ZA200106646B

ZA200106646B - Novel sulfonamide compounds and uses thereof.

Info

Publication number: ZA200106646B
Application number: ZA200106646A
Authority: ZA
Inventors: David W Smith; Benito Munoz; Kumar Srinivasan; Carl P Bergstrom; Prasad V Chaturvedula; Milind S Deshpande; Daniel J Keavy; Wai Yu Lau; Michael F Parker; Charles P Sloan; Owen B Wallace; Henry Hui Wang
Original assignee: Merck & Co Inc; Bristol Myers Squibb Co
Priority date: 1999-02-26
Filing date: 2001-08-13
Publication date: 2002-11-13

Description

NOVEL SULFONAMIDE COMPOUNDS AND USES THEREOF

FIELD OF INVENTION

The present invention relates to novel compounds which contain a sulfonamide moiety, and pharmaceutical compositions containing invention compounds. In addition, the present invention relates to therapeutic methods for the treatment and prevention of various disease conditions, especially

Alzheimer’s disease and other diseases relating to the deposition of amyloid.

BACKGROUND OF THE INVENTION

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, and indifferent attitude. It is the most common form of dementia, affecting nearly 50% of the elderly population over 85 years of age. There is currently no effective treatment to prevent the disease.

One of the major histopathological hallmarks of Alzheimer’s disease is senile plaques which are found only in the brain, and especially in regions associated with memory, reasoning and cognition.

The major constituent of senile plaques is amyloid B protein, an insoluble 40-42 amino acid polypeptide. Amyloid B protein is normally found in the plasma and cerebrospinal fluid of healthy individuals although its function is unknown. In the disease state increased production and/or reduced removal of amyloid f protein results in increases in protein levels in plasma and cerebrospinal fluid and : accumulation of the protein in the brain.

Amyloid B protein is derived from amyloid precursor protein (APP) by proteolytic cleavage.

Processing of APP to amyloid B protein and other APP cleavage fragments is governed by a group of enzymes termed secretases. One type of secretase, y-secretase, is responsible for the protein cleavage that gives rise to amyloid B protein. Although the existence of a protein having the activity of y- secretase has been suggested, neither the gene encoding the protein, nor the protein itself has been completely isolated and characterized.

Thus, there is a continuing need in the art for compounds that can specifically inhibit proteolytic cleavage of APP, thereby inhibiting amyloid B protein production. The present invention meets this and rclated needs by providing a family of novel compounds and related methods of use.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, we have discovered a class of sulfonamide compounds that inhibit amyloid $ protein production. Compounds of the invention contain a core sulfonamide group. Variable moieties are connected to the sulfur atom and nitrogen atom of the 5S sulfonamide group and include substituted or unsubstituted hydrocarbyl moieties, substituted or unsubstituted heterocyclic moieties, polycyclic moieties, halogen, alkoxy, ether, ester, amide, sulfonyl, sulfonamidyl, sulfide, and carbamate.

Invention compounds are capable of a wide variety of uses. For example, invention sulfonamide compounds can act to modulate amyloid fp protein and are useful in the prevention and/or treatment of a variety of diseases. Without wishing to be bound by any theory, invention compounds are believed to act by blocking the proteolytic processing pathways that result in the formation of amyloid f proteins. Invention compounds are believed to act by inhibiting proteolytic cleavage of amyloid precursor protein (APP), the large precursor protein from which amyloid B protein is derived.

Therapeutic indications for compounds with this inhibitory activity include disorders of the central nervous system in which amyloid B protein accumulates in the cerebral extracellular perivascular space, such as Alzheimer’s disease. Pharmaceutical compositions containing invention compounds also have wide utility.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided compounds having the structure:

D G v

NY 0

A and pharmaceutically acceptable salts thereof, wherein:

D is hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, halogen, alkoxyl, ester, amide, or

D and G, taken together, form a substituted or unsubstituted cyclic moiety; and

E, is hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, alkoxyl, amide, sulfonyl, sulfonamidyl, sulfide or alkoxyl; or

E and J, taken together, form a substituted or unsubstituted cyclic moiety; and

G, when not part of a cyclic moiety including D, is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, amine, amide, ester, ether or carbamate; and

J, when not part of a cyclic moiety including E, is substituted or unsubstituted hydrocarbyl, heterocycle optionally having one or more double bonds.

As employed herein, “hydrocarbyl” refers to straight chain, branched chain and cyclic (i.e, ring- containing) monovalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms. Straight and branched chain radicals have in the range of about 1 up to 12 carbon atoms and cyclic hydrocarbyl radicals have in the range of about 3 up to about 20 carbon atoms. The term “substituted hydrocarbyl!” refers to hydrocarbyl moieties further bearing substituents as set forth below.

Exemplary straight or branched chain hydrocarbyl moieties include alkyl moieties, alkenyl moieties, polyalkenyl (e.g., dialkenyl moieties, and trialkenyl moieties), alkynyl moieties, alkadiynal moieties, alkatriynal moieties, alkenyne moieties, alkadienyne moieties, alkenediyne moieties, and the like.

Exemplary cyclic hydrocarbyl moieties include cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, aromatic moieties, spiro hydrocarbon moieties wherein two rings are joined by a single atom which is the only common member of the two rings (e.g., spiro[3.4]octanyl, and the like), bicyclic hydrocarbon H moicties wherein two rings are joined and have at least two atoms in common (e.g., bicyclo (3.2.1]octane, bicyclo [2.2.1]hept-2-ene, and the like), ring assemblies wherein two or more cyclic systems (i.e., single rings or fused systems) are directly joined to each other by single or double bonds, and the number of such ring junctions is one less than the number of cyclic systems involved (e.g: biphenylyl, biphenylylene, radicals of p-terphenyl, cyclohexylbenzyl, and the like), polycyclic moieties, and the like; “alkyl” refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; “substituted alkyl” refers to alkyl radicals further bearing one or more substituents such as cycloalkyl, cycloalkenyl, aryl, heterocycle optionally having one or more double bonds, halogen, alkoxy, cyano, cyanomethyl, nitro, amino, amide, amidine, hydroxy, carboxyl, carbamate, ether, ester, sulfonyl, sulfonamide, mercapto, and the like; “lower alkyl” refers to alkyl radicals having in the range of about 1 up to 6 carbon atoms; “substituted lower alkyl” refers to lower alkyl radicals further bearing one or more substituents as set forth above;

“alkenyl” refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon double bond, and having in the range of about 2 up to 12 carbon atoms, and “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituents as set forth above; “lower alkenyl” refers to alkenyl radicals having in the range of about 2 up to 6 carbon atoms; “substituted lower alkenyl” refers to lower alkenyl radicals further bearing one or more substituents as set forth above;

“alkynyl” refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon triple bond, and having in the range of about 2 up to 12 carbon atoms, and “substituted alkynyl” refers to alkynyl radicals further bearing one or more substituents as set forth above;

“cycloalkyl” refers to ring-containing radicals containing in the range of about 3 up to 20 carbon atoms, and “substituted cycloalkyl” refers to cycloalkyl] radicals further bearing one or more substituents as set forth above;

“cycloalkenyl” refers to ring-containing radicals having at least one carbon-carbon double bond in the ring, and having in the range of about 3 up to 20 carbon atoms, and “substituted cycloalkenyl” refers to cyclic alkenyl radicals further bearing one or more substituents as set forth above;

“cycloalkynyl” refers to ring-containing radicals having at least one carbon-carbon triple bond in the ring, and having in the range of about 7 up to 20 carbon atoms, and “substituted cycloalkynyl” refers to cyclic alkynyl radicals further bearing one or more substituents as set forth above;

“aromatic” refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, and having in the range of about 6 up to about 14 carbon atoms, and “substituted aromatic” refers to aromatic radicals further bearing one or more substituents as set forth above; &

“aryl” refers to mononuclear aromatic radicals having 6 carbon atoms and fuscd ring aromatic radicals having up to about 14 carbon atoms, i.e. polynuclear aromatic radicals, and “substituted aryl” refers to aryl radicals further bearing one or more substituents as set forth above;

“alkylene” refers to divalent alkyl moieties wherein said moiety serves to link two structures together; “substituted alkylene” refers to alkylene moieties further bearing one or more substituents as set forth above;

“alkenylene”, refers to divalent alkenyl moieties wherein said moiety serves to link two structures together; “substituted alkenylene” refers to alkenylene moieties further bearing one or more substituents as set forth above;

“arylene” refers to divalent aryl moieties wherein said méiety serves to link two structures together; “substituted arylene” refers to arylene moieties further bearing one or more substituents as set forth above; “heterocycle” refers to ring-containing monovalent and bivalent radicals having one or more heteroatoms (e.g, N, O, S) as part of the ring structure, and having in the range of 3 up to 20 atoms in the rings. Heterocyclic moieties may be saturated or unsaturated containing one or more double bonds, and may contain more than one ring. Heterocyclic moieties include, for example, monocyclic moieties such as piperazinyl, morpholinyl, thiomorpholinyl, imidazoly], pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, furanyl, pyranyl, thienyl, isoimidazolyl, triazolyl, dithiolyl, oxadithiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyronyl, dioxinyl, pyridinyl, pyridazinyl, triazinyl, oxazinyl, isoxazinyl, and the like, bicyclic heterocyclic moieties such as azabicycloalkanyl moieties, oxabicycloalkyl moieties, and the like, spiro compounds containing heteroatoms, and ring assemblies containing heteroatoms. The term “substituted heterocycle” refers to heterocycles further bearing one or more substituents as set forth above. Exemplary radicals include radicals of polycyclic, bicyclic and spiro

N N lo}

C10 Le (B,O0 heterocycles such as , N , and 0 ; “halogen” refers to fluoride, chloride, bromide or iodide radicals; “cyclic moiety” refers to substituted and unsubstituted cyclic hydrocarbyl moieties, as described above, and substituted and unsubstituted heterocycles, as described above; “alkoxy” refers to radicals of the general formula -O-R, where R is substituted or unsubstituted : hydrocarbyl; exemplary alkoxy radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like; “ether” refers to radicals of the general formula -R’-O-R"’, where R” and R’” are independently substituted or unsubstituted hydrocarbyl, or substituted or unsubstituted heterocycle optionally having onc or more double bonds, “ester” refers to radicals of the general formulae -C(O)O-R and -O-C(O)R , where R is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds; it is understood that the carbon atom of the ester group may be linked directly to the moiety of which ester is a substituent, or may be linked via a linker, such as substituted or unsubstituted alkylene, alkenylene, arylene, and the like;

“amine” refers to radicals of the general formula -NRR’, R and R’ are independently hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, alkoxy, ether, ester, amide. Thus, the radical may be a primary amine of the ~ general formula, -NH,, a secondary amine of the general formula -NHR, or a tertiary amine of the general formula -NRR'". It is understood that R and R’ may cooperate to form a cyclic moiety having a nitrogen atom as a member of a ring; and that the nitrogen atom of the amine group may be linked directly to the moiety of which amine is a substituent, or may be linked via a linker, such as substituted or unsubstituted alkylene, alkenylene, arylene, and the like; “amide” refers to radicals of the general formula -C(O)NRR', wherein R and R’ are independently hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds; it is understood that R and R’ may cooperate to form a cyclic moiety having a nitrogen atom as a member of a ring; and that the carbon atom of the amide group may be linked directly to the moiety of which amide is a substituent, or may be linked via a linker, such as substituted or unsubstituted alkylene, alkenylene, arylene, and the like; “sulfide” refers to radicals of the general formula -SR, wherein R is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, ester, amine, amide, and the like; “sulfonyl” refers to moieties containing a sulfonyl radical (-SO,-); “sulfonamidyl” refers to moieties containing a sulfonamide radical (-SO;"NRR"), wherein R and R’ are independently substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds; it is understood that R and R" may cooperate to form a cyclic H moiety having a nitrogen ator as a member of a ring; and that the sulfur atom of the sulfonamide radical may be linked directly to the moiety of which amide is a substituent, or may be linked via a linker, such as substituted or unsubstituted alkylene, alkenylene, arylene, ether, ester, and the like; “carbamate” refers to moieties containing a radical having the general formula -O-C(O)-NRR’ wherein R and R” are independently substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds; it is understood that R and R” may cooperate to form a cyclic moiety having a nitrogen atom as a member of a ring; and that the oxygen atom of the carbamate group may be linked directly to the moiety of which carbamate is a substituent, or may be linked viaa linker, such as substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, ether, ester, and the like;

In accordance with the present invention, D is hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, halogen, alkoxyl,

ester or amide, or D and E, taken together, form a substituted or unsubstituted cyclic moiety. In accordance with one embodiment of the invention, D is substituted or unsubstituted hydrocarbyl. Moieties contemplated for use in this embodiment of the invention include those wherein D is hydrogen or substituted or unsubstituted lower alkyl, with hydrogen and unsubstituted lower alky! preferred, and hydrogen and unsubstituted methyl especially preferred.

Further in accordance with the present invention, E is selected from substituted or unsubstituted hydrocarbyl, heterocycle optionally having one or more double bonds, alkoxyl, amide, sulfonyl, sulfonamidyl or sulfide. Presently preferred compounds of the invention are those wherein E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, substituted or unsubstituted polycyclic moiety, substituted or unsubstituted aryl, and the like,

Especially preferred moieties include substituted or unsubstituted aryl; when E is substituted aryl, a mono- substituted or di-substituted aryl is preferred, and preferred substituents are halogen, ester, alkyl, sulfur- linked alkyl, NO,, SO,, and the like, with halogen especially preferred.

In accordance with the present invention, G is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, amine, amide, ester, ether or carbamate. Thus, G can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cyclic moiety, ester, amide, carboxylate, and the like.

In one embodiment of the invention, G is substituted or unsubstituted alkyl, with substituted lower alkyl presently preferred. Presently preferred substituents are halogen and heterocycle optionally £ containing one or more double bonds such as imidazolyl, morpholinyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, ) 1,2,4-triazoly), tetrazolyl, and S-methyltetrazolyl, and the like. In another embodiment of the invention, G is substituted or unsubstituted alkenyl, with substituted lower alkenyl preferred. A presently preferred substituent of lower alkenyl is halogen. In yet another embodiment of the invention, G is unsubstituted alkynyl, with lower unsubstituted alkynyl presently preferred. In still another embodiment of the invention,

G is unsubstituted cycloalkyl.

In accordance with another embodiment of the invention, G is a substituted or unsubstituted cyclic moiety. Presently preferred cyclic moieties include substituted or unsubstituted naphthalenyl; when substituted, preferred substituents are ether moieties, especially 1-piperidinyl propoxyl.

In accordance with still another embodiment of the invention, G is an ester, represented by the formula -C(0)-OR. In presently preferred embodiments of the invention, R is substituted or unsubstituted lower alkyl or substituted aryl.

In accordance with another embodiment of the invention, G is carboxylate.

In accordance with a further embodiment of the invention, G is substituted or unsubstituted aryl.

When G is substituted aryl, presently preferred substituents are substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, amide, ester, hydroxy, . 5 sulfonamide, sulfonyl, ether, and radicals of the general formula -O-(CH,),-S-aryl, wherein n is 1 to 6. } In accordance with the present invention, J is a moiety attached to the sulfur atom of a sulfonamide group. J is substituted or unsubstituted hydrocarbyl, heterocycle optionally having one or more double bonds, or J and E, taken together, form a substituted or unsubstituted cyclic moiety. Thus J can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle optionally having one or more double bonds, or J and E, taken together can form a substituted or unsubstituted polycyclic moiety or substituted or unsubstituted ring assembly.

In accordance with a particular embodiment of the invention, J is substituted or unsubstituted alkyl, with substituted or unsubstituted lower alkyl presently preferred. Substituents of alkyl presently preferred in this embodiment are substituted and unsubstituted aryl. In accordance with another embodiment of invention, J is substituted or unsubstituted alkenyl with substituted lower alkenyl preferred, and aryl a preferred substituent.

In accordance with still another embodiment of the invention, J is a substituted or unsubstituted polycyclic moiety. Thus J can be pentalene, indene, naphthalene, azulene, and the like. Moieties contemplated for use in this embodiment of the present invention include substituted or unsubstituted naphthalene; preferred substituents are secondary and tertiary amines. :

In accordance with yet another embodiment of the invention, J is substituted or unsubstituted heterocycle optionally containing one or more double bonds. Moieties contemplated for use in this cmbodiment of the invention include those where J is isothiazolyl, thiazolyl, thiazinyl, thiazepinyl, and the like, with substituted thiazolyl preferred.

In still another embodiment of the invention, J is substituted or unsubstituted aryl. When J is substituted, preferred substituent moieties include alkyl, -O-alkyl, -S-alkyl, -S-aryl, halogen, nitro and trifluoromethyl.

In yet another embodiment of the invention, J cooperates with E to form a substituted or unsubstituted polycyclic moiety. Thus, J can be a fused moiety such as substituted or unsubstituted bicyclic, or a substituted or unsubstituted ring assembly. Moieties contemplated for use in this embodiment include substituted and unsubstituted naphthalenyl and substituted and unsubstituted biphenylyl.

Those of skill in the art will recognize that multiple isomers exist for a single chemical formula; each of the possible isomeric forms of the various empirical formulae set forth herein are contemplated by the invention.

Those of skill in the art recognize that invention compounds may contain one or more chiral

S centers, and thus can exist as racemic mixtures as well as in individual enantiomeric forms. For many applications, it is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions. Those of skill in the art will further recognize that invention compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.

In accordance with another embodiment of the present invention, there are provided pharmaceutical compositions comprising sulfonamide compounds as described above, in combination with pharmaceutically acceptable carriers. Optionally, invention compounds can be converted into non-toxic acid addition salts, depending on the substituents thereon. Thus, the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of medicaments useful for the treatment of a variety of indications. “Pharmaceutically acceptable salt” refers to a salt of the compound used for treatment which possesses the desired pharmacological activity and which is physiologically suitable. The salt can be formed with organic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, £ butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ) ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tartrate, toluenesulfonate, undecanoate, and the like. The salt can also be formed with inorganic acids such as sulfate, bisulfate, chlorate, perchlorate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, and the like. In addition, the salt can be formed with a base salt, including ammonium salts, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like.

Sulfonamidc compounds as described above can be readily prepared using synthetic chemistry techniques known to those of skill in the art. Sce the Examples section herein for detailed description of numerous exemplary synthetic protocols.

In accordance with the present invention, a method of modulating the level of Amyloid

Precursor Protein (APP) is provided. The method includes contacting APP with at least one sulfonamide compound according to the invention. As employed herein, the phrase “modulating the level of” refers to altered levels of protein so that the level is different as a result of employing the invention method when compared to the level without employing the invention method. Modulating the level of APP includes the suppression or augmentation of the level of any one of a number of APP proteins such as a full-length APP, APP proteins having deletions, additions or substitutions of amino acids, APP proteins that are fragments of full-length APP protein, soluble APP (s-APP), insoluble APP, and the like. Exemplary APP proteins include APP, APPssi, APPeoswi, APPsrosn, APPerosnima, sAPP, a-sAPP, B-sAPP, and the like. :

A varicty of APP proteins are found in neural and non-neural tissues. APP;y and APPy, are wild-type APPs of 770 and 751 amino acid residues, respectively, that are found in non-neural tissues.

APPggsuq 1s an APP of 695 residues that is expressed in neurons. APP; is human APP, 695 residues in length, that has mutations at codons 670 and 671 (Swedish double mutation). APPgsn1m7 is a similar to APPgjo With an additional mutation at codon 717 (Phe for Val). sAPP is soluble APP, a-sAPP is a-secretase-cleaved soluable APP and B-sAPP is B-secretase-cleaved APP.

In accordance with another embodiment of the invention, there are provided methods of treating a wide variety of disease conditions, said method comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the sulfonamide compounds described above.

APP is believed to be involved in numerous disease states. Therefore, modulating the level of

APP also provides a variety of therapeutic applications, such as the treatment of amyloid angiopathy, . cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer's discase, hereditary cerebral : hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, Down’s syndrome, and the like.

As used herein, “treating” refers to inhibiting or arresting the development of a disease, disorder or condition and/or causing the reduction, remission, or regression of the symptoms of a disease, disorder or condition. Those of skill in the art will understand that various methodologies and assays may be used to assess the development of a disease, disorder or condition, and similarly, various methodologies and assays may be used to assess the reduction, remission or regression of a disease, disorder or condition.

As used herein, “administering” refers to means for providing sulfonamide compounds and/or salts thereof, optionally employing pharmaceutically acceptable carriers, as described herein, to a patient, using any suitable method of delivery, e.g, oral, sublingual intravenous, subcutaneous, transcutaneous,

intramuscular, intracutaneous, intrathecal, epidural, intraoccular, intractéhial, inhalation, rectal, vaginal, and the like administration. Administration in the form of creams, lotions, tablets, capsules, pellets, dispersible powders, granules, suppositories, syrups, elixirs, lozenges, injectable solutions, sterile aqueous or non-aqueous solutions, suspensions or emulsions, patches, and the like, is also contemplated. The active ingredients may be compounded with non-toxic, pharmaceutically acceptable carmers including, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea, dextrans, and the like. “Contacting” as employed herein may include administering in solution or in solid phase.

For purposes of oral administration, tablets, capsules, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, elixirs and lozenges containing various excipients such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, and the like may be employed along with various granulating and disintegrating agents such as com starch, potato starch, alginic acid, and the like, together with binding agents such as gum tragacanth, corn starch, gelatin, acacia, and the like. Lubricating agents such as magnesium striethylaminerate, striethylamineric acid, talc, and the like may also be added. Preparations intended for oral use may be prepared according to any methods known to the art for the manufacture of pharmaceutical preparations and such preparations may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, saccharin, and the like, flavoring agents such as peppermint, oil of wintergreen, and the like, coloring agents and preserving agents in order to provide pharmaceutically palatable preparations. Preparations for oral use may also contain suitable carmers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like. Tablets may E be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time.

For the preparation of oral liquids, suitable camers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.

For the preparation of fluids for parenteral administration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. For parenteral administration, solutions for the practice of the invention may comprise sterile aqueous saline solutions, or the corresponding water soluble pharmaceutically acceptable metal salts, as previously described. For parenteral administration, solutions of the compounds used in the practice of the invention may also comprise non-aqueous solutions, suspensions, emulsions, and the like. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and com oil, gelatin, and injectable organic esters such as ethyl oleate, and the like. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.

Aqueous solutions may also be suitable for intravenous, intramuscular, intrathecal, subcutaneous, and intraperitoneal injection. The sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, by heating the compositions, and the like. They can also be manufactured in the form of sterile water, or some other sterile medium capable of injection immediately before use.

Compounds contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal or vaginal administration. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, and the like, such materials being solid at ambient temperatures but liquify and/or dissolve in internal cavities to release the drug.

The preferred therapeutic compositions for inocula and dosage will vary with the clinical indication. Some variation in dosage will necessarily occur depending upon the condition of the patient being treated, and the physician will, in any event, determine the appropriate dose for the individual patient. The effective amount of compound per unit dose depends, among other things, on the body : weight, physiology, and chosen inoculation regimen. A unit dose of compound refers to the weight of ) compound without the weight of carrier (when carrier is used).

The route of delivery compounds and compositions used for the practice of the invention is determined by the disease and the site where treatment is required. Since the pharmacokinetics and pharmacodynamics of the compounds and compositions described herein will vary somewhat, the most preferred method for achieving a therapeutic concentration in a tissue is to gradually escalate the dosage and monitor the clinical effects. The initial dose, for such an escalating dosage regimen of therapy, will depend upon the route of administration.

In accordance with invention methods, the medicinal preparation can be introduced parenterally, by dermal application, and the like, in any medicinal form or composition. It is used as a solitary agent of medication or in combination with other medicinal preparations. Single and multiple therapeutic dosage regimens may prove useful in therapeutic protocols.

As employed herein, the phrase “a therapeutically effective ifhount”, when used in reference to invention methods employing sulfonamide compounds and pharmaceutically acceptable salts thereof, refers to a dose of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated, the scverity of the disorder, the activity of the specific compound used, the route of administration, the rate of clearance of the specific compound, the duration of treatment, the drugs used in combination or coincident with the specific compound, the age, body weight, sex, diet and general health of the patient, and like factors well known in the medical arts and sciences. Dosage levels typically fall in the range of about 0.001 up to 100 mg/kg/day; with levels in the range of about 0.05 up to 10 mg/kg/day being preferred.

In stil] another embodiment of the invention, there are provided methods for preventing disease conditions in a subject at risk thereof, said method comprising administering to said subject a therapeutically cffcctive amount of at least one of the sulfonamide compounds described above.

As used herein, the phrase “preventing disease conditions” refers to preventing a disease, disorder or condition from occurring in a subject who may be at risk for the disease, but has not yet presented any symptoms thereof. Those of skill in the art will understand that a variety of methods may be used to determine a subject at risk for a disease, and that whether a subject is at risk for a disease will depend on a variety of factors known to those of skill in the art, including genetic make-up of the subject, age, body weight, sex, diet, general physical and mental health, occupation, exposure to environmental conditions, marital status, and the like, of the subject. g "Subject in need thereof” is intended to mean a mammal, e.g., humans, domestic animals and livestock, having or at risk of having one or more diseases associated with a modified level of APP.

Those of skill in the art can readily identify a variety of assays that can be used to assess the activity of sulfonamide compounds of the invention. For example, one can use in vitro cell-based assays to assess amyloid f protein production in cells that are exposed to invention compounds compared to cells exposed to control conditions. For such assays, transfected cells that stably express various forms of APP and from which amyloid p protein is secreted are used. Methods to measure amyloid B protein, such as immunoprecipitation, enzyme-linked immunosorbant assay (ELISA) and radioimmunoassay, and the like are known in the art. Immunoprecipitation methodology can be used to detect radiolabeled amyloid PB protein derived from transfected cells having *°S-methionine-labeled

APP (Haass et al., (1992) Nature, 359:322-325 and Shoji er al. (1992) Science, 258:126-129). ELISA can be used to detect unlabeled amyloid PB protein (Seubert er al. (1992) Nature, 359:325-327).

The invention Will now be described in greater detail by reference to the following non-limiting examples.

EXAMPILE1 (5)-5-[[dimethyl(1,1-dimethylethyl)silyljoxy]-1-pentanol

To a stirred solution of (4S)-pentane-1,4-diol [CAS 24347-57-7] (21.0 g, 0.202 mol) and ¢- butyldimethylsilyl chloride (30.5 g, 0.202 mol) in CH,Cl, (400 mL) was added triethylamine (43.0 mL, 0.305 mol) followed by 4-(dimethylamino)pyridine (2.50 g, 20.2 mmol) at 0 °C. The mixture was stirred for 3 h at 0 °C and was diluted with diethyl ether (300 mL). The white precipitate was filtered : and washed with diethyl ether. The filtrate was concentrated under reduced pressure. The pale yellow oil was distilled (100 °C-103 °C at 0.7 mm) to afford the title compound (41 g, 92%) as a colorless oil. 'H NMR (CDCl;) § 3.81 (m, 1H), 3.65 (m, 2H), 1.48-1.63 (m, 4H), 1.19 (d, 3H), 0.91 (s, 9H), 0.07 (s, 6H).

EXAMPLE2 4-chloro-2-nitro-1-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzene pel ct A NO,

A magnetically stitred solution of 4-chloro-2-nitrobenzyl alcohol (25.0 g, 133 mmol) and 3,4- dihydro-2H-pyran (18.2 mL, 16.8 g, 200 mmol) in anhydrous dichloromethane (250 mL) was treated at 25 °C with pyridinium p-toluenesulfonate (PPTS, 50 mg). The solution was stirred for 12 h, washed * with 1 N NaOH (250 mL), brine (250 mL), dried (K,CO,), filtered, and concentrated in vacuo. Silica gel chromatography (4:1 hexane:ethyl acetate) of the concentrate gave 22.5 g (62%) of the title compound as an oil.

EXAMPLE3 5-chloro-2-[[(tetrahydro-2H-pyran-2-yl)oxyjmethyl]benzenamine

ZZ

Ci NH,

A Parr bottle containing 4-chloro-2-nitro-1-{[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzene (22.6 g, 82.8 mmol) and cthanol (150 mL) was treated with Raney nickel (50% slurry in water, 2.0 g), charged with hydrogen (60 psi) and rocked until hydrogen uptake ceased (3 h). The resultant suspension was filtered through celite, and the celite cake thoroughly washed with fresh ethanol (5 x 150 mL). The combined organic extracts were concentrated in vacuo to give an orange oil that crystallized on standing. Recrystallization (ethyl acetate/hexane) gave the title compound as a white solid (19.64 g, 98%). 'H NMR (CDCl;) 57.00 (d, J = 8 Hz, 1H), 6.65-6.60 (m, 2H), 4.72 (A of ABq, J = 12 Hz, 1H), 4.79-4.77 (m, 1H), 4.45 (B of ABq, J = 12 Hz, 1H), 4.27 (bs, 2H), 3.94-3.85 (m, 1H), 3.58-3.50 (m, 1H), 1.88-1.65 (m, 2H), 1.58-1.46 (m, 4H).

EXAMPLE 4 4-chloro-N-{5-chloro-2-(hydroxymethyl)phenyl]benzencsulfonamide cr NA NH “0

ZN Cl

To a magnetically stirred solution of 5-chloro-2-[[(tetrahydro-2H-pyran-2- yl)oxy}methyl}benzenamine (4.38 g, 18.1 mmol) in anhydrous pyridine (100 mL) at 25 °C was added 4-chlorobenzenesulfonyl chloride (3.82 g, 18.1 mmol). The solution was stirred for 24 h and concentrated in vacuo. The residue was dissolved in dichloromethane (150 mL), washed with brine (3 x 150 mL) and concentrated in vacuo. Silica gel chromatography (6:1 hexane:ethyl acetate) of the concentrate afforded the title compound (5.27 g, 76%) as a crystalline solid. 'H NMR (CDCl,) 88.70 (bs, 1H), 7.71 (d, J= 8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.05-6.99 (m, 2H), 4.52-4.48 (m, 1H), 4.31 (A of ABq, J = 12 Hz, 1H), 4.24 (B of ABq, J = 12 Hz, 1H), 4.13-4.05 (m, 1H), 3.63- 3.55(m, 1H), 1.88-1.71 (m, 2H), 1.62-1.45 (m, 4H).

EXAMPLES

4-chloro-N-[5-chloro-2-[[0-(2-tetrahydropyranyl)methyljphenyl]}-N-{[4-[dimethyl(1,1- dimethylethyl)silyljoxy]-1(R)-methylbutyl]benzenesulfonamide

AL) ci SZ NTN oTBS $-0

FOL

Cl

To a solution of 4-chloro-N-[5-chloro-2-[O-(2-tetrahydropyranyl)methyl) phenyl]benzenesulfonamide (2.70 g, 6.40 mmol), triphenylphosphine (3.40 g, 12.8 mmol) and (S)-5- [[dimethyl(1,1-dimethylethyl)silyljoxy]-2-pentanol (2.40 g, 12.8 mmol) in THF (25 mL) was added diisopropylazodicarboxylate (2.40 mL, 12.8 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to warm to 22 °C with stirring. Stirring was continued for a period of 18 hand diethyl ether (100 mL) was added. The white solid was filtered, washed with ether (50 mL), and the combined ether solution was concentrated under reduced pressure. Silica gel chromatography (3:17 ethyl acetate:hexanes) of the concentrate afforded the title compound (4.00 g, 100%) as a colorless oil.

MS (ESI) m/e 615 (M-H).

EXAMPLE 6 4-chloro-N-[5-chloro-2-[[0-(2-tetrahydropyranyl)methyl) phenyl}}-N-(4-hydroxy-1- . methylbutyl)benzenesulfonamide = 0 joa) 0

Ci Z

To a solution of 4-chloro-N-[5-chloro-2-[[O-(2-tetrahydropyranyl)methyl] phenyl]}-N-[[4- [dimethyl(1,1-dimethylethyl)silylJoxy]-1-methylbutyl]benzene sulfonamide (3.80 g, 6.40 mmol) in

THF (10 mL) was added IM tetrabutylammonium fluoride (10 mL, 10 mmol) at 0 °C. The resulting solution was allowed to stir at 0 °C for 2 h and concentrated under reduced pressure. Silica gel chromatography (1:1 ethyl acetate:hexane) of the concentrate afforded the title compound (3.20 g, 100%) as a colorless oil. MS (ESI) m/e 500 (M-H).

EXAMPLE 7 4-chloro-N-[5-chloro-2-[[O-(2-tetrahydropyranyl)mcthyl]phenyl]}-N-(4-bromo-1- methylbutyl)benzenesulfonamide je cl Z NTE $70

JOL

ZZ

Cc

To a solution of 4-chloro-N-[5-chloro-2-{[O-(2-tetrahydropyranyl)methyl] phenyl]]}-N-(4- hydroxy-1-methylbutyl)benzenesulfonamide (3.20 g, 6.40 mmol) and triphenylphosphine (2.10 g, 8.03 mmol) in methylene chloride (30 mL) was added carbon tetrabromide (2.60 mL, 8.03 mmol) dropwise at 0 °C. The resulting solution was allowed to stir and warm to 22 °C for 12 h. A saturated solution of ammonium chloride (25 mL) was added. The reaction was extracted with methylene chlonde (2 X 100 mL). The organic phase was dried over Na,SO,, filtered, and concentrated under reduced pressure.

Silica gel chromatography (3:17 ethyl acetate:hexanes) of the concentrate afforded the title compound (2.10 g, 56%) as a colorless oil. MS (ESI) m/e 564 (M+H).

H

EXAMPLES

4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl}-N-{(R)-1-methyl-4-[(1,1- dimethylethyl)dimethylsilyl]oxy)butyljbenzenesulfonramide

OAc jot io cl N TBS 0=8=0

Cl

To a solution of 4-chloro-N-[5-chloro-2-(acetoxyoxymethyl)phenyl]benzenesulfonamide (13.7 g 36.6 mmol), triphenylphosphine (21.1 g, 80.6 mmol) and S5S-[[(1,1- dimethylethyl)dimethylsilyljoxy]-2-pentanol (16.0 g, 73.3 mmol) in THF (130 mL) was added diisopropylazodicarboxylate (15.9 mL, 80.6 mmol) dropwise at 0 °C under nitrogen. The resulting mixture was allowed to warm to 22 °C with stirring. Stirring was continued for a period of 12 h followed by the addition of 150 ml of H,O. The mixture was extracted with ether (3 X 100 mL). The combined organic extracts were washed with 1M NaHCO, and sat. brine. The organic phase was dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 16.6 g of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl}-

N-[(R)-1-methyl-4-[(1,1-dimethylethyl)dimethyisilylJoxy)butyl]benzenesulfonamide as a yellow oil in 79% yield.

EXAMPLES

4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl}-N-[(R)-1-methyl-4- hydroxybutyl]benzenesulfonamide

OAc cl Ia 0=8=0 :

To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-[(1,]- dimethylethyl)dimethylsilylJoxy)butyl]benzenesulfonamide (15.9 g, 27.8 mmol) in acetonitrile (45 mL) was added 48% aqueous HF (16 mL) dropwise at 0 °C. The resulting solution was stirred for 1h at 0 °C c followed by addition of 50 mL of 1M NaHCO;. The product was extracted with ether (2 X 50 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate) of the concentrate afforded 10.4 g of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl}-N-[(R)- 1-methyl-4-hydroxybutyl]benzenesulfonamide as a colorless oil in 81% yield.

EXAMPLE 10 4-chloro-N-[5-chioro-2-(acetoxymethyl)phenyl}-N-((R)-1-methyl-4- bromobutyljbenzenesulfonamide

OAc cl I I NT Br 0=5=0

Cl

To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4- hydroxybutyl]benzenesulfonamide (500 mg, 1.09 mmol) in acetonitrile (2 ml) was added triphenylphosphine (571 mg, 2.18 mmol) and carbon tetrabromide (720 mg, 2.18 mmol) at 0 °C. The resulting mixture was allowed to stir at 22 °C for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2 X 25 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 479 mg of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4- bromobutyl]benzenesulfonamide as a colorless oil in 84% yield.

EXAMPLE 11 5 (4R)-4-[5-chloro-2-(acetoxymethyl)phenyl][4-chlorophenyl)sulfonyl}-amino}pentylsulfonic acid =

OAc cI” _ \ 3

S$=0 [NY cl SO;H

To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4- bromobutyl]benznesulfonamide (1.00g, 1.91mmol) in methanol/water (1:1, 4 mL) was added Na,SO; (0.723g, 5.74mmol). The mixture was heated to reflux for 12 hours and then evaporated under reduced pressure. 2M HCI (25 mL) was added to the resulting oil. This mixture was extracted with CH,Cl, (2x 50 mL), dried over Na,SQ,, and filtered. Solvent was concentrated under reduced pressure to afford (4R)-4-[S-chloro-2-(acetoxymethyl)phenyl] [4-chlorophenyl) sulfonyl}-aminejpentylsulfonic acid (821mg ) as colorless oil in 88% yield. MS (ESI), 526 (M +1).

EXAMPLE 12 (4R)-4-[5-chlore-2-(hydroxymethyl)phenyl](4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride

OAc

AX 3 $0

JON cl S0,Cl

To a solution of (4R)-4-[5-chloro-2-(acetoxymethyl)phenyl] [4-chlorophenyl) sulfonyl] — amino] pentylsulfonic acid (560mg, 1.07mmol) in benzene (5 mL) was added phosphorus pentachloride (445mg, 2.14mmol) at 22 °C. The mixture was heated to reflux for 2 hours. This mixture was concentrated under reduced pressure and rediluted with CH,Cl, (100mL). This solution was washed with water (100 mL), dried over Na,SO, and filtered. The organic solution was concentrated to afford 442mg of (4R)-4-[S-chloro-2-(acetoxymethyl)phenyl](4-chlorophenyl)sulfonyl}-amino]pentylsulfonyl chloride as a pale yellow oil in 76% yield.

EXAMPLE 13 4-chloro-N-|5-chloro-2-chlorophenyl]-N-[(R)-1-methyl-4-|(1,1- dimethylethyl)dimethylsilyljoxy)butyl]benzenesulfonamide cl _ H

Or A ~_O. cr N TBS 0=8=0

Cl

To a solution of 4-chloro-N-[5-chloro-2-chlorophenyl]benzenesulfonamide (1.00 g, 2.97 mmol), triphenylphosphine (1.64 g, 6.24 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2- pentanol (1.30 g, 5.94 mmol) in THF (12 mL) was added diisopropylazodicarboxylate (1.23 mL, 6.24 mol) dropwise at 0 °C under nitrogen. The resulting mixture was allowed to warm to 22 °C with stirring. Stirring was continued for a period of 12 h followed by the addition of 25 mL of H,O. The mixture was extracted with ether (3 X 25 mL). The combined organic extracts were washed with 1M

NaHCO; and sat. brine. The organic phase was dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:heéxanes) of the concentrate afforded 830 mg of 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[{(R)-1-methyl-4-[(1,1-dimethylethyl)- dimethylsilyljoxy) butyl]benzenesulfonamide as a yellow oil in 52% yield.

EXAMPLE 14 4-chloro-N-{5-chloro-2-chlorophenyl}-N-[(R)-1-methyl-4-hydroxybutyl]benzenesulfonamide ) Cl _ 0=8S=0

Cl

To a solution of 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[(R)- 1-methyl-4-[(1,1- dimethylethyl)dimethylsilylJoxy)butylJbenzenesulfonamide (650 mg, 1.21 mmol) in acetonitrile (4 mL) was added 48% aqueous HF (2 mL) dropwise at 0 °C. The resulting solution was stirred for 1h at 0 °C followed by addition of 10 ml of IM NaHCO;. The product was extracted with ether (2 X 25 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate) of the concentrate afforded 430 mg of 4-chloro-N-[S-chloro-2-chlorophenyl]-N-[(R)-1- methyl-4-hydroxybutyl]benzenesulfonamide as a yellow oil in 84% yield.

EXAMPLE 15 4-chloro-N-(2,5-dichlorephenyl)-N-(3-(carboxy)-1(R) methylpropyl)benzenesulfonamide : : OH

It 0=8=0 (0)

Cl 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[(R)- 1-methyl-4-hydroxybutyl]benzenesulfonamide (1.57 g, 0.0037 moles) was dissolved in acetonitrile (25 mL) and water (2 mL). RuCl3 (50 mg), and

NalO4 (1.19 g, 0.0056 moles, 1.5 eq) were added and the mixture was stirred at room temperature for 18 hours. The mixture was filtered, concentrated, dissolved in CH2Cl2, washed with IN HCI, dried over NapSOg4 and evaporated. Chromatography over silica gel using 50-100% ethyl] acetate/ Hexane gave pure product (1.00 g, 62%) as a beige solid.

EXAMPLE 16 4-chloro-N-[2,5-dichlorophenyl]-N-{(R)-1-methyl-4-bromobutyl] benzenesulfonamide cl NT Br 0=8=0 cl

To a solution of 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-hydroxybutyl]benzene- 5S sulfonamide (3.90 g, 9.20 mmol) in CH,Cl, (20 mL) was added triphenylphosphine (4.87 g, 18.4 mmol) and carbon tetrabromide (6.09 g, 18.4 mmol) at 0 °C. The resulting mixture was allowed to stir at 22 °C overnight. To the reaction was added sat. ammonium chloride (200 mL). The product was extracted with CH,Cl; (2 x 200 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 3.13g of 4- chloro-N-{2,5-dichlorophenyl}-N-[(R)-1-methyl-4-bromobutyl}benzenesulfonamide as a colorless oil in 70% yield. MS (ESI) 486 (M+H).

EXAMPLE 17 (4R)4-[2,5-dichlorophenyl] [4-chlorophenyl) sulfonyl]-amine]pentylsulfonic acid jod cl N— ‘ go 0

Cl SOzH

To a solution of 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzne- sulfonamide (2.85 g, 5.88 mmol) in methanol/water (1:1, 12 mL) was added Na,SO; (7.40 g, 58.8 mmol). The mixture was heated to reflux for 12 hours and then evaporated under reduced pressure. 2M HCI was added to the resulting oil. This mixture was extracted with CH,Cl, (2 X 50mL), dried over

Na,SO,, and filtered. Solvent was concentrated under reduced pressure to afford (4R)-4-[2,5 dichlorophenyl] [4-chlorophenyl) sulfonyl]-amine]pentylsulfonic acid (2.34 g) as colorless oil in 82% yield. MS (ESI) 486 (M +1).

EXAMPLE 18 (4R)-4-(2,5-dichlorophenyl}[4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride

Cl 850

Jos lo] SO.Cl

To a solution of (4R)-4-[2,5-dichloropheny!]{4-chlorophenyl)sulfonyl]-amino] pentylsulfonic acid (2.34 g, 4.80 mmol) in benzene (10 mL) was added phosphorus pentachloride (1.48 g, 7.21 mmol) at 22 °C. The mixture was heated to reflux for 2 hours. This mixture was concentrated under reduced pressure and rediluted with CH,Cl, (120 mL). This solution was washed with water (100 mL), dried over Na,SQ, and filtered. The organic solution was concentrated to afford 2.21g of (4R)-4-[2, 5- dichlorophenyl!][4- chlorophenyl) sulfonyl]-amino] pentylsulfonyl chloride as pale yellow oil in 91% yield. LC/MS 504.

EXAMPLE 19 4-chloro-N-[2,5-dichlorophenyl}-N-[(R)-1-methyl-4-azidobutyl] benzenesulfonamide

Cl _

IX NN

0=8=0 = %

Cl

To a solution of 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-bromobutyl}benzene- sulfonamide (1.06 g, 2.50 mmol) in DMF (2.5 mL) was added diphenylphosphoryl azide (1.08 mL, 5.00 mmol) and 1,8-diazabicyclo[5.4.0Jundec-7-ene (0.935 mL, 6.25 mmol) at 0 °C. The resulting mixture was allowed to stir at 100 °C overnight. To the reaction was added sat. ammonium chloride (200 mL). The product was extracted with CH,Cl, (2 X 100 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 977 mg of 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-azidobutyl}- benzenesulfonamide as a colorless oil in 87% yield. MS (ESI) 447 (M+H).

EXAMPLE 20 4-chloro-N-{2,5-dichlorophenyl}-N-[(R)-1-methyl-4-aminobutyl] benzenesulfonamide cl NTN NH, 0=8§8=0

Cl

To a solution of 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-azidobutyl]benzene-

S sulfonamide (1.20 g, 2.68 mmol) in THF (5 mL) was added a THF solution of lithium aluminum hydride (1.0 M, 2.68 mL) at -20 °C. The resulting mixture was allowcd to stir at -20 °C overnight. To the reaction was added 0.5M NaOH (6 mL). This mixture was filtered through celite, dried over

Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 methanol/CHCls) of the concentrate afforded 972 mg of 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1- methyl-4-aminobutyl]benzenesulfonamide as a colorless oil in 86% yield. MS (ESI) 421 (M+H).

EXAMPLE 2] (S)-(3-[(1,1-dimethylethyl)dimethylsilyljoxy]-2-propanol

OH

A OTe

To a solution of (S)-1,2-propanediol (20.0 g, 0.263 mol), triethylamine (31.9 g, 0.315 mol), 4- z dimethylaminopyridine (1.28 g, 10.5 mmol) in CH,Cl, (200 mL) was added fert-butyldimethylsiloxy i chloride (47.3 g, 0.315 mol) at 22 °C. The mixture was allowed to stir for 18 h. The mixture was diluted with CH,Cl,, washed with water and sat. aqueous NH,Cl. The organic solution was dried over

Na,SO,, filtered and concentrated under reduced pressure. Silica gel chromatography (5% ethyl acetate/ hexanes) of the concentrate gave 45.0 g of the title compound as a clear oil in 90% yield.

EXAMPLE 22 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-4-[(1,1-dimethylethyl) dimethylsilyljoxy}-ethyl] benezenesulfonamide ) )

Cl TN

Jon OTBS 0

Cl

RN) To a solution of 4-chloro-N-[2,5-dichlorophenyl]benzenesulfonamide (5.74 g,17.1 mmol), triphenylphosphine (6.70 g, 25.7 mmol), (8)-3-[(1,1-dimethylethyl)dimethylsilylJoxy]-2-propanol (4.90 g, 25.7 mmol) in THF (50 mL) was added diisopropylazodicarboxylate (5.19 g, 25.7 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to warm to 22 °C.

Stirring was continued for a period of 18 h followed by the addition of water. The mixture was extracted with diethyl ether. The combined organic extracts were washed with NaHCO, sat. brine and dried over Na,SO.. Silica gel chromatography (1:10 ethyl acetate:hexanes) of the concentrate produced the title compound in 90% yield.

EXAMPLE 23 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1 -methyl-(2-hydroxyethyl]benzenesulfonamide or H ; Eo

A

Le

Ci

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-[[4-(1,1-dimethylethyl)- dimethylsilyljoxy]ethyl]benzenesulfonamide (07.80 g, 15.3 mmol) in CH3CN was added HF (5.5 mL) at 0 °C. The resulting mixture was allowed to stir at 0 °C for 2h and concentrated under reduced pressure. Silica gel chromatography (1:1 ethyl acctate:hexanes) of the concentrate afforded the title compound (5.70 g, 95%) as a colorless oil.

EXAMPLE 24 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl(2-iodoethyl)) benzene sulfonamide ) i

Ci N z

I \ §=0 \

JOR

Cl

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl(2-hydroxyethyl) benzene- sulfonamide (0.660 g,1.67 mmol), triphenylphosphine (0.530 g, 2.00 mmol) and imidazole (0.136 g, 2.00 mmol) in diethyl ether/CH,CN(2:1, 3.0 mL) was added iodine (0.430, g, 1.67 mol) at 0 °C under nitrogen and stirred for 12 hr. This mixture was concentrated under reduced pressure and diluted with

CH;Cl,, This solution was washed with water (50 ml), dried over Na,SO, and filtered. The organic solution was concentrated to afford the title compound as a light yellow oil in 96% yield.

EXAMPLE 25 (S)-4-triphenylmethylyloxy-2-butanol

OH

ZNNom

To a solution of (S)-(+)-1,3-butanediol (10.0 g, 0.110 mol), was added triphenylmethylchloride : (33.0 g, 0.330 mol), 4-dimethylaminopyridine (1.40 g, 11.5 mmol) in CH,Cl/pyridine (1:1, 500 mL). i

Stirring was continued over 48h. The solvent was removed, the mixture was diluted with cther, washed with brine and dried over Na,SO,. The organic solution was filtered and concentrated. Silica gel chromatography with (5% ethyl acetate/hexanes) produced a clear oil (24g) in 70% yield.

EXAMPLE 26 4-chloro-N-(2,5-dichlorophenyl)-N-[1(R)-methyl-(3-triphenyimethyloxy)-propyl] benezencsulfonamide

Cl

A LL

Oo

Cl

To a solution of 4-chloro-N-(2,5-dichlorophenyl)benzenesulfonamide (7.00 g, 20.8 mmol), triphenylphosphine (7.00 g, 27.0 mmol), (S)-4-triphenylmethyloxy-2-butanol (8.60 g, 27.0 mmol) in

THF (30 mL) was added diisopropylazodicarboxylate (5.48 g, 27.0 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to warm to 22 °C with stirring. After 18 h the mixture was washed with water, brine, dried over Na,SO, and filtered. Silica gel chromatography (1:10 ethyl acetate/ hexanes) of the concentrate produced the title compound in 90% yield.

EXAMPLE 27 4-chloro-N-(2,5dichlorophenyl)-N-[1(R)-methyl-(3-hydroxy)-propyl]benzenesulfonamide

Cl

Jot

Cl NE 0]

Cl -

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[1(R)-methyl-(3-triphenylmethyloxy)- propyl]benzenesulfonamide (2.00 g, 3.00 mmol) in CH;CN (20 mL) was added Amberlyst 15 ion- exchange resin (6.0 g). The resulting mixture was allowed to stir at 22 °C for 12 h and filtered. Silica gel chromatography (1:1 ethyl acetate: hexanes) of the concentrate afforded the title compound as a colorless oil in quantitative yield.

EXAMPLE 28 4-chloro-N-(2,5-dichlorophenyl)-N-{1(R)-methyl-(3-iodo)-propylibenzene sulfonamide

Cl cI” 3 , i lo \ \ jog

Cl

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[ 1(R)-methyl-(3-hydroxy)-propyl]benzene- sulfonamide (1.40 g, 3.40 mmol), triphenylphosphine (0.900 g, 3.40 mmol) and imidazole (0.230 g, 3.40 mmol) in diethyl ether/CH,CN (2:1, 7.0 mL) was added iodine (0.860 g, 3.40 mmol) at 0 °C under nitrogen and stirred for 12 h. The solvent was removed, the residue was taken into CH,Cl, , washed with water, dried over Na,SO, and filtered. The organic solution was concentrated to afford the title compound as a light yellow oil in 96% yield.

EXAMPLE 29 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-azidopropyl]Jbenzenesulfonamide ol NT Ns 0=8=0

Cl &

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-bromopropylbenzene- sulfonamide (1.188 g, 2.295 mmol) in THF/H,0 (20/4, 24 mL) was added sodium azide (1.49 g, 22.9 mmol) at 22 °C. The resulting mixture was allowed to stir at 22 °C for 4 days. The mixture was extracted with cther (3 X 60 mL). The combined organic extracts were washed with sat. NaHCO;, dried over MgSQ,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.941 g of 4-chloro-N-(2,5-dichlorophenyl)-N-{(R)- 1-methyl-3-azidopropyl]lbenzenesulfonamide as a colorless oil in 94% yield.

EXAMPLE 30 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide

Cl — oi) JO N ANN NH, 0=8:0 2

To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzene- sulfonamide (0.941 g, 2.16 mmol) in THF (21 mL) was added lithium aluminum hydride (4.33 mL, 1

M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to stir at 0 °C for 1 h and subsequently treated by successive dropwise addition of 0.165 mL of water, 0.165 mL of 15% sodium hydroxide solution, and 0.493 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 0.748 g of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)- I -methyl-3-aminopropyl]benzenesulfonamide as a light brown oil in 85% yield.

EXAMPLE 31 (3S)-(1,1-dimethylethyl)dimethylsiloxy butanal ots

ANT

A solution of methyl (S)-3-tert-butyldimethylsiloxy butyrate (35.0 g 151 mmol) in hexane (400 mL) was cooled to -78 °C. DIBAL-H (195 mL, 195 mmol, IM in hexanes) was added dropwise. H

Stiming was continued for 1 h after which time water (75 ml.) was cautiously added dropwise, after addition was complete stirring was continued at 22 °C for 18h. The reaction was diluted with diethyl ether and then decanted several times. The solvents were removed to afford (3S)-(1,1- dimethylethyl)dimethylsiloxy butanal as a clear oil in quantitative yield. '"H NMR (CDCl,) 89.85 (s br,

TH), 4.40-4.51 (m, 1H), 2.42-2.65 (m, 2H), 1.29 (d, 3H, J=6.0Hz), 0.96 (s, 9H), 0.14 (d, 6H, J=3Hz).

EXAMPLE 32 (trans)1,1-dimethylethyl-(5S)-(1,1-dimethylethyl)dimethylsiloxy-hex-2-enoate, o7Bs 0] P

AA oN

To a solution of (3S)-(1,1-dimethylethyl)dimethyisiloxy butanal (24.0 g 121 mmol), in dichloromethane (400 mL) at 0 °C was added tert-butoxy carbonylmethylene triphenylphosphorane

(50.0 g, 133 mmol). Stirring was continued for 2h after which time the reaction was concentrated and the resulting oil was purified by silica gel chromatogrphy (5% ethyl acetate / Hexane) to afford (trans)1,1-dimethylethyl-(5S)-(1,1-dimethylcthyl)dimethylsiloxy-hex-2-enoate as a clear oil in 93% yield. 'H NMR (CDCl;) §6.79-6.90 (m, 1H) 5.75 (d,'H, J=15.6Hz), 3.85-3.87 (m, 1H), 2.26-2.32 (m, 2H), 1.47 (s, 9H), 1.15 (d, 3H, J=6.0Hz), 0.90 (s, 9H), 0.06 (s, GH).

EXAMPLE 33 1,1-dimethylethyl-butyl-(5S)-(1,1-dimethylethyl)dimethylsiloxy-hexanoate, 018s 0]

SH GK o

A suspension of (trans)tert-butyl-(5S)-tert-butyldimethylsiloxy-hex-2-encate (33.5 g, 111 mmol), 10% Pd/C (5 g), in ethanol (250 mL), was hydrogenated at 45 psi for 1h. The catalyst was filtered off and the filtrate was concentrated to afford 1,1-dimethylethyl-butyl-(5S)-(1,1- dimethylethyl)dimethylsiloxy-hexanoate as a white wax in quantitative yield. 'H NMR (CDCl,) §3.72- 3.84 (m, 1H), 2.20 (t, 2H, J=7.0Hz), 1.60-1.74 (m, 2H), 1.35-1.70 (m, 4H), 1.44 (s, 9H), 1.35 (d, 3H,

J=6.0Hz), 0.88 (s, 9H), 0.10 (s, 6H).

EXAMPLE 34 1,1-dimethylethyl (5S)-5-hydroxyhexanoate

OH O

AA kK g

A solution of 1,1-dimethylethyl-(5S)-(1,1-dimethylethyl)dimethylsiloxy-hexanoate (19.0 g, 63.0 mmol) in THF (250 mL) was treated with tetrabutylammonium fluoride (94 mL, 94 mmol, 1M in

THF) at 0 °C. The reaction mixture was allowed to warm to 22 °C, and stirring was continued for 18h.

The reaction mixture was diluted with diethyl ether, washed with water, and dried over MgSO,. Silica gel chromatography (20% ethyl acetate/hexane) of the concentrate produced 1,1-dimethylethyl (5S)-5- hydroxyhexanoate in 89% yield. 'H NMR (CDC;) §3.74-3.86 (m. 1H), 2.32 (1, 2H, J=6.6Hz), 1.60- 1.74 (m, 2H), 1.57 (s, 1H, OH), 1.44-1.48 (m, 2H),1.45 (s, 9H), 1.20 (d, 3H, J=6.0Hz).

EXAMPLE 35 1,1-dimethylethyl(SR)-5-[(2,5-dichlorophenyl)-{(4-chlorophenyl)sulfonyl}-amino}hexanoate

CC cl Aa,

SO,

AT

To a solution 2,5-dichloro-N[{(4-chlorophenyl)]amino]phenyl)sulfonamide (2.42 g, 7.20 mmol), triphenyl phosphine (3.70 g, 14.4 mmol) and 1,1-dimethylethyl(5S)-5-hydroxyhexanoate (2.70 g, 14.4 mmol) in THF (100 mL) was added diisopropylazodicarboxylate (2.51 g, 14.4 mmol) dropwise at 0 °C under nitrogen. The reaction mixture was allowed to warm to 22 °C with stirring for a period of 18h. The reaction mixture was diluted with ethyl acetate then washed with water, brine and dried over

MgSO,. Silica gel chromatography (20% ethyl acetate/hexane) of the concentrate produced 1,1- dimethylethyl(5R)-5-[(2,5-dichlorophenyl)-[(4-chlorophenyl)sulfonyl]-amino]hexanoate in 60% yield.

EXAMPLE 36 (5R)-5-{(2,5-dichlorophenyl][(4-chlorophenyl)sulfonyl]-amino]hexanoic acid

JOS cl Ao

SO,

AT

He 1, 1-dimethylethyl(5R)-5-[(2,5-dichlorophenyl)-[(4-chlorophenyl)sulfonyl]-amino]hexanoate ) (700 g, 1.40 mmol) was treated with a 50% solution of trifluoroacetic acid in dichloromethane (20 mL).

After 3h the reaction was diluted with dichloromethane then washed with water, brine and dried over

MgSO,. Concentration under reduced pressure afforded (5R)-5-[(2,5-dichlorophenyl][(4- chlorophenyl)sulfonyl]-amino}hexanoic acid in quantitiative yield. MS (ESI), (M-H) 450. IR- 2975,1706,1466,1348.

EXAMPLE 37 4-chloro-N(2,5-dichlorophenyl)-N-{5-(1R)-methyl-5-0x0-(4- thiomorpholinyl)pentyl]benzenesulfonamide

Cl ct N NY ot

Cl

To a solution of (5R)-5-[(2,5-dichlorophenyl][(4-chlorophenyl)sulfonyl] -amino]hexanoic acid (2.00 g, 4.40 mmol), N,N-diisopropylethylamine (1.62 mL, 8.80 mmol) and 1-hydroxybenzotriazole (645 mg, 4.80 mmol), in dichloromethane (100 mL) was added 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (920 mg, 4.80 mmol). After 18 h the solvent is removed and the residue is taken into ethyl acetate and successively washed with aqueous HCI, water, brine and then concentrated to afford the title compound as a white solid (1.43g) in 61% yield. MS (ESI), (MH") 537.2. IR- 2910,1643,1581,1466,1348.

EXAMPLE 38 4-chloro-N(2,5-dichloropbeny!)-N-[5-(1R)-methyl-5-0x0-(1.1-dioxido-4- thiomorpholinyl)pentyl]benzenesulfonamide cl SSA NTN [] ® SO; L_ so; cl )

A solution of 4-chloro-N(2,5-dichlorophenyl)-N-[5-(1R)-methyl-5-0xo-(4-thiomorpholinyl)- pentyl}benzenesulfonamide (1.10 g, 2.10 mmol) in dichloromethane (100 mL) was treated with 3- chloroperoxybenzoic acid (1.10 g, 5.10 mmol) at 0 °C. After stirring for 1 h the ice bath was removed and stirring was continued for 18 h. The reaction mixture was diluted with dichloromethane, and washed with IN NaOH, H,O, brine, and dried over MgSO,. Concentration produced the title compound (1.01 g) in 91% yield. MS (ESI), M+H)" 569.2. IR-3441,2935,1653,1467,1428,1318.

EXAMPLE 39 4-chloro-N-{5-chloro-2-fluorophenyl]-N-|(R)-1-methyl-4-{(1,1- dimethylethyl)dimethylsilyljoxy)butyl]benzenesulfonamide

JO

H oTBS cl NTN 8

Cl

To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl}benzenesulfonamide (500 mg, 1.56 mmol), triphenylphosphine (859 mg, 3.28 mmol) and 5S-{[(1,1-dimethylethyl)dimethylsilyljoxy]-2- pentanol (682 mg, 3.12 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.645 mL, 3.28 mol) dropwise at 0 °C under nitrogen. The resulting mixture was allowed to warm to 22 °C with stirring. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H,O. The mixture was extracted with ether (3 X 15 mL). The combined organic extracts were washed with

NaHCO; and sat. brine. The organic phase was dried over Na,SQ,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 495 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)- dimethylsilylJoxy)butyl]benzenesulfonamide as a yellow oil in 61% yield.

EXAMPLE 40 4-chloro-N-[5-chloro-2-fluorophenyl}-N-{(R)-1-methyl-4-hydroxybutyl]benzenesulfonamide : OH

Cl NTN

Cl

To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-{(R)- 1-methyl-4-[(1,1-dimethylethyl)- dimethylsilylJoxy)butyl}bcnzenesulfonamide (495 mg, 0.951 mmol) in acetonitrile (4 mL) was added 48% aqucous HF (2 mL) dropwise at 0°C. The resulting solution was stirred for 1h at 0 °C followed by addition of 10 mL of 1M NaHCO,;. The product was extracted with ether (2 X 25 ml), dried over

Na,SQ,, filtered, and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate) of thc concentrate afforded 336 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4- hydroxybutyl]benzenesulfonamide as a yellow oil in 87% yield.

EXAMPLE 41 4-chloro-N-[5-chloro-2-fluorophenyl|-N-[(R)-1-methyl-4-bromobutyl| benzenesulfonamide

Jo 8 ol N ANN Br

Ci

To a solution of 4-chloro-N-{5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-hydroxybutyl]- benzenesulfonamide (336 mg, 0.827 mmol) in acetonitrile (4 mL) was added triphenylphosphine (433 mg, 1.65 mmol) and carbon tetrabromide (548 mg, 1.65 mmol) at 0 °C. The resulting mixture was allowed to stir at 22 °C for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2 X 25 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 349 mg of 4-chloro-N-{5-chloro-2-fluorophenyl]-N-[(R)- 1-methyl-4-bromobutyl]benzenesulfonamide as a yellow oil in 88% yield.

EXAMPLE 42 (4R)-4-[N-[S-chloro-2-fluorophenyl] {(4-chlorophenyl)sulfonyljamino|pentylsulfonic acid od of N—

Sg0 oO & cl SO3H ) (4R)-4-[N-[S-chloro-2-fluorophenyl}[(4-chlorophenyl)sulfonyljamino]pentylsulfonic acid was prepared analogous to (4R)-4-{2,5 dichlorophenyl] [4-chlorophenyl) sulfonyl)-amine]pentylsulfonic acid by reacting 4-chloro-N-{5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4- bromobutyl]benzenesulfonamide with Na,SO;. Yield=86%; MS (ESI) 470 (M +1).

EXAMPLE 43 (4R)-4-[N-[5-chloro-2-fluorophenyl][(4-chlorophenyl)sulfonyljamino]pentylsulfonyl chloride cr cl N 3

S50

Oo cl SO,Cl (4R)-4-[N-[5-chloro-2-fluorophenyl][(4-chlorophenyl)sulfonylJamino]pentylsulfonyl chloride was prepared analogous to (4R)-4-[N-[2,5-dichlororophenyl][(4-chlorophenyl)sulfonyl}amino]pentyl- sulfonyl chloride by reacting (4R)-4-[N-[5-chloro-2-fluorophenyl]{(4-chlorophenyl)sulfonyljamino]- pentylsulfonic acid with phosphorus pentachloride: Yield=81%; MS (ESI) 489 (M +1).

EXAMPLE 44 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-4-azidobutyl}benzenesulfonamide jo: - N ci Na 3 0=8=0

Cl t

To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R})-1-methyl-4-bromobutyl]- benzenesulfonamide (0.343 g, 0.730 mmol) in THF/H,0 (8/2 mL) was added sodium azide (0.237 g, 7.30 mmol) at 22 °C. The resulting mixture was allowed to stir at 22 °C for 10 days. The mixture was extracted with ether (3 X 20 mL). The combined organic extracts were washed with sat. NaHCO,, dried over MgSO, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.227 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N- [(R)-1-methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 72% yield.

EXAMPLE 45 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-4-aminobutyl]benzenesulfonamide

AL al NT NH» 0=8=0

Cl

To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]- benzenesulfonamide (0.325 g, 7.77 mmol) in THF (7 mL) was added lithium aluminum hydride (1.55 mL, 1 M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to stir at 0 °C for 1 h and subsequently treated by successive dropwise addition of 0.060 mL of water, 0.060 ml of 15% sodium hydroxide solution, and 0.180 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 0.207 g of the title compound as a light brown oil in 91% yield.

EXAMPLE 46 4-chloro-N-(S-chloro-2-flucrophenyl)-N-[(R)-1-methyl-3-azidopropyl|benzenesulfonamide jo cl NTN 0=8=0

Cl

To a solution of 4-chloro-N-(5-chioro-2-fluorophenyl)-N-[(R)-1-methyl-3-bromopropyl)- benzenesulfonamide (1.64 g, 3.27 mmol) in THF/H,O (20/4, 24 mL) was added sodium azide (2.13 g, 32.7 mmol) at 22 °C. The resulting mixture was allowed to stir at 22 °C for 4 days. The mixture was extracted with ether (3 X 60 mL). The combined organic extracts were washed with sat. NaHCO;, dried over MgSQ,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 1.38 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N- [(R)-1-methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.

EXAMPLE 47 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide

OX 2 cl NT" NH, 0=8=0

Cl

To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-azidopropyl}- benzenesulfonamide (1.34 g, 3.27 mmol) in THF (32 mL) was added lithium aluminum hydride (6.53 mL, 1 M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to stir at 0 °C for 1 h and subsequently treated by successive dropwise addition of 0.248 mL of water, 0.248 mL of 15% sodium hydroxide solution, and 0.744 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 1.12 g of 4-chloro-N-(S-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzene- sulfonamide as a light brown oil in 85% yield.

EXAMPLE 48 4-chloro-N-[5-fluoro-2-flurophenyl}-N-[(R)-1-methyl-4-[(1,1- dimethylethyl)dimethylsilyljoxy)butyl]benzenesulfonamide

F — r IX ANOTBS : cl

To a solution of 4-chloro-N-[5-fluoro-2-fluorophenyllbenzenesulfonamide (500 mg, 1.65 mmol), triphenylphosphine (909 mg, 3.47 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyljoxy]-2- pentanol (719 mg, 3.30 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.682 mL, 3.47 mol) dropwise at 0 °C under nitrogen. The resulting mixture was allowed to warm to 22 °C with stimng. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H,O. The mixture was extracted with ether (3 X 15 mL). The combined organic extracts were washed with

NaHCO, and sat. brine. The organic phase was dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 466 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[{(R)-1-methyl-4-[(1,1-dimethylethyl)- dimethylsilyl]oxy)butyl]benzene-sulfonamide as a yellow oil in 56% yield.

EXAMPLE 49 4-chloro-N-[S-fluoro-2-flurophenyl}-N-[(R)-1-methyl-4-hydroxybutyl]benzenesulfonamide

JO:

H OH

Ci

To a solution of 4-chloro-N-[5-flucro-2-flurophenyl}-N-{(R)- 1-methyl-4-[(1,1-dimethylethyl)- dimethylsilylJoxy)butyljbenzenesulfonamide (466 mg, 0.924 mmol) in acetonitrile (4 mL) was added 48% aqueous HF (2 mL) dropwise at 0 °C. The resulting solution was stirred for 1h at 0°C followed by addition of 10 ml of IM NaHCO. The product was extracted with ether (2 X 25 mL), dried over

Na,SO0,, filtered, and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate) of the concentrate afforded 317 mg of 4-chloro-N-{5-fluoro-2-flurophenyl}-N-{(R)-1-methyl-4- hydroxybutyl]benzenesulfonamide as a yellow oil in 88% yield.

EXAMPLE 50 4-chloro-N-[S-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide jo 8.

F N AUB

Cl :

To a solution of 4-chloro-N-[S-fluoro-2-flurophenyl]}-N-[(R)-1-methyl-4-hydroxybutyl}- benzenesulfonamide (317 mg, 0.813 mmol) in acetonitrile (4 mL) was added triphenylphosphine (425 mg, 1.62 mmol) and carbon tetrabromide (537 mg, 1.62 mmol) at 0 °C. The resulting mixture was allowed to stir at 22 °C for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2 X 25 mL), dried over Na,SO,, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 323 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)- 1-methyl-4-bromobutyl]benzenesul fonamide as a yellow oil in 86% yield.

EXAMPLE 51 (4R)-4-[N-[2,5-difluorophenyl}[(4-chlorophenyl)sulfonyl) amino]pentylsulfonic acid od

F N J t

S=0 \

J §1 AN cl SOsH (4R)-4-[N-[2,5-difluorophenyl]{(4-chlorophenyl)sulfonyl Jamino]pentylsulfonic ~~ acid was prepared analogous to (4R)-4-[2,5-dichlorophenyl]{4-chlorophenyl)sulfonyl]-amine]pentylsulfonic acid by reacting 4-chloro-N-[2,5-difluorophenyl]-N-{(R)-1-methyl-4-bromobutyl]benznesulfonamide with

Na,S0,;. Yield=84%; MS (ESI) 453 (M +1).

EXAMPLE 52 (4R)-4-[N-|2,5-difluorophenyl]{(4-chlorophenyl)sulfonyl]amino]pentylsulfonyl chloride od

F N—

S=0

Wn

Cl S0,C! (4R)-4-[N-{2,5-difluorophenyl][(4-chlorophenyl)sulfonyljJamino]pentylsulfonyl chloride was prepared analogous to (4R)-4-[2, 5-dichlorophenyl]}[4- chlorophenyl) sulfonyl]-amino] pentylsulfonyl c chloride by reacting (4R)-4-[N-[2,5-difluorophenyl][(4-chlorophenyl)sulfonyljamino]pentyisulfonic ; acid with phosphorus pentachloride Yield=88%; MS (ESI) 434 (M +1).

EXAMPLE S3 - 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzenesulfonamide

F NTT N3 0:=S=0

Cl

To a solution of d-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]- benzenesulfonamide (0.505 g, 1.12 mmol) in THF/H,O (8/2, 10 mL) was added sodium azide (0.363 g,

5.58 mmol) at 22 °C. The resulting mixture was allowed to stir at 22 °C for 10 days. The mixture was extracted with ether (3 X 20 mL). The combined organic extracts were washed with sat. NaHCO;, dried over MgSO, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.455 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1- methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 98% yield.

EXAMPLE 54 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-aminobutyl]benzenesulfonamide

F — x X N A NH» 0:8:0

Cl

To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzene- sulfonamide (0.394 g, 0.949 mmol) in THF (10 mL) was added lithium aluminum hydride (1.90 mL, 1

M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to stir at 0 °C for 1 h and subsequently treated by successive dropwise addition of 0.072 mL of water, 0.072 mL of 15% sodiurn hydroxide solution, and 0.216 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetatc:hexanes) of the concentrate afforded 0.329 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)- 1-methyl-4-aminobutyl]benzenesulfonamide as a light brown oil in 89% yield.

H

EXAMPLE 55 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-azidopropyl)benzenesulfonamide 02

F NTN

0=8=0

Ci

To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-bromopropyl]- benzenesulfonamide (1.74 g, 3.58 mmol) in THF/H,O (20/4, 24 mL) was added sodium azide (2.33 g, 35.8 mmol) at 22 °C. The resulting mixture was allowed to stir at 22 °C for 4 days. The mixture was extracted with ether (3 X 60 mL). The combined organic extracts were washed with sat. NaHCO;,

dried over MgSO, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 cthyl acetate:hexanes) of the concentrate afforded 1.53 g of 4-chloro-N-(2,5-difluorophenyl)-N-{(R)-1- methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.

EXAMPLE 56 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide

F NT NH, ' 0=S=0

Cl

To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzene- sulfonamide (0.144 g, 3.59 mmol) in THF (35 mL) was added lithium aluminum hydride (7.16 mL, 1

M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was allowed to stir at 0 °C for 1 h and subsequently treated by successive dropwise addition of 0.272 mL of water, 0.272 mL of 15% sodium hydroxide solution, and 0.816 mL of water. The mixture was concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 1.12 g of 4-chloro-N-(2,5-difluorophenyl)-N-{(R)-1-methyl-3-aminopropyl]Jbenzenesulfonamide as a light brown oil in 97% yield.

EXAMPLE 57 4-chloro-N(2,5-dichlorophenyl)-N-(5-(1.1-dioxido-4-thiomorpholinyl)-1(R)- : methylpentyl)benzenesulfonamide

ACN cl N NT jon (so;

Ci

A solution of 4-chloro-N(2,5-dichlorophenyl)-N-[5-(1R)-methyl-5-oxo0-(1.1-dioxido-4- thiomorpholinyl)pentyl]benzenesuifonamide (700 mg, 1.20 mmol) in THF (45 mL) was treated with a solution of borane-methyl sulfide complex (2M in THF, 1.8 mL, 3.6 mmol) dropwise at room temperature. After stirring for 18 h the reaction was cooled to 0 °C and quenched with methanol (50 mL), followed by treatment with HCI gas. The solvents were removed and the material was then purified by flash chromatography (silica gel, 15% ethyl acetate/hexane) to afford the title compound (300 mg) as a white solid in 50% yield. MS (ESI), (M+H)" 553.0. IR-3430,2933,1467,1348,1326.

EXAMPLE 58

N-cyclopropylmethyl-3-(1H)-imidazolylprepylamine

N

AN “ (2

N

1-(3-aminopropyl)imidazole (Aldrich, 10.0 g, 0.0799 moles) was dissolved in CH2Cl2 (100 ml) along with pyridine (7.57 g, 0.0959 moles, 1.2 eq.). Cyclopropanecarbonyl chloride (Aldrich, 8.76 g, 0.0839 moles, 1.05 eq.) was added dropwise and the mixture was stirred for 18 hours. The solvent was removed and the crude mixture was chromatographed over silica gel using 5-10% methanol in

CH2Cl with 0.5% NH4OH, give the amide (14.3 g, 93%). The purified amide intermediate (14.3 g, 0.074 moles) was dissolved in THF (300 mL). Lithium aluminum hydride (0.148 moles, 148 mL of 1M soln. in THF, 2.0 eq.) was added and the mixture was refluxed for 3 days. The mixture was carefully quenched with IN NaOH (10 mL) and refluxed for three hours. The hot solution was filtered over celite, and the solvent was removed to give pure N-cyclopropylmethyl-3-(‘H)-imidazolylpropylamine (7.57 g, 57%) as a viscous yellow oil. NMR (CDCl); 0.09 (m, 2H); 0.46 (m, 2H); 0.90 (m, 1H); 1.89 (quintet, J=6.9Hz, 2H); 2.43 (d, J=6.9 Hz, 2H); 2.61 (t, J=6.8Hz, 2H); 4.05 (t, J=6.9Hz, 2H); 6.92 (s, 1H); 7.05 (s, 1H); 7.48 (s, 1H).

EXAMPLE 59 4-chloro-N-(2,5-dichlorophenyl)-N-[3-[(N’-cyclopropylmethyl)-N’(3-(1H)-imidazolylpropyl)}- 1(R)-methylpropylcarboxamido}benzenesulfonamide /\ N € cl p

TNT NTT

0=8=0 (0)

Cl 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(carboxy)- 1(R)-methylpropyl)benzenesul fonamide (405 mg, 0.928 mmoles) was dissolved in THF (10 mL) and CH)Cl2 (15 mL). N-Cyclopropylmethyl-3- (1H)-imidazolylpropylamine (166 mg, 0.928 mmoles) was added along with 1-(3- (dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (230 mg, 0.0012 moles, 1.3 eq.) and

Hunig's base (1 drop). The mixture was stirred at room temperature for 18 hours and the solvents were removed. The residue was dissolved in CHCl, washed with sat. NaHCO3, and brine. The organic layer was dried over Na2S0O4 and evaporated. Chromatography over silica gel using 2-10% methanol in CHCl with 0.5% NH40H gave 4-chloro-N-(2,5-dichlorophenyl)-N-[3-[(N’-cyclopropyimethyl)-

N’(3-(1H)-imidazolylpropyl)]-1(R)-methylpropylcarboxamido]benzenesulfonamide (370 mg, 67%).

Yellow viscous oil: IR (neat, CH»Clp) 1637, 1467, 1348, 1166, 1095, 622 cm-l: MS (ESI+), 599 (M+H)™.

EXAMPLE 60 4-chloro-N-(2,5-dichlorophenyl)-N-[4-(N’-cyclopropylmethyl)-N’(3-(1H)-imidazolylpropylamino)- 1(R)-methylbutyl]benzenesulfonamide

N a, Og

I Ei N wv (od NTT NZ 0=8=0

Cl 4-chloro-N-(2,5-dichloropheny!)-N-(4-(N-cyclopropylmethyl-N-3-(1H)-imidazolylpropyl)- 1(R)-methylbutylcarboxamide)benzenesulfonamide (1.00 g, 1.67 mmoles) was dissolved in THF (50 mL). Borane dimethyl sulfide (2.51 moles, 1.25 mL of a 2.0M solution in toluene, 1.5 eq.) was added and the mixture was refluxed for 6 hours, then allowed to stir at room temperature for 18 hours. The mixture was slowly quenched with methanol (5 mL), and IN HCl (SmL). The solvent was removed, the residue was dissolved in CH2Cl7 and washed with IN NaOH, then brine. Prep HPLC (Reverse phase, methanol/H20/0.1% trifluoroacetic acid) gave a small amount of pure product (75.2 mg, 8%). H

Yield=8%,; Colorless viscous oil: IR (neat, CHCl) 1467, 1350, 1167, 1094, 753, 622 cm-l; MS (ESI+), 583 (M+H)*.

EXAMPLE 61 - 2-(methylsulfonylmethyl)piperidinel) 2-(methylsulfonylmethyl)pyridine

Picolyl chloride hydrochloride (15.9 g, 0.0967 moles) was dissolved in DMF (70 mL) and methanesulfinic acid sodium salt (10.9 g, 0.106 moles, 1.1 eq.) was added along with triethylamine (10.7 g, 0.106 moles, 1.1eq.). The mixture was refluxed for 1 hour. The DMF was removed, the residue dissolved in CH2Clp, washed with sat. Na3CO3, and brine. The organic layer was dried over NapSOgq and evaporated to give crude product. Purification was performed over silica gel using 20-100% ethyl acetate/hexane to give a yellow oil which solidified on standing (4.50 g, 27%).

EXAMPLE 62 (2) 2-(methylsulfonylmethyl)piperidine 2-(Methylsulfonylmethyl)pyridine (4.40 g, 0.0257 moles) and PtO2 (0.50 g) were suspended in ethanol (80 mL) with IN HCI (15 mL). The mixture was hydrogenated at 50 psi for 18 hours. The catalyst was filtered and the solvent removed. The residue was dissolved in CHCl) and washed with sat, NapCO3. The aqueous layer was extracted with CH2Cl2 (3 x 25 mL). The organic layers were combined and dried over NapSO4 and evaporated to give a yellow oil (4.11 g, 90%) which solidified on standing. Further purification was unnecessary. LCMS (178, M+H).

EXAMPLE 63 4-(methylsulfonylmethyl)piperidine

To a stirred solution of 4-(hydroxymethyl)piperidine (6.00 g, 52.0 mmol) in 100 mL of CH,Cl, was added di-fert-buty! dicarbonate (12.52 g, 57.0 mmol) at 0 °C and stirred for 1h. The reaction mixture was warmed to room temperature over a period of 1 h. The solvents were removed and the solid was diluted with 250 mL of ethyl acetate, washed with 1M NaOH (200 mL), brine (200 mL), and and dried over Na,SO,. The solvent was evaporated to afford an oil.

The resulting oil was dissolved in toluene (300 mL) and triphenylphosphine (14 g, SS mmol), iodine (14 g, 55 mmol), and imidazole (4.3 g, 63 mmol) were added. The reaction mixture was stirred at room temperature for 1h and the solvent was removed. The crude product was passed through silica gel using 10% ethyl acetate in hexanes as the eluent to yield an oil after concentration of the desired fractions.

The resulting oil was dissolved in THF (100 mL) and sodium thiomethoxide (1.20 g, 16.0 : mmol) was added at room temperature. The reaction mixture was stirred for 12 h and then diluted with cthyl acetate (100 mL), washed with water (200 mL), and dried over Na,SO,. The solvents were removed to afford an oil.

The resulting oil was dissolved in CH,Cl, and 3-chloroperoxybenzoic acid (5.90 g, 34.0 mmol) at room temperature and allowed to stir overnight. The reaction mixture was washed with IN NaOH (50 mL), and dried over Na,SO.. The crude sulfone was purified using silica gel chromatography (ethyl acetate) to yield the title compound as an oil in 41% overall yield.

Claims

WHAT IS CLAIMED IS:

1. A compound having the structure: D G NY 0 ) E Oo and pharmaceutically acceptable salts thereof, wherein: D is hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, halogen, alkoxyl, ester, amide, or D and G, taken together, form a substituted or unsubstituted cyclic moiety; and E, is hydrogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, alkoxyl, amide, sulfonyl, sulfonamidyl, sulfide or alkoxyl; or J and E, taken together, form a substituted or unsubstituted cyclic moiety; and G, when not part of a cyclic moiety including D, is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocycle optionally having one or more double bonds, amine, amide, ester, ether or carbamate; or ; J, when not part of a cyclic moiety including E, is substituted or unsubstituted hydrocarbyl, ’ heterocycle optionally having one or more double bonds.

2. The compound of claim 1, wherein: D is H or lower alkyl; E, G and J are independently substituted or unsubstituted aromatic.

3. The compound of claim 1, wherein: E, G and J are independently substituted or unsubstituted 5-, 6- or 7-membered aromatic.

4. The compound of claim 3, wherein: E, G and J are independently substituted or unsubstituted aryl.

5. The compound of claim 4 wherein: substituent(s) on E is(are) independently substituted or unsubstituted alkyl, halogen, hydroxy, ester, -S-alkyl, NO, or SO, substituent(s) on G is(are) independently substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, halogen, amide, amine, hydroxy, sulfonyl, sulfonamide, -(CH,)n-0-(CH;)m-amine, -(CH,),-O-(CH;)n-heterocycle, or -(CH;),-0-(CH,)m~amide, wherein n and m are independently 0, 1, 2, 3, 4 or 5; and substituent(s) on J is (are) independently substituted or unsubstituted alkyl, halogen, ether, -S-alkyl, or -S-aryl.

6. The compound of claim 5, wherein: substituent(s) on E and J is (are) halogen; and substituent(s) on G is (are) halogen and/or substituted alkyl.

7. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted polycyclic radical.

8. The compound of claim 1, wherein: D is H or lower alkyl, : E is substituted or unsubstituted aryl; ; G is substituted or unsubstituted aryl; and J 1s substituted or unsubstituted alkyl, alkenyl or alkynyl.

9. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted heterocycle optionally having or more double bonds. i

10. The compound of claim 1, wherein: D is H or lower alkyl; G is substituted or unsubstituted aryl; E and J, taken together, form a substituted or unsubstituted bicyclic or polycyclic moiety.

11. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted alkyl, alkenyl, or alkynyl; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted aryl.

12. The compound of claim 1, wherein: Dis H or lower alkyl; E is substituted or unsubstituted cycloalkyl, cycloalkenyl, or cycloalkynyl; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted aryl.

13. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted polycyclic radical; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted aryl. ‘

14. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted heterocycle optionally having one or more double bonds; G is substituted or unsubstituted aryl; and J is substituted or unsubstituted aryl.

15. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is substituted or unsubstituted alkyl, alkeny! and alkynyl; and J is substituted or unsubstituted aryl.

-

16. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is substituted or unsubstituted cycloalkyl, cycloalkenyl or cycloalkynyl; J is substituted or unsubstituted aryl.

17. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is ester or carboxylate; J 1s substituted or unsubstituted aryl.

18. The compound of claim 1, wherein: D 1s H or lower alkyl; E is substituted or unsubstituted aryl; J is substituted or unsubstituted aryl; and G is substituted or unsubstituted polycyclic radical.

19. The compound of claim 1, wherein: D is H or lower alkyl; E is substituted or unsubstituted aryl; G is -(CHR,),-O-(CHR;)~-CONR;R,, wherein nis 1,2, 3o0r4 mis0,1,2,3or4; R, and R; are independently H, or substituted or unsubstituted alkyl; R; and R, are independently H, substituted or unsubstituted alkyl; or R; and R, cooperate to form a substituted or unsubstituted cyclic moiety; and J is substituted or unsubstituted aryl.

20. A composition comprising a compound according to claim 1 in a pharmaceutically acceptable carrier therefor.

21. A method of modulating the level of Amyloid Beta Precursor Protein (APP), said method comprising contacting said protein with at least one compound according to claim 1.

22. A method according to claim 21, wherein said APP is APP, APPgos... APPgger1 APP 0611 117, SAPP, a-sAPP, or B-sAPP.

23. Use of at least one compound according to claim 1, in the manufacture of a preparation for treating disease conditions, by administering to a patient having a disease condition a therapeutically effective amount of said preparation.

24. Use according to claim 23, wherein said disease condition is amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, an Alzheimer’s disease, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, and Down's syndrome.

25. A method for preventing disease conditions in a subject at risk thereof, said method comprising administering to said subject an effective amount of at least one compound according to claim 1.

26. A method for treating a subject to decrease production of AP, said method comprising administering to said subject an effective amount of the compound according to claim 1.

27. Use of at least one compound according to claim 1, in the manufacture of a preparation for modulating the level of Amyloid Beta Precursor Protein (APP), by contacting said protein with said preparation.

28. Use according to claim 27, wherein said APP is APP, APPosuis APPgroiens APP 0671 717, SAPP, a-sAPP, or B-sAPP.

29. Use of at least one compound according to claim 1, in the manufacture of a preparation for preventing disease conditions in a subject at risk thereof by administering to said subject an effective amount of said preparation.

30. Use of the compound according to claim 1, in the manufacture of a preparation for treating a subject to decrease production of AP by administering to said subject an effective amount of said preparation.

31. A substance or composition for use in a method of modulating the level of Amyloid Beta Precursor Protein (APP), said substance or composition comprising at least one compound according to claim |, and said method comprising contacting said protein with said substance or composition.

32. A substance or composition for use in a method of treatment according to claim 31, wherein said APP is APP,q,, APP sui, APPergisni, APPioiri 117, SAPP, a-sAPP, or B-sAPP.

33. A substance or composition for use in a method for treating disease conditions, said substance or composition comprising at least one compound according to claim 1, and said method comprising administering to a patient having a disease condition a therapeutically effective amount of said substance or composition.

34. A substance or composition for use in a method of treatment according to claim 33, wherein said disease condition is amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, an Alzheimer’s disease, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, and Down's syndrome.

35. A substance or composition for use in a method for preventing disease conditions in a subject at risk thereof, said substance or composition comprising at least one compound according to claim 1, and said method comprising administering to said subject an effective amount of said substance or composition.

36. A substance or composition for use in a method for treating a subject to decrease production of Ap, said substance or composition comprising the compound according to claim 1, and said method comprising administering to said subject an effective amount of said substance or composition.

37. A compound according to claim 1, substantially as herein described and illustrated.

38. A composition according to claim 20, substantially as herein described and illustrated.

39. A method according to claim 21, claim 25, or claim 26, substantially as herein described and illustrated.

40. Use according to any one of claims 23, 27, 29 or 30, substantially as herein described and illustrated.

41. A substance or composition for use in a method of treatment according to any one of claims 31. 33, 35 or 36, substantially as herein described and illustrated.

42. A new compound, a new composition, a new non-therapeutic method of treatment, a new use of at least one compound as claimed in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described.