnamine.

Preparation of 4-{2-r(tert-butoxy)-N-(methylsulfonyl)carbonylamino1ethyl)benzene boronic acid.

To a room temperature solution of (tert-butoxy)-N-(methylsulfonyl)-N-{2-[4- (4,4,5,5-tetramethyl(1 ,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide (81.0% potent, 95 g, 0.18 mol, prepared in example 1 ) in acetone (2 L) was added 1 N ammonium acetate (1 L) and sodium periodate (145 g, 0.678 mol) with stirring. The reaction was allowed to proceed overnight. The reaction mixture was concentrated to remove the acetone, and the aqueous phase was decanted away from the oily product. The aqueous phase was extracted with CH₂CI₂ (100 mL) and MTBE (2 x 100 mL). The combined oily product and organic phases were adjusted to pH 12.5 with the addition of 1 N NaOH. The phases were separated, and the organic phase was extracted with 1 N NaOH (100 mL) and water (2 x 100 mL). HPLC analysis (60% CH₃CN / 40% H₂0, 2 mL / min, Zorbax C-18, 205 nm) of the organic phase indicated that the product had been removed from this phase. The aqueous phases (containing product) were finally combined and washed with CH₂CI₂ (100 mL) and MTBE (2 x 100 mL). The aqueous phase was added to CH2CI2 (450 mL) and 1 N H₂S0₄ was added until the aqueous phase was at pH 3.05. The phases were separated and the aqueous phase was extracted with CH₂CI₂ (100 mL). The combined organic extracts (containing product) were concentrated to an oil (58.5 g) that crystallized overnight. The resulting solid mass was triturated with 10% MTBE in heptane (100 mL) to afford, after filtration and drying under reduced pressure, the intermediate title compound, 4-{2-[(tert-butoxy)-N- (methylsulfonyl)carbonylamino]ethyl}benzene boronic acid , (47.7 g, 77.2%) as a white powder.

¹H NMR (£/₆-DMSO, 300 MHz) δ 7.83 (d, 2H, J= 4.8), 7.24 (d, 2H, J=5.1), 7.12 (s, 2H), 3.90 (t, 2H, J=3.9), 3.12 (s, 3H), 2.95 (t, 2H, J=4.5), 1.52 (s, 9H).

Preparation of final title compound.

Run 1. Within a 3-neck, 1000 mL round-bottom flask was placed [(2R)-2- (4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (15.0 g, 0.0408 mol, prepared in example 1 ), 4-{2-[(tert-butoxy)-N-(methylsulfonyl)carbonylamino]ethyl}benzene boronic acid (19.1 g, 0.0557 mol), K₂C0₃ (6.8 g, 0.0490 mol) and 1-propanol (300 mL). To this mixture was then added water (42 mL) and finally Pd(OAc)₂ (18 mg, 8.17 x 10^"5 mol, 0.2 mol %). The resulting clear, pale amber solution was heated to reflux (87 °C) to become a dark amber, then a clear olive solution with stirring black particulates (Pd°). The reaction was allowed to stir for 20 h and was allowed to cool to room temperature. TLC analysis (1 :9 EtOAc / CH₂CI₂) of the resulting off-white suspension indicated desired product (R_f 032), complete consumption of [(2R)-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (R_f 0.60) and only a trace of 4-{2- [(tert-butoxy)-N-(methylsulfonyl)carbonylamino]ethyl}benzene boronic acid (R_f 0.49). The suspension was diluted with EtOAc (300 mL) to give a clear, pale yellow solution that was filtered through Celite^® (presaturated with EtOAc).

After washing the Celite^® through with EtOAc, the filtrate was combined with that of an identical Run 2 which was conducted identically as described above. The combined filtrates from both runs were concentrated under reduced pressure to afford white solids that were diluted with EtOAc (1 L) and 10% K₂C0₃ (300 mL) to form a clear, amber biphasic solution that was agitated. The aqueous phase (light pink) was separated and the organic phase was washed with additional 10% K₂C0₃ (4 x 300 mL). The aqueous phase was back extracted with EtOAc (300 mL) and the combined organic phases (1500 mL) were dried (MgS0₄), filtered, and concentrated to a volume of about 620 mL within a 3 L round-bottom flask. The clear, pale yellow solution was stirred slowly while heating to 60 °C. Heptane (400 mL) was added dropwise from a 5 separatory funnel to the stirring EtOAc solution at 60 °C (17 volumes of EtOAc / 11 volumes of heptane). The heptanes were added over a period of 1.5 h and the clear, pale yellow solution was allowed to cool slowly with slow stirring overnight. The resulting white crystalline solids were cooled to 0 °C, filtered, and washed with a minimum of 1 :1 EtOAc / heptanes to afford the final title 0 compound, {(2R)-2-[4-(4-{2-

[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, (27.1 g, 75.7%) as a white crystalline powder.

Alternative preparation of ((2R)-2-phenylpropy0r(methylethv0sulfonyllamine. 5

Preparation of (2R)-2-phenylpropan-1-ol.

An oven dried 500.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen o blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2 mmol) and toluene (75.0 mL). Reaction solution was then chilled to -60°C with dry ice/acetone bath. To this solution was then added R-styrene oxide dissolved in 100.0 mL of toluene over a period of 50.0 minutes (reaction is quite exothermic and can be controlled by the rate of addition of substrate). After stirring at this 5 temperature for 60.0 minutes, reaction was brought to room temperature and stirred for 4.0 hours. Reverse quenched reaction at room temperature into a slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g) very cautiously over a period of 90.0 minutes (quenching was quite exothermic with evolution of gas). Filtered the precipitate formed over hyflo, then concentrated filtrate to o provide the intermediate title compound, (2R)-2-phenylpropan-1 -ol, (11.03 g,

92.6%) as an oil; 1 H nmr (CDCI₃) δ 1.28-1.29 (d, 3H, J = 6.9Hz), 1.5 (b, 1 H), 2.9- 3.0 (m, 1 H), 3.69-3.70 (d, 2H, J = 6.64Hz), 7.24-7.35 (aromatic); 13C nmr (CDCI₃) δ 18.31 , 43.15, 69.40, 127.38, 128.20, 129.26144.39.

Preparation of 2-((2R)-2-phenylpropyl)isoindoline-1 ,3-dione An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50°C by the end of addition went from clear to reddish color). Stirred reaction t room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1:1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2-((2R)-2- phenylpropyl)isoindoline-1 ,3-dione, (4.27 g, 96%) as an oil which solidified on equilibratin to room temperature; 1 H nmr (CDCI₃) δ 1.3 (d, 3H), 3.3-4.0(m, 1 H), 3.7-3.9 (m, 2H), 7.1- 7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H).

Preparation of (2R)-2-phenylpropylamine.

A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1 ,3- dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL,

86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90°C-95°C for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2- phenylpropylamine, (5.58 g, 94.9%) an oil; 1H nmr (CDCI₃) δ 1.21 (d,3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1 H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H).

Preparation of final title compound.

To a solution of the (2R)-2-phenylpropylamine (1.2g, 8.87mmol) in hexane (16.0m was added triethylamine (2.47 mL, 17.74 mmol) and dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5°C, then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with 1 N HCI (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate t provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1 %) an oil; 1 H nmr (CDCI₃) δ 1.25 (d,3H, J=6.9Hz), 1.29(d, 3H, J=6.9Hz), 1.30 (d, 3H, J= 7.2Hz), 2.98 (m, 1 H), 3.05 (m, 1H), 3.22 (m, 1 H), 3.36 (m, 1 H), 3.89 (b, 1 H), 7.23 (m, 2H), 7.34 (m, 2H).

Example 2b Preparation of {(2S)-2-r4-(4-f2- f(methylsulfonyl)aminolethyl>phenyl)phenyllpropyl)r(methylethyl)sulfonyllamine.

The title compound can be prepared in a manner analogous to the procedure set forth in example 2a starting with, for example, ((2S)-2- phenylpropyl)[(methylethyl)sulfonyl]amine.

Example 3

Preparation of N-2-(4-(3-thienyl)phenylpropyl 2-propanesulfonamide.

The title compound can be prepared in a manner analogous to the procedure set forth in WO 98/33496 published August 6, 1998, Example 28. Example 4 Preparation of r2-fluoro-2-(4-{3- [(methylsulfonyl)aminolphenyl)phenyl)propylir(methylethyl)sulfonvnamine.

Preparation of 1-amino-2-(4-iodophenyl)propan-2-ol.

The trimethylsilyl-protected cyanohydrin derivative of 4-iodoacetophenone was prepared in situ following generally the method disclosed by Greenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Accordingly, cyanotrimethylsilane (21.4 g, 0.216 mol) was added dropwise over 5 minutes to a dry, room temperature solution containing 4-iodoacetophenone (44.3 g, 0.180 mol), 18-crown-6 (1.6 g, 6.1 mmoles) and KCN (1.17g, 0.018 mol) in THF (100 mL). The resulting solution was allowed to stir for 2.5 h. TLC analysis (3:7 EtOAc / Hexanes) showed consumption of starting acetophenone. A 10M solution of borane in dimethylsulfide (25 mL, 0.25 mol) was added rapidly to the reaction solution and the resulting mixture was heated at reflux for 16 h. The mixture was cooled to room temperature and anhydrous 10% (by wt) HCI in methanol was added slowly over 1 h (GAS EVOLUTION). The solution was allowed to stir for an additional hour, and was concentrated under reduced pressure to give the crude title compound as white solid and as the hydrochloride salt. This salt was triturated with methyl f-butyl ether and filtered. The free base was prepared by adding 1 N NaOH to a suspension of the HCI salt in CH₂CI₂ (150 mL) and THF (350 mL) until pH 12.3 was reached. The phases were separated and the organic phase was washed with brine (25 mL). The organic phase containing the free amine was concentrated under reduced pressure and the resulting solids were triturated with diethyl ether (30 mL) to afford 1-amino-2- (4-iodophenyl)propan-2-ol (35.6 g, 71.3%) as an off-white powder after vacuum drying. ¹H NMR (CD₃OD, 300 MHz): δ 7.68 (d, 2H, J = 8.4), 7.24 (d, 2H, J = 8.7), 2.78 (m, 2H), 1.46 (s, 3H).

Preparation of r2-hvdroxy-2-(4-iodophenyl)propyπr(methylethyl)sulfonvπamine.

Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4- iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL CH₂CI₂ while stirring at 0°C under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H₂O and the layers were separated. The organic layer was washed once with H₂0, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum . The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide [2-hydroxy-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (744 mg, 19%) as a solid material.

FDMS 382 (M*).

Analysis for Cι₂Hι₈N0₃ S I: Theory: C, 37.61 H, 4.73 N, 3.65 Found: C, 38.08 H, 4.26 N, 3.55

Alternative preparation of r2-hvdroxy-2-(4- iodophenyl ropyHr(methylethvnsulfonvnamine.

In a 250 mL-3 neck flask fitted with a stirrer and thermometer, 2.10 g. of propanesulfonyl chloride was added dropwise to 2.77 g. of 1-amino-2-(4- iodophenyl)propan-2-ol and 2.30 g. of DBU in CH₂CI (150 mL) while stirring at

0°C under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the reaction was diluted with CH2CI₂ (100 mL) and the organic layer was washed two times with H₂O, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum to yield a viscous oil. This material was purified via silica gel chromatography employing the Chromatotron, using a 4000 micron rotor and eluting with a solvent of methylene chloride/methanol 19:1 to yield [2-hydroxy-2- (4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.0 g, 31%) as a viscous oil. Ion spray M.S. 382 (M* - 1 ).

Preparation of |^"2-fluoro-2-(4-iodophenyl)propylir(methylethyl)sulfonyl1amine.

Into a 10 mL single neck flask, a solution of [2-hydroxy-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (158 mg, 0.41 mmol) in 1.7 mL CH₂CI₂ was added syringe wise slowly to a solution of DAST (66 mg, 0.41 mmol) in 0.3 mL CH₂CI₂ while stirring at -78°C under nitrogen. The reaction was then allowed to warm to room temperature and the mixture was diluted with H2O and CH₂CI₂. The layers were separated and the organic layer was washed twice with H₂O, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum to [2-fluoro-2- (4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg) as a solid. Ion spray M.S. 384 (MM).

Additional preparation of r2-fluoro-2-(4- iodophenvDpropyπr(methylethvDsulfonvπamine. Into a 100 mL 3-neck flask fitted with a stirrer and thermometer, 1.0 g. of

[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine in CH₂CI₂ (15 mL) was added dropwise to 0.3 mL DAST in CH₂CL₂ (10 mL) while stirring at -78°C under a nitrogen atmosphere. Reaction was allowed to warm to room temperature and diluted with CH₂CI (50 mL). This organic layer was washed with H₂0, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum to yield an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a gradient solvent of hexane/ethyl acetate 9:1 to hexane/ethyl acetate 3:1 to yield [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine

(0.906 g) as a white solid. Ion spray M.S. 384 (M* - 1 ).

5 Analysis for Cι₂H ₇N0₂SFI:

Theory: C, 37.42 H, 4.44 N, 3.64 Found: C, 37.27 H, 4.33 N, 3.61

Preparation of (2-[4-(3-aminophenyl)phenyll-2- 0 fluoropropyl)f(methylethyl)sulfonyl1amine.

Into a 50 mL single neck flask [2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.53 mmol), 3- 5 aminobenzene boronic acid (188 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol) and tetrakis(triphenyl phosphine)palladium(O) (41 mg, 0.036 mmol) were combined in dioxane/water (20 mL, 3:1). The mixture was heated at 100 °C under stirring for 18 hours. The reaction was cooled to room temperature and poured into H₂0. The desired product was extracted with ethyl acetate and the o organic layer was separated and washed twice with H₂O, dried over K₂CO₃ , and concentrated under reduced vacuum to yield the crude material (276 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate 1 :1 to yield the title compound (164 mg, 90%) as a viscous 5 oil. Ion spray M.S. 351.4 (M*+1 ).

Analysis calculated for: Cis H₂₃ N₂ 0₂ S F: Theory: C, 61.69 H, 6.62 N, 7.99 Found: C, 61.53 H, 6.55 N, 8.13

0 Preparation of final title compound.

A 50 mL flask fitted with a stirrer and thermometer was charged with DBU (67 mg, 1.1 eq), {2-[4-(3-aminophenyl)phenyl]-2- fluoropropyl}[(methyIethyl)sulfonyI]amine (140 mg, 0.44 mmol) and methylene chloride (10 mL) under an atmosphere of nitrogen, and cooled to 0°C. To this stirring solution was added dropwise chloro-methane sulfonyl chloride (69 mg,

1.5 eq). The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H₂0 and the layers were separated. The organic layer was washed once with H₂O, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum to yield the crude material (192 mg) as a yellow oil. This crude material was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Methylene Chloride/ethyl acetate 9:1 to yield the final title compound, [2-fluoro-2-(4-{3-

[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine, (50 mg, 29%) as a white foam. Ion spray mass spectra 427.1 (M*-1).

Analysis for C₁₉ H25 N₂0₄ S₂ F: Theory: C, 53.25 H, 5.88 N, 6.54 Found: C, 53.56 H, 6.11 N, 6.29

Example 4a Preparation of r2-Fluoro-2-(4-(3- r(methylsulfonvπamino1phenyl>phenvπpropyn[(methylethvπsulfonvnamine (enantiomer 1). Preparation of (+)-r2-fluoro-2-(4-iodophenyl)propyll[(methylethyl)sulfonvnamine and (-)-[2-fluoro-2-(4-iodophenyl)propynr(methylethyl)sulfonyl1amine.

[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.0 g, prepared in example 3) was dissolved into 3A ethanol (30 mL) and was further diluted with heptane (20 mL). [As used herein the term "3A ethanol" refers to ethanol containing 5% methanol.] The mixture was agitated via ultrasound to form a clear, colorless solution. This lot was loaded upon a 8 x 28 cm preparative Chiralpak AD chromatographic column that was pre-equilibrated with 60% 3A ethanol/40% heptane. Eluent flow was 300 mL/min and detection wavelength was 240 nm. The first eluting substance was (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine, [α]_D = +18.5 (c=1.08, MeOH), and the subsequent eluting substance was (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine, [α]_D = -23.5 (c=1.02, MeOH). The above procedure was repeated twice in an analogous manner with [2-fluoro- 2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (second run, 3.0 g dissolved in 50 mL 3A ethanol/heptane, 3:2 and a third run, 2.0 g dissolved in 0.8 g dissolved in 40 mL 3A ethanol/heptane, 3:2). Thus, in three runs, a total of 5.8 g of [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine was resolved into its component enantiomers in the following yields after concentration (in vacuo) of fractions:

(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.38 g, 41.0%); (-)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.2 g, 20.7%).

Analysis conditions: 0.46 x 35 cm Chiralpak AD 60% ethanol (5% methanol)/40% Heptane; Flow: 1.0 mL/min, detection wavelength: 240 nm.

For (+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine: R_t= 5.4 min, MS (ES+) 384 (M-1).

¹H NMR (CDCI₃, 300 MHz): δ 7.73 (d, 2H, J=8.1 ), 7.09 (d, 2H, J=8.4), 4.27 (t, 1 H,

J=6.2), 3.50 (m, 2H), 3.03 (m, 1 H), 1.69 (d, 3H, J=22), 1.30 (d, 3H, J=7), 1.27 (d,

3H, J=7).

Analysis for C₁₂H₁₇FINO₂S: Theory: C 37.41 , H 4.45, N 3.64.

Found: C 37.54, H 4.43, N 3.64.

For (-)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine: R_t= 10.1 min. MS (ES+) 384 (M-1). ¹ H NMR spectrum identical to that of (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine. Analysis for Cι₂H₁₇FIN0₂S: Theory: C 37.41 , H 4.45, N 3.64. Found: C 37.56, H 4.43, N 3.59.

(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.78 mmol), the borate of formula:

(347 mg, 1.5 eq.), potassium carbonate (156 mg, 1.5 eq), tetrakis(triphenyl phosphine)palladium(O) (75 mg, 0.06 mmol) and dioxane/water (36 mL, 3:1 ) were mixed together in a 100 mL single neck flask and stirred at 80°C for 4 hours.

The reaction was cooled to room temperature and poured into H₂O and the desired product was extracted with ethyl acetate. The organic layer was backwashed once with H₂O, dried over K₂CO₃, filtered, and concentrated under reduced pressure to yield 191 mg as a viscous oil. This material was purified via silica gel chromatography employing the chromatotron and using a 2000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1 :1 to yield the title compound (86 mg, 26%) as a white solid. Ion spray M.S. 427.1 (MM ).

Calculated for: C₁₉H25N2θ₄S2 F- H₂0 : Theory: C 51.08, H 6.09, N 6.27. Found : C 51.29, H 5.63, N 6.29.

Example 4b Preparation of r2-Fluoro-2-(4-{3- r(methylsulfonyl)aminolphenyl)phenyl)propynr(methylethyl)sulfonvnamine (enantiomer 2).

(-)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (493 mg,

1.28 mmol, prepared in example 3a), the borate of formula:

(385 mg, 1.30 mmol), 2.0 M Na₂C0₃/H₂0 (2.2 mL, excess), tetrakis(triphenyl phosphine)palladium(O) (100 mg, 0.09 mmol) and dioxane (15 mL) were mixed together in a 50 mL single neck flask and stirred at 80°C overnight. In the morning the reaction was cooled to room temperature and poured into H₂O and the desired product was extracted with ethyl acetate. The organic layer was backwashed once with H₂0, dried over K₂CO₃, filtered, and concentrated under reduced pressure to yield 571 mg as a foam. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1 :1 to yield the title compound (294 mg, 56%) as a brown solid. Ion spray M.S. 427.3 (MM ).

Calculated for: C₁₉H_{25 2}O₄S₂ F- H₂0: Theory: C 51.08, H 6.09, N 6.27. Found : C 51.29, H 5.63, N 6.29.

Example 5 Preparation of 4-r4-(1-methyl-2- {[(methylethvπsulfonvnaminolethvDphenvπbenzenecarbonitrile.

The title compound is prepared in a manner analogous to the procedure set forth in WO 98/33496 at example 58.

Example 5a Preparation of 4-l4-((1 RV1-methyl-2- [(methylethvDsulfonvπaminoTethvπphenvnbenzenecarbonitrile.

The title compound is prepared in a manner analogous to the procedure set forth in WO 98/33496 at example 58 from [(2R)-2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine. [(2R)-2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine is readily prepared by one of ordinary skill in the art, for example, by resolution of [2-(4- bromophenyl)propyl][(methylethyl)sulfonyl]amine using chiral chromatography.

Example 6a Preparation of 4-f4-((1 S)-1 -fluoro-1 -methyl-2- (ffmethylethvDsulfonvnaminolethvDphenyllbenzenesulfonamide.

Preparation of 1-amino-2-(4-iodophenyl)p τopan-2-ol.

The trimethylsilyl-protected cyanohydrin derivative of 4-iodoacetophenone was prepared in situ following generally the method disclosed by Greenlee and Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Accordingly, cyanotrimethylsilane (21.4 g, 0.216 mol) was added dropwise over 5 minutes to a dry, room temperature solution containing 4-iodoacetophenone (44.3 g, 0.180 mol), 18-crown-6 (1.6 g, 6.1 mmoles) and KCN (1.17g, 0.018 mol) in THF (100 mL). The resulting solution was allowed to stir for 2.5 h. TLC analysis (3:7 EtOAc / Hexanes) showed consumption of starting acetophenone.

Scheme IV, step B: A 10M solution of borane in dimethylsulfide (25 mL, 0.25 mol) was added rapidly to the reaction solution and the resulting mixture was heated at reflux for 16 h. The mixture was cooled to room temperature and anhydrous 10% (by wt) HCI in methanol was added slowly over 1 h (GAS

EVOLUTION). The solution was allowed to stir for an additional hour, and was concentrated under reduced pressure to give the crude title compound as white solid and as the hydrochloride salt. This salt was triturated with methyl f-butyl ether and filtered. The free base was prepared by adding 1 N NaOH to a suspension of the HCI salt in CH₂CI₂ (150 mL) and THF (350 mL) until pH 12.3 was reached. The phases were separated and the organic phase was washed with brine (25 mL). The organic phase containing the free amine was concentrated under reduced pressure and the resulting solids were triturated with diethyl ether (30 mL) to afford the intermediate title compound (35.6 g, 71.3%) as an off-white powder after vacuum drying. ¹H NMR (CD₃OD, 300 MHz): δ 7.68 (d, 2H, J = 8.4), 7.24 (d, 2H, J = 8.7), 2.78 (m, 2H), 1.46 (s, 3H).

Preparation of r2-hvdroxy-2-(4-iodophenyl)propyn[(methylethyl)sulfonyl1amine.

Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4- iodophenyl)propan-2-ol (2.77 g, 0.01 mol) in 125 mL CH₂CI₂ while stirring at 0°C under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H₂O and the layers were separated. The organic layer was washed once with H₂O, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum . The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material.

FDMS 382 (M*).

Analysis for C₁₂H-₁-₃NO₃ S I: Theory: C, 37.61 H, 4.73 N, 3.65 Found: C, 38.08 H. 4.26 N, 3.55 Alternative preparation of r2-hvdroxy-2-(4- iodophenyl)propynr(methylethyl)sulfonyl1amine.

In a 250 mL-3 neck flask fitted with a stirrer and thermometer, 2.10 g. of propanesulfonyl chloride was added dropwise to 2.77 g. of 1-amino-2-(4- iodophenyl)propan-2-ol and 2.30 g. of DBU in CH₂CI₂ (150 mL) while stirring at 0°C under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the reaction was diluted with CH₂CI₂ (100 mL) and the organic layer was washed two times with H₂O, dried over anhydrous Na₂S0 , filtered, and concentrated under reduced vacuum to yield a viscous oil. This material was purified via silica gel chromatography employing the Chromatotron^®, using a 4000 micron rotor and eluting with a solvent of methylene chloride/methanol 19:1 to yield the intermediate title compound (1.0 g, 31%) as a viscous oil. Ion spray M.S. 382

(M* - 1).

Preparation of f2-fluoro-2-(4-iodophenyl)propyn[(methylethvπsulfonvnamine.

Into a 10 mL single neck flask, a solution of [2-hydroxy-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (158 mg, 0.41 mmol) in 1.7 mL CH₂CI₂ was added syringe wise slowly to a solution of DAST (66 mg, 0.41 mmol) in 0.3 mL CH₂CI₂ while stirring at -78°C under nitrogen. The reaction was then allowed to warm to room temperature and the mixture was diluted with H₂0 and CH₂CI₂. The layers were separated and the organic layer was washed twice with H₂O, dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced vacuum to provide the intermediate title compound (113 mg) as a solid. Ion spray M.S. 384 (MM ).

Additional preparation of f2-fluoro-2-(4- iodophenvOpropylir(methylethyl)sulfonyllamine.

Into a 100 mL 3-neck flask fitted with a stirrer and thermometer, 1.0 g. of

[2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine in CH₂CI₂ (15 mL) was added dropwise to 0.3 mL DAST in CH₂CL₂ (10 mL) while stirring at -78°C under a nitrogen atmosphere. Reaction was allowed to warm to room temperature and diluted with CH₂CI₂ (50 mL). This organic layer was washed with H₂0, dried over anhydrous Na₂Sθ₄, filtered, and concentrated under reduced vacuum to yield an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a gradient solvent of hexane/ethyl acetate 9:1 to hexane/ethyl acetate 3:1 to yield the intermediate title compound (0.906 g) as a white solid.

Ion spray M.S. 384 (M* - 1 ).

Analysis for Cι₂H₁₇N0₂SFI: Theory: C, 37.42 H, 4.44 N, 3.64 Found: C, 37.27 H, 4.33 N, 3.61 Preparation of (+)-[2-fluoro-2-(4-iodophenyl)propylir(methylethyl)sulfonvnamine and (-V[2-fluoro-2-(4-iodophenyl)propylll^'(methylethyl)sulfonvnamine. [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.0 g, prepared above) was dissolved into 3A ethanol (30 mL) and was further diluted with heptane (20 mL). [As used herein the term "3A ethanol" refers to ethanol containing 5% methanol.] The mixture was agitated via ultrasound to form a clear, colorless solution. This lot was loaded upon a 8 x 28 cm preparative Chiralpak AD chromatographic column that was pre-equilibrated with 60% 3A ethanol/40% heptane. Eluent flow was 300 mL/min and detection wavelength was 240 nm. The first eluting substance was (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine, [α]o = +18.5 (c=1.08, MeOH), and the subsequent eluting substance was (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine, [α]_D = -23.5 (c=1.02, MeOH).

The above procedure was repeated twice in an analogous manner with [2-fluoro- 2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (second run, 3.0 g dissolved in 50 mL 3A ethanol/heptane, 3:2 and a third run, 2.0 g dissolved in 0.8 g dissolved in 40 mL 3A ethanol/heptane, 3:2). Thus, in three runs, a total of 5.8 g of [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine was resolved into its component enantiomers in the following yields after concentration (in vacuo) of fractions:

¹H NMR (CDCI₃, 300 MHz): δ 7.73 (d, 2H, J=8.1), 7.09 (d, 2H, J=8.4), 4.27 (t, 1H, J=6.2), 3.50 (m, 2H), 3.03 (m, 1 H), 1.69 (d, 3H, J=22), 1.30 (d, 3H, J=7), 1.27 (d, 3H, J=7).

Analysis for C₁₂H₁₇F1N0₂S: Theory: C 37.41 , H 4.45, N 3.64. Found: C 37.54, H 4.43, N 3.64. For (-)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine: R_t= 10.1 min. MS (ES+) 384 (M-1).

¹H NMR spectrum identical to that of (+)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine.

Analysis for C₁₂H₁₇FIN0₂S:

Theory: C 37.41 , H 4.45, N 3.64.

Found: C 37.56, H 4.43, N 3.59.

Preparation of final title compound. Into a 500 mL single neck flask fitted with a stirrer was placed (+)-[2- fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (3.42 g, 8.87 mmol), pinacolato diboron (2.40 g, 9.45 mmol), and potassium acetate (2.58 g, 3 equivalents) in DMF (180 mL). This mixture was stirred at room temperature and de-gassed with argon for 10 minutes. Then, PdCl₂(dppf) (180 mg) was added portion wise and the reaction was stirred at 80°C under a nitrogen atmosphere for 2 hours. The dark mixture was allowed to cool to room temperature and 4- bromo-phenylsulfonamide (3.97 g, 16.8 mmol) and an additional amount of PdCI₂(dppf) (180 mg) was added portion wise. This was followed by the addition of 21.6 mL of 2.0 M sodium carbonate/water syringe wise. The mixture was then heated to 80°C and stirred overnight. In the morning, the reaction was allowed to cool to room temperature and poured into water. The desired material was extracted into ethyl acetate. The organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 6.41 g of crude material (2 spots by thin layer chromatography, TLC) as a dark oil. This material was separated and purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with an isocratic solvent of methylene chloride/ethyl acetate (9:1) to provide the final title compound (2.47 g, 67%, lower spot by TLC) as a white solid. Melting point was 119.5-121°C; Ion spray M.S. 413 (M* - 1): Rotation = +18.69 in methanol at room temperature at Sodium D.

Calculated for: C₁₈H₂3 N₂0₄S₂F: Theory: C 52.16, H 5.59, N 6.76 Found : C 52.37, H 5.96, N 6.19 Example 6b Preparation of 4-l^"4-((1 R)-1 -fluoro-1 -methyl-2- {[(methylethyl)sulfonyl1amino)ethyl)phenvnbenzenesulfonamide.

The title compound can be prepared in a manner analogous to the procedure set forth in example 1 from (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine and 4-bromo-phenylsulfonamide.

Example 7 Preparation of (1S.2R) Trans 4'-[2-(Propane-2-sulfonylamino)-cvclopentvπ- biphenyl-4-carboxylic acid methylamide.

Preparation of (+,-) trans-bromophenylcvclopentyl carbinol.

A 500 mL three necked flask equipped with a mechanical stirrer, thermometer, addition funnel under a blanket of nitrogen was charged with 4- bromophenylmagnesium bromide (43.6 g, 167.57 mmol), anhydrous THF (120.0 mL) and catalytic copper iodide (1.59 g, 8.38 mmol) with vigorous stirring at room temperature for 10.0 minutes. To this mixture was then added dropwise a solution of cyclopentene oxide (14.62 mL, 167.57 mmol) dissolved in THF (20.0 mL) over a period of 20.0 minutes. Reaction was quite exothermic, reaching the reflux of THF by the end of addition. The reaction was brought to room temperature and stirred for 120.0 minutes, after which reaction was reversed quenched carefully into a 25% ammonium chloride solution (100.0 mL).

Extracted with methylene chloride (150.0 mL), dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give an oil (19.0 g).

Silica gel plug filtration of the oil with 1 :1 ethyl acetate and hexane, and subsequent concentration of fractions 2 and 3 afforded the bromophenylcyclopentyl carbinol as a light red oil (mass = 13.61g, 34% wt. Yield;

¹H NMR (CDCI₃) δ 1.60-2.20 (m, 6H), 2.80-2.90 (m, 1H), 4.10-4.20 (m, 1H), 7.10 (d, 2H), 7.40-7.50 (d, 2H); ¹³C NMR (CDCI₃) δ 22.38, 32.45, 54.40, 80.98, 121.00, 129.86, 132.25, 143.00.

Preparation of (+,-) Cis Benzoic acid 2-(4-bromo-phenyl)-cvclopentyl ester.

Scheme IB, step E: Into 250 mL 3 neck flask fitted with a stirrer and thermometer was placed 5.00 g (24.7 mmol) of DEAD and 3.50 g (28.7 mmol) benzoic acid in THF (50 mL). 5.78 g (24.0 mmol) of (+)-trans- bromophenylcyclopentyl carbinol and 7.50 g. (28.6 mmol) of triphenylphosphine in THF (50 mL) was added dropwise while stirring at 0°C under a nitrogen atmosphere. After 2 hours at this temperature, TLC showed that the reaction was complete. Solution was let warm to room temperature and then concentrated under reduced vacuum to yield 9.14 g of an oil. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with an isocratic solvent of hexane/methylene chloride 1 :1 to yield 3.74 g (45%) of the intermediate title compound as a slowly crystallizing oil. Ion spray M.S. 344 (M* - 1): Calculated for: C₁₈H₁₇0₂Br Theory: C 62.62, H 4.96 Found : C 62.40, H 4.90

Preparation of (+.-) cis 2-(4-Bromo-phenyl)-cvclopentanol.

HO To (+,-) cis benzoic acid 2-(4-bromo-phenyl)-cyclopentyl ester (3.70 g, 10.7 mmol) was added 5% NaOH/MeOH (75 mL, excess) in a 250 mL single- neck flask and stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to yield a semi-solid. This material was taken into ether and washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 3.01 g of an oil. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with an isocratic solvent of hexane/methylene chloride 1 :1 to yield 2.31 g (90%) of a clear oil. NMR was consistent with the proposed structure. Ion spray M.S. 241 (M*): Calculated for: C-nH-i₃θBr. Theory: C 54.79, H 5.43 Found : C 54.91 , H 5.12

Preparation of (+,-) Trans Propane-2-sulfonic acid r2-(4-bromo-phenvD- cyclopentyll-amide.

Into a 250 mL 3 neck flask fitted with a stirrer and thermometer, 3.73 g

(15.4 mmol) of 2-propanesulfonyl chloride was added dropwise to 3.30 g (14 mmol) of (+,-) cis 2-(4-bromo-phenyl)-cyclopentanol and 4.23 g (16.8 mmol) DBU in methylene chloride (90 mL) while stirring at 0°C under a nitrogen atmosphere. The reaction was then allowed to warm to room temperature and stirred overnight. In the morning, the mixture was diluted with methylene chloride (100 mL), washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 5.63 g of a solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with an isocratic solvent of hexane/ethyl acetate 7:3 to yield 3.54 g (73%) of a white solid. M.P. 128°-130°C: Ion spray M.S. 346 (M*): Calculated for: C₁₄H₂₀

N0₂SBr Theory: C 48.56, H 5.82, N 4.04 Found : C 48.88, H 5.83, N 4.12 Preparation of (1 S.2R) Trans Propane-2-sulfonic acid r2-(4-bromo-phenyl)- cyclopentyl]-amide.

(+,-) Trans Propane-2-sulfonic acid [2-(4-bromo-phenyl)-cyclopentyl]- amide (11.2 g) was separated into individual enantiomers by chiral chromatography. The prep column used was 8 x 29 cm Chiralcel OD eluting with 90% Heptane / 10% IPA at a flow of 330.0 mL/min monitoring at a UV wavelength of 250 nm. The analytical column was 0.46 x 25 cm Chiralcel OD-H eluting with 90% Heptane / 10% IPA at a flow of 1.0 mL/min monitoring at a UV wavelength of 240 nm. The late eluting compound had a retention time of 8.5 min. The yield was 4.9 g. Enantiomeric excess was estimated to be 98% by HPLC. Mass Spectrum (ES MS): M -1 = 346. Preparation of 4-(4,4,5,5-Tetramethyl-H ,3,2]dioxaborolan-2-yl)-benzoic acid.

4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration and rinsed with toluene. The intermediate title compound was vacuum dried to 12.2 g (81 %). Mass Spectrum (FD MS): M = 248.

Analysis calculated for C13H17BO4: %C, 62.94; %H, 6.91 Found: %C, 62.71 ;

%H, 6.91. Preparation of N-Methyl-4-(4,4,5,5-tetramethyl-H ,3,2]dioxaborolan-2-vD- benzamide.

4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzoic acid (6.0 g, 24.2 mmol) was suspended in 20 mL of thionyl chloride, 3 drops of DMF added and the reaction heated to reflux under nitrogen. The solid dissolved upon warming. After refluxing 2 h the reaction was concentrated in vacuo and dried to a white solid under vacuum. The acid chloride was dissolved in 30 mL of THF and cooled to 0°C. 40% aqueous methylamine (10.4 mL) was added dropwise. After the addition was complete the ice bath was removed and stirring continued for 30 min. The reaction was concentrated in vacuo (3 x 1:1 EtOAσ.toluene) then extracted with ether/water. The organic layer was dried over sodium sulfate, filtered and concentrated to 5.2 g (83%) of the intermediate title compound, N- methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzamide, as a white solid.

Mass Spectrum (FD MS): M = 261.

Analysis calculated for C14H20BNO3: %C, 64.40; %H, 7.72; %N, 5.36. Found: %C, 64.09; %H, 7.70, %N, 5.28.

Preparation of final title compound.

Into a 50 mL single neck flask (1S.2R) trans-propane-2-sulfonic acid [2-(4- bromo-phenyl)-cyclopentyl]-amide (200 mg, 0.58 mmol, prepared above), N- Methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzamide (170 mg, 0.63 mmol, prepared above), palladium tetrakistriphenylphosphine (50 mg, 0.10 mmol), and 1.0 mL of 2M sodium carbonate were mixed together in 10 mL of 1 ,4- dioxane and stirred overnight at 80°C. In the morning, the reaction was let cool to room temperature and poured into water. The desired material was extracted into ethyl acetate. The organic layer was washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 370 mg of a dark oil. This material was purified via silica gel chromatography employing the Chromatotron^® with a 4000 micron rotor and eluting with an isocratic solvent of methylene chloride/ethyl acetate 7:3 to yield the final title compound, (1S,2R) trans 4'-[2-(propane-2-sulfonyIamino)-cyclopentyl]-biphenyl-4-carboxylic acid methylamide, 110 mg (47%) as a semi-solid. Ion spray M.S. 399.2 (M* - 1): Calculated for: C₂₂H₂₈ N₂θ₃S Theory: C 65.97, H 7.04, N 6.99

Found : C 66.26, H 6.81 , N 6.84.

Example 8 Preparation of {2-[4-(4- CvanophenvOphenoxy]propyl)r(methylethyl)sulfonyl]amine.

Preparation of 4-Cvanobenzeneboronic acid.

Following a modified literature procedure of Pernia, G. J.;et al., J. Am. Chem. Soc, 118, 10220-10227 (1996), a solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 A molecular sieves at room temp. This solution was filtered and cooled to -100 °C. Next, 1.6 M solution of n-butyllit ium in hexanes (355 mL; 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between - 105 and -93 °C. To the resulting orange reaction mixture trimethylborate (81 g, 0.78 mol) was added over 3 min, briefly increasing the reaction temperature to - 72 °C. The reaction mixture was re-cooled to -100 °C over 5 min and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCI to pH 2.2 and was diluted with CH₂CI₂ (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2 x 200 mL), dried (MgS0₄), filtered, and reduced under pressure to give a pale yellow solid. This solid was additionally purified by dissolution in 1 N NaOH and extraction into CH₂CI₂ / THF (1 :1 , 2 x 200 mL). The aqueous phase was acidified with 4N HCI to pH 2.2 and was extracted into CH₂CI₂ / THF (1 :1 , 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9%) as a white powder. ¹H NMR (de-acetone, 300 MHz): δ 8.03 (d, 2H, J = 8.1 ), 7.75 (d, 2H, J = 8.4), 7.54 (s, 2H).

Preparation of Methyl 2-(4-bromophenoxy)propanoate.

In a 3 L round-bottomed flask fitted with a stir bar, at room temperature, and under a nitrogen atmosphere, 4-bromophenol (50.0 g, 289 mmol) in 290 mL of N-N-dimethylformamide was added dropwise to sodium hydride (7.6 g, 317 mmol) in 290 mL of N-N-dimethylformamide. After mixing for 45 minutes, 2- bromopropionate (47.0 g, 290 mmol) in 290 mL of N-N-dimethylformamide was added dropwise from an addition funnel, and was followed with the addition of sodium iodide (52.0 g, 347 mmol, neat). The reaction mixture was then brought to reflux at 80 °C for 3 hours. The reaction mixture was allowed to cool to room temperature, whereby it was diluted with 1.6 L H₂O, and extracted three times with 500 mL of ethyl acetate. The organic layer was washed two times with 500 mL of H₂O, dried with potassium carbonate, filtered, and concentrated under reduced vacuum to yield 81.8 g of viscous brown oil. This crude material was purified via silica gel chromatography, employing a Hewlett-Packard HPLC 2000 and eluting with a 1 :1 hexane:ethyl acetate solvent system to yield the intermediate title compound (37.0 g, 49%) as a viscous oil. Electrospray-MS 260, d (M*+1),

Preparation of 2-(4-Bromophenoxy)propanamide.

Methyl 2-(4-bromophenoxy)propanoate (37.01 g, 143 mmol), ammonia (1.86 L of a 2M solution in methanol) and tetrahydrofuran (475 mL) were combined in a 3 L round bottom flask at room temperature, under a nitrogen atmosphere, and stirred b stirbar, for 48 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to yield the intermediate title compound (35.9 g, 100%) as a viscous oil. Electrospray-MS 245, d (M*+1 ).

Preparation of [2-(4-Bromophenoxy)propyπ[(methylethyl)sulfonyl1amine.

n a 1000 mL 3-neck flask, fitted with a thermometer, a stirbar and a condenser, 2-(4-bromophenoxy)propanamide (6.7 g, 27.4 mmol) was combined with borane-methyl sulfide complex (27.5 mL of a 10 M concentration in excess methyl sulfide), and tetrahydrofuran (330 mL). The reaction mixture was heated at reflux with stirring, at 70 °C, overnight, under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and 82.4 mL of 1 :1 tetrahydrofuran methyl alcohol was added dropwise, slowly, until foaming ceased. Next, 5N sodium hydroxide (257 mL) was added, and the reaction mixture was refluxed for 5 hours. The mixture was then permitted to cool to room temperature and extracted three times with 200 mL methylene chloride. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced vacuum, yielding 5.3 g of viscous purple oil. This oil was dissolved in diethyl ether, and acidified with anhydrous hydrochloric acid gas (until precipitation occurred). The acid mixture was allowed to stir at room temperature for 1 hr, forming a white precipitate. The precipitate was captured by vacuum filtration yielding 4.4 g of white solid. The precipitate was then dissolved into methylene chloride (185 mL) and added to triethylamine (10 mL, 69 mmol) in a 500 mL 3-neck flask fitted with a thermometer under a nitrogen atmosphere. The mixture was then cooled to 0 °C and 2-propanesulfonyl chloride (5.0 mL, 41 mmol) was added by syringe. The mixture was permitted to come to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum, yielding

5.03 g viscous oil. Purification was conducted using a Hewlett-Packard HPLC

2000, with two silica cartridges, and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding the intermediate title compound (3.5 g, 38%) as a slow crystallizing, yellow viscous oil. Electrospray-MS 337, d (M*+1).

Analysis

Theory: C 42.87, H 5.40, N 4.16.

Found: C 42.82, H 5.38, N 4.12. 0

Preparation of final title compound.

The final title compound (128 mg, 60%) is prepared from [2-(4- bromophenoxy)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.595 mmol, prepared in example 1), 4-cyanobenzeneboronic acid (105 mg, 0.715 mmol), 5 tetrakis(triphenylphosphine)palladium(0) (3.7 mg, 0.003 mmol), 2 M sodium carbonate (212 mg in 1 mL water) and 1 ,4-dioxane (4 mL) are combined in a 15 mL round bottom flask, fitted with a condenser, stirbar, and in a temperature regulated oil bath. The reaction mixture is heated at reflux (70° C) under a nitrogen atmosphere overnight. The reaction is quenched with water, extracted 0 three times with 25 mL of methylene chloride, and the organic layer is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material is purified via silica gel chromatography, utilizing a Chromatotron^® (the Chromatotron^® is available from Harrison Research Inc., 840 Moana Court, Palo Alto CA 94306) with a 2000 μm rotor utilizing an eluent of 1 :1 5 hexane:ethyl acetate, to provide the final title compound. It is understood that the final title compound name, {2-[4-(4- cyanophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine, is equivalent to the alternative name of 4-[4-(1-methyl-2-

{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzenecarbonitrile. o Electrospray-MS 359.0 (M*+ 1 ). Analysis

Theory: C 63.66, H 6.19, N 7.82.

Found: C 63.67, H 5.84, N 8.00. 5 Example 8A Preparation of 4-r4-f(1 R -methyl-2- {Kmethylethvπsulfonyl]amino>ethoxy)phenvπbenzenecarbonitrile.

Preparation of (2R)-2-(4-bromophenoxy)propanamide:

and preparation of (2S)-2-(4-bromophenoxy)propanamide.

H₃C NH₂

2-(4-Bromophenoxy)propanamide (prepared in example 8) is separated into the (2R)-2-(4-bromophenoxy)propanamide and (2S)-2-(4- bromophenoxy)propanamide enantiomers using standard techniques well known in the art. For example, 2-(4-bromophenoxy)propanamide can be separated into the corresponding enantiomers using chiral chromatography on a Chiralcel OD^® column (Chiral Technologies, Inc., 730 Springdale Drive, Exton, Pennsylvania 19341 , 4.6 X 250 mm) with an eluent of 20% isopropanol/heptane at a flow rate of 1 mL/min.

Elemental Analysis for (2S)-2-(4-bromophenoxy)propanamide. C(Theory): 44.2872 C(Found): 41.17 H(Theory): 4.1295 H(Found): 4.02 N(Theory): 5.7383 N(Found): 5.72

Elemental Analysis for (2R)-2-(4-bromophenoxy)propanamide. C(Theory): 44.2872 C(Found): 44.51 H(Theory): 4.1295 H(Found): 4.21 N(Theory): 5.7383 N(Found): 5.60 Preparation of [(2RV2-(4-bromophenoxy)propylir(methylethyl)sulfonvnamine.

(2R)-2-(4-bromophenoxy)propanamide (4.0 g, 16.4 mmol), borane dimethylsulfide reagent (16.4 mL, 164 mmol), and THF (196 mL) were combined in a 2000 mL 3-neck round bottomed flask, affixed with a thermometer, condenser, and rubber stopper. Under a nitrogen atmosphere, with stirring, the reaction mixture was refluxed at 70°C overnight. When the reaction was complete by TLC, it was cooled to ambient temperature. THF:methanol (49.2 mL, 1 :1) was added by syringe, and when foaming ceased, 5N NaOH added by syringe. The reaction mixture was heated at 55°C for an additional five hours, monitoring occasionally to determine if the borane complexes had been thoroughly broken up. Upon completion, the reaction mixture was cooled to room temperature, and extracted three times with methylene chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 5.88 g of a viscous yellow oil. This oil was dissolved into 200 mL of diethyl ether, and acidified with concentrated HCI gas, to pH < 2. The acidic solution was stirred at RT for one hour, then vacuum filtered off white precipitate. The precipitate was heated under vacuum for two hours at 40°C, yielding 2.85 g white solid. This solid was dissolved in methylene chloride 110 mL) in a 500 mL 3-neck round bottomed flask, fitted with a thermometer, rubber stopper, and under a nitrogen system. The reaction mixture was then cooled to 0°C, triethylamine (5.7 mL, 41.0 mmol) and isopropylsulfonyl chloride (2.76 mL, 24.6 mmol) respectively, were added by syringe and stirred overnight monitored until complete. The reaction was monitored by TLC until complete. The reaction was then quenched with 200 mL water, and the layers were separated. The organic layer was washed with water, dried with sodium sulfate, filtered, and concentrated under reduced pressure yielding 4.16 g viscous brown oil. The product was further purified by chromatography on a waters Prep 2000 using two Prep-Paks, in a 50:50 hexanes:ethyl acetate solvent system. This yielded the intermediate title compound (2.81 g, 51 %) as a slow crystallizing viscous brown oil.

Preparation of final title compound. 4-r4-((1 R)-1-methyl-2- {[(methylethyl)sulfonyl1amino)ethoxy)phenyl1benzenecarbonitrile.

4-Cyanobenzeneboronic acid (171 mg, 1.16 mmol, prepared in example

8), tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.063 mmol), 2 M sodium carbonate (1.6 mL), and [(2R)-2-(4- bromophenoxy)propyl][(methylethyl)sulfonyl]amine (310 mg, 0.922 mmol) were combined in a 15 mL round bottomed flask with dimethylethylene glycol (6.15 mL, DME), fitted with a condenser, stirbar, and in a temperature regulated oil bath, and refluxed in a nitrogen system to 85°C, overnight. The reaction was allowed to cool to room temperature, and quenched with 15 mL of water, and extracted three times with 15 mL ethyl acetate. The organic layer was dried with magnesium sulfate, filtered through Celite^®, and concentrated under reduced pressure, yielding 470 mg viscous black oil. This material was further purified using a 4000 uM rotor on a Chromatotron^® in a 1 :1 hexanes:ethyl acetate solvent system yielding the final title compound (57.5 mg, 18%) as white crystals.

MS-ES M*+1 (359.5). Elemental Analysis:

C(Theory): 63.66 C(Found): 62.81 H(Theory): 6.19 H(Found): 5.99 N(Theory): 7.81 N(Found): 7.73

Example 8B

Preparation of 4-r4-((1 S)-1 -methyl-2- {[(methylethyl)sulfonyl1amino)ethoxy)phenvπbenzenecarbonitrile.

The title compound is prepared in a manner analogous to the procedure set forth in example 8a from (2S)-2-(4-bromophenoxy)propanamide (prepared above in example 8a). Example 9a Preparation of 6-r4-(1 -fluoro-1 -methyl-([(methylethyl)sulfonyl]amino}ethylphenyl]- indolin-2-one (enantiomer 1).

Preparation of 6-Bromo-1 ,3- dihydro-indol-2-one.

To a stirred solution of 4-bromo-2-nitrophenylacetic acid (1.00 g, 3.85 mmol) dissolved in 50% H₂S0₄ (8.2 mL)/EtOH (10.9 mL) is added Zn dust (1.01 g, 15.38 mmol) at 90° C under nitrogen. The reaction is stirred for 30 minutes at ambient temperature and then at 70 °C for 30 minutes. The reaction is then cooled to ambient temperature and poured into H₂0 (100 mL) and extracted with EtOAc (2 x 50mL). The combined organic layers are dried (Na₂Sθ₄), filtered, and evaporated. The crude residue is then purified by chromatography on silica gel eluting with a gradient EtOAc-hexane system (1 :10 to 1 :1) to provide the intermediate title compound.

Preparation of final title compound.

(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine.(10.2, 26.47 mmol) bis(pinacolato)diboron (0.7.40 g, 29.14 mmol), PdCI₂(dppf).CH₂CI₂ (0.86 g, 1.05 mmol) and potassium acetate (9.04 g, 92.13 mmol) were heated and stirred at 80° C in dry DMF (150.0 mL) for 6 hours under N₂. The reaction mixture was allowed to cool to ambient temperature and 6-bromo-1 ,3-dihydro- indol-2-one (6.18 g, 29.14 mmol), PdCI₂(dppf).CH₂CI₂ (0.86g, 1.0 mmol.), and 2M Na₂C0₃ (40.0 mL, 80 mmol) were added respectively. The resulting mixture was stirred and heated at 80° C for 20 hours. The reaction mixture was allowed to cool to ambient temperature and poured into EtOAc and extracted with H₂O. The aqueous layer was separated and extracted with EtOAc and Et 0. The organic layers were combined and filtered through Celite^®. The purple Celite^® cake was washed repeatedly with EtOAc and Et₂0. The combined organic layers were washed with brine and dried (MgS0₄). Filtration and concentration in vacuo gave 40.0 g of a dark brown oil. Flash chromatography using a gradient system consisting of 1 Lhexane, 2L EtOAc/hexane 3:7, 2L EtOAc/hexanel :1 , 4L

EtOAc/hexane7:3 after evaporation gave 9.1 g of a yellow brown oil. Triturated with dry Et₂0 precipitated 5.1 g of a solid. Recrystallization (EtOAc 125 mL- hexane 125 mL gave the title compound (4.2 g, 40%), mp 150-151 ° C. Anal. Clacd. C,61.52; H, 5.94; N, 7.17; S, 8.21 ; F, 4.86 Found: C, 61.31 ; H, 5.94; N, 7.17; S, 8.14; F, 5.08

Example 9b Preparation of 6-[4-(1 -fluoro-1 -methyl-f f(methylethyl)sulfonyl1amino)ethylphenvπ-

Scheme II, step A': (-)-[2-fluoro-2-(4- iodophenyl)propyl][(methylethyl)sulfonyl]amine (0.345 g, 0.896 mmol). bis(pinacolato)diboron (0.250 g, 0.984 mmol), PdCI₂(dppf).CH₂CI₂ (0.024 g, 0.029 mmol) and potassium acetate (0.338 g, 3.44 mmol) were heated and stirred at 80° C in dry DMF (25.0 mL) for 3 hours under N₂. The reaction mixture was allowed to cool to ambient temperature and 6-bromo-1 ,3-dihydro-indol-2-one (0.209 g, 0.986 mmol), PdCI₂(dppf).CH₂CI₂ (0.024 g, 0.029 mmol), and 2M Na₂C0₃ (2.5 mL, 5.0 mmol) were added respectively. The resulting mixture was stirred and heated at 80° C for 6 hours. The reaction mixture was allowed to cool to ambient temperature and poured into EtOAc and extracted with H₂0. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine and dried (MgS0₄). Filtration and concentration in vacuo gave the crude product which when chromatographed provided the final title compound, (0.025 g). MS(ES) 391.4 (M+1) The ability of compounds to potentiate glutamate receptor-mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate-evoked influx of calcium into GluR4 transfected HEK293 cells, as described in more detail below. In one test, 96 well plates containing confluent monolayers of HEK 293 cells stably expressing human GluR4B (obtained as described in European Patent Application Publication Number EP-A1-583917) are prepared. The tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 μl of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium chloride, 1mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutes in the dark with 20 μM Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well. After the incubation, each well is washed once with 100 μl buffer, 200 μl of buffer is added and the plates are incubated for 30 minutes.

Solutions for use in the test are also prepared as follows. 30 μM, 10 μM, 3 μM and 1 μM dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 μM cyclothiazide solution is prepared by adding 3 μl of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prepared by adding 1.5 μl DMSO to 498.5 μl of buffer.

Each test is then performed as follows. 200 μl of control buffer in each well is discarded and replaced with 45 μl of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life

Sciences International Pic). The buffer is then removed and replaced with 45 μl of buffer and 45 μl of test compound in buffer in appropriate wells. A second fluorescent reading is taken after 5 minutes incubation. 15 μl of 400 μM glutamate solution is then added to each well (final glutamate concentration 100 μM), and a third reading is taken. The activities of test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 μM cyclothiazide.

In another test, HEK293 cells stably expressing human GluR4 (obtained as described in European Patent Application Publication No. EP-A1-0583917) are used in the electrophysiological characterization of AMPA receptor potentiators. The extracellular recording solution contains (in mM): 140 NaCI, 5 KCI, 10 HEPES, 1 MgCI2, 2 CaCI2, 10 glucose, pH = 7.4 with NaOH, 295 mOsm kg-1. The intracellular recording solution contains (in mM): 140 CsCI, 1 MgCI2, 10 HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA (ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH = 7.2 with CsOH, 295 mOsm kg-1. With these solutions, recording pipettes have a resistance of 2-3 MΩ. Using the whole-cell voltage clamp technique (Hamill et al.(1981)Pflϋgers Arch., 391 : 85-100), cells are voltage-clamped at -60mV and control current responses to 1 mM glutamate are evoked. Responses to 1 mM glutamate are then determined in the presence of test compound. Compounds are deemed active in this test if, at a test concentration of 10 μM or less, they produce a greater than 10% increase in the value of the current evoked by 1 mM glutamate and this effect can be blocked by a specific AMPA receptor antagonist such as NBQX. In order to determine the potency of test compounds, the concentration of the test compound, both in the bathing solution and co-applied with glutamate, is increased in half log units until the maximum effect was seen. Data collected in this manner are fit to the Hill equation, yielding an EC50 value, indicative of the potency of the test compound. Reversibility of test compound activity is determined by assessing control glutamate 1 mM responses. Once the control responses to the glutamate challenge are re-established, the potentiation of these responses by 100 μM cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.

Rat islets

Islets of Langerhans are isolated from the pancreata of male Wistar rats weighing 200 to 250 g. The animals are anaesthetized with pentobarbitone and after surgical opening of the abdomen the pancreas is distended by injection of collagenase (17mg/10ml; Serva Bioproducts, Heidelberg, Germany) into the bile duct. After careful removal the distended pancreas is subjected to collagenase digestion in a plastic tube for 15-20 min. Islets are purified on a single layer of ficoll-histopaque 1077 (Sigma, Taufkirchen, Germany) by centrifugation at 770 x g for 25 min. After centrifugation and washing the islets are transferred into RPMI-1640 (Sigma, Taufkirchen, Germany) supplemented with 2 mM L- glutamine, 10% foetal calf serum, 100 lU/ml penicillin, 100 μg/ml streptomycin (Life Technologies, Karlsruhe, Germany), and cultured overnight at 37°C in a humidified atmosphere (95% air, 5% C02).

Insulin secretion studies are performed in static incubations. Islets are hand-picked into culture dishes and pre-incubated in Earle^'s Balanced Salt Solution (EBSS, Sigma, Taufkirchen, Germany) containing 0.1 % BSA (Sigma, Taufkirchen, Germany) and supplemented with 3.3 mM glucose for 30 min at 37°C. Batches of 5 islets are hand picked into 24-well tissue culture plates and incubated for 90 min at 37°C in EBSS (+ 0.1 % BSA) supplemented with 3.3 mM or 16.7 mM glucose and the respective test compound is added. Chilling the test plates on ice terminates the incubations. The supernatant is removed and stored at -20°C until it is assayed for insulin.

IVGTT and Euglycemia in rats.

The intravenous glucose tolerance test (IVGTT) is performed in overnight fasted anaesthetised male Wistar rats weighing 280-350g. Under pentobarbitone anaesthesia (50 mg/kg ip) polyethylene catheters are placed in the left jugular vein and in the left common carotid artery. Glucose (10% solution) is administered intravenously at a dose of 0.5 g/kg, followed directly by an iv injection of the test compound. Blood samples are drawn before and 3, 6, 10, 15, 30 and 45 min after glucose administration, sampled into 300 μl heparinized microcuvettes (Sarstedt LH 300, Germany) by tailbleeding, centrifuged and the obtained plasma is stored at -20°C for analysis. Test compounds are examined along with a reference (positive control) and a vehicle control with n=8 animals per group. In order to examine the effects of test compounds on insulin and blood glucose at euglycemia in vivo the protocol of the IVGTT as described above is used except the administration of intravenous glucose.

Statistical analysis is carried out using^' Student's t-test by means. Data are analyzed with SIGMASTAT and SIGMAPLOT software package (Jandel Scientific Software, S. Raffael, CA USA). Data are shown as means ± SEM and P< 0.05 is accepted as statistically significant.

The present invention provides a pharmaceutical composition, which comprises a suitable AMPA receptor potentiator or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. As used herein the term "active ingredient" refers to a suitable AMPA receptor potentiator. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 micrograms to about 500 mg, more preferably about 5 micrograms to about 300 mg of the active ingredient. The term "active ingredient" refers to the suitable AMPA receptor potentiator. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.

As used herein the term "patient" refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.

As used herein, the terms "treating" or "to treat" each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder. As such, the method of this invention encompasses both therapeutic and prophylactic administration.

As used herein, the term "effective amount" refers to the amount of a suitable AMPA receptor potentiator which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.

An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. For example, a typical daily dose may contain from about 5 micrograms to about 500 mg of the active ingredient. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.

Additional examples of AMPA receptor potentiators are listed in table

Table I. Additional AMPA Receptor Potentiators

Claims

WHAT IS CLAIMED IS:

1. A method of treating type 2 diabetes, comprising administering to a patient an effective amount of a suitable AMPA receptor potentiator.

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2. A method according to claim 1 wherein the suitable AMPA receptor potentiator augments insulin secretion only during high glucose levels.

3. The use of a suitable AMPA receptor potentiator, or a pharmaceutically o acceptable salt thereof for the manufacture of a medicament for treating type 2 diabetes.

4. The use of a suitable AMPA receptor potentiator according to claim 3 wherein the suitable AMPA receptor potentiator augments insulin secretion only 5 during high glucose levels.

5. Use of a suitable AMPA receptor potentiator or a pharmaceutically acceptable salt thereof for treating type 2 diabetes.

0 6. An article of manufacture comprising packaging material and a suitable

AMPA receptor potentiator contained within said packaging material, wherein said packaging material comprises a label which indicates that said suitable AMPA receptor potentiator can be used for treating type 2 diabetes.

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