Title of Invention

FLUORO-AND TRIFLU0ROALKYL-CONTANING HETEROCYCLIC SULFONAMIDE INHIBITORS OF BETA AMYLOID PRODUCTION AND DERIVATIVES THEREOF

Abstract Compounds of Formula (I), are provided where T is CHO, COR8, or C(OH)R1R2; R1 and R2 are hydrogen, optionally substituted lower alkyl, CF3, optionally substituted alkenyl, or optionally substituted alkynyl; R3 is hydrogen or optionally substituted lower alkyl; R4 is (CF3)nalkyl, (CF3)n(substitutedalkyl), (CF3)nalkylphenyl, (CF3)nalkyl(substitutedphenyl), or (F)ncycloalkyl; n=1-3; R5 is hydrogen, halogen, CF3, diene fused to Y when Y=C, or substituted diene fused to Y when Y=C; W, Y and Z are C, CR6 or N where at least one of W, Y or Z are C; R6 is hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO2, or NR7; R7 is hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and R8 is lower alkyl, CF3, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer"s Disease and Down"s syndrome are also described.
Full Text WO 2004/092155 PCT/U'S2004/009268
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FLUORO- AND TRIFLUOROALKYL-CONTAINING HETEROCYCLIC
SULFONAMTDE INHIBITORS OF BETA AMYLOID PRODUCTION AND
DERIVATIVES THEREOF
This invention relates to fluoro- and trifluoroalkyl-containing heterocyclic
sulfonamide inhibitors of beta amyloid production and derivatives thereof to
processes for their preparation, compositions comprising them, and methods of
treatment employing them In particular, these inhibitors have utility in the treatment
of Alzheimer's disease.
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is the most common form of dementia (loss of
memory) in the elderly. The main pathological lesions of AD found in the brain
consist of extracellular deposits of beta amyloid protein in the form of plaques and
angiopathy and intracellular neurofibrillary tangles of aggregated
hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta
amyloid levels in brain not only precede tau pathology but also correlate with
cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent
studies have shown that aggregated beta amyloid is toxic to neurons in cell culture.
Beta amyloid protein is composed mainly of 39 to 42 amino acid peptides and
is produced from a larger precursor protein called amyloid precursor protein (APP) by
the sequential action of the proteases beta and gamma secretase. Although rare, cases
of early onset AD have been attributed to genetic mutations in APP that lead to an
overproduction of either total beta amyloid protein or its more aggregation-prone 42
amino acid isoform. Furthermore, people with Down's Syndrome possess an extra
chromosome that contains the gene that encodes APP and thus have elevated beta
amyloid levels and invariably develop AD later in life.
There continues to be a need for compositions useful in inhibiting beta
amyloid production and in the treatment of the effects of conditions associated
therewith.

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SUMMARY OF THE INVENTION
These compounds are useful for the treatment of conditions in -which beta
amyloid levels are elevated (e.g., AD, Down's Syndrome). Systemic administration
of these compounds to subjects at risk of; or suffering from, these diseases lowers beta
amyloid protein levels with subsequent reduction in the toxic beta amyloid aggregates
in the brains of these patients.
Advantageously, the trifluoroalky1- and fluoro-containing heterocyclic
sulfonamids compounds within formula (I) have been found to have unexpectedly
good beta-amyloid inhibitory activity. The compounds of formula (I) are
characterized by increased stability against oxidation (Phase 1 metabolic stability), as
compared to the corresponding compounds without the trifluoroalkyl or fluoro
groups. Further, compounds within formula (I) as identified herein have been found
to have increased metabolic stability and circulating half-life, and thus, enhanced
bioactivity as compared to the corresponding compound without the trifluoroalkyl or
fluoro groups.
Additionally, trifluoroalkyl- and fluoro-containing compounds within formula
(I) have been found to have increased potency as compared to the corresponding
unfluorinated compounds. Thus, the compounds of the invention are anticipated to be
useful in lower doses than prior art compounds.
These and other aspects of the invention will be apparent to one of skill in the
art upon reading of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention discloses compounds of Formula (I), their
pharmaceutical formulations, and their use in modulating beta amyloid production in
subjects at risk for, or suffering from, AD or other diseases resulting from elevated
levels of beta amyloid protein in the brain. The present invention therefore provides
compounds of Formula (I);

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wherein:
T is selected from the group consisting of CHO, COR8, and C(OH)R1R2;
R1 and R2 are independently selected from the group consisting of hydrogen,
lower alkyl, substituted lower alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl;
R3 is selected from the group consisting of hydrogen, lower alkyl and
substituted lower alkyl;
R4 is selected from the group consisting of (CF3)nalkyl,
(CF3)n(substitutedalkyl), (CF3)naIkyIphenyl, (CF3)nalkyl(substitutedphenyl), and
(F)ncycloalkyl;
n=l-3;
R5 is selected from the group consisting of hydrogen, halogen, CF3, diene
fused to Y when Y=C, and substituted diene fused to Y when Y=C;
W, Y and Z are independently selected from the group consisting of C, CR6
and N with the proviso that at least one of W or Y or Z must be C;
R6 is selected from the group consisting of hydrogen, halogen, lower alkyl,
and substituted lower alkyl;
X is selected from the group consisting of O, S, SO2, and NR7;
R7 is selected from the group consisting of hydrogen, lower alkyl, substituted
lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl; and
R8 is selected from the group consisting of lower alkyl, CF3, phenyl, and
substituted phenyl;
and pharmaceutically acceptable salts and/or hydrates or prodrugs thereof
Of these compounds, the preferred members are those in which R4 is
(CF3)naIkyl, such as CF3, CF3CH2, CH(CH3)CH2CF3, CH(CH2CF3)2, or CH(CF3)2.
Other preferred members include compounds where R4 is (F)ncycloalkyl, preferably,

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(F)2cycloalkyl, more preferably (F)2cyclohexane and bicyclo[3.1.0]hexane. and most
preferably 4,4-difluoro-cycIohexane and 4,4-difluorobicycIo[3.1.0]-3-hexane.
In one embodiment, T is C(OH)R1R2, R1 and R2 are hydrogen, R3 is hydrogen,
R4 is (CF3)2CH, preferably R4 is of S-stereochemistry, R5 is halogen, and W=C, X-S,
Y=CH, Z=CH with the sulfonamide attached to C-2 of the thiophene ring.
In another embodiment, T is CHO, R1 and R2 are hydrogen, R3 is hydrogen, R4
is CH(CH3)CH2CF3, R5 is halogen, and W=C, X=S, Y=CH, Z=CH with the
sulfonamide attached to C-2 of the thiophene ring.
In a further embodiment, T is C(O)R8, R1 and R2 are hydrogen, R3 is
hydrogen, R4 is CF3CH2(CH3)CH, R5 is halogen, R8 is CH3, and W=C, X=S, Y=CH,
Z=CH with the sulfonamide attached to C-2 of the thiophene ring.
In yet another embodiment, T is C(OH)R1R2, R1 and R.2 are hydrogen, R3 is
hydrogen, R4 is (CH2CF3)2CH, Rs is halogen, and W=C, X=S, Y=CH, Z==CH with the
sulfonamide attached to C-2 of the thiophene ring.
In still a further embodiment, T is C(OH)R1R2, R1 and R2 are CH3, R3 is
hydrogen, R4 is CF3CH2(CH3)CH, R5 is halogen, and W=C, X=S, Y-CH, Z=CH with
the sulfonamide attached to C-2 of the thiophene ring.
In another embodiment, T is C(OH)R1R2, R1 is CH3, R2 is hydrogen, R3 is
hydrogen, R4 is (CF3)2CH, R5 is halogen, and W=C, X=S, Y=CH, Z=CH with the
sulfonamide attached to C-2 of the thiophene ring.
In yet a further embodiment, T is C(OH)R1R2 R1 and R2 are hydrogen, R3 is
hydrogen, R4 is (F)2cycloalkyl, Rs is halogen, and W=C, X=S, Y=CH, Z=CH with the
sulfonamide attached to C-2 of the thiophene ring.
The point of attachment of the W-X-Y-Z-C heterocyclic ring to the SO2 group
is not a limitation of the present invention. However, in one preferred embodiment,
the ring is attached to the SO2 group through a carbon-atom. However, the ring may
be attached through a N heteroatom.
The compounds of the invention may contain one or more asymmetric carbon
atoms and some of the compounds may contain one or more asymmetric (chiral)
centers and may thus give rise to optical isomers and diastereomers. While shown
without respect to stereochemistry in Formula (I), when the compounds of Formula
(I) contain one or more chiral centers, at least the chiral center of the β-amino alcohol

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is of S-stereochemistry. Most preferably, the carbon atom to which N, R3 and R4 are
attached is of S-stereochemistry. Thus, the invention includes such optical isomers
and disastereomers; as well as the racemic and resolved, enantiomerically pure
stereo isomers; as well as other mixtures of the R and S stereoisomers, and
pharmaceutically acceptable salts, hydrates, and prodrugs thereof
The term "alky1" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having one to ten carbon atoms, preferably
one to eight carbon atoms and, most preferably, one to six carbon atoms; as used
herein, the term "lower alky1" refers to straight- and branched-chain saturated
aliphatic hydrocarbon groups having one to six carbon atoms; "alkeny1" is intended to
include both straight- and branched-chain alkyl group with at least one carbon-carbon
double bond and two to eight carbon atoms, preferably two to six carbon atoms;
"alkyny1" group is intended to cover both straight- and branched-chain alkyl groups
with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably
two to six carbon atoms.
The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl"
refer to alkyl, alkenyl, and alkynyl groups as just described having from one to three
substituents preferably independently selected from the group consisting of halogen,
CN, OH, NO2, amino, ary1, neterocyclic, substituted ary1, substituted heterocyclic,
alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alky1carbonyl, alkylcarboxy,
alkylamino, and arylthio. These substituents may be attached to any carbon of an
alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable
chemical moiety.
The term "cycloalky1" is used herein to describe a carbon-based saturated ring
having more than 3 carbon-atoms and which forms a stable ring. The term cycloalkyl
can include groups where two or more cycloalkyl groups have been fused to form a
stable multicyclic ring. Preferably, cycloalkyl refers to a ring having about 4 to about
9 carbon atoms, and more preferably about 6 carbon atoms.
The term "substituted cycloalkyl" is used herein to refer to a cycloalkyl group
as just described and having from one to five substituents preferably independently
selected from the group consisting of hydrogen, halogen, CN, OH,NO2j amino, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted

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alky1oxy, alky1carbonyl, alkylcarboxy, alkylamino, substituted alkylamino, arylthio,
heterocyclic, substituted heterocyclic, aminoalkyl, and substituted aminoalkyl.
The term "aryl" is used herein to refer to a carbocyclic aromatic system, which
may be a single ring, or multiple aromatic rings fused or linked together as such that
at least one part of the fused or linked rings forms the conjugated aromatic system.
The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, and indane.
The term "substituted aryl" refers to aryl as just defined having one to four
substituents preferably independently selected from the group consisting of halogen,
CN, OH, NO2, amino, alky1, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted
alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio.
The term "diene" refers to an unsaturated hydrocarbon or diolefin having two
double bonds. The term "substituted diene" refers to a diene which is substituted with
one to two substituents preferably independently selected from the group consisting of
halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,
substituted alkoxy, aryloxy, substituted aryloxy, alkyloxy, substituted alkyloxy,
alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substituted alkylcarboxy,
alkylamino, substituted alkylamino, arylthio, or substituted arylthio.
As "diene" and "substituted diene" are used in the context of R5, an
embodiment in which the substituted diene is 3-chloro-l,3-butadiene which is fused to
the thiophene ring at R5 and Y to form a benzothiophene. Other suitable dienes
include 1, 3- butadienyl- and 2-trifluoromethyl-l,3-butadienyl However, other
suitable substituted and unsubstituted dienes may be readily selected from among the
compounds as defined herein.
The term "substituted benzyl" refers to a benzyl group, having substituted on
the benzene ring, one to five substituents preferably independently selected from the
group consisting of halogen, CN, OH,NO2 amino, alkyl, cycloalkyl, alkenyl, alkynyl,
alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and
arylthio.
The term "heterocyclic" is used herein to describe a stable 4- to 7-membered
monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially

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unsaturated, or unsaturated, and which includes carbon atoms and from one to four
heteroatoms preferably independently selected from the group consisting ofN, O, and
S atoms. The N and S atoms may be oxidized, The heterocyclic ring also includes
any multicyclic ring in which any of above defined heterocyclic rings is fused to an
aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom
provided the resultant structure is chemically stable. Such heterocyclic groups
include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxo piperidinyl,
azepinyl, pyrrolidinyl, imidazolyl, pyridy1, pyraziny1, pyrimidinyl, pyridazinyl,
oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, isoquinolinyl, and
tetrahy drothi opyran.
The term "substituted heterocyclic" is used herein to describe the heterocyclic
just defined having one to four substituents preferably independently selected from
the group consisting of halogen, CN, OH, NO2: amino, alkyl, substituted alky1,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkyloxy, substituted
alkyloxy, alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substituted
alkylcarboxy, alkylamino, substituted alkylamino, arylthio, or substituted arylthio.
Where the terms "substituted alkyl" or "substituted alkylphenyl" are recited,
the substitution may occur at the alkyl group or on the corresponding base compound.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or
substituted alkyl.
The term "aryloxy" is used herein to refer to the OR group, where R is aryl or
substituted aryl.
The term "arylthio" is used herein to refer to the SR group, where R is aryl or
substituted aryl.
The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is
alkyl or substituted alkyl.
The term "alkylcarboxy" is used herein to refer to the COOR group, where R
is alkyl or substituted alkyl.

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The term "aminoalky1" refers to both secondary and tertiary amines wherein
the alkyl or substituted alky1 groups, containing one to eight carbon atoms, which may
be either same or different and the point of attachment is on the nitrogen atom.
The term "halogen" refers to Cl, Br, F, or I.
The term "ring" structure, includes a monocyclic structure, a bridged cyclo
structure, and fused cyclo structures, unless the type of ring structure is otherwise
specified.
The compounds of the present invention can be used in the form of salts
derived from pharmaceutically or physiologically acceptable acids or bases. These
salts include, but are not limited to, the following salts with organic and inorganic
acids such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, mallic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, toluenesulfonic and similarly known acceptable acids, and mixtures
thereof. Other salts include diethanolamine, ethylenediamine, and salts with alkali
metals or alkaline earth metals, such as sodium (e.g., sodium hydroxide), potassium
(e.g., potassium hydroxide), calcium (e.g., calcium hydroxide) or magnesium (e.g.,
magnesium hydroxide).
These salts, as well as other compounds of the invention may be in the form of
esters, carbamates and other conventional "pro-drug" forms, which, when
administered in such form, convert to the active moiety in vivo. In a currently
preferred embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell,
"Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design",
Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
In one embodiment, the compounds of Formula (I) are thiophenesulfonamides,
and more desirably, 5-halo thiophenesulfonamides, and most desirably, 5-halo
thiophene sulfonamides with β-branches in the side chain of a primary alcohol. Thus,
with respect to Formula (I), the compound of the invention desirably has a structure in
which R1 and R2 are hydrogen; R3 is hydrogen, R4 is (CF3)2CH of S-stereochemistry,
R5 is halogen, W=C, X=S, Y=CH, Z=CH with the sulfonamide attached to C-2 of the
thiophene ring.
In another embodiment, the compounds of Formula (I) are furransulfonamides.
Thus, with respect to Formula (I), the compound of the invention has a structure in

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which X is O. In one desirable embodiment, the furansulfonarnides are characterized
by β-branches in the side chain of a primary alcohol.
In yet another embodiment, the compounds of Formula (I) are pyrazole
sulfonamides. Thus, with respect to Formula (I), the compound has a structure in
which X is NR7, W is N and Z and Y are C or CR6, with the proviso that at least one
ofYorZmustbeC.
These and the other compounds of the invention can be prepared following the
Schemes illustrated below.
Synthesis
The compounds of the present invention can be prepared in a number of ways
well known to one skilled in the art of organic synthesis. The compounds of the
present invention can be prepared using the methods described below, together with
synthetic methods known in the synthetic organic arts or variations of these methods
by one skilled in the art. (See, generally, Comprehensive Organic Synthesis,
"Selectivity, Strategy & Efficiency in Modem Organic Chemistry", ed., I. Fleming,
Pergamon Press, New York (1991); Comprehensive Organic Chemistry, "The
Synthesis and Reactions of Organic Compounds", ed. J.F. Stoddard, Pergamon Press,
New York (1979)). Preferred methods include, but are not limited to, those outlined
below.
A first method of preparation consists of reaction of a 1,2-aminoalcohol II
with the appropriate sulfony1 halide in the presence of a base such as triethylamine
(TEA) and in a suitable solvent to afford compounds of Formula III. For compounds
where R2 and R1 are hydrogen, oxidation of the N-sulfonyl primary alcohol with
pyridinium chlorochrornate (PCC), the Dess Martin periodinane reagent [D.B. Dess,
J.C. Martin, J. Org. Chem., 48:4155 (1983)] or under Swem conditions [Omura et al,
J. Org. Chem., 41:957 (1976)] then affords the corresponding aldehyde IV which can
be reacted with Grignard reagents (RMgX, where R is an organic radical and X is a
halogen) to afford the secondary alcohols V as a mixture of diastereomers which can
be separated by high performance liquid chromatography (HPLC) (Scheme 1).

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A second method of preparation involves reaction of an α-amino acid or ester
IX with the appropriate sulfonyl halide in the presence of a base such as triethylamine
and in a suitable solvent to afford compounds of FormulaX (Scheme 2). The
intermediate N-sulfonyl acid X (Rx=H) can be converted to the corresponding
primary alcohol VIII (R1-R2-H) utilizing standard methodology such as lithium
aluminum hydride (LiAlH1), B2H6 or cyanuric chloride/NaBH4 The intermediate N-
sulfonyl ester X (Rx=alkyl, Bn) can also be reduced to the corresponding primary
alcohol VIII (R1=R2=H) utilizing standard methodology such as LiAlH4.
Alternatively, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be converted to
the aldehyde IV with DIBAL. Finally, the intermediate N-sulfonyl ester X (Rx=alkyl,
Bn) can be reacted with 2 equivalents of Grignard reagent to afford the tertiary
alcohols III with R1=R2. Alternatively, for tertiary alcohols III with R1 not equal to
R2, the corresponding Weinreb amide of the N-sulfonyl acid can be prepared and
sequentially reacted with R1MgX and R2MgX,

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In a variation of the second method to prepare the primary alcohols, an α-
amino acid or ester (or N-protected derivative thereof) VI is first converted to the
corresponding primary 1,2-aminoalcohol VII (using the methodology outlined in the
previous paragraph), which is subsequently, after deprotection (if necessary), reacted
with the appropriate sulfonyl halide (Scheme 3) to afford compounds of Formula
VIII

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For preparation of compounds derived from unnatural α-amino acids
containing beta branching in the amino acid side chain, a method of preparation based
on the work of Hruby (Tet. Lett. 38: 5135-5138 (1997)) is outlined in Scheme 4. This
route entails formation of the α, β-unsaturated amide XIV of the Evans chiral
auxiliary from an acyIbromide XI via a Homer-Emmons reaction sequence, followed
by conjugate addition of an organocuprate, trapping of the resulting enolate anion XV
with N-Bromosuccinarnide (NBS), displacement of the bromide XVI with azide anion
(provided by tetramethylguanidinium azide (TMGA) or sodium azide to afford XVII,
followed by reduction to the 1,2-amino alcohol and subsequent sulfonylation to afford
the target compound XVIII.

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When the heterocycle attached to the sulfonamide in the above alcohols is
thiophene, the corresponding sulfone derivative XX may be obtained by oxidation of
the thiophene compound XIX with 3-Chloroperoxybenzoic acid (MCPBA) (Scheme
5).

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An alternate preparation of sulfonamides derived from unnatural 1,2-
aminoalcohols utilizes the Bucherer modification of the Strecker α-amino acid
synthesis (Scheme 6). In this route, an aldehyde XXI is reacted with cyanide anion
and ammonium carbonate to afford the hydantoin XXII, which is hydrolyzed to the α-
amino acid XX1H. This compound is then reduced to XXIV and sulfonylated to
afford the desired compounds of Formula XXV. Alternatively, the intermediate
amino acid XXIII can be first sulfonylated to afford XXVI which is then reduced to
XXV. The racemic products XXIII, XXV or XXVI can be resolved to the desired S
enantiomer using standard methodology by one skilled in the art.

For sulfonamides derived from 1,2-aminoalcohols in the secondary alcohol
series with R1=H and R2=CF3 (compound XXVII), a method of preparation has been
devised that is outlined in Scheme 7 starting from the aldehyde IV (prepared as in
Scheme 1).

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rv xxvII
When the heterocycle attached to the sulfonamide in the above alcohols is
thiophene, the corresponding 5-iodo and 5-fluoro-thiophene derivatives may be
obtained by conversion of the 5-bromo-thiophene derivative XXVIII (obtained as in
Scheme 1) to a 5-trialkyItin-thiophene intermediate XXIX which can be converted to
either the 5-iodo-thiophene (XXXI) by treatment with sodium iodide and chloramine
T or the 5-fluoro-thiophene analog (XXX) by treatment with the SELECTFLUOR®
reagent (Aldrich Chem Co.) (Scheme 8).

Another method of preparing chirally pure N-sulfonyI 1,2-amino alcohols
derived from α-amino acids is outlined in Scheme 9. This method initially involves
formation of the α,β-unsaturated amide XXXIV of the Evans chiral auxiliary from the
bromoacetyl bromide XI via a Horner-Emmons reaction sequence. Conjugate
addition of an organocuprate and protonation of the resulting enolate anion affords
XXXV, which is then converted to the corresponding enolate and electrophilically
aminated with trisyl azide to afford the key intermediate XXXVI (J. Am. Chem. Soc.

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109: 6881-6883 (1987)). The azide intermediate XXXVI is then hydrolyzed to the α-
azido acid XXXVII and reduced to the chirally pure α-amino acid XXXVIII which
can be converted to the corresponding N-sulfonyI1,2-amino alcohols by methods
previously described above (e.g., Schemes 2 or 3),

Finally, chirally pure α-amino acids XLI, one of the possible synthetic
precursors of chiral N-sulfonyl 2-amino alcohols XLIII, can also be prepared utilizing
asymmetric variants of the Strecker α-amino acid synthesis as outlined in Schemes 10
(J. Org. Chem. 61:440-441 (1996)) and 11 (J. Org. Chem. 54:1055-1062 (1989)).

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A method of preparing chirally pure trifluoroalkyl- or fluoro-containing
heterocyclic sulfonamide compounds according to Formula (I) is outlined in Schemes
12 and 13, Scheme 12 outlines procedures described in the literature for formation of
a suitable aminoester XLVII [W.H. Vine, et al, JMed Chem. 1981, 24: 1043-1047
and R Keese, et al, Synthesis, 1996, 695-696], Based on the literature and the
teachings herein, one of skill in the art will recognize that, depending upon the desired
aminoester, one can readily select another trifluoromethyl aldehyde in step 3
depending upon the substituents selected for R4 and R3, another chiral auxiliary in
step 4, or utilize other reagents, substituents, or other reaction conditions in any of the
outlined steps. However, if R3 is not equal to R4, then a mixture of olefin isomers is
obtained in step 3 of Scheme 12 which requires separation before Step 4.

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In Scheme 13, the aniinoester XL VIII is filtered; it has been found that
recrystallization at this step, which is described in the literature as essential, is not
required. The intermediate aminoester XLVIII is converted to N-benzyl amino
alcohol with DIBAL-H. The N-benzyl amino alcohol XLIX is hydrogenated in the
presence of a suitable catalyst to provide an aminoalcohol L. The catalyst is removed
via filtration and the solution concentrated to a solid. The aminoalcohol L is
sulfonylated with BSA/triethylamine/DMAP (or another suitable agent, e.g..
TMSC1/amine base) and a desired heterocyclic sulfonylchloride. The reaction is
quenched to remove the silyI ether group (e.g., with aqueous HC1/THF) and filtered
(e.g., using an SiO2 plug) with ethyl acetaie/hexane in a ratio which permits
crystallization of the chirally puretrifluoromsthyl-containing heterocyclic
sulfonamide of Formula (I) of the invention.

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In addition to being useful for preparing the compounds of the invention, the
method of Scheme 13 may be readily used forthe preparation of trifluoroalkyl-,
including trifluoro methyl-, and fluoro-containing compounds. More particularly, this
method may be useful for preparing other trifluoroalkyl-, trifluoromethyl-, or fluoro-
containing sulfonamides from a diastereomeric mixture of an aminoester having at
least one chiral center and at least one trifluoroalkyl or fluoro group attached to at
least one chiral center through an alky1 group or at least one fluoro group attached to a
cycloalkyl group. As defined herein, the alkyl group may link one or more
trifluoroalkyl to the chiral center directly. Alternatively, the trifluoroalkyl can be
located on a substituent of a substituted alkyl group.
The compounds of the invention can also be prepared by reacting a secondary
alcohol V with pyridinium chlorochromate (PCC) orthe Dess Martin periodinane
reagent [D.B. Dess, J.C. Martin, J. Org. Chem., 48:4155 (1983)] to afford the
corresponding aldehyde LI (Scheme 14).

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Another method of preparing trifluoromsthylated or fluorinated heterocyclic
sulfonamide compounds includes treating a trifluoromsthylated or fluorinated
aldehyde with a dehydrating agent and a chiral sulfinamide to form a
trifluoromethylated or fluorinated chiral sulfinamide. One of skill in the art would
readily be able to determine a suitable dehydrating agent for use in the present method
including, without limitation, titanium ethoxide, magnesium sulfate, or molecular
sieves such as 4A molecular sieves. The trifluoromethylated or fluorinated chiral
sulfinamide can then be treated with a cyanating agent to form a trifluoromethylated
or fluorinated diastereomeric α-amino nitrile, respectively. The selection of the
cyanating agent for use in the present invention is within one skilled in the art and can
include ethyl isopropoxy aluminum cyanide, among others. The trifluoromsthylated
or fluorinated diastereomeric α-amino nitrile can then be isolated and optionally
purified using techniques known to those of skill in the art. Alternatively, the
trifluoromethylated or fluorinated diastereomeric a-amino nitrile can be hydrolyzed to
a trifluoromethylated or fluorinated a-amino acid, respectively, using techniques and
agents known to those of skill in the art. The trifluoromethylated or fluorinated α-
amino acid can then be reduced to a trifluoromsthylated or fluorinated β-amino
alcohol, respectively, using techniques and agents known to those of skill in the art.
The trifluoromethylated or fluorinated β-amino alcohol can be reacted with a
heterocyclic sulfonyl chloride to form the corresponding trifluoromethylated or
fluorinated heterocyclic sulfonamide of the present invention.
In a one embodiment, the invention relates to a method of preparing a
trifluoromethylated or fluorinated heterocyclic sulfonamide compound, the method
including the steps of:

WO 2004/092155 PCT/US2004/009268
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(a) filtering a diastereomeric mixture of an aminoester, said
aminoester having at least one chiral center and at least one trifluoromethyl or fluoro
group attached to at least one chiral center through an alkyl group;
(b) treating the aminoester with DIBAL-H in toluene to afford N-
benzyl amino alcohol;
(c) hydrogenating the N-benzyl amino alcohol with a catalyst and
affording an amino alcohol;
(d) sulfonylating the amino alcohol of (c) with aheterocyclic
sulfonyl chloride; and
(e) crystallizing the sulfonylated product of (d) to afford to chirally
pure trifluoromethylated or fluorinated heterocyclic sulfonamide compound.
In still a further embodiment, the invention relates to a method of preparing a
trifluoromethylated or fluorinated heterocyclic sulfonamids compound, the method
including the steps of:
(a) treating a trifluoromethylated or fluorinated aldehyde with a
dehydrating agent and a chiral sulfmamide to form atrifluoromethylated or
fluorinated chiral sulfmamide;
(b) treating said trifluoromethylated or fluorinated chiral
sulfinimide with a cyanating agent to form a trifluoromethylated or fluorinated
diastereomeric α-amino nitrile;
(c) hydrolyzing said trifluoromethylated or fluorinated
diastereomeric α-amino nitrile to a trifluoromethylated α-amino acid;
(d) reducing said trifluoromethylated or fluorinated α-amino acid
to atrifluoromethylated or fluorinated β-amino alcohol; and
(e) reacting said trifluoromethylated or fluorinated β-amino
alcohol with a heterocyclic sulfonyl chloride to form said trifluoromethylated or
fluorinated heterocyclic sulfonamide.

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Methods of Use
Compounds of Formula (I) are inhibitors of beta amyloid production. In
preliminary studies using protease specific assays, exemplary compounds of Formula
(I) have been shown to exhibit specific inhibition with respect to protease activity.
Thus, the compounds of the present invention are useful for treatment and prevention
of a variety of conditions in which modulation of beta amyloid levels provides a
therapeutic benefit. Such conditions include, e.g., amyloid angiopathy, cerebral
amyloid angiopathy, systemic amyloidosis, Alzheimer's Disease (AD), hereditary
cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis,
Down's syndrome, mild cognitive impairment (MCI), among others.
In addition, the compounds of Formula (I) may be utilized in generating
Teagents useful in diagnosis of conditions associated with abnormal levels of beta
amyloid. For example, the compounds of Formula (I) may be used to generate
antibodies, which would be useful in a variety of diagnostic assays. Methods for
generating monoclonal, polyclonal, recombinant, and synthetic antibodies or
fragments thereof, are well known to those of skill in the art. (See, e.g., E. Mark and
Padlin, "Humanization of Monoclonal Antibodies", Chapter 4, The Handbook of
Experimental Pharmacology, Vol. 113, The Pharmacology of Monoclonal
Antibodies, Springer-Verlag (June, 1994); Kohler and Milstein and the many known
modifications thereof; PCT Patent Application No. PCT/GB85/00392; British Patent
Application Publication No. GB218863SA; Amit et al., Science, 233:747-753 (1986);
Queen et at.,-Proc. Nat'l Acad, Sci, USA, 86:10029-10033 (1989); International
Patent Publication No. WO90/07861; and Riechmann et al., Nature, 332:323-327
(1988); Huse et al, Science, 246:1275-1281 (1988)). Alternatively, the compounds of
Formula (I) may themselves be used in such diagnostic assays. Regardless of the
reagent selected (e.g., antibody or compound of Formula (I)), suitable diagnostic
formats including, e.g., radioimmunoassays and enzyme-linked immunosorbent
assays (ELISAs), are well known to those of skill in the art and are not a limitation on
this embodiment of the invention.
The beta amyloid inhibitory activity of many of the compounds of the present
invention has been determined using the Repressor Release Assay (RRA). See, Table

WO 2004/092155 PCT/US2004/009268
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5 below. A compound is considered active in RRA if it leads to at least a 1.5 fold
increase in luciferase activity at 20 μg/mL and is non-toxic.
Additionally, cellular, cell-free and in vivo screening methods to detect
inhibitors of beta amyloid production are known in the art. Such assays may include
radioimmunoassays and enzyme-linked immunosorbent assay (ELISA), among
others. See, e.g., P.D. Mehla, et al, Techniques in Diagnostic Pathology, vol. 2, eds.,
Bullock et al, Academic Press, Boston, pages 99-112 (1991), International Patent
Publication No. WO 98/22493, European Patent No, 0652009, and US Patent Nos.
5,703,129 and 5,593,846. Selection of an appropriate in vitro or in vivo screening
assay is not a limitation of the present invention.
Pharmaceutical Formulation
The compounds of this invention may be administered to a subject by any
desirable route, taking into consideration the specific condition for which it has been
selected. By subject is meant any suitable mammal, including humans, domestic
animals (e.g., canines and felines), and livestock, which have been recognized as
having or at risk of having one or more of the conditions for which modulation of beta
amyloid levels is desirable. Thus, the compounds of the invention are useful for
treatment and/or prevention of a number of human and veterinary conditions. As used
herein, "prevention" encompasses prevention of symptoms in a subject who has been
identified as at risk for the condition, but has not yet been diagnosed with the same
and/or who has not yet presented any symptoms thereof.
These compounds may be delivered or administered by any suitable route of
delivery, e.g., oral, injection, inhalation (including oral, intranasal and intratracheal),
intravenous, subcutaneous, intramuscular, sublingual, intracranial, epidural,
intratracheal, rectal, vaginal, among others. Most desirably, the compounds are
delivered orally, by inhalation or by a suitable parenteral route, The compounds may
be formulated in combination with conventional pharmaceutical carriers that are
physiologically compatible. Optionally, one or more of the compounds of the
invention may be mixed with other active agents.
Suitable physiologically compatible carriers may be readily selected by one of
skill in the art. For example, suitable solid carriers include, among others, one or

WO 2004/092155 PCT/US2004/009268
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more substances which may also act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating
agents or an encapsulating material. In powders, the carrier is a finely divided solid,
which is in admixture with the finely divided active ingredient. In tablets, the active
ingredient is mixed with a carrier having the necessary compression properties in
suitable proportions and compacted in the shape and size desired. The powders and
tablets preferably contain up to 99% of the active ingredient Suitable solid carriers
include, for example, calcium or dicalcium phosphate, magnesium stearate, talc,
starch, sugars (including, e.g., lactose and sucrose), cellulose (including, e.g.,
microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose),
polyvinylpyrrolidine, low melting waxes, ion exchange resins, and kaolin.
Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be dissolved or
suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, a mixture of both or pharmaceutically acceptable oils or fet. The liquid
carrier can contain other suitable pharmaceutical additives such as solubilizers,
emulsifiers, buffers, suspending agents, thickening agents, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and
parenteral administration include water (particularly containing additives as above
e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and
their derivatives, and oils (e.g., fractionated coconut oil, arachis oil, corn oil, peanut
oil, and sesame oil). For parenteral administration the carrier can also be an oily ester
such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
Optionally, additives customarily employed in the preparation of
pharmaceutical compositions may be included in the compositions of the invention.
Such components include, e.g., sweeteners or other flavoring agents, coloring agents,
preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA.
Liquid pharmaceutical compositions that are sterile solutions or suspensions
can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous

WO 2004/092155 PCT/US2004/009268
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injection. Sterile solutions can also be administered intravenously. Oral
administration may be either liquid or solid composition form
Suitably, when prepared for use as an inhalant, the pharmaceutical
compositions are prepared as fluid unit doses using a compound of the invention and a
suitable pharmaceutical vehicle for delivery by an atomizing spray pump, or by dry
powder for insufflation. For use as aerosols, the compound of the invention is
formulated for and packaged in a pressurized aerosol container together with a
gaseous or liquefied propellent, for example, dichlorodifluoromethane, carbon
dioxide, nitrogen, propane, and the like, with the usual components such as cosolvents
and wetting agents, as may be necessary or desirable. For example, the invention
provides for deliver)' of a metered dose for oral or intranasal inhalation in one, two, or
more actuations. Suitably, a dose is delivered in one or two actuations. However,
other suitable delivery methods may be readily determined.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as
tablets or capsules. In such form, the composition is sub-divided in unit dose
containing appropriate quantities of the active ingredient; the unit dosage forms can
be packaged compositions, for example packeted powders, vials, ampoules, prefilled
syringes or sachets containing liquids. The unit dosage form can be, for example, a
capsule or tablet itself, or it can be the appropriate number of any such compositions
in package form.
As described herein, a therapeutically or prophylactically useful amount of a
compound of the invention is that amount of a compound which alleviates the
symptoms of the disease, e.g., AD, or which prevents the onset of symptoms, orthe
onset of more severe symptoms. The useful amounts of a compound may vary
depending upon the formulation and route of delivery. For example, higher amounts
may be delivered oraliy than when the compound is formulated for injection or
inhalation, in order to deliver a biologically equivalent amount of the drug. Suitably,
an individual dose (i.e., per unit) of a compound of the invention is in the range from
about 1 μg/kg to about 10 g/kg. However, because compounds of the invention have
improved bioactivity as compared to similar compounds lacking the trifluoroalkyl or
fluoro substiruents of the invention, these doses may suitably be selected from a lower
range, e.g., from about 1 μg/kg to about 200 μg/kg more preferably 10 μg/kg to about

PCT/US2004/00926S
WO 2004/092155
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10 mg/kg, and most preferably about 100 μg/kg to about 1 mg/kg. Desirably, these
amounts are provided on a daily basis, However, the dosage to be used in the
treatment or prevention of a specific cognitive deficit or other condition may be
subjectively determined by the attending physician. The variables involved include
the specific cognitive deficit and the size, age and response pattern of the patient. For
example, based upon the activity profile and potency of the compounds of this
invention, a starting dose of about 375 to 500 mg per day with gradual increase in the
daily dose to about 1000mgper day may provide the desired dosage level in the
human.
Alternatively, the use of sustained delivery devices may be desirable, in order
to avoid the necessity for the patient to take medications on a daily basis. "Sustained
delivery" is defined as delaying the release of an active agent, ie,, a compound of the
invention, until after placement in a delivery environment, followed by a sustained
release of the agent at a later time. Those of skill in the art know suitable sustained
delivery devices. Examples of suitable sustained delivery devices include, e.g.,
hydrogels (see, e.g., US PatentNos. 5,266,325; 4,959,217; and 5,292,515), an osmotic
pump, such as described by Alza (US Patent Nos. 4,295,987 and 5,273,752) or Merck
(European Patent No. 314,206), among others; hydrophobic membrane materials,
such as ethyl enemcthacrylate (EMA) and ethylenevinyl acetate (EVA); bioresorbable
polymer systems (see, e.g., International Patent Publication No. WO 98/44964, Bioxid
and Cellomeda; US PatentNos, 5,756,127 and 5,854,388); other bioresorbable
implant devices have been described as being composed of, for example, polyesters,
polyanhydrides, or lactic acid/glycolic acid copolymers (see, e.g., US Patent No.
5,817,343 (Alkermes Inc.)). For use in such sustained delivery devices, the
compounds of the invention may be formulated as described herein.
In another aspect, the invention provides a pharmaceutical kit for delivery of a
product. Suitably, the kit contains packaging or a container with the compound
formulated for the desired delivery route. For example, if the kit is designed for
administration by inhalation, it may contain a suspension containing a compound of
the invention formulated for aerosol or spray delivery of a predetermined dose by
inhalation. Suitably, the kit contains instructions on dosing and an insert regarding
the active agent. Optionally, the kit may further contain instructions for monitoring

WO 2004/092155 PCT/US2004/009268
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circulating levels of product and materials for performing such assays including, e.g.,
reagents, well plates, containers, markers or labels, and the like. Such kits are readily
packaged in a manner suitable for treatment of a desired indication. For example, the
kit may also contain instructions for use of the spray pump or other delivery device.
Other suitable components to such kits will be readily apparent to one of skill
in the art, taking into consideration the desired indication and the delivery route. The
doses may be repeated daily, weekly, or monthly, for a predetermined length of time
or as prescribed.
EXAMPLES
The following examples are provided to illustrate the production and activity
of representative compounds of the invention and to illustrate their performance in a
screening assay, One skilled in the art will appreciate that although specific reagents
and conditions are outlined in the following examples, these reagents and conditions
are not a limitation on the present invention.
EXAMPLE 1
5-Chloro-N-[(lS,2R)-4,4,4-trifluoro-l-(hydroxymethyl)-2-methylbutyI]thiophene-2-
sulfonamide
A Method 1
1. 2-Methyl-4,4,4-trifiuorobutanal
To 2-methyI-4,4,4-trifluoro-l-butanol (7.5 g, 53 mmol) in
methylene chloride (CH2CI2) (125 mL) at 0 °C was added Dess-Martin periodinane
(26.5 g, 63.3 mmol). The reaction mixture was warmed to 25 °C and stirred for 20
min. To this mixture was added diethyl ether (Et2O - 200 mL) followed by a solution
ofNa2S2O3(29,0 g, 185 mmol) in a saturated aqueous solution of sodium bicarbonate
(NaHCOa) (200 mL) and 100 mL of water. The milky white mixture was stirred until
both phases were homogeneous. The phases were separated and the organic extract
was washed with saturated aqueous NaHCO3 (25 mL) and aqueous 1 N Na2S2O3 (25
mL) and dried using magnesium sulfate (MgSO4). Solvents were removed by
distillation at atmospheric pressure to give 2-methyl-4,4,4-trifluorobutanaI (6.5 g,

PCT/US2004/009268
WO2004/092155
28
88%). IH nuclear magnetic resonance (NMR) spectrum matched that which was
reported in the literature (J. Fluorine Chem. 36:163-170 (1987).
2. 5-(3,3,3-Trifluoro-J -methylpropyI)imidazolidlne-2,4-dione
To sodium cyanide (18.4 g, 375 mmol) and ammonium
carbonate (39.0 g, 500 mmol) in H2O (450 mL) was added 2-methyl-4,4,4-
trifluorobutanal (17.5 g, 125 mmol) in ethanol (450 mL). The reaction mixture was
heated to 90 °C for 17 h. After cooling to 25 °C, about 500 mL of solvent was
removed in vacuo. Concentrated HC1 was added to acidify the mixture to a pH of
about 1 to about 2 and a precipitate formed. The mixture was filtered and washed
with aqueous 1 N HCI to give 5-(3,3,3-txifluoro-l-methylpropyI)imidazoIidine-2,4-
dioneas a white solid (15.5 g, 59%).
Mass Spectrum (-ESI): 309 (M-H)
Anal: Calc'd for C7H9F3N2O2 C, 40.01; H, 4.32; N, 13.33.
Found: C, 39.91;H, 4,10; N, 13.20.
3. N-[(5-Chlorothien-2-yl)sulfonyl]~5,5,5-trifluoroisoleucine
5-(3,3,3-Trifluoro-l-methylpropyI)imidazolidine-2,4-dione
(15.54 g, 73.95 mmol) was dissolved in a 150 mL solution of aqueous sodium
hydroxide (NaOH -11.83 g, 295.8 mmol). The solution was heated by microwave in
a sealed vessel for 1 hour. (Microwave conditions". 15 min. at about 100 % power,
150°C, 50 psi, then 5 min 0% power, then 15 min at about 100% power, 150 °C, 50
psi, then repeat sequence.) Water and ammonium hydroxide were removed from the
reaction mixture in vacuo and the resulting crude amino acid and NaOH mixture was
used in the next reaction without further purification.
The crude amino acid and NaOH mixture was dissolved in 300
mL of water. The mixture was cooled to about 0 °C in an ice bath. 5-
ChIorothiophene-2-sulfonyl chloride (17.6 g, 81 mmol) was dissolved in 100 mL of
Tetrahydroruran (THF) and added dropwise to the reaction mixture over 0.5 h. After
1 h the reaction mixture was allowed to warm gradually to 25 °C and stirred for 16 h.
THF was removed in vacuo and then the mixture was acidified to pH of about 1 with
aqueous 1 N HCl. After about 15 min, a precipitate began to crash out of the milky
white mixture. After 1 h the mixture was cooled to 0°C for 1 h and then filtered. The

WO 2004/092155 PCT/US2004/009268
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precipitate was washed with aqueous 1 N HC1 to give N-[(5-chlorothien-2-
yI)sulfonyl]-5,5,5-trirluoroisoIeucine as a white solid (15.2 g, 56%).
Mass Spectrum (-ESI): 364 (M-H)
Anal: Calc'd for CLoH11F3N04S2 C, 32.84; H, 3.03; N, 3.83.
Found; C, 32.45; H, 2.94; N, 3.79.
4. 5-Chloro-N-[(IS,2RHl4>4-trifluoro-l-(hydroxymethyl)-2-
methylbutyl]thiophene-2-sulfonam ide
ToN-[(5-chlorofliien-2-y0sulfonyI]-5,5,5-trifluoroisoleucine
(15.2 g, 41.6 mmol) in THF (500 mL) at 0 °C was added a solution of 1 M borane
tetrahydrofuran complex in THF (208 mL, 208 mmol) dropwise. After 15 min the
reaction mixture was warmed to 25 °C and stirred for 18 h. It was then quenched
slowly with a solution of 10% AcOH in MeOH (100 mL). Volatiles were removed in
vacuo. The residue was then dissolved in ethyl acetate (EtOAc) (500 mL) and
washed with saturated aqueous NaHCO3 (3 x 100 mL), dried using sodium sulfate
(Na2SO4), and concentrated to a white solid (13.3 g, 91% yield). Diastereomers were
separated by HPLC (Luna silica gel column, 3:7 MTBE-hexane, diastereomer 1 elutes
at 10.9 min, diastereomer 2 elutes at 15.3 min). Diastereomer 2 was resolved into pure
enantiomers by preparative chiral SFC [chiralpak AD, 3:7 isopropanol-carbon
dioxide, enantiomer 1 elutes at 4.5 min and enantiomer 2 elutes at 5.6 min].
Enantiomer ] was then recrystallized with EtOAc/heptane, 1:4 to give 5-chloro-N-
[(lS,2R)-4,4J4-trifluoro-l-(hydroxymethyl)-2-methyIbutyl]thiophene-2-sulfonamide,
mp 136-137 °C.
[ α]D25 = +45.62° (c= 1% SOLUTION, MeOH).
Mass Spectrum (-ESI); 350 (M-H):
Anal: Calc'd for C10HI3ClF3N03S2 C, 34.14; H, 3.72; N, 3.98.
Found: C, 34.12; H, 3.45; N, 3.88.
B. Method 2
1. (4R)-4~Benzyl-3-(4,4,4-trifluorobutanoyl)-l,3-oxazolidln-2-one
To a solution of 4,4,4-trifluorobutyric acid (10.00 g, 70.38
mmol) in THF (150 mL) at -78 °C was added triethylamine (10.3 mL, 73.9 mmol)
and pivaloyl chloride (9.1 mL, 74 mmol). The reaction mixture was warmed to 0 °C
and stirred for 1.5 h. In a separate flask a solution of n-BuLi (31 mL, 2.5 M in

WO 2004/092155 PCT/US2004/009268
30
hexane, 77 mmol) was added over 10 min to a -78°C solution of (R)-(+)-4-benzy 1-2-
oxazolidinone (13.7 g, 77.4 mmol) inTHF (150 mL) and the mixture was stirred for 1
hour.
The thick slurry of the mixed anhydride was cooled to -78 °C,
and poured through an addition funnel into the lithiated oxazolidinone solution. The
mixture was allowed to warm gradually to 25 °C overnight. The mixture was then
diluted with EtOAc (500 mL) and washed with aqueous 1 N HC1 (500 mL), saturated
aqueous NaHCO3 (500 mL), and saturated aqueous NaCl (500 mL), then dried
(Na2SO4) and concentrated. Flash chromatography (eluent: 1:4 EtOAc-hexane)
provided (4R)-4-benzyl-3-(4,4,4-trifluorobutanoyI)-I,3-oxa2olidin-2-one (18.29 g,
86%) as a colorless oil.
[α]D25 = -89.10° (c = 1% SOLUTION, DMSO).
Mass Spectrum (-ESI): 300 (M-H)'.
Anal: Calc'd for C14H14F3NO3 C, 55.82; H, 4.68; N, 4.65.
Found: C, 56.03; H, 4.67; N, 4.62.
2. (4R)-4-Beixzyl-3-[(2R)-4,4,4-n-tfluoro-2-methylbutanoyl]-l,3-
oxazolidin-2-one
To asolution of sodium bis(trimethylsilyl)amids (57 mL, 1.0 M
in THF, 57 mmol) in THF (250 mL) at -40 °C was added (4R)-4-benzyl-3-(4:4,4-
trifIuorobutanoyl)-l,3-oxazolidin-2-one (15,60 g, 51,78 mmol) inTHF (250 mL)
dropwiseover 15 min. After 1 h, iodomethane (4.2 mL, 67 mmol) was added. After
3 h, the reaction mixture was wanned to -20 °C for about 20 min The mixture was
quenched with saturated aqueous ammonium chloride (NH4Cl) (300 mL) and then
extracted with EtOAc (2 x 300 mL), dried using Na2SO4, and concentrated. Flash
chromatography (eluent: 1:9 EtOAc-hexane) provided (4R)-4-benzyl-3-[(2R)-4,4,4-
trifluoro-2-methylbutanoyl]-l,3-oxazoIidin-2-one (12.04 g, 74%) as a colorless oil.
[α]D25 = -98.68° (c = 1% SOLUTION, DMSO).
Mass Spectrum (+EI): 315 (M+H)+.
Anal: Calc'd for C15H16F3NO3 C, 57.14; H, 5.11; N, 4.44,
Found: C, 57.18; H, 5.24; N, 4.38.

WO 2004/092155 PCT/US2004/009268
31
3. (2R)-4,4,4-Trifluoro-2-methylbutan-l-ol
A solution of lithium borohydride (23 mL, 2.0 M in THF, 45
mmol) was added dropwise to a solution of (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-
methylbutanoy]]-l,3-oxazolidin-2-one (12.9 gf 40.9 mmol) and water (810 μL, 45.0
mmol) in diethyl ether (200 mL) at 0 °C. The reaction mixture was allowed to warm
to 25 °C and, after 1 h, was cooled to 0 °C and quenched with aqueous 1 N NaOH
(124 mL). The mixture was warmed to 25 °C and stirred until both layers were
homogeneous. The layers were separated and the organic extract was washed with
brine, dried using MgSO4 and concentrated. Flash chromatography (eluent: 3:7 ether-
petether) provided (2R)-4,4,4-trifluoro-2-methylbutan-l-ol (5.05 g, 87%) as a
colorless oil. lH NMR was identical to that which was found in the literature (J. Med.
Chem. 37: 1282-1297(1994)).
4. (S)-N~[(3R)-Methyl-4,4,4-mfluoro-butylidene]-p-
to luen es ulfinam ide
To (2R)-4,4,4-trifluoro-2-methyIbutan-l-oI (2.90 g, 20.4 mmol)
in CH2C12 (50 mL) at 0 °C was added Dess-Martin periodinane (10.24 g, 24.49
mmol). After 15 min, the reaction mixture was ■warmed to 25 °C and stirred for 1 h.
This mixture was then diluted with diethyl ether (50 mL) and added to Na2S2O3
(11.29 g, 71.44 mmol) dissolved in a saturated solution of aqueous NaHCO3 (100
mL). The milky white mixture was stirred until both layers were homogeneous. The
phases were separated and the organic extract was dried (MgSO4) and filtered to give
a solution of (2R)-4,4,4-trifluoro-2-methylbutanal which was used in the next step
without removal of solvents.
To the crude aldehyde solution was added titanium (IV)
ethoxide (15 mL, 20% Ti, 82 mmol) followed by (S)-(+)-toIuenesulfinamide (3.48 g,
22.4 mmol) and the solution was heated to reflux for 3 h. The mixture was then
cooled to 0 °C and water (75 mL) was added to precipitate titanium salts. The
suspension was filtered through the Celite® reagent and the filter cake was washed
with CH2Cl2, The layers of the filtrate were separated and the aqueous layer was
extracted with CH2C12. The combined organic extracts were dried using Na2SO4 and
concentrated. Flash chromatography (eluent; 1:9 EtOAc-hexane) provided (S)-N-

WO 2004/092155 PCT/US2004/009268
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[(3R)-methyl-4,4,4-trifluoro-butyIidene]-p-toluenesuIfmamide (3.03 g, 54%) as a
yellow oil. Mass Spectrum (-ESI): 276 (M-H)
5. N-[(lS,2R)-l~Cyano-4,4,4-trtfiuoro-2-methylbutyl]-4-
methylb enzenesulfmamide
To di ethyl aluminum cyanide (16 mL, 1.0 M in toluene, 16
mmol) in THF (40 mL) at 0 °C was added isopropanol (i-PrOH) (840 μL, 11.0 mmol).
After 15 min, this solution was added to a -78 °C solution of (S)-N-[(3R)-raethyl-
4,4,4-trifluoro-butyIidene]-p-toluenesulfinamide (3.03 g, 10.9 mmol) in THF (60 mL).
After 15 min, the reaction mixture was warmed to 25 °C. After 1 h, thin layer
chromatography (TLC - 1:9 EtOAc-hexane) indicated consumption of starting
material. The mixture was cooled to -78 °C and saturated aqueous ammonium
chloride (100 mL) was added. The resulting suspension was filtered through the
Celite® reagent, and the filter pad was washed with EtOAc (100 mL). The layers of
the filtrate were separated and the aqueous layer was extracted with EtOAc. The
combined organic extracts were dried using Na2SO4 and concentrated. The crude
mixture, which according to 1H NMR. was a 1:3 mixture of diastereomers, was
precipitated with diethyl ether/hexanes and the product was collected. Two additional
crops of product were obtained by repeating the precipitation procedure on the
concentrated filtrate. N-[(lS, 2R)-l-cyano-4,4,4-trifluoro-2-methylbutyl]-4-
methylbenzenesulfinamide (2.34 g, 70%) was obtained as a single diastereomer.
[α]D25 = +35.46° (c = 1% SOLUTION, CHCl3).
Mass Spectrum(+ESI): 305 (M+H)+.
Anal: Calc'd for C13H15F3N2OS C, 51,31; H, 4.97; N, 9.20.
Found: C, 51.16; H, 4.96; N, 9.08.
6. 5,5,5-Trifluoro-L-alloisoleucinehydrochloride
A suspension ofN-[(lS, 2R)-l-cyano-4,4,4-trifluoro-2-
methylbutyl]-4-methylbenzenesulfmamide (2.34 g, 7.69 mmol) in concentrated
hydrochloric acid (75 mL) was heated to reflux for 18.5 h. After cooling to 25 °C, the
reaction mixture was washed with diethyl ether several times. The aqueous layer was
concentrated to give a mixture of 5,5,5-trifluoro-L-alloisoleucine, NH4C1, and
toluenesulfonic acid (2.35 g). The crude amino acid was used in the next step without
further purification. Mass spsctrum (-ESI); 309 (M-H),

WO 2004/092155 PCT/US2004/009268
7. (2S, 3R)-2-Amino-5,5,5-trijliioro-3-methylpentan-l-ol
To a solution of lithium borohydride (7.7 mL, 2.0Nin 1HF, 15
mmol) in THF (20 mL) at 0 °C was added chlorotrimethylsilane (3.9 mL, 31 mmol).
The reaction mixture was warmed to 25°C and, after 30 min, added dropvvise to a 0 °C
suspension of crude amino acid hydro chloride salt (7.7 mmol) in THF (60 mL). The
mixture was warmed to 25°C, and after 21 h, quenched with methanol (MeOH). The
volatiles were removed in vacuo to give a residue which was dissolved in about 50
mL of aqueous 1 NNaOH, extracted with chloroform (CHCI3) (4 x 75 mL), dried
(Na2SO4) and concentrated to {2S, 3R)-2-amino-535,5-trifluoro-3-methylpentan-l-ol
as a yellow oil (1.07 g, 81%). Mass Spectrum (+ES1): 172 (M+H)+.
8. 5-Chloro-N-[(lS,2R)-4,4l4-trifluoro-l-(hydroxymethyl)-2-
methylbutyl]thiophene-2-sulfonamide
To (2S, 3R)-2-amino-5,5,5-trifluoro-3-methylpentan-l-ol (1.07
g, 6.25 mmol) and triethylamine (0.87 mL 6.2 mmol) in CH2C12 (15 mL) at 0 °C was
added dropwise a solution of 5-chlorothiophene-2-sulfonylchloride (1.34 g, 6.25
mmol) in CH2Cl2 (15 mL). The reaction mixture was warmed to 25°C and stirred for
24 h. It was then diluted with EtOAc (100 mL) and washed with aqueous 0.1 NHCl
(50 mL) and brine (50 mL). The aquaous layer was extracted with EtOAc (50 mL).
The combined organic extracts were dried using Na2SO4 and concentrated. Flash
chromatography (eluent: 3:7 EtOAc-hexane) provided 5-chloro-N-[(lS, 2R)-4,4,4-
trifluoro-l-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (1.66 g, 75%) as
a white solid. Re crystallization (EtOAc-heptane, 1:4) provided white needles (1.39 g,
84% recovery), mp 136-137°C.
Anal: Calc'd for C10H13CIF3NO3S2 C, 34.14; H, 3,72; N, 3.98.
Found: C, 34.24; H, 3,97; N, 3.87.
C. Method 3
1. (4S)-4-Benzyl-3-(bromoacetyl) -J, 3-oxazolidin -2-one
To a solution of S-(-)-4-benzyl-2-oxazolidinone (20.0 g, 112.86
mmol) in THF (200 mL) was added nBuLi(2.5M in hexanes, 47.4 mL, 118.51 mmol)
dropwise at -78 ° C. The solution was stirred at -78 ° C for 30 min followed by the
addition of bromo acetyl bromide (25.0 g, 10.81 mL, 124.15 mmol). The solution
was allowed to warmto 25 0C overnight (19 h). An aliquot was taken and TLC (1:2

WO2004/092155 PCT/US 2004/009268
34
EtOAc-hexane) indicated that the reaction was complete. It was diluted with ethyl
acetate (200 mL) and the organic layer was washed with saturated aqueous NaHCO3
(2x50 mL). The organic layer was dried over MgSO4, filtered and concentrated to
obtain a crude brown oil (34 g). The crude product was purified by flash
chromatography, eluenf. 1:4 EtOAc-hexane, to furnish (4S)-4-benzyl-3-
(bromoacetyl)-l,3-oxazolidin-2-one as a colorless oil (33.2 g, 98.6 %). Mass
Spectrum (-ESI): 297 (M-H).
2. DimethyI-2-[(4S)-4-benzyl-2-oxo-l,3-oxazolidin-3-yl]-2-
oxoethylphosphona te
(4S)-4-BenzyI-3-(bromoacetyI)-l,3-oxazolidin-2-one (33.0 g,
120.68 rnmol) and triethylphosphite (39.2 mL, 33.2 mmol) were heated at 120 °C for
18h. Art aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The reaction was cooled to 25 °C, diluted with ethyl acetate (200 mL) and
the organic layer was washed with saturated aqueous NaHCO3 (2x50 mL). The
organic layer was dried over MgSC4, filtered, and concentrated to obtain dimethyl-2-
[(4S)-4-benzyI-2-oxo-I!3-oxa2olidin-3-yl]-2-oxoethylphosphonate as crude yellow oil
(36 g, 99.3 %). Mass Spectrum (-ESI): 326 (M-H).
3. (4S)-4-Benzyl-3-[(2E)-5, 5, 5-trifluoropent-2-enoyl]I,3-
oxazolidin-2-one
To asolutionofdimeihyl-2-[(4S)-4-benzyl-2-oxo-l,3-
oxazolidin-3-yI]-2-oxoethylphosphonate (36 g, 109.97 mmol) in THF (200 mL) was
added KHMDS (0.5M, 242 mL, 120.97 mmol), at -78° C. The solution was allowed
to warm to 25 °C over 30 min and 3,3,3-trifluoropropionaIdehyde (13.55 g, 120.97
mmol) was added at-20 °C. The solution was allowed to warm to 25°C overnight (19
h). An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The reaction was quenched by addition of saturated aqueous NaHCO3 (50
mL). The aqueous layer was washed with ethyl acetate (3 x 100 mL). The organic
layer was dried over MgSO4, filtered and concentrated to obtain a light brown oil
(32.lg). The crude product was purified by flash chromatography, eluent: 1:6 EtOAc-
hexane, to furnish (4S)-4-benzyl-3-[(2E)-5,5,5-trifluoropent-2-enoyl]l,3-oxazolidin-
2-one as a colorless oil (17.7 g, 55.1 %).
Mass Spectrum (-ESI); 312 (M-H).

WO 2004/092155 PCT/US2004/009268
35
Anal: Calc'd for C15H14NF3O3 C, 57.51; H, 4.50; N, 4.47
Found: C, 57,05; H3 4.75; N, 4.52.
4. (4S)-4-Benzyl-3-[(3S)-5, 5, 5-trijluoro-3-methylpentanoyl]-l,3-
oxazolidin-2-one
A slurry of copper bromide (I)-dimethyl sulfjde complex (9.45
g, 45.96 mmol) in THF (200 mL) and dimethyl sulfide (100 mL) as co-solvent was
cooled to -40°C and methyl magnesium bromide (30.64 mL, 91.93 mmol) was added
drop wise for 10 min. The slurry was stirred for 40 min while warming to -15°C. The
greenish slurry was cooled to -40°C and (4S)-4-benzyl-3-[(2E)-5;5;5-lrifluoropent-2-
enoyl]l,3-oxazolidin-2-one (12 g, 38.30 mmol) was added dropwise as a solution in
THF (15 mL) at -40°C. The reaction was allowed to warm to 25°C overnight (18 h).
The reaction was quenched with saturated aqueous NH4CI (20 mL). A precipitate
formed. It was filtered, the mother liquor was diluted with EtOAc (250 mL) and the
organic layer was washed with saturated aqueous sodium chloride (NaCl -100 mL),
The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude
semi-solid. The crude semi-solid was not soluble in CH2Cl2, MeOH, and EtOAc,
partially soluble in dimethylsulfoxide (DMSO). The crude product was treated with
IN HC1 (100 mL) and the aqueous layer was washed with EtOAc (2x150 mL). The
organic layer was dried over MgSO4j filtered, concentrated to obtain a yellow oil
(12.1g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-
hexane, to furnish (4S)-4-benzyI-3-[(3S)-5,5,5-trifluoro-3-methylpentanoyl]-l,3-
oxazoIidin-2-one as a colorless oil (8.2 g, 67.8 %).
Mass Spectrum (+ESI): 330 (M+H)+.
Anal: Calc'dfor C1SH15NF3O3 C, 58.36;- H, 5.51; N, 4.25.
Found: C, 58.36;H, 5.70; N, 4.19.
5. (S)-3-[(2S, 3R)~2-Azido-5, 5, 5~trifluoro-3-methylpentanoyl]-4-
benzyl-1,3-oxazolidin-2-one
A solution of (4S)-4-benzyI-3-[(3S)-5,5,5-trifluoro-3-
methylpentanoyI]-l,3-oxazoIidin-2-one (8.2 g, 24.90 mmol) in THF (100 mL) was
cooled to -78 °C and KHMDS (potassium hexamethyldisilazane - 59.7 mL, 29.88
mmol) was added dropwise over a period of 10 min. After stirring at -78 °C for Ih, a
pre-c'ooled (-78 °C, 50 min) solution of 2.4,6-triisopropylbenzenesulfonyl azide (10.1

WO 2004/092155 PCT7US2004/009268
36
g, 32.37 mmol) was added via cannula over a period of 10 min. After an additional 10
min at -78 °C, glacial acetic acid (6.7 mL, 112.05 mmol) was added all al once
through a funnel. After 5 min at -78 °C anhydrous potassium acetate (9.77 g, 99.6
mmol) was added. The -78 °C bath was lowered and the reaction mixture was
allowed to warm to 25 °C overnight (19 h), The reaction mixture was diluted with
EtOAc (200 mL) and the organic phase was washed with saturated aqueous potassium
phosphate monobasic (2x100 mL) and saturated aqueous NaCl (100 mL). The
organic layer was dried over MgSO4, filtered and concentrated to obtain a yellow oil
(9.5 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-
hexane, to furnish (S)-3-[(2S,3R)-2-azido-5,5,5-trifluoro-3-methylpentanol]-4-benzyl-
1,3-oxazoIidin-2-one as a colorless oil (7.2 g, 73.7%),
Mass Spectrum (-ESI): 342 (M-N2).
6. (2S, 3R)-2-Azido-5, 5, 5-trifiuoro-3-methylpentanoic acid
To a solution of (S)-3-[(2S, 3R)-2-azido-5, 5,5-trifluoro-3-
methylpentanol]-4-benzyI-l,3-oxazolidin-2-one (7.2 g, 19.44 mmol) in THF:H2O
(3:1, 120 mL) in N2 atmosphere was added lithium hydroxide (LiOH) monohydride
(1.63g, 38.88 mmol) at 0 °C. The reaction was monitored by TLC (1:2 EtOAc/Hex).
After 3h, solid NaHCO3 (6.0 g) was added. The slurry was diluted with saturated
aqueous NaHCO3 (20 mL) and H2O (40 mL) and extracted with EtO Ac (3x100 mL).
The organic layer was extracted with saturated aqueous NaHCO3 (20 mL). The
EtOAc contains the chiral auxiliary and was set aside. The combined NaHCO3 layers
were acidified to a pH less than 2. The acidified aqueous layer was extracted with
EtOAc (3x100 mL). The organic layer was dried over MgSO4, filtered and
concentrated to obtain (2S, 3R)-2-azido-5, 5, 5-trifluoro-3-methylpentanoic acid as a
yellow oil (3.2g 98%). Mass Spectrum (-ESI): 183 (M-N2).
7. 5,5,5-Trifluoro-L-alloisoleucine
(2S,3R)-2-azido-5,5J5-trifIuoro-3-methylpentanoic acid (3.2 g,
17.27 mmol), 10% palladium on carbon (0.79 g), glacial acetic acid (37 mL) and
water (90 mL) was placed under an atmosphere of hydrogen (40 psi) and shaken on
Parr hydrogenator. After 20 h, the reaction mixture was filtered through a pad of the
Celite® reagent which was rinsed well with H2O (20 mL). The filtrate was
concentrated under reduced pressure to produce a white solid. The solid was

WO 2004/092I55 PCT/US2004/009268
37
triturated with EtOAc (200 ni), filtered and washed once more with EtOAc (200
mL) then air dried to give 5,5,5-trifluoro-L-alloisoleucine as a white solid (2.7 g,
96%). Mass Spectrum (-ESI): 184 (M-H).
Anal: Calc'd for C6H10NF302 + 0.12HC1 C, 38.13;H, 5.50;N, 6,94.
Found: C, 38.03, H, 5.38; N, 7.39.
8. (2S, 3R)-2-Amino-5,5,5-trifluoro-3-methylpentan-l-ol
To a stirring solution of lithium borohydride (14.5 mL of a 2M
solution in THF, 29 mmol) at 0° C was added chlorotrimethylsilane (7.38 mL, 58
mmol) dropwise over a period of 30 min. The ice bath was removed and the resulting
slurry was stirred at 25 °C for 30 min. The reaction mixture was cooled to 0 DC and
5,5,5-trifluoro-L-alloisoleucine (2.7 g, 16.98 mmol) was added in portions as a solid
over a period of 15 min. The reaction mixture was allowed to warm slowly to 25 °C as
the ice bath melted, After 3 days at 25 °C, the reaction mixture was cooled to 0 °C,
and methanol (22 mL) was carefully added over a period of 30 min. The solution was
stirred at 25 °C for an additional 40 min, then concentrated under reduced pressure in
a water bath at 60 °C. The resulting slurry was made basic with 20 % sodium
hydroxide (10 mL). Water (10 mL) was added, and the entire aqueous layer was
extracted with methylene chloride (100 mL) and dried over MgSO4. The organic
phase was filtered and evaporated to produce (2S, 3R)-2-arnino-5,5,5-trifluoro-3-
methylpentan-l-ol as a crude oil (2.6 g, 89.6 %). Mass Spectrum (-ESI): 170 (M-H)".
9. 5-ChlQro-N-[(lS,2R)-4,4,4-trijluoro-l-0iydrQxymethyl)-2-
methylbutyl]thiophene-2-sulfonamide
To a stirred solution of (2S, 3R)-2-amino-5,5,5-trifluoro-3-
methylpentan-1-oI (2.6 g, 15.18 mmol), triethylamine (4.2 mL, 30.38 mmol) and
methylene chloride (50 mL) cooled to 0 °C, was added 5-chlorothiophene-2- sulfonyl
chloride (4.8 g, 18.22 mmol) as a solution in methylene chloride (5 mL), dropwise.
After 15 min, the ice bath was removed and the reaction allowed to attain 25 °C
overnight. The reaction was quenched by pouring it into saturated sodium
bicarbonate solution (25 mL) and additional methylene chloride (150 mL). The
organic phase was separated and washed sequentially with 1N HCl solution, H2O,
brine and dried over MgSO4. The organic phase was filtered and evaporated to
produce a crude oil (6.1 g) that was purified by flash chromatography using ethyl

WO 2004/092155 PCT/US2004/009268
38
acetate-hexane, 1 -6 as eluent. This produced the title compound 5-chloro-N-[(lS,
2R)-4,4,4-trifluoro-l-(hydroxymethyI)-2-inethylbutyI]thiophene-2-sulfonamideas a
white amorphous solid (5.15 g, 96.4 %). The product contained impurities. The white
amorphous solid was further purified by recrystallization from 1:4 EtOAc-heptane.
The mixture of solvents was added to 5-chloro-N-[(lS,2R)-4,4,4-trifluoro-l-
(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution,
allowed to cool to 25 °C for 3 h and then stored at 0 °C for 19 hours. A crystalline
white solid precipitated, was filtered and washed with ice-cold heptane to obtain a
white crystalline solid (2.7 g, 40.9 %). The recrystallized material still contained
impurities. The white solid (2.7 g) was further purified by prep-chiral HPLC [SFC;
AD, 25 x 0.46 cm; mobile phase, 8:2 hexane-I-PrOH (1 mL/min)] to obtain 5-chloro-
N-[(1S, 2R)-4,4,4-tnfluoro-l -(hydroxymethyl)-2 -methylbutyl]thiophene-2-
sulfonamide as a white crystalline solid, mp 132-133 QC (0.93g, 14.1 %, chiral purity
100 %, analytical purity 100%).
Mass Spectrum (-ESI): 350 (M-H).
Anal: Calc'd for C10H13ClF2NO3S2 C, 34.14; H, 3.72, N, 3.98.
Found: C, 34.44; H, 3.70; K, 3,74.
In a comparative study between the compound of this example and a
similar compound which lacks the trifluoromethyl groups and differs in the
stereochemistry of the C-2 center but is otherwise identical, the compound of this
example demonstrated significantly longer metabolic stability (-193 minute vs 12.7
min half-life) in an assay of Phase I rat liver microsome metabolism.
In a comparative study between the compound of this example and the
corresponding analog which lacks the trifluoromethyl groups, the compound of this
example demonstrated significantly longer metabolic stability in an assay of Phase 1
and 2 rat (14 min vs 2 min half-life), mouse (10 min vs 2 min half-life), human (22
min vs 13 min half-life), and dog (31 min vs 4 min) liver microsome metabolism
Thus, the compound of the invention remains in the circulation for a
longer period of time than its corresponding non-CF3 analog, increasing its
bio availability.

WO 2004/092155 PCT/US2004/009268
39
EXAMPLE 2
5-Chloro-N-[(lS,2R)-2-ethyI-4,4,4-trifiuoro-l-(hydroxymethyI)butyl]thiophene-2-
sulfonamide
A. Method 1
1. (4S)-4'Benzyl-3-[(3S)-B-ethyl-5l5,5~mfluoropentanoyl]-l,3-
oxazo lidin-2-one
A slurry of copper bromide (I)-dimethyl sulfide complex (1.26
g, 6.13 mmol) in THF (20 mL) and dimethyl sulfide (10 mL) as co-solvent was
cooled to —40 °C and ethyl magnesium bromide (3M in diethyl ether, 4.08 mL, 12.26
mmol) was added dropwise for 10 min. The slurry was stirred for 40 min while
warming to -15 °C. The greenish slurry was cooled to -40 aC and (4S)-4-benzyl-3-
[(2E)-5,5,5-trifluoropent-2-enoyI] l,3-oxazolidin-2-one (prepared as in Example 1:
method 3, Part C) (1.6 g, 5.10 mraol) was added dropwise as a solution in THF (5
mL) at -40 °C. The reaction was allowed to warm to 25 °C overnight (18h). The
reaction was quenched with saturated aqueous NH4Cl (20 mL). A precipitate formed
which was filtered off. The mother liquor was diluted with EtOAc (250 mL) and the
organic extract was washed with saturated aqueous NaCl (100 mL). The organic
extract was dried over MgSO4, filtered and concentrated to obtain a crude semi-solid.
The crude semi-solid was not soluble in CH2CI2, MeOH, or EtOAc, but was partially
soluble in DMSO. The crude product was treated with 1N HC1 (100 mL) and the
aqueous solution was washed with EtOAc (2x150 mL). The organic layer was dried
over MgSO4, filtered and concentrated to obtain a yellow oil (1.41g). The crude
product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish
(4S)-4-benzyl-3-[(3S)-3-ethyl-5,5,5-tnfluoropentanoyl]-l,3-oxazolidin-2-oncas a
colorless oil (0.96 g, 55 %).
Mass Spectrum (+ESI): 344 (M+H)+,
Anal: Calc'd for C17H20NF3O3 C, 59.47; H, 5.87; N, 4.08.
Found: C, 59.58;H, 5.91; N, 4.03.
2. (S)-3-[(2S, 3R)-2-Mdo-3-ethyU5,5,5-trifiuoropentanol]-4-
benzyl-1,3-oxazolidin-2-one
To a solution of (4S)-4-benzyl-3-[(3S)-3-ethyl-5,5,5-
trifluoropentanoyl]-l,3-oxazolidin-2-one (0.9 g, 2.62 mmol) in THF (10 mL) cooled

WO 2004/092155 PCT/US2004/009268
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to-78 °C was added dropwise over a period of 10 minKHMDS (0.5 M in toluene, 6.3
mL, 3.14 mmol). After stirring at -78 °C for Ih, apre-cooled (-78 °C, 50 min)
solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.04 g, 3.38 mmol) in 20 mL of
THF was added via cannula over a period of 10 min. After an additional 10 min at -
78 °C, glacial acetic acid (0.7 mL, 11.79 mmol) was added all at once through a
funnel. After 5 min at -78 °C anhydrous potassium acetate (1.07 g, 10,48 mmol) was
added. The -78 °C bath was lowered and the reaction mixture was allowed to warm
to 25 °C overnight (19 h). The reaction mixture was diluted with EtOAc (200 mL) and
washed with saturated aqueous potassium phosphate monobasic (2x100 mL) and
saturated aqueous NaCl (100 mL). The organic layer was dried over MgSO4 filtered
and concentrated to obtain a yellow oil (1.09 g). The crude product was purified by
flash chromatography, eluenf. 1:4 EtOAc-hexane, to furnish (S)-3-[(2S, 3R)-2-azido-
3-ethyl-5,5,5-trifluoropentanol]-4-ben2yI-l,3-oxazolidin-2-one as a colorless oil
(0.587 g, 59 %). Mass Spectrum (-ESI): 357 (M-N2).
3. (2S, 3R)-2-Azido-3'etkyl-5,5,5-trifiuoropentanoicacid
To a solution of (S)-3-[(2S, 3R)-2-azido-3-ethyl-5,5,5-
trifluoropentanol]-4-benzyl--l,3-oxazolidm-2-one (287 mg, 0.746 mmol) in THF:H2O
(3:1, 4 mL) under aN2 atmosphere was added LiOH monohydrate (62.66 rag, 1.49
mmol) at 0 °C. The reaction was monitored by TLC (1:2 EtOAc/Hex), after 3 h; solid
NaHCO3 (1.0 g) was added. The slurry was diluted with saturated aqueous NaHCO3
(2 mL) and H2O (4 mL) and extracted with EtOAc (3x50 mL). The organic layer was
extracted with saturated aqueous NaHCO3 (10 mL). The EtOAc contains the chiral
auxiliary and was set aside. The combined aqueous extracts were acidified to a pH of
less than 2, extracted with EtOAc (3x50 mL), dried over MgSO4, filtered and
concentrated to obtain (2S, 3R)-2-azido-3-ethyl-5,5,5-trifluoropentanoic acid as a
yellow oil (130mg,94%).
Mass Spectrum (-ESI): 197 (M-N2).
4. (2S, 3R)-2-Am.ino-3-ethyl-5,5,5-trifiuoropentan-l-ol
To a gray slurry of lithium aluminumhydride(LAH -110.6
mg, 2.91 mmol) in THF (2 mL) at 0 °C was added dropwise over 5 min (2S, 3R)-2-
azido-3-ethyl-5,5,5-trifluoropentanoic acid (130 mg, 583 mmol). The resulting slurry
was allowed to warm to 25 °C for 19 h. The reaction was quenched by sequential

WO 2004/092155 PCT/US2004/009268
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addition of H2O (0.5 mL), lN NaOH (1.5 mL) and H2O (0.5 niL) at 0 °C. The white
precipitate that formed after 5 h was filtered off, the organic solvent was dried over
MgS04, filtered and concentrated to obtain (2S, 3R)-2-amino-3-ethyl-5,5,5-
trifluoropentan-1-ol as a crude oil (120 mg, 96%). Mass Spectrum (+ESI): 186
(M+H)+.
5. 5-Chloro-N-[(lS, 2R)-2-ethyl-4,4,4-trljluoro-l-
(hydroxymethyl)butyl]th iophene-2-sulfonamide
To a stirred solution of (2S, 3R)-2-amino-3-ethyl-5,5,5-
trifiuoropentan-1-ol (120 mg, 0.701 tnmol), triethylamine (0.1 mL, 1.4 mmol) and
methylene chloride (50 mL) cooled to 0 °C, was added 5-chlorothiophene-2- sulfonyl
chloride (220 mg, 0.841 mmol) as a solution in methylene chloride (5 mL), dropwise.
After 15 min, the ice bath was removed and the reaction was allowed to attain 25 °C
overnight. Additional methylene chloride (15 mL) was added and the reaction mixture
was poured into saturated sodium bicarbonate solution (25 mL). The organic phase
was separated and washed sequentially with IN HC1 solution, H2O, brine and dried
over MgSO4. The organic phase was filtered and evaporated to produce a crude oil
(0.36 g) that was purified by flash chromatography using ethyl acetate-hexane. 1 -4 as
eluent. This provided the title compound 5-chloro-N-[(1S, 2R)-2-ethyl-4,4,4-
trifluoro-l-(hydro\7methyl)butyl]thiophene-2-sulfonamide as an oil (125 mg, 53 %).
The oil (125 mg) was further purified by prep-chiral HPLC [SFC; AD, 25 x 0.46 cm,
mobile phase, 8:2 hexane-ipa (1 mL/min)] to obtain 5-chloro-N-[(lS, 2R)-2-ethyl-
4,4,4-trifluoro-l-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white
crystalline solid (0.15 mg, 6.4%, chiral purity 100%, analytical purity 100%).
Mass Spectrum (-ESI): 364 (M-H).
Anal: Calc'd for C11H15NClF3O3S2 + 0.24 C4HgOz C, 37.50; H, 4.08; N, 3.73,
Found: C, 37,12; H, 4.41; N, 3.62,
B. Method 2
1. 2-Ethyl-4,4,4-trifluorobutyrlc acid
A solutionofdiisopropylamine(17.1 g, 169 mmol) in TKF
(180 mL) was stirred under nitrogen at 0 °C. n-Butyl lithium (n-BuLi - 67.6 mL, 2.5
M in hexane) was added dropwise over 15 min and the resulting solution stirred for
0.5 h at 0 °C. After this time period, the reaction was cooled to -78 °C, and 4,4,4-

WO 2004/092155 PCT/US2004/009268
42
trifluorobutyric acid (10.0 g, 70.4 mmol) in THF (20 mL) was added dropwise over
0.5 h. The resulting solution was stirred for an additional 0.5 h at -78 °C. After this
time period, ethyl iodide (6.3 9 mL, 77.4 mmol) was added dropwise over 15 min. The
resulting solution was stirred for 15 min. at -78 0C then warmed to 25 °C for 24 h.
After this time period, the reaction mixture was quenched by slow addition of H2O
(-20 mL). After concentration, the residue was acidified to pH 1 with 2 N aq. HCl and
then extracted with Et2O (400 mL). The organic layer was then dried using MgSO4.
After concentration, the resulting residue was used directly in the next reaction
without further purificatioa
2. 2-Ethyl-4,4,4-trijluorobutanol
A solution of LAH (2.74 g, 72.3 mmol) in Et2O (230 mL) was
stirred under nitrogen at 0 °C. 2-Ethy 1-4,4,4-trifluoro butyric acid (12.3 g, 72.3 mmol)
in Et2O (20 mL) was added dropwise, and the solution stirred for 15 min at 0 °C and
then 2 h at 25 °C. After this time period, the solution was quenched with the dropwise
addition of H2O (2.74 mL), 15% NaOH (2.74 mL), and H2O (8.22 mL) with efficient
stirring. Solid Na2SO4 was added to dry the solvent, and the resulting mixture was
stirred for 1 h. The resulting slurry was filtered, and the filter cake washed with
excess Et2O. After concentration, the crude product was purified by the Biotage
Flash™ 40 chromatography instrument, eluent; 20:80 to 30:70 Et2O:PE to obtain 2-
ethyl-4,434-trifluorobutanol as an oil (6.18 g, 55 % yield for two steps).
3. 2-Ethyl-4,4,4-trijluorobutyl aldehyde
A solution of 2-ethyI-4J4,4-trifluorobutanol (6.18 g, 39.6 mmol)
in CH2Cl2 (50 mL) was stirred under nitrogen at 0 DC. Dess-Martin periodinane
reagent (20.16 g,47.5 mmol) was added in one portion and the solution stirred for 1 h
at 0 °C. After an additional 5 h at 25 °C, the reaction was complete by NMR. The
solution was diluted with Et2O (100 mL), and to this solution was added Na2S2O3 (55
g) in sat. aq. NaHCO3 (100 mL). The resulting mixture was stirred for 0.5 h. The
liquid layers were separated and the organic layer was washed with additional sat. aq.
NaHCO3 (50 mL) and brine (50 mL) and then dried using Na2SO4. Most of the
solvent was removed via distillation using a Vigreux column (flask heated at about 50
to about 55 °C and head temperature equal to about 38 °C). The resulting residue in

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the reaction flask was used directly in the next reaction without further purification
(aldehyde very volatile).
4. 5-(I-Ethyl-3,3,3-p-ifluompropyI)-imidazolidme-2,4-dione
A solution of crude 2-ethyl-4,4,4-trifluorobutyl aldehyde (6.10
g, 39.6 mmol) in H2O (100 mL) was stirred at 0 °C. To this solution was added
sodium cyanide (5,82 g, 119 mmol), ammonium carbonate (15.2 g, 158 mmol), and
EtOH (100 mL). The reaction mixture was heated to 90 °C for 3 days. After cooling to
25 °C and concentration, ths resulting residue was acidified to a pH of about 1 to
about 2 with concentrated HC1. The solid which formed was filtered off, washed with
2 N HC1 and excess H2O, and then dried on the vacuum pump overnight to afford 5-
(l-ethyl-3,3,3-trifluoropropyl)-imidazoIidine-2,4-dione (2.74 g, 31% yield for two
steps). Mass Spectrum (+ESI): 225 (M+H)+ and (-ESI): 223 (M-H)
5. 2-[(5 -Chtoro-2 -thieniyl)sulfonylammo]-3-ethy!-5,5,5-
irifluoropentanoic acid
A solution of 5-(l-ethyl-3,3,3-trifluoropropyl)-imidazolidine-
2,4-dione (1.76 g, 7.85 mmol) in 20 mL of aq. NaOH (1.26g, 31.4 mmol) was heated
by microwave in a sealed vessel for 0,5 h (Microwave conditions: 15 min. at about
100% power, 150 °C, 50 psi; then 5 min. 0% power; then 15 min. at about 100%
power, 150 °C, 50 psi). After cooling to 25 °C, water and ammonia were removed
from the reaction mixture in-vacuo, and the resulting crude amino acid sodium salt
mixture was dissolved in H2O (15 mL). To this solution at 0 °C was added THF (25
mL) followed by 5-chloro-thiophene-2-5ulfonyl chloride (1.87 g, 8.64 mmol) in THF
(5 mL) dropwise. After 18 h at 25 °C, the reaction was concentrated and the residue
was acidified to a pH of 1 with 2 N aqueous HC1. This aqueous layer was extracted
with Et2O (2 x 100 mL), and the resulting organic layer was washed with brine (20
mL) and dried using MgSO4. After concentration, the crude residue was
recrystallized from EtOAc:hexane to remove by-products. Concentration of the
filtrate afforded the product as a solid (1.31 g, 44%). Mass Spectrum (+ESI): 380
(M+H)+ and (-ESI): 378 (M-H)

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6. 5 '-Chloro-N-[(1S,2R)-2-ethyl, 4,4,4-trifluoro-l-
(hydroxymethyl)butyl]thiophene-2'-sulfonamide
A solution of 2-[(5'-chloro-2'-thienyI)sulfonyIamino]-3-ethyl-
5,5,5-trifluoropentanoic acid (2.19 g, 5.77 mmol) in THF (60 mL) was stirred under
nitrogen at 25 °C. Borane-THF complex (23.1 mL, 1.0 M in THF) was added
dropwise, and theresulting solution stirred for 18 h at 25 °C. After this time period,
the reaction was complete by TLC (10:90 MeOH:CHCL3). The reaction mixture was
quenched by slow addition of 10% acetic acid (HOAc) in MeOH (80 mL). After
concentration, the residue was dissolved in EtOAc (200 mL) and washed with
saturated aqueous NaHCO3 (3 x 20 mL) and brine (20 mL), and then dried using
Na2SO4. After concentration, the crude product (2.20 g) was purified by the Biotage
Flash™ 40 chromatography system, eluent: 20:80 to 30:70 EtOAc:PE to obtain one of
two pairs of racemic mixtures (0.623 g). This compound was then further purified
using chiral HPLC conditions (the Chiralccl™ AD column; 25 x 2.2 cm, 254 nm, 0.5
mL injections; mobile phase: 25 mL/rtvin 12% MeCN in hexane; product is peak one,
Rf = 6.7, >99.9% purity) to afford enantiornerically pure 5'-chIoro-N-[(lS,2R)-2-
ethyl, 4,4,4-trifluoro-l-(hydroxymethyl)butyl]thiophene-2'-sulfonamide as a white
solid, mp 128-129 °C (0.238 g, 45% yield related to specific enantiomer).
Mass Spectrum (-ESI): 364 (M-H)"
Anal: Calc'd for C1IH15C1F3NO3S2 C, 36.12; H, 4.13; N, 3.83.
Found: C, 36.22; H, 4.20; N, 3.78.
EXAMPLE 3
5'~Chloro-N-[(lS,2R)-2-ethyl,4,4,4-trifluoro-l-(l-hydroxyethy])butyI]thiophene-2'-
sulfonamide
A 5'-Chloro-N-[(lS, 2fy-2-ethyl, 4,4,4-trifluoro-1-
(formyl)butyl]thiophene-2'-sulfonamtde
A solution of 5'-chloro-N-[(lS, 2R)-2-ethyl, 4,4,4-trifluoro-l-
(hydroxymethyl)butyl]thiophene-2'-sulfonamide(prepared as inExample2, 0.100 g,
0,273 mmol) in CH2C12 (4 mL) was stirred under nitrogen at 0 °C. Dess-Martin
periodinane reagent (0.151 g3 0.355 mmol) was added in one portion and the solution
stirred for 1 h at 0 °C. After an additional 1 h at 25 °C, the reaction was complete by

PCT/US2004/009268
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TLC (30:70 EtOAc.PE). The solution was diluted with Et2O (50 mL), and to this
solution was added Na2S2O3 (0.363 g) in saturated aqueous NaHCO3 (10 mL). The
resulting mixture was stirred for 0.5 h. The liquid layers were separated, and the
organic layer was washed with additional sat. aq. NaHCO3 (5 mL) and brine (5 mL)
and then dried (Na2SO4- After concentration, the crude product was purified by
preparatory plate chromatography, eluent: 30:70 EtOAc:PE to obtain 5'-chloro-N-
[(1S, 2R)-2-ethyl, 4,4,4-trifluoro-l-(formyl)butyl]thiophene-2'-sulfonamide as a solid
(0.036 g, 36%).
B. 5'-Chloro-N-[(1S,2R)-2-ethyl, 4,4,4-trifluoro-l-(l-
hydroxyethyl)butly]thiophene-2'sulfonamide
A solution of5'-cWoro-tf-t(iS,2R)-2-ethyl, 4,4,4-trifluoro-l-
(formyl)butyl]thiophene-2'-sulfonamide (0.035 g, 0,0962 mmol) in THF (3 mL) was
stirred under nitrogen at 0 °C. Methyl magnesium bromide (0.206 mL, 1.4 M in
toluene:THF) was added diopwise and the lesulting solution was stirred for 1 h at
25 °C. After this time period, the reaction was complete by TLC (30:70 EtOAc;PE).
The solution was quenched with saturated aqueous NR4Cl (2 mL) and extracted with
Et2O (20 mL). The organic layer was washed with brine (3 mL) and then dried using
Na2SO4. After concentration, the crude product was purified by preparatory plate
chromatography, eluent: 30:70 EtOAc:PE to obtain5'-chloro-N-[(IS,2R)-2-ethyl,
4,4,4-trifluoro-l-(l-hydroxyethyl)butyIJthiophene-2'-sulfonamideas an off-white
solid (0.027 g, 73 %),
Mass Spectrum (-ESI): 378 (M-H).
Anal: Calc'd for C12H17ClF3NO3S2 C, 37,94; H, 4.51; N, 3.69.
Found: C, 38.35; H, 4.32; N, 3.29.
EXAMPLE4
5'-Chloro-Ar-[3,3J3-trifluoro-2-(trifluoromethyI)-l-(hydroxymethyl)propyl]thiophsne-
2'-sulfonamide
A. 3,3,3-Trifluoro-2-(trifluoromethyl)-l -(hydroxymethyl)propylamine
A solution of 4,4,4,4'J4',4'-hexafluoro-DL-valine (0.500 g, 2.22
mmol) in THF (20 mL) was stirred under nitrogen at 25 °C. Borane-THF complex
(6.66 mL, 1.0 M in THF) was added dropwise and the resulting solution stirred for 4 h

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at 25 °C. After this time period, the reaction was complete by TLC (10:2:1
EtOAc:EtOH:H20). The reaction mixture was quenched by slow addition of 10%
HOAc in MeOH (23 mL). After concentration, the residue was dissolved in Et2O (200
mL) and washed with saturated aqueous NaHCO3 (3 x 20 mL) and brine (20 mL), and
then dried using Na2SO4. After concentration, the resulting residue was used directly
in the next reaction without further purification.
B. 5'-Chloro-N-[3,3,3-hifluoro-2-(trtfluoromthyl)-l-
(hydroxymethyt)propyl]thiophene-2'-sulfonamide
A solution of 3,3,3-tniluoro-2-(trifluoromethyI)-l-
(hydroxymethyl)propylamine (0.400 g, 1.89 mmol) in CH2Cl2 (20 mL) was stirred
under nitrogen at 0 °C. Triethylamine (Et3N - 0.369 mL, 2.65 mmol) was added
dropwise followed by 5-chloro-thiophene-2-sulfonyl chloride (0.492 g, 2.27 mmol) in
one portion, and the resulting solution was stirred for 18 h at 25 °C. After this time
period, the reaction was complete by TLC (30:70 EtOAc:PE). After quenching with
MeOH and concentration, the residue was taken up in Et2O (200 mL) and washed
with 1 N aqueous HC1 (20 mL), saturated aqueous NaHCC>3 (20 mL), and brine (20
mL), and then dried (MgSO4). After concentration, the crude product was purified by
the Biotage Flash™ 40 chromatography system, eluent: 10:90 to 30:70 EtOAc:PE to
obtain 5'-chloro-N-[3,3,3-trifluoro-2-(trifluoroinethyI)-l-
(hydroxymethyI)propyl]thiophene-2'-sulfonamide as an off-white solid (0.108 g, 14
% yield for two steps, racemic mixture).
Mass Spectrum (-ESI): 390 (M-H).
Anal: Calc'd for C9H8CIF6NO3S2 C, 27.59; H, 2.06; N, 3.58;
Found: C, 28.24; H, 1.90; N, 3.48.
EXAMPLE 5
S'-Chloro-N-[3,3,3-trifluoro-2-(trifluoromethyl)-l-S-
(hydroxymethyl)propyl]thiophene-2'-sulfonamide
A. Methyl 2-amino-3-(trifluoromethyl)~4,4,4-trijluorobutanoate
A solution of 4,4,4,4',4',4'-hexafluoro-DL-valine (2.00 g, 8.89 mmol)
in CH2Cl2:Me0H (4:1, 50 mL) was stirred under nitrogen at 0 °C. Tetramethylsilane
(TMS) diazomethane (5.33 mL, 2.0 M inhexane) was added dropwise, and the

WO 2004/092155 PCT/US2004/009268
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resulting solution stirred for 3 h at 25 °C. After this time period, the reaction was
complete by TLC (10% MeOH: chloroform). After concentration, the resulting residue
(1.34 g, 63%) was used directly in the next reaction without further purification.
B. Methyl 2-[(5'-chloro-2'-thienyl)sulfonylamino]-3-trifluoromethyl-
4,4,4-trifluorobutanoate
A solution of methyl 2-amino-3-(1rifluoromethyI)-4,4,4-
trifluorobutanoate (1.34 g, 5.60 mmol) in CH2C12 (10 mL) was stirred under nitrogen
at 25 °C. Pyridine (10 mL, 126 mmol) was added dropwise followed by 5-chloro-
thiophene-2-sulfonyl chloride (1.82 g, 8.40 mmol) in one portion and the resulting
solution stirred for 72 h at 25 °C. After this time period, the reaction was complete by
TLC (20:80 EtOAc:PE). After quenching with H2O, the mixture was diluted with
Et2O (200 mL). The organic layer was washed with 1 N aq. HC1.(2O mL), sat. aq.
NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration,
the crude product was purified by the Biotage Flash™ 40 chromatography system,
eluent. 5:95 to 25:75 EtOAc:PEto obtain methyl 2-[(5'-Chloro-2'-
thienyl)suIfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate as a solid (1.61 g,
69%). Mass Spectrum (-ESI): 418 (M-HV,
C. 5'-Chhro-N-[3,3,3-trijluoro-2-(trifluoromethyI)-]-S-
(hydroxymethyl)propyl]thiophene-2'-sulfonamide
A slurry of LAH (0.146 g, 3.84 mmol) in Et2O (17 mL) was stirred
under nitrogen at 0 °C. To this mixture was added dropwise methyl 2-[(5'-chloro-2'-
thienyl)sulfonylamino]-3-trifluorornethyl-4,4,4-trifliiorobutaiioate (1.61 g, 3.84
mmol) in Et2O (3 mL). After stirring at this temperature for 0.25 h, the reaction was
complete by TLC (30:70 EtOAc:PE). This mixture (with efficient stirring) was
quenched with the dropwise addition of H2O (0.146mL), 15% aqueous NaOH (0.146
mL), and H2O (0.438 mL) and then stirred an additional 2 h at 25 °C. The resulting
slurry was dried (Na2SO4) and then filtered. After concentration, the crude product
was purified by the Biotage Flash™ 40 chromatography system, eluent: 5:95 to 40:60
EtOAc:PE to ohtain5'-chloro-JV-[3,3,3-trifluoro-2-(trifluoromethyl)-l-
(hydroxymethyl)propyl]-thiophene-2'-sulfonamide as a solid (0,590 g, 39%, racemic
mixture). The active enantiomer, 5'-chloro-N-[3,3,3-trifluoro-2-(trifluoroinethyl)-l-S-
(hydroxymethyl)propyl]thiophene-2'-sulfonamide (0.185 g), was then isolated as an

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off-white solid (mp 148-150 °C) using chiral HPLC [the Chiralpak® AS column; 2 x
25 cm, 254 nm, 0.5 mL injections; mobile phase: 15 mL/min 8% IPA in hexane/O.1%
TFA(preraix); product is peak two, Rf = 12.3, 98.5% purity].
Mass Spectrum (-ESI): 389.9 (M-H)'.
Anal; Calc'd for C9H8CIF6NO3S2 C, 27.59; H, 2.06; N, 3.58;
Found: C, 27.76; H, 1.96; N, 3.47.
In a comparative study between the compound of this example and a similar
compound which lacks the trifluoromethyl groups but is otherwise identical, the
compound of this example demonstrated significantly higher (about 72 to about 133
fold) potency in a cellular assay and significantly longer metabolic stability (46 min
vs 10 min half-life in an assay of transgenic mice (Tg2576) liver microsome
metabolism). Thus, the compound of the invention may be used in lower doses than
the corresponding compounds lacking the trifluoromethyl groups.
EXAMPLE 6
5-Chloro-N-[(lR,2S)-2-ethyl-4,434-trifluoro-l-(hydroxymethyl)butyl]thiophene-2-
sulfonamide
A. (4R)-4-Benzyl-3-(bromoacetyl)-l, 3-oxazolidin-2-one
To a solution of R-(-)-4-benzyI-2-oxazoIidinone (15.0 g, 84.65 mmol)
in THF (200 mL) was added nBuLi (2.5M in hexanes, 34 mL, 84.65 mmol) dropwise
at -78 °C. The solution was stirred at -78 0 C for 30 min and then bromo acetyl
bromide (18.65 g, 7.8 mL, 124.15 mmol) was added. The solution was allowed to
warm to 25 °C overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-bexane)
indicated that reaction was complete. It was diluted in ethyl acetate (200 mL) and the
organic layer was washed with saturated aqueous NaHCO3 (2x50 mL). The organic
layer was dried over MgSO4, filtered and concentrated to obtain a crude brown oil
(24.6 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-
hexane, to furnish (4R)-4-benzyI-3-(bromoacetyl)-l,3-oxazoIidin-2-one as a colorless
oil (19.9 g, 79.6 %). Mass Spectrum (+ESI): 300, 299 (M+H)+,

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B. Diethyl-2-[(4R)-4-benzyl-2-oxo-l,3-oxazotidin-3-yl]-2'
oxoethylphosphonate
(4R)-4-Benzyl-3-(bromoacetyl)-l,3-oxazolidin-2-one (19.7 g, 66.07
mmol) and triethylphosphite (33.99 mL, 198.2 mmol) were heated at 120 °C for 18 h.
An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The reaction was cooled to 25 °C, diluted with ethyl acetate (200 mL). The
organic layer was washed with saturated aqueous NaHCO3 (2x50 mL), dried over
MgSO4, filtered, and concentrated to obtain diethyl-2-[(4R)-4-ben2yl-2-oxo-l,3-
oxazolidin-3-yl]-2-oxoethyIphosphonate as crude yellow oil (14.27 g, 60.77 %).
Mass Spectrum (-ESI): 326 (M-H).
C. (4R)-4-Benzyl-3-[(2E)-5,5,5-trifluoropent-2-enoyl]l,3-oxazolidin-2-
one
To a solution of diethyl-2-[(4R)-4-benzyl-2-oxo-l,3-oxazolidin-3-yl]-
2-oxoethylphosphonate (14.27 g, 40.17 mmol) in THF (200 mL) was added KHMDS
(0.5M, 88 mL, 44,63 mmol), at -78 °C. The solution was allowed to warm to 25 °C
over 30 min and 3,3,3-triiluoropropionaldehyde (5.0 g, 44.63 mmol) was added at -20
°C. The solution was allowed to warm to 25 °C overnight (19 h). An aliquot was taken
and TLC (1 ;2 EtOAc-hexane) indicated that reaction was complete. The reaction was
quenched by addition of saturated aqueous NaHCO3 (50 mL). The aqueous layer was
washed with ethyl acetate (3 x 100 mL). The organic layer was dried over MgSO4,
filtered and concentrated to obtain a light brown oil (32. lg). The crude product was
purified by flash chromatography, eluent: 1:6 EtOAc-hexane, to furnish (4R)-4-
benzyl-3-[(2E)-5,5,5-trifluoropent-2-enoyl]-l,3-oxazoIidin-2-one as a colorless oil
(3.7 g, 29.4%).
Mass Spectrum (+ESI): 314 (M+H)+.
Anal: Calc'd for C15H14NF3O3 + 0.25 H2O C, 56.70; H, 4.60; N, 4.41
Found: C, 56.44; H, 4.49; N, 4.41.
D. (4R)-4-Benzyl-3~[(2R,3S)-2-bromo-3-ethyl-5,5,5-trijluoropentanoyl]-
1,3 -oxazo lidin -2 -one
A slurry of copper bromide (I)-dimethyl sulfide complex (1.57 g, 7.66
mmol) in THF (20 mL) and dimethyl sulfide (10 mL) as co-solvent was cooled to -40
°C and ethyl magnesium bromide (5 mL, 15.3 mmol) was added dropwise for 10 min.

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The slurry was stirred for 40 min while warming to -15 °C. The greenish slurry was
cooled to-40 °C and (4R)-4-ben2yl-3-[(2E)-5,5,5-trifluoropent-2-enoyl]l,3-
oxazolidin-2-one (2 g, 6.38 mmol) was added dropwise as a solution in THF (5 mL)
at -40 0C. The reaction was allowed to warm to 25 °C overnight (20 h). The black
slurry was cooled down to -78 °C and N-bromosuccinimide (2.3 g 12.76 mmol) was
added portionwise. It was allowed to warm to -40 °C and stirred for an additional 30
mia After this period the black slurry became greenish to blue. A precipitate formed
and was filtered off. The mother liquor was diluted with EtOAc (150 mL) and the
organic layer was washed with saturated NaCl (50 mL). The organic layer was dried
over MgSO4, filtered and concentrated to afford (4R)-4-benzyl-3-[(2R, 3S)-2-bromo-
3-ethyl-5,5,5-trifluoropentanoyI]-l,3-oxazolidin-2-one as a green semi-solid (1.6 g,
59.5 %). Mass Spectrum (-ESI): 421,420 (M-H).
E. (4R)-3-[(2S,3S)-2-Azido-3-ethyl-5,5.5-triJluoropentanoyl]-4-benzyl-
1,3-oxazolidin-2~one
To a solution of (4R)-4-benzyl-3-[(2R, 3S)-2-bromo-3-ethyl-5,5,5-
triGuoropentanoyl]-l,3-oxazoIidin-2-one (1.6 g, 3.79 mmol) in DMF (20 mL) was
added sodium azide (0.468 g, 7.199 mmol). The slurry was stirred at 25 °C for 20 h
and the solvent was removed in vacua. The crude product was dissolved in EtOAc
(100 mL) and the organic phase was washed with H2O (3x20 mL) and saturated
aqueous NaCl (20 mL). The organic layer was dried over MgSO4, filtered and
concentrated to obtain ayellow oil (1.4 g). The crude product was purified by flash
chromatography, eluent: 1:4 EtOAc-hexane, to furnish (4R)-3-[(2S, 3S)-2-azido-3-
ethyl-5,5,5-trifluoropentanoyl]-4-ben2yl-l,3-oxazolidin-2-one as a colorless oil (1.21
g, 83.2 %), Mass Spectrum(-ESI): 357 (M-Nz), 380, 381.
F. (2S,3S)-2-Amino-3-ethyl-5,5,5-trifluoropentan-l-ol
To a gray slurry of LAH (100 mg, 2.65 mmol) in THF (3 mL) at -10°C
was added (4R)-3-[(2S, 3S)-2-azido-3-ethyI-5J5>5-trifluoropentanoyl]-4-ben2yI-l,3-
oxazolidin-2-one (300 mg, 0.78 mmol) as a solution in THF (2 mL) dropwise over 5
min. The resulting slurry was allowed to warm to 25 °C for 19 h. The reaction was
quenched by sequential addition of H2O (0.3 mL), IN NaOH (0.9 mL) and H2O (0.3
mL) at 0 °C. The precipitate that formed after 5 h was filtered off. The mother liquor

WO 2004/092155 PCT/US2004/009268
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was dried over MgSO4, filtered and concentrated to obtain (2S, 3S)-2-amino-3-ethyI-
5,535-trifluoropentan-l-oI as a light yellow oil (145 ing, 98 %). Mass Spectrum
(-ESI); 184 (M-H).
G. 5-Chloro-N~[(lS,2S)-2-ethyl-4,4,4-trifiuow-l-
(ljydroxyme(hyl)butyljthiophene-2sulfonamide
To a stirred solution of (2S, 3S)-2-amino-3-ethyl-5,5,5-trifluoropentan-
l-ol (145 ing, 0.78 mmol), triethylamine (0.22 mL, 1.56 mmol) and methylene
chloride (5 mL) cooled to 0 °C, was added 5-chlorothiophene-2- sulfonyl chloride
(225 mg, 0.861 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15
min, the ice bath was removed and the reaction mixture was allowed to attain 25 °C
overnight. Additional methylene chloride (15 mL) was added and the reaction was
quenched by pouring it into saturated sodium bicarbonate solution (25 mL). The
organic phase was separated and washed sequentially with IN HC1 solution, H2O,
brine and dried over MgSO4. The organic phase was filtered and evaporated to
produce a crude oil (0.250 g) that was purified via flash chromatography, eluent: 1:6
ethyl acetate-hexane. This produced the title compound 5-chioro-N-[(lS, 2S)-2-ethyl-
4,4,4-trifluoro-l-(hydroxymethyl)butyl]thiophene-2-sulfonamide as an oil (140 mg,
53.8 %). The crude oil was further purified by recrystallization from 1:4 EtOAc-
heptane. The mixed solvent system was added to 5-chloro-N-[(lS,2S)-4,4,4-trifluoro-
I-(hydroxymethyI)-2-methyIbutyl]thiophene-2-sulfonamide, heated to obtain a
solution, allowed to cool to 25 °C for 3 h and then stored at 0 °C for 19 h. A
crystalline white solid precipitated which was filtered and washed with ice-cold
heptane to afford 5-chIoro-N-[(lR,2S)-2-ethyI-4,434-trifluoro-l-
(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (50 mg,
19.2 %, chiral purity 91 %, analytical purity 100%).
Mass Spectrum (-ESI): 364 (M-H)".
Anal; Calc'd for C11H]5NC1F3O3S2 + 0.10 C4HSO2 C3 36.55; H, 4.25; N, 3.74.
Found: C, 36.94; H, 4.15; N, 3.57.

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EXAMPLE 7
5-Chloro-N-[4,4,4-trifluoro-l-(hydroxymethyI)butyl]thiophene-2-sulfonainide
A 4,4,4-Trifluorobutanal
Diisobutylaluminum hydride (35 mL, 35.26 mmol) was added to a
solution of ethyl-4,4,4-trifIuorobutanoate (5 g, 29.38 mmol) in CH2CI2 (50 mL) under
N2 atmosphere at -70 °C. After 6 h, IN HC1 (6 mL) was added and after warming to
-60 OC, the reaction mixture was poured into H2O (5 mL) and extracted with CH2CI2
(2x50 mL). The combined organic extracts were washed with H2O (2x10 mL). The
organic extracts were dried over MgSO4 filtered and concentrated to obtain 4,4,4-
trifluorobutanal as acolorless non-viscous oil (3.7 g, 100 %).
B. 5-(3,3,3-TriJluoropropyl)imidazolidine-2,4-dione
Sodium cyanide (4.31 g, 88.04 mmol) and 4,4,4-trifluorobutanal (3.7 g,
29.34 mmol) were added to ammonium carbonate (9.1 g, 117.4 mmol) inH2O (60
mL). The black reaction mixture was heated to 90 °C. After 1 h, the mixture became
homogeneous and it was stirred at 90 0C for 18 h. After cooling to 25 °C, about 60 mL
of solvent was removed in vacuo. Concentrated HC1 (4 mL) was added to acidify the
mixture to a pH of about 2 and a precipitate formed. It was filtered. The mother liquor
was washed with EtOAc (3x50 mL). The organic layer was dried over MgSO4,
filtered and concentrated to obtain 5-(3,3,3-trifluoropropyi)imidazolidine-2,4-dione as
a brown oil (3.95 g, 69.7 %). Mass Spectrum (-ESI): 195 (M-H).
C. 5,5,5-Trifluoronorvaline
5-(3,3,3-trifluoropropyl)imidazolidine-2,4-dione (0.9 g, 4.59 mmol)
was dissolved in a 10 mL solution of aqueous NaOH (0.734 g in 10mLH2O, 18.35
mmol). The solution was divided in 2 special vessels for microwave technology. The
solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15
min at about 100 % power, 150°C, 50 psi, then 5 min at rest, 0 % power. Repeat
sequence twice or until reaction is done. Water and ammonia were removed from the
reaction mixture in vacuo and the resulting crude 5,5,5-trifluoronorvaline (1.1 g, 140
%) and NaOH mixture was used in the next reaction without further purification.
Mass Spectrum (+ESI): 172 (M+H)+.

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D. N~[(5-Chlorothien-2-yl)sulfonyl]-S,5,5-trifluoronorvaline
To a solution of the crude 5,5,5-trifluoronorvaline (0.785 g, 4.59
mmol) and NaOH mixture dissolved in THF (10 ml) and 2N NaOH (10mL) was
added dropwise a solution of 5-chlorothiophene-2-suIfonyl chloride (1.32 g, 5.04
mmol) in THF(10 ml) over 30 min. After 60 min, the reaction mixture was allowed to
warm gradually to 25 °C and stirred for 16 h. THF was removed in vacuo and the
mixture was acidified to a pH of about 2 with IN HC1. After 15 min, a precipitate
began to crash out of the milky white solution. After 60 min, the mixture was cooled
to 0 °C for 45 min and then filtered. The precipitate was washed with IN HC1 (10 mL)
to provide a white solid. The white solid giimmed out. It was dissolved in EtOAc
(100 mL). The aqueous was washed with EtOAc (3x50 mL) and the organic layers
were washed with saturated aqueous NaCI (50 mL). The organic layer was dried over
MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yI)sulfonyl]-5,5,5-
trifluoronorvaline as a dark red oil (1.1 g, 68.3%). Mass Spectrum (-ESI): 350
(M-H).
E. 5-Chloro-N-[4,4,4-t}-ifluoro-l-(hydroxymethyl)buryl]thiophene-2-
sulfonamide
Borane-THF (1 M, 15 mL, 14.21 mmol) was added dropwise over 30
min at 0 °C to a solution of N-[(5-ch]orothien-2-yI)sulfonyl]-5,5,5-trifiuoronorvaline
(1.0 g, 2.84 mmol) in THF (10 mL). The reaction was allowed to warm to 25 °C for
18 h and then was quenched by addition of 50 mL of 10 % acetic acid in methanol.
After solvent evaporation, the crude product was dissolved in EtOAc and washed with
IN HC1, H2O and saturated NaHCO3. The organic layer was dried over MgSO4,
filtered and concentrated to produce a crude oil (0.83 g) that was purified via flash
chromatography, eluent: 1:6 ethyl acetate-hexane. This produced the title compound
5-chioro-N-[4,4J4-trifluoro-l-(hydroxymethyI)butyI]thiophene-2-sulfonamide as a
colorless oil (0.46 g, 48%). Mass Spectrum (-ESI): 337 (M-H)'.
Anal: Calc'd for CUH15NC1F3O3S2 + 0.30 C4H8O2 C, 33.64;H, 3.71; N, 3.85.
Found: C, 34.01; H, 3.65; N, 3,67.

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EXAMPLES 8 AND 9
5-Chbro-N-{ClS,2R)-4,4,4-trifluoro-l-[(lS)-l-hydroxyethyI]-2-
methyIbutyl}thiophene-2-5uIfonamide
and
5-Chloro-N-{(lS,2R)-4,4J4-trifluoro-l-[(lR)-l-hydroxyethyl]-2-
methylbutyl}thiophene-2-sulfonamide
To5-chloro-N-[(lS,2R)-4,4,4-trifluoro-l-(hydroxymethyl)-2-
methylbutyl]thiophene-2-suIfbnamide (prepared as in Example 1, 290 mg, 0.824
mmol) in CH2CI2 (15 mL) at 0 °C was added Dess-Martin periodinane (410 mg, 0.989
mmol). The reaction mixture was warmed to 25 °C. After 10 min, TLC (3:7 EtOAc-
hex,) indicated presence of starting material. Additional Dess Martin periodinane
(410 mg, 0.989 mmol) was added and after 15 min TLC indicated consumption of
starting material. Diethyl ether (30 mL) was added, followed by aqueous 1 N
Na2S2O3 (25 mL) and saturated aqueous NaHC3 (25 mL). The milky white solution
was stirred vigorously until both phases were homogenous. The layers were
separated and the aqueous phase was extracted with diethyl ether. The combined
organic extracts were dried (Na2SO4) and concentrated. Flash chromatography
(eluent: 3:7 EtOAc-hexane) provided 5-chIoro-N-[(lS, 2R)-4,4,4-trifluoro-l-(forniyI-
2-methylbutyl)]thiophene-2-sulfonamide (100 mg, 35%) as a white solid.
To5-chloro-N4(lS,2R)-4,4Atrifluoro-l sulfonamide (100 mg, 0.286 mmol) in THF (3 mL) at 0 °C was added a solution of
methylmagnesium bromide (0.61 mL, 1.4 M in THF/toluene, 0,86 mmol) dropwise.
The reaction mixture was warmed to 25 °C and stirred for 3 h. It was then quenched
with saturated aqueous ammonium chloride, extracted with EtOAc (2 x 40 mL), dried
(Na2SO4) and concentrated, Flash chiomatography (eluent: 3:7 EtOAc-hexane)
provided 5-chloro-N-{(lS,2R)-4,4,4-trifluoro-l-[l-hydroxyethyl]-2-
methyIbutyI}lhiophene-2-sulfonamide (75 mg, 74%) as a 3:1 mixture of
diastereomers. Diastereomers were separated by HPLC (the Zorbax® silica gel
column, 25 x 5 cm, eluent: 3:2 Methyl tertiary butyl ether (MTBE)-hexane,
diastereomer 1 elutes at 11.4 min, diastereomer 2 elutes at 14.1 min).
Diastereomer 1: Mass Spectrum (-ESI): 364 (M-H).
Diastereomer 2: Mass Spectrum (-ESI): 364 (M-H).

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EXAMPLE 10
5-ChIoro-N-[(lS,2S)-4,4,4-trifluoro-l-Chydroxymethyl)-2-methyIbutyI]thiophene-2-
sulfonamide
A. 5,5,5-Trlfluoro-L-isoleuclmhydrochloride
To (S)-(-)-α-rnethylbenzy]amine hydro chloride salt (0.340 g, 2.16
mmol) in 20 mL of 1:1 MeOH/H2O was added potassium cyanide (0.139 g, 2.13
mmol) and (2S)-4,4,4-trifluoro-2-methylbutanal (0.300 g, 2.14 mmol, prepared by the
procedure reported in Example 1, method 2 but using (S)-(-)-4-benzyl-2-
oxazolidinone as the chiral auxiliary) and the reaction mixture was stirred for 17 h.
Methanol was removed in vacuo and the product was extracted with EtOAc. The
organic extract was washed with aqueous 0.1 N HC1, dried (Na2SO4) and
concentrated. Flash chromatography (eluent: 1:9 EtOAc-hexane) provided the α-
amino nitrile (0.224 g, 39%) as a yellow oil. 1H-NMR indicated that the product is a
3:1 mixture of diastereomers.
Sulfuric acid (3 mL) was added to the mixture of diastereomers (0.224
g, 0.829 mmol) and the solution was stirred for 22 h. Then the reaction mixture was
poured over crushed ice (-10 g). Concentrated aqueous ammonium hydroxide was
added to neutralize the acid. This mixture was extracted with EtOAcg dried (Na2SO4),
filtered and concentrated to give the resulting amide (0.224 g, 94%), which was used
in the next step without purification
A mixture of the amide (0.224 g, 0.777 mmol) and 5% palladium/C
(Pd/C - 40 mg) was shaken for 2 days in a Parr apparatus under 3 atm of hydrogen
(H2). The mixture was filtered through a plug of the Celite® reagent and the solvent
was removed in vacuo to give the resulting amine as a white solid (128 mg, 90%),
which was used in the next reaction without further purification.
The amine (128 mg, 0.695 mmol), in concentrated hydrochloric acid (3
mL), was heated to reflux for 24 h. The reaction mixture was cooled to room
temperature and concentrated to give a mixture of ammo acid hydrochloride salt (3:1
diastereomeric ratio) and 1 equivalent of ammonium chloride as a white solid (183
mg, 95%). Mass Spectrum (+ESI); 186 (M+H)+.

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B. (2S, 3S)-2-Amlno-5,5,5-trijluoro-3-methylpentan-ol
To a solution of lithium borohydride (1.0 mL, 2.0 N in THF, 2.0
mmol) in THF (5 mL) at 0 °C was added chlorotriraethylsilane (0.51 mL, 4.01 mmol).
The reaction mixture was wanned to 25 °C and, after 30 min, added dropwise to a 0
°C suspension of crude amino acid hydrocliloride salt (184 mg, 0.669 mmol) in THF
(5 mL). The mixture was warmed to 25 °C, and after 21 h, quenched with MeOH.
The volatiles were removed in vacuo and the resulting residue was dissolved in
aqueous 1 N NaOH, extracted with CHCI3 (4 x 20 mL), dried (Na2SO4) and
concentrated to give the amino alcohol as a yellow oil (92 mg, 81%) which, according
to its 1H NMR spectra, is a 3:1 mixture of diastereomers. Mass Spectrum (+ESI): 172
(M+H)+.
C. 5-Chloro-N-[(lS, 2S)-4,4,4-trifluoro-l-(hydroxymethyI)-2-
methylbutyl]thiophene-2-sulfonamide
To the amino alcohol (168 mg, 0.981 mmol)inCH2Cl2(10mL) was
added triethylamine (170 μL, 1.20 mmol) and 5-chlorothiophene-2-sulfonyl chloride
(256 mg, 1.18 mmol). The reaction mixture was stirred at 25 °C for 21 h. The
solution was diluted with EtOAc (50 mL), washed with 0.1 N HC1 twice, dried and
concentrated. Careful removal of impurities and the minor diastereomer by flash
chromatography (eluent: 3:7 EtOAc-hexane) provided 5-chloro-N-[(lS, 2S)-4,4,4-
trifluoro-l-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (97 mg, 28%) as
a white solid, mp 99-100 °C. HPLC (Zorbax® silica gel column, eluent: 3:2MTBE-
hcxane) indicated a 97:3 mixture of diaslereomers. Chiral HPLC (AD column, eluent:
1:9 isopropanol-hexane) indicated >99% enantiomeric purity.
[α]D25 = +8.95° (c = 1% SOLUTION, MeOH).
Mass Spectrum (-ESI): 350 (M-H)
Anal: Calc'd for C10H13ClF3NO3S2 C, 34.14; H, 3.72, N, 3.98.
Found: C, 34.43; H, 3.70; N, 3.91.

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EXAMPLE 11
(2S,3S)-2-(5-Chloro-3-methylbenzo[b]thiophene-2-suIfonyl)-amido-5,5,5-trifluoro-3-
ethyl-pentan-1 -ol
A. (R)-4-Benzyl-3-(2-R-bromo-3-S-ethyl-5,5,5-trifluoro-pentanoyl)-
oxazolidin-2-one
To copper (I) bromide-dimethyl sulfide complex (328 mg, 1.56 mmol)
in THF/DMS (2:1, 60 mL), cooled to -40 °C, was added ethyl magnesium bromide
(1.06 mL, 3 M solution in THF, 3.2 mmol). The solution was allowed to stir for 10
min while warming to -15 °C. The mixture was re-cooled to -40 °C and (R)-4-
benzyl-3-(5,5,5-trifluoro-pent-2-enoyl)-oxazolidin-2-one (prepared as m Example 6
part C, 416 mg, 1.3 mmol) in THF (15 mL) was added. The solution was stirred at 25°
C for 16 h. The solution was re-cooied to -78° C and N-bromosuccinimide (473 mg,
2.6 mmol) in THF (10 mL) was added. The solution was allowed to warm to 0 °C
and shaken at 0 °C for 3 h. The reaction was quenched with a 1:1 solution of
saturated ammonium carbonate and 0.5 N potassium bisulfate (15 mL). The organic
phase was decanted off and concentrated to give (R)-4-benzyl-3-(2-R-bromo-3-S-
ethyl-5,5,5-trifluoro-pentanoyI)-oxazoIidin-2-one, identified by liquid
chromatography mass spectrometry (LCMS).
B. 3-(2-S-Azido-3-S-ethyl-5,5,5-trifiuoro-pentanoyl)-4R-benzyl-
oxazolidin-2-one
To(R)-4-benzyl-3-(2R-bromo-3S-ethyl-5:5,5-1rifluoro-pentanoyl)-
oxazolidin-2-one dissolved in dimethylformamide (DMF -10 mL) was added sodium
azide (172 mg., 2.6 mmol). The solution was stirred for 72 h, diluted with water (20
mL), extracted into ethyl acetate (2 x 20 mL) and concentrated to give 3-(2-S-azido-3-
S-ethyl-5,5,5-trifluoro-pentanoyl)-4R-ben2yl-oxazolidin-2-one, identified by LCMS.
C. (2S, 3S)-2-Azido-3-ethyl-5,5,5-trlfluoro-pentanoicacid
3-(2-S-Azido-3^-ethyI-5,5,5-trifluoro-pentanoyl)-4-beiizyl-
oxazolidin-2-one was dissolved in a 2:1 mixture of THF and water (20 mL) at 0 °C
and lithium hydroxide mono hydrate (1.4 mmol, 60 mg) was added. The solution was
shaken for 1 h at 0 °C and then saturated sodium carbonate (20 mL) was added. The
mixture was extracted with ethyl acetate (20 mL), The aqueous phase was acidified

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with 2N hydrochloric acid and extracted with ethyl acetate (20 mL) to give (2S, 3S)-
2-azido-3-ethyl-5,5,5-trifluoro-pentanoic acid, identified by LCMS,
D. (2S, 3S)-2-Amino-3-ethyl-5,5,5~trifiuoro-pentan-l-ol
(2S,3S)-2-Azido-3-ethyl-5,5,5-trifiuoro-pentanoic acid was dissolved
in THF (5 mL) at 0 °C and lithium aluminum hydride (1 M solution in THF) (1 mL, 1
mmol) was added. The resulting solution was stirred at 40 °C for 2 h. The reaction
was quenched by sequential addition of water (60 μL), 15% aqueous sodium
hydroxide (60 μL), and water (150 μL) with vigorous stirring between each addition.
The mixture was men filtered and concentrated to give (2S, 3S)-2-amino-3-ethyl-
5,5,5-trifluoro-pentan-l-ol.
E. (2S, 3S)-2-(5-Chloro-3-methylbenzo[b]thiopkane-2-sulfonyl)-arnido-
5,5,5-trifluoro-3-ethyl-pentan-l-ol
To the solution of (2S, 3S)-2-amino-3-ethyl-5,5)5-trifluoro-pentan-l-
ol (0.1 mmol) in THF (2 mL) was added triethylamine (83.7 uL, 0.6 mmol) and 5-
chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (28 mg, 0.1 mmol). The
solution was stirred for 16 h and then concentrated The solvent was removed and the
residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative reverse
phase (RP)-HPLC using the conditions below.
Semi-preparative RP-HPLC conditions:
Column: the Phenomenex® Cl 8 Luna® 21.6 mm x 60 mm column, 5 μM
Solvent A: Water (0.02% TFA buffer)
Solvent B: Acetonitrile (0.02 % TFA buffer)
Solvent Gradient: Time 0: 10 % B; 2,5 min: 10 % B; 14 min: 90 % B.
Flow Rate: 22.5 mL/min
The product peak was collected based on UV absorption and
concentrated to give the title compound, 1.7 mg, HPLC retention time 2.97 min,
observed ion 428 (M-H).

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EXAMPLE 12
(2S,3R)-2-C5-Chloro-l,3-dimethyI-lH-pyrazole-4-sulfonyI)-amido-5,5,5-trifluoro-3-
pheny 1-pentan-1 -ol.
Following essentially the same procedure as Example 11 but using phenyl
magnesium bromide and 5-chloro-l,3-dimethylpyrazoIe-4-sulfonyl chloride, (2S,
3R)-2-(5-chloro-l,3-dimethy]-lH-pyrazols-4-sulfonyl)-amido-555,5-trifluoro-3-
phenyl-pentan-l-ol was prepared, 7.1 mg, HPLC retention time 2.25 min, observed
ion424(M-H).
EXAMPLE 13
Synthesis of Trifluoromethyl-ContairungHeterocyclic Sulfonamide
In one embodiment, the method outlined in Scheme 13 is performed using the
following exemplary reagents and conditions. However, one of skill in the art will
readily understand that certain reaction conditions, e.g., times, temperatures, catalysts,
and certain reagents may be modified.
With reference to Scheme 13, the aminoester XLVIII (250 g, 0.64 mol) was
suspended in toluene (4 L) and neutralized to pH 7-8 with 0.4 N NaOH (1.6 L). The
layers were separated and the. organic phase was washed with water (1.6 L) followed
by drying with Na2SO4 (250 g). The toluene solution was cooled to -68 °C to -62°C
and treated with 25% diisobutylaluminum hydride (DIBAL-H) in toluene (1278 raL,
1.9 mol, 3 eq.), keeping the temperature below-60 °C. The mixture was warmed to
room temperature and stirred for 1 hour. The reaction was quenched with 10%
aqueous NaOH (128 mL) followed by sodium citrate dihydrate (500 g) and anhydrous
sodium sulfate (385 g). After stirring for 1 hour, the solids were removed via
filtration and the solution concentrated to an oil. This was dissolved in diethyl ether
(2.6 L), cooled to 5 °C and treated with IN HC1 in ether (750 mL). After stirring for
30 minutes, the solids were collected via filtration, washed with ether and dried under
vacuum to give 189 g (85%) of a benzyl amine as a white solid. The benzyl amine
(150 g, 0.43 mol) in methanol (150 mL) was hydrogenated at 40 psi in the presence of
40gof 10%Pd/C catalyst. After 1.5 hours, the catalyst was removed via filtration
and the solution concentrated to a solid. The solid was triturated with ether/hexane,
collected via filtration and dried to give 94.8 g (90%) of an aminoalcohol as a solid.

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The aminoalcohol (100.2 g, 0.41 mol) in CH2C12 (1150 mL) was treated with
N,O-Bis(trimethylsilyl)acetarnide (BSA -110 mL, 0.45 mol) followed by
triethylamine (152.4 mL, 1.09 mol) and dimethylaminopyridine (DMAP -13 g).
After 15 minutes, a solution of sulfonylchloride (105.5 g, 0.49 mol) in CH2C12 (186
mL) was added and the mixture was allowed to stir at room temperature for 19 hours
(overnight). THF (450 mL) and 5% aq. HCl (800 mL) were added and the mixture
stirred for 1 hour. The layers were separated and the organic layer was washed with
5% NaHCO3 followed by water. The solution was concentrated to give an oil and
passed through a silica gel plug eluting with 30% EtOAc/hexanes. The fractions
containing product were concentrated under vacuo, which promoted crystallization.
Hexane was added and the solids collected via filtration to give 87.1 g (55%) of the
target compound as a white solid. Concentration of the mother liquors gave a second
crop of target compound, 12.6 g in 8% yield.
EXAMPLE 14
5-Chloro-N-[l-(4J4-difIuorocyclohexyl)-2-hydroxyethyl]thiophene-2-sulfonamide.

The amino(4,4-difluorocyclohexyl)acetic acid (2.68g, 10.973 mmol)
was dissolved in 2N NaOH (20 mL). The solution was cooled to 0°C, 5-
chlorothiophene-2-sulfonyl chloride (3.25g: 12.42 mmol) was added (5 min)
dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25°C
overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a
pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer was washed with
EtOAc (4x50 mL). The combined organic layers were dried over MgSO4 filtered, and

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concentrated to produce {[(5-chlorothien-2-yI)sulfonyI]amino}(4,4-
difluorocyclohexyl)acetic acid as a crude oil (3.8g, 98.2%).
Mass Spectrum (-ESI): 372 (M-H)
B. 5-Chloro-N-[1-(4J-dijluorocyclohexyl)-2-hydroxyeihyl]thiophene-2-
sulfonamide
To a slurry of LAH (0.406g, 10.70 rnmol) in THF (20 mL) was added
{[(5-chlorothien-2-yl)sulfonyl]amino}(4:4-difluorocyclohexyI)acetic acid (2.0g, 5.35
mmol) dropwise at 0°C over 20 min.
The reaction was heated to 70°C for 18 h. The reaction slurry (light
brown) was cooled to 0°C and the reaction was quenched with H2O (1.5 mL), lN
NaOH (4.5 mL) andH2O(1.5 mL). The reaction was stirred for 4 h to obtain a white
slurry. The slurry was filtered and the mother liquor was further dried over MgSO4:
filtered, and concentrated in vacuo to obtain a crude yellow oil (1.68g). The crude
product was purified by Biotage Flash™ 40 chromatography, eluent: 1:2 EtOAc-
hexanes, to afford 5-chloro-N-[l-(4,4-difluorocyclohexyl)-2-hydroxyethyl]thiophene-
2-suIfonamide as a white amorphous solid (0.15g, 7.8%).
Mass Spectrum (-ESI): 358 (M-H).
Anal: Calc'd for CI2H16ClNF2O3S2-0.17EtOAc C, 41.02; H, 4.49; N, 3.76.
Found: C, 40.63; H, 4.67; N, 3.74.
EXAMPLE 15

To a solution of amino(6,6-difluorobicyclo[3.1,0]hex-3~yl)acetic acid
(1.0 g, 5.23 mmol) in CH2Cl2:Me0H (4:1) was added dropwise TMSCHN2 (10.5 mL)
5-Chloro-N-[l-(6,6-difluorobicycio[3.1.0]hex-3-yI)-2-hydroxyethyl]thiophene-2-

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over 10 min at 0° C until a neon yellow color persisted, The reaction mixture was
allowed to warm to 25°C over 19h. The solvent was removed in vacuo to obtain
methyl amino(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate as a light yellow oil (0.9g,
84.1 ]%). Mass Spectrum(-ESI): 206 (M+H)+.
B. Methyl {[(5-chlorothien-2-yl)sulfonyl]amino}(6,6-
difluorobicyclo[3.1.0]hex-3-yl)acetate
5-Chlorothiophene~2-sulfonyl chloride (1.26 g, 4.82 mmol) was added
dropwise (5 min) as a solution inCH2Cl2 (10mL) to a0°C solution of methyl
amino(6;6-difluorobicycIo[3.1.0]hex-3-yl)acetate (0.9g, 4.38 mmol) in CH2C12 (10
mL) and triethylamine (1.22 mL, 8.77 mmol). The solution was allowed to warm to
25°C overnight (19 h). An aliquot was taken and TLC (1:4 EtOAc-hexane) indicated
that the reaction was complete. It was diluted in CH2C12 (100 mL) and the organic
layer was washed with 1N HC1 (20 mL) and saturated aqueous NaCl (20 mL), The
organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude off-
yellow solid (L69g). The crude product was purified by the Biotags Flash™ 40
chromatography instrument, eluent: 1:4 EtOAc-hexanes, to afford methyl {[(5-
crdorothien-2-yl)sulfonyl]arnino}(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate as a
colorless oil (0.230g, 12.23%). Mass Spectrum (-ESI): 384 (M+H)+.
C. 5-Chbro-N-[l-(6,6-difiuorobicyclo[3.1.0]hex-3-yl)-2-
hydroxyethyl]thiophene~2-sulfonamide
To a slurry of LAH (0.030g; 0.78 mmol) in THF (5 mL) was added
methyl {[(5-chlorothien-2-yI)sulfonyI]amino}(6,6-difluorobicyclo[3.1.0]hex-3-
yl)acetate (0.154g, 0.38 mmol) dropwise at 0°C over 20 min. The slurry (gray) was
allowed to warm to 25 °C over 19h. The reaction slurry was cooled to 0°C and the
reaction was quenched with H2O (0.5 mL), IN NaOH (1.5 mL) andH2O (0.5 mL).
The reaction was stirred 4 h to obtain a white slurry, The slurry was filtered and the
mother liquor was further dried over MgSO4, filtered, and concentrated in vacuo to
obtain a crude yellow oil (0.162g). The crude product was purified by the Biotage
Flash™ 40 chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-
[l-(6,6-difluorobicycIo[3.1.0]hex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamideas a
colorless oil (0.105g, 77.77%).
Mass Spectrum (-ES1): 356 (M-H).

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Anal: Calc'd for C13H14ClNF2O4S2-O.20 Et.OAc C, 41.41; H, 3.84; N, 3.56.
Found: C, 41.08; H, 3.90; N, 3.47.

methyl butyl] thiophene-2-sulfon amide (prepared as in Example 1, 3.0g, 8.53 mmol) in
CH2C12 saturated with water (30 mL) was stirred under nitrogen at 0°C. D ess-Martin
periodinane reagent (7.59 g, 17.90 mmol) was added in one portion. The resulting
suspension was stirred at 25 °C, monitoring the progress of reaction by TLC analysis
(1:2 EtOAc/hexane). As the rate of conversion of the starting material slowed,
additional 2 mL portions of CH2CI2 saturated with water were added (three portions
over 15 min). After 19h at 25 °C, the reaction was complete by TLC. The solution was
diluted with Et20 (50 mL) and a solution of sodium thiosulfate, Na2S2O3 (93.83
mmol, 14.Sg, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (50 mL)
was added. The mixture was stirred rapidly for 10 min until both phases were clear.
The Layers were separated and the aqueous phase was extracted with ether (30 mL).
The combined organic layers were washed sequentially with saturated aqueous
sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and
concentrated to obtain a crude oil (2.67g). The crude product was purified by the
Biotage Flash™ 60 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-
chloro-N-[(lS,2R)-4,4,4-trifluoro-l-formyl-2-methyIbutyl]thiophene-2-sulfonamide
as a colorless oil (2.65g, 88.93%).
Mass Spectrum (+ESI): 350 (M+H)+.
Anal: Calc'dfor CI0H11ClNF3O3S2-0.35 H2O C, 33.34; H, 2.83; N, 3,87.
Found: C, 33.74; H, 3.31, N, 3.93.

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methylbutyl]thiophene-2 -sulfonamide
A solution of 5-chloro-N-[(lS:2R)-4,4,4-trifluoro-l-formyl-2-
methylbutyl]thiophene-2-sulfonamide (prepared as in Example 16, 1.0 g, 2.86 mmol)
inTHF (10 mL) was stirred under nitrogen at 0°C. Methyl magnesium bromide (3.0
M in ethyl ether, 1.9 mL, 5.71 rnmoL) was added dropwise and the resulting solution
was stirred for 1 h at 25 °C. After this time period, the reaction was complete by TLC
(l:2EtOAc/hexane). The solution was quenched with saturated aqueous NH4CI (10
mL) and extracted with ether (40 mL). The organic layer was washed with brine (20
mL) and then dried over MgSO4 to obtain a crude oil (0.867 g). The crude product
was purified by the Biotage Flash™ 60 chromatography system, eluent: 1:6 EtOAc-
hexanes, to afford S-chloro-N-[(1S,2R)-4,4,4-trifluoro-l-(l-hydroxyethyl)-2-methyl
butyl]thiophene-2-sulfonamide as a colorless oil (0.495 g, 49.5%). Mass Spectrum (-
ESI):364(M-H).
B. N-[(lS,2R)-l-acetyl-4,4,4-trifluoro-2-methylbutyl]-5-chlorothiophene-
2-sulfonamide
A solution of S-chloro-N-[(1S,2R)-4,4,4-trifluoro-l-(l-hydroxyethyl)-
2-methylburyl]thiophene-2-sulfonamide (0.390 g, 1.06 mmol) in CH2C12 saturated
with water (30 mL) was stirred under nitrogen at 0°C. Dess-Martin periodinane
reagent (0.95g, 2.23 mmol) was added in one portion. The resulting suspension was
stirred at 25 °C, monitoring the progress of reaction by TLC analysis (1:2
EtOAc/hexane). As the rate of conversion of the starting material slowed, additional 1
mL portions of CH2Cl2 saturated with water were added (three portions over 15 min).

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After 19 h at 25 °C, the reaction was complete by TLC. The solution was diluted with
Et2O(50mL) and a solution of sodium thiosulfate, Na2S2O3 (11.83 mmoL 4.8g, 11
eq) in 80% saturated aqueous sodium bicarbonate solution (40 mL) was added. The
mixture was stirred rapidly for 10 min until both phases were clear. The layers were
separated and the aqueous phase was extracted with ether (20 mL). The combined
organic layers were washed sequentially with saturated aqueous sodium bicarbonate
(10 mL) and brine (15 mL), then dried over MgSO4j filtered and concentrated to
obtain a crude oil (0.38 g). The crude product was purified by the Biotage Flash™ 40
chromatography system, eluent: 1:6 EtOAc-hexanes, to afford N-[(lS.2R)-l-acetyl-
4,4,4-trif]uoro-2-methylbutyl]-5-chlorothiophene-2-sulfonamide as a white solid
(0.265g, 73.10%).
Mass Spectrum (-ESI): 362 (M-H);
Anal: Calc'd for C11H13CINF3O3S2 C, 36.32; H, 3.6; N, 3.85.
Found; C5 36.08; H, 3.2; N, 3.74.
EXAMPLE 18
5-Chloro-N-[(lS,2R)-4,4,4-trifluoro-l- methylbutyI]thiophane-2-sulfonamide.

A solution of N-[(lS,2R)-l-aceryl-4,4,4-trifluoro-2-methyIbutyl]-5-
chlorothiophene-2-sulfonamide (prepared as in Example 17, 0.100 g, 0.275 mmol) in
THF (5 mL) was stirred under nitrogen at 0°C. Methyl magnesium bromide (3.0 M in
ethyl ether, 0.266 mL, 0.824 mmoL) was added drop wise and the resulting solution
was stirred for 19 h at 25 °C. After this time period, the reaction was complete by TLC
(1:2 EtOAc/hexane). The solution was quenched with saturated aqueous NH4CI (10
mL) and extracted with ether (40 mL). The organic layer was washed with brine (20

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mL) and then dried over MgSO4 to obtain a crude oil (0.110 g). The crude product
was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:4 EtOAc-
hexanes, to afford 5-chloro-N-[(lS,2R)-4,4,4-tiifluoro-l-(l-hydroxy-l-rnethyIethyl)2-
raethylbutyl]thiophene-2-sulfonamide as a white solid (0.049 g, 46.6 %).
Mass Spectrum (-ESI): 378 (M-H).
Anal: Calc'd for CI2H17CINF3O3S2 C, 37.94; H, 4.51; N, 3.69.
Found: C, 37.45; H, 4.03; N, 3.68.
EXAMPLE 19
4-Bromo-5-chloro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluororaethyl)propyl]thiophene-2-suIfonamide.

A. Methyl 4,4,4,4 ',4 ',4'-hexafluoro-dl-valinate
A solution of 4,4,4,4',4',4'-hexafluoro-dl-valine (1.1 g, 4.88 mmol) in
CH2Cl2-Me0H (4:1, 25 mL) was stirred under nitrogen at 0°C. TMS-diazomethane
(2.0 M in hexane, 20 mL, 19.55 mL) was added dropwise and the resulting neon
greenish solution stirred for 19 h at 25°C. After this time period, the reaction was
complete by TLC (10% MeOH in chloroform). After concentration, the resulting
residue of methyl 4,4,4,4',4',4'-hexafluoro-dl-valinate (1.1 g) was used directly in the
next step without further purification. Mass Spectrum (-ESI): 238 (M-H).
B. Methyl N-[(4-bro?no-5~chlorothien-2-yl)sulfonyl]~4,4,4,4 ',4 ',4'-
hsxafluoro-dl-valinate
A solution of methyl 4,4,4,43,4',4'-hexafluorovalinate (1.0 g, 4.18
rnmol) in CH2C12 (10 mL) was stirred under N2 atmosphere at 25°C. Pyridine (0.81
mL, 10.04 mmol) was added dropwise followed by 4-bromo-5-chlorothiophene-2-
sulfonyl chloride (1.486 g, 5.05 mmol) in one portion and the resulting solution stirred

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for 19 h at 25°C. After this time period, the reaction was complete by TLC (1:4
EtOAc-hexane). After quenching with water (1.0 mL), the mixture was diluted with
CH2Cl2 (30 mL). The organic layer was washed sequentially with IN aqueous HC1
(10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over
MgSO4, filtered and concentrated to obtain a crude oil (2.1 g). The crude product was
purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-
hexanes, to afford methyl N-[(4-bromo-5~chloro-thien-2-yl)sulfonyl]-4,4,4,4',4',4'-
hexafluoro-dl-valinateas a white solid (1.62 g, 83.07%). Mass Spectrum (-ESI): 497
(M-H).
C. 4-Bromo-5-ch!oro-N-[3,3,3-trifluoro-l-{hydroxymethyl)-2-
(trijluoromethyl)propyljth iophene-2-sulfonam ide
To a solution of methyl N-[(4-bromo-5-chloro thien-2-yl)suIfonyl] -
4,4,4,4',4',4'-hexafluorovalinate (1,45 g, 2.907 mmol) in THF (20 mL) was added
. lithium borohydride (LiBH4) (5.82 mL, 11.64 mmol) under N2 atmosphere at 0°C.
The reaction was allowed to warm to 25°C for 19 h. The reaction was cooled to 0°C,
quenched with 2N HC1 (slow addition), diluted in ether (40 mL) and the organic layer
was washed sequentially with IN aqueous HC1 (10 mL), saturated aqueous NaHCO3
(10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to
obtain a crude oil (1.3 g). The crude product was purified by the Biotage Flash™ 40
chromatography system, eluent; 1:6 EtOAc-hexanes, to afford 4-bromo-5-chloro-N-
[3,3,3-trifluoro-l-(hydroxymethyl)-2-(trifluoromethyl)propyl]thioph3ne-2-
sulfonamide as a white solid (1.13 g, 84.32%).
Mass Spectrum (-ESI): 469 (M-H).
Anal: Calc'd for C9H7ClBrNF6O3S2 C, 22.97; H, 1.50; N, 2.98.
Found: C, 23.11;H, 1.16;N, 2.78.

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EXAMPLE 20
4-Bromo-5-chloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyI)propyl]miophene-2-sulfonarnide

4-Bromo-5-chlorothiophene-2-sulfonyI chloride (0.193 g, 0.654 mmol) was
added dropwise (5 min) as a soiution in CH2Cl2 (1.0 mL) to a 0° C solution of (2S)-2-
amino-3,3,3-trifluoro-3-(trifluoromethyl)butan-l-oI (prepared according to the
method of Example 13, 0.115 g, 0.548 mmol) inCH2CI2(l0 mL) and pyridine (0.9
mL, 1.09 mmol). The solution was allowed to warm to 25°C overnight (19 h). An
aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete.
The reaction mixture was diluted with CH2Cl2 (100 mL) and the organic layer was
washed with IN HC1 (2x50 mL) and saturated aqueous NaCI (50 mL), dried over
MgSO4, filtered, and concentrated to obtain a crude off-white solid (0.270 g). The
crude product was purified by the Biotage Flash™ 40 chromatography system, eluent:
1:6 EtOAc-hexanes, to afford 4-bromo-5-crdoro-N-[(lS)-3,3,3-trifluoro-l-
(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid
(39 mg, 15.11 %). Mass Spectrum (-ESI): 469 (M-H).

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EXAMPLE 21
5-Chloro4-fluoro-N-[3,3,3-trifluoro-l-(hydroxymethyI)-2-
(trif]uoromethyl)propyl]thiophene-2-sulfonamide

A. 5-thloro-N-[3,3,3-trlfluoro-l-(hydroxymemyl)-2-
(trifluoromethyl)propyi]thwphene-4-(tributylstannyl)-2-sulfonamide
Bis(tributyltin) (0.939 g, 2.87 mmol) and tetrakis(triphenyl
phosphine)palladium (0) (0.22 Ig, 0.191 mmol) were added to asolution of 4-bromo-
5-chloro-N-[3,3,3-trifluoro-l-(hydroxymethyI)-2-(trifluoromethyl) propyl]thiophene-
2-sulfonamide (prepared as in Example 19, 0.9 g, 1.91 mmol) in l,4-dioxane(42 mL).
The brown solution was heated to reflux overnight (19h). An aliquot was taken and
TLC (1:1 EtOAc-hexane) indicated that reaction was complete. The slurry was then
filtered and the solvent removed in vacuo to obtain a yellow-oil (1.31 g). The crude
product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6
EtOAc-hexanes, to afford 5-chloro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
({rifluoromethyl)propyl]thiophene-4-(tributylstannyl)-2-su]fonamide as a white solid
(0.220 g, 18.86 %). Mass Spectrum (-ESI): 554 (M-H)
B. 5-Chloro-4-fluoro-N-[3,3,3-ti-ifluoro-l-fnydroxymethyl)-2-
(trifiuoromethyl)propyl]thiophene-2-sulfonamide
A solution of S-chloro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-4-(tributylstannyl)-2-SuIfonamide (0.220 g, 0.396
mmol) in dry acetonitrile(10 mL) was stirred under nitrogen at 25°C. The
Selectfluor© reagent (0.147g, 0.416 mmol) was added in one portion and the solution
Stirred for 19 h at 25°C. After 3h,a white precipitate began to appear. After 19 h, an
aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was not
complete. Mainly, starting material was present. The reaction was heated to 80°C for

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6 h. An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The slurry was then filtered and the solvent removed in vacuo to obtain a
yellow oil (0.1 lg). The crude product was purified by prep RP-HPLC (the
Primesphere™ 2x25 cm column, eluent: 55% MeCN in 0.01% aqueous trifluoroacetic
acid (TFA), flow rate=25 mL/min, Rt, 4.401 min) to obtain 5-chloro 4-fluoro-N-
[3,3,3-triiluoro-l-(hydroxymetliyl)-2-(trifluoromethyl)propyl]thiophene-2-
sulfonamide as an amorphous white solid (0.004g, 24.69 %). Mass Spectrum (-ESI):
408 (M-H).
EXAMPLE 22
5-Bromo-N-[3,3,3-trifluoro-l-(hydro>:ymethyl)-2-(txifluoromethyI)propyl3thiophene-

A. Ethyl N-[(5-bromothien-2-yl)sulfonyl]-4,4,4,4',4',4'-hexafiuoro-dl-
valinate
A solution of ethyl 4,4,4,4',4',4'-hexafluoro-dl-valinate (1.64 g, 6.48
mmol), prepared as described (J. Med Chera 1981,24, 1043-1047), in CH2Cl2 (10
mL) was stirred under N2 atmosphere at 25°C. Pyridine (0.81 mL, 10.04 rnmol) was
added dropwise followed by 5-bromothiophene-2-sulfonyl chloride (2.034 g. 7.77
mmol) in one portion and the resulting solution stirred for 19 h at 25°C. After this
time period, the reaction was complete by TLC (1:4 EtOAc-hexane). After quenching
with water (2.0 mL), the mixture was diluted with CH2C12 (40 mL), The organic layer
was washed sequentially with IN aqueous HCI (20 mL), saturated aqueous NaHCO3
(20 mL) and brine (15 mL), dried over MgSO4, filtered, and concentrated to obtain a
crude oil (3.3 g). The crude product was purified by the Biotage Flash™ 40

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chromatography system, eluenf. 1:6 EtOAc-bexanes, to afford ethyl N-[(5-
bromothien-2-yl)su]fonyI]-4,4,4,4',4',4'-he:xafluoro-dl-valinate as a white solid (2.40
g, 80.0 %). Mass Spectrum (-ESI): 477 (M-H)
B. 5-Bromo-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trijluoromethyl)propyl]thiophene-2sulfonamide
To a solution of ethyl N-[(5-bromo-thien-2-yl)sulfonyl]-4,4,4,4',4',4'-
hexafluorovalinate (2.4 g, 5.02 mmol) in THF (20 mL) was added LiBH4 (20 mL,
20.07 mmol) under N2 atmosphere at 0°C. The reaction was allowed to warm to 25°C
for 19 h. The reaction was cooled to 0°C and quenched with 2N HC1 (slow addition),
diluted in ether (50 mL) and the organic layer was washed sequentially with lN
aqueous. HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then
dried over MgSO4 filtered and concentrated to obtain a crude oil (2.31 g). The crude
product was purified by the Biotage Flash™ 40 chromatography system, eluenf. 1:6
EtOAc-hexanes, to afford S-bromo-N-[3,3,3-tiifluoro-l-Chydroxymethyl)-2-
(trifluoromethyI)propyl]thiophene-2-sulfonamide as a white solid (1.3 g, 59.63 %).
Mass Spectrum (-ESI): 435 (M-H).
Anal: Calc'd for C9H8BrNF6O3S2 C, 24.78;H, 1.85;N, 3.21.
Found: C, 24.74; H, 1.32; N, 3.11.

A. N-[3,3,3-TrijJuoro-l-(hydroxymethyl)-2-
(nijluorome thyl)propyl]th iophene-5-(tribu tylstannyl)-2-sulfonamide
Bis(tributyltin) (1.36 g,4.13 mmol) and tetrakisftriphenyl
phosphine)palladium (0) (0.32g, 0.275 mmol) were added to asolution of 5-bromo-N-

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[3,3,3-trifluoro-l-(hydroxymethyl)-2-(trifluoromethyI) propyl]thiophene-2-
sulfonamide (prepared as in Example 22, 1.2 g, 2.75 mmol) in 1,4-dioxane (40 mL).
The brown solution was heated to reflux overnight (19h). An aliquot was taken and
TLC (1:2 EtOAc-hexane) indicated that reaction was complete. The slurry was then
filtered and the solvent removed in vacuo to obtain a yellow-oil (1.4 g). The crude
product was purified by the Biotage Flash™ 40 chromatography system, eluent; 1:6
EtOAc-hexanes, to afford N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-5-(tributyIstannyI)-2-sulfonamide as a white solid
(0.400 g, 27.97 %). Mass Spectrum (-ESI): 520 (M-H).
B. 5-Fluoro-N-[-3,3,3-trifiuoro-l-(hydroxymethyl)-2-
(fiifluoromethyl)propyl]thiophene-2-sulfonamide
A solution of N-fS^^-trifluoro-l-fhydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-5-(tributyl stannyl)-2-sulfonamide (0.400 g, 0.76
mmol) in dry acetonitrile (10 mL) was stirred under nitrogen at 25°C. The
Selectfluor® reagent (0.285g, 0.806 mmol) was added in one portion and the solution
stirred for 19 h at 25°C. After 3 h, a white precipitate began to appear. After 19 h, an
aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was not
complete. Mainly, starting material was present. The reaction was heated to 80°C for
6 h. An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The slurry was then flllered and the solvent removed in vacuo to obtain a
yellow oil (0.191g). The crude product was purified by the Biotage Flash™ 40
chromatography system, eluent; 1:6 EtOAc-hexanes, to obtain 5-fluoro-N-[3,3,3-
trifluoro-1 -(hydroxyrnethyl)-2-(trifluorornethyl)propyl]thiophene-2-sulfonamide as an
amorphous white solid (O.OlOg, 34.72 %). Mass Spectrum (-ESI): 374 (M-H).

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dropwise (5 min) as a solution in CH2C12 (1.0 mL) to a 0° C solution of (2S)-2-amino-
4,4,4-trif]uoro-3-(trifluoromethyl)butan-l-ol (0.100 g, 0.474 mmol) in CH2C12 (10
mL) and pyridine (0.1 mL, 0.95 mmol). Tbe solution was allowed to warm to 25°C
overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that
reaction was complete. It was diluted with CH2Cl2 (10 mL) and the organic layer was
washed with IN HC1 (2x10 mL), saturated aqueous NaCI (10 mL). The organic layer
was dried over MgSO4, filtered and concentrated to obtain a crude off white solid
(0.120 g). The crude product was recrystallized from CH2Cl2:hexane (1:7) to afford 5-
bromo-N-[(lS)-3,3,3-tnfluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white fluffy solid (0.0541g,
27.05 %). Mass Spectrum (-ESI): 435 (M-H).



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A. N-[(lS)-3,3,3-Trifluoro-1 -(hydroxymethyl)-2-
(trijluoromsthyl)propyl]thiophene-5-(tributyls tannyi)-2-sulfonamide
Bis(tributyltin) (1.36 g, 4.13 mmol) and tetrakis(triphenyl
phosphine)palladium (0) (0.32g, 0.275 mmol) were added to a solution of 5-bromo-N-
[(lS)-3,3,3-trifluoro-l-(hydroxymethyI)-2-(trifluoromethyl)propyI]thiophene-2-
sulfonamide (prepared as in Example 243 1.1 g, 2.52 mmol) in 1,4-dioxane (40 mL).
The brown solution was heated to reflux overnight (19h). An aliquot was taken and
TLC (1:2 EtOAc-hexane) indicated that reaction was complete. The slurry was then
filtered and the solvent removed in vacuo to obtain a yellow-oil (1.05 g). The crude
product was purified by the Biotage Flash 40 chromatography system, eluent: 1:6
EtOAc-hexanes, to afford N-[(lS)-3,3,3-trifIuoro-l-(hydroxymethyl)-2-
(trifluoromethyl) propyl] thiophene-5-(tributyIstannyl)-2-sulfonamide as a white solid
(0,350 g, 26.7 %). Mass Spectrum (-ESI): 520 (M-H)B. 5-Fluoro-N-[(lS)-3,3,3-trijluoro-l -(hydroxymethyl)-2-
(tnjl uorometkyl)propyl]thiophene-2 sulfonamide
A solution of N-[(lS>333>trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-5-(tributyl stannyl)-2-sulfonamide (0.400 g, 0.76
mmol) in dry acetonitrile (10 mL) was stirred under nitrogen at 25°C. The
Selectfluor® reagent (0.285g, 0.806 mmol) was added in one portion and the solution
stirred for 19 h at 25°C. After 3 h, a white precipitate began to appear. After 19 h, an
aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was not
complete. Mainly, starting material was present. The reaction was heated to 80°C for
6 h. An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was
complete. The slurry was then filtered and the solvent removed in vacuo to obtain a
yellow-oil (0,078g). The crude product was purified by the Biotage Flash™ 40
chromatDgraphy system, eluent: 1:6 EtOAc-hexanes, to obtain 5-fluoro-N-[(lS)-3,3,3-
trifluoro-l-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamideas an
amorphous white solid (0.0061g, 2.8%).
Mass Spectrum (-ESI): 374 (M-H)".

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To a solution of l-iodo-3,3,3-trifluoropropans (19,3 g, 86.1 mmol) in
toluene (50 mL) at 23 °C was added triphenylphosphine (25.8 g, 98.5 mmol). The
reaction mixture was warmed to reflux and stirred for 28 h. The resulting mixture
was cooled to 0°C in an ice bath and filtered to collect the white solid product. The
product was washed with toluene (3x) and air-dried to afford the pure product as
white solid (33.4 g, 80%).
B. 4,4,4-Trijluoro-2-(triphenyl-l5-phosphanylidene)-butyric acid ethyl
ester
To a suspension of (3,3,3-trifluoropropyI)-triphenylphosphonium
iodide (23.5 g, 48.4 mmol) in THF (100 mL) at - 78°C was added slowly a solution of
potassium bis (tri methyl si lyl) amide (0.5 M in toluene, 175 mL) through an addition
funnel under nitrogen. The resulting mixture was stirred at - 780C for 45 min
followed by dropwise addition of ethylchloroformate (neat, 5.0 mL). The reaction
mixture was then allowed to warm up to -200C over 3 h while stirring. The reaction
was then quenched by pouring into brine (100 mL) and extracted with ethyl acetate
(100 mL x 2). The organic extract was dried (Na2SO4) and concentrated under
reduced pressure. Flash chromatography with ethyl acetate-hexane (0-100%) through
a silica gel column (120 g) afforded the product as light yellow solid.
Re crystallization of this material with Et2O afforded the pure product as white solid
(6.7 g, 32%). Mass Spectrum (+ESI): 431 [M+H]+

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C. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic acid ethyl ester
To a solution of 4,4,4-trifluoro-2-(triphenyl-λs-phosphanylidene)-
butyric acid ethyl ester (2.0 g, 4.65 mrnol) in THF (5 mL) was added 1 mL of
trifluoroacetaldehyde hydrate (tech.). The mixture was sealed in a pressure tube and
heated at 100°C for 3.5 h. After cooling to 23 °C, the reaction mixture was eluted
through a pad of silica gel (100 g) andNa2SO4 withEt2O (100 mL) to remove the by-
products triphenylphosphine oxide and water. The eluent was distilled to remove Et2O
and to afford the product as a colorless liquid (1.0 g, 86%).
D. 4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-butyric acid ethyl ester
4,4,4-Trifluoro-2-(2,232-trifluoroethyl)-but-2-enoic acid ethyl ester (5.0
g, 20.0 mmol) in THF (20 mL) was treated with Pd/C (2.5 g, 5%), and H2 (1 atm.) at
25°C for 17 h. The reaction mixture was filtered through a pad of the Celite® reagent,
rinsed with Et2O (50 mL) and the filtrate was distilled to remove Et2O and THF to
afford the product as colorless liquid (5.0 g, 99%).
E. 4,4,4-Tnfluoro-2-(2,2,2-trifluoroethyl)-butan-l-ol
To a suspension of LAH (1.0 g) in Et2O (100 mL) at 25°C was added
slowly 4,4,4-tritluoro-2-(2,2,2-triiluoroethyl)-butyric acid ethyl ester (5.0 g, 19.8
mmol). The resulting mixture was stirred at reflux for 4 h. The cooled reaction
mixture was quenched sequentially with water (1.0 mL), 15% NaOH in water (1.0
mL) and water (3.0 mL). After the resulting mixture was allowed to stir at 25°C for
17 h, Na2SO4 (20 g) was added and stirring at 25°C continued for 1 h. The resulting
suspension was filtered through a pad of the CeliteS reagent and Na2SO4. The filtrate
was distilled to remove all solvents to afford the desired product as a colorless liquid
(1.7 g, 41%). Mass Spectrum (-ESI): 269 [M+OAc]
F. 4,4,4-Trifluoro-2-(2,2,2-trifluoro-ethyl)-bulyraldehyde
A solution of 4,4,4-trifluoro- 2-(2,2,2-trifluoroethyl)butan-l-oI (1.5 g,
7.14 mmol) in CH2C12 saturated with water (30 mL) was stirred under nitrogen at 0°C.
Dess-Martin periodinane reagent (6.35g, 14.99 mmol) was added in one portion. The
resulting suspension was stirred at 25 °C, monitoring the progress of reaction by TLC
analysis (1:2 EtOAc/hexane). As the rate of conversion of the starting material
slowed, additional 2 mL portions of CH2Cl2 saturated with water were added (three
portions over 15 min). After 19 h at 25 °C, the reaction was complete by TLC. The

WO 2004/092155 PCT/US2004/009268
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solution was diluted with Et2O (50 mL) and a solution of sodium thiosulfate, Na2S2O3
(73,33 mmoL 11.6g, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (50
mL) was added. The mixture was stirred rapidly for 10 min until both phases were
clear. The layers were separated and the aqueous phase was extracted with ether (30
mL). The combined organic layers were washed sequentially with saturated aqueous
sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and
concentrated to 50 % of its original volume to give 4,4,4-trifl.iioro-2-(2,2J2-trifluoro-
ethyl)-butyraldehyde as a solution (20 mL). Mass Spectrum (+ESI): (M+H)+.
G. 5~(3,3,3-Trifluoro-l-(2,2,2-triJluoroethyl)propyl)imidazolidine-2,4-
dione
To sodium cyanide (0.425 g, 8.65 mmol) and ammonium carbonate
(0.9 g, 11.54 mmol) in H2O (30 mL) was added 4,4)4-trifluoro-2-(2,2,2-
trifluoroethyl)butyraldehyde (0.6 g, 2.88 mmol) in ethanol (30 mL). The black
reaction mixture was heated to 90°C. After 1 h, the mixture became homogeneous and
was stirred at90°C for 18 h. After cooling to 25°C, about 40 mL of solvent was
removed in vacuo. Concentrated HC1 (4 mL) was added to acidify the mixture to pH
1-2 and a precipitate formed. It was filtered. The mother liquor was washed with
EtOAc (3x50 mL). The organic layer was dried over MgSO4, filtered and
concentrated to obtain 5-(3,3,3-trifluoro-l-(2,2,2-trifluoroethyl)propyl) imidazolidine-
2,4-dione as a brown oil (l.Olg, 100 %). Mass Spectrum (+ESI): 279, 280 (M+H)+.
H. 5,5,5-Trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline
5-(3,3,3-Trifluoro-l-(2,2,2-trifluoroethyl)propyl)imida2oIidine-2,4-
dione (1.0 g, 3.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.575
g in 10 mL H2O, 14.38 mmol). The solution was divided in 2 special vessels for
microwave technology. The solution was heated by microwave in sealed vessels for 1
h. Microwave conditions: 15 min at about 100 % power, 150°C, 50 psi, thsn 5 min at
rest, 0 % power. The sequence was repeated until the reaction was done. Water and
ammonia were removed from the reaction mixture in vacuo and the resulting crude
5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dI-norvaline (0.92 g, 100 %) and NaOH
mixture was used in the next reaction without further purification.
Mass Spectrum (+ESI): 254 (M+H)+.

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I. N-[(5-ChIorotkien-2-y!)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-
trifluoroelhyl) -dl-norvaline
The crude 5,5,5-trifluoro-3-(2)2,2-trifluoroethyl)-dI-norvaIine (0,92 g,
3.56 mmol) and NaOH mixture was dissolved in water (10 ml). The mixture was
cooled to 0°C in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (0.852 g, 3.9
mmol) was dissolved in THF (10 mL) and added dropwise to the reaction mixture
over 10 min. After 60 min, the reaction mixture was allowed to warm gradually to
25°C and stirred for 16 h. THF was removed in vacuo and the mixture was acidified
to pH white mixture. After 60 min, the mixture was cooled in a refrigerator for 45 min and
then filtered. The precipitate was washed with IN HCI (10 mL) to provide a white
solid which gummed out. It was dissolved in EtOAc (100 mL). The aqueous layer was
washed with EtOAc (3x50 mL) and the organic layers were washed with saturated
aqueous NaCl (50 mL). The organic layer was dried over MgSO4 filtered and
concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-
trifluoroethyl)-dl-norvaline as a brown oil (1.3 g, 86.3 %).
Mass Spectmm (+ESI): 434 (M+H)+.
J. Methyl N-[(5-chlorothien-2~yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-
trifluoroethyl)-dl-norvalinate
To a solution of N-[(5-chlorotliien-2-yl)sulfonyl]-5,5,5-trifluoro-3-
(2,2,2-trifluoroethyI)-dl-norvaline (1.3 g, 5.23 mmol) in CH2Cl2:Me0H (4:1)
TMSCHN2 (6 mL, 12 mmol) was added dropwise over 10 min at 0°C until a neon
yellow color persisted. When the dropwise addition was completed, the reaction
mixture was allowed to warm to 25°C over 19h. The solvent was removed in vacuo to
obtain methyl N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-
dl-norvalinate (0.5g, 37.31 %). Mass Spectrum (-ESI): 445 (M-H)".
K. 5-Chloro-N-[4,4,4-trifluoro-l -(hydroxymethyl)-2-(2,2,2-
trifluoroethyl)butyl]thiophene-2-sulfonamide
To a solution of methyl N-[(5-chlorothien-2-yl)sulfonyl]-5t5,5-
trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvalinate(0.5 g, 1.11 mmol) in THF (10 mL)
was added L1BH4 (2.28 mL, 4,46 mmol) under N2 atmosphere at 00C. The reaction
was allowed to warm to 25°C for 19 h. The reaction was cooled to 0°C and quenched

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with 2N HC1 (slow addition), diluted in ether (40 mL) and the organic layer was
washed sequentially with IN aqueous HC1 (10 mL), saturated aqueous NaHCO3 (10
mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a
crude oil (0.362 g). The crude product was purified by the Biotage Flash™ 12
chromatography system, eluent: l:6EtOAc-hexanes, to afford 5-chloro-N-[4,4,4-
trifluoro-l-(hydroxyrnethyl)-2-(2)2,2-trifluoroethyl)butyl]tniophene-2-sulfonamideas
a colorless oil (0.001 g, 2.36 %). Mass Spectrum (-ESI): 418 (M-H).

trifluoroe thy!) b u tylidenejbenzenesulfina m ide
To the crude organic extract of 4,4,4-trifluoro-2-(2,2,2-
trifluoroethyl)butyraldehyde (prepared as in Example 26, part F, 0.6 g, 2.88 mmol) in
ether (5 mL) was added titanium (FV) ethoxide (2.63 g, 11.54 mmol) followed by (S)-
(+)-toluene sulfmamide (0.537 g, 3.46 mmol) and the solution was heated to reflux for
5 h. The mixture was then cooled to 0°C and water (35 mL) was added to precipitate
titanium salts. The suspension was filtered through a pad of the Celite® reagent and
the filter cake was washed with CH2Cl2. The layers of the filtrate were separated and
the aqueous layer was extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (1.05 g).
The crude product was purified by the Biotage Flash™ 40 chromatography system,
eluent: 1:9 EtOAc-hexanes, to afford 4-methyI-N-[(lZ)-4,4,4-trifluoro-2-(2,2,2-
trifluoroethyl)butylidene]benzenesulfinamideas a yellow oil (0.41g, 41.2 %). Mass
Spectrum (-ESI): 344 (M-H).

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B. 4-MethyI-N-[(lS)-4,4,4-trifluoro-l-isocycmo-2-(2,2,2-
trifiuoroethyl) butyljbenzenesulfmimide
To diemyl aluminum cyanide (0.223 mL, 1.73 mmol) in THF (10 ml.)
at 0°C was added isopropyl alcohol (76 mg, 1.27 mmol). After 15 min, this solution
was added to a-78°C solution of 4-methyl-N-[(lZ)-4,4,4-trifiuoro-2-(2,2,2-
trifluoroethyl)butylidene]benzene sulfonamide (0.4g, 1.158 mmol) in THF (10 mL).
After 15 min, the reaction mixture was warmed to 25°C, After 5h, TLC (1:4 EtOAc-
hexane) indicated consumption of starting material. The mixture was cooled to -78°C
and saturated aqueous NH4CI (30 mL) was added. The resulting suspension was
filtered through a pad of the Celite® reagent and the filter pad was washed with
EtOAc (2x50 mL). The layers of the filtrate were separated and the aqueous layer
was extracted with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated to obtain a crude oil (0.360 g).
The crude product was purified by the Biotage Flash™ 40
chromatography system, eluent; 1:6 EtOAc-hexane, to afford 4-methyl-N-[(lS)-4,4,4-
tnfiuoro-l-isocyano-2-(2J2,2-trifluoroethyl)butyI]benzenesulfinimide as a colorless
oil(0.065g, 15.18%). Mass Spectrum (-ESI): 371 (M-H);
C. 5,5,5-Trifluoro-3-(2,2,2-trifluoroethyl)-L-norvahne,
A solution of 4-methyl-N-[(lS)-4,4,4-trifluoro-l-isocyano-2-(2,2,2-
trifluoroethyl)butyl]benzenesulfinimide (0.065 g, 0.170 mmol) in concentrated HC1
(10 mL) was heated to 1000C for 19 h. After cooling the mixture to 25°C, it was
washed with diethyl ether several times. The aqueous layer was concentrated in vacuo
to give a mixture of 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-L-non'aline NH4CI, and 4-
methylbenzenesulfinic acid (0.045 g, 100 %). The crude amino acid was used in the
next step without further purification. Mass Spectrum (+ESI): 255 (M+H)+.
D. (2S)-2rAmino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentan-l-ol
To a solution of LiBH4 (0.35 mL, 0.71 mmol) in THF (5 mL) at 0°C
was added chlorotrimethylsilane (0,112 mL, 0.885 mmol). The reaction mixture was
warmed to 25°C and, after 30 min, added dropwise to a 0°C suspension of crude
5,5,5-trifluoro-3-(2,2,2-trifluoroethyI)-L-norvalinehydrochloridesalt (0.045 g, 0.177
mmol) in THF (1 mL). The mixture was warmed to 25°C and, after 21 h, quenched
with MeOH. The volatiles were removed in vacuo to give a residue, which was

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dissolved in IN aqueous NaOH (5 mL) and extracted with CH2C12 (4x10 mL). The
organic layer was dried over MgS04, filtered and concentrated to obtain (2S)-2-
amino-5,5,5-rifluoro-3-(2,2,2-trifluoroethyl)pentan-l-ol as a crude light yellow oil
(0.046g, 100 %). The crude amino alcohol was used in the next step without further
purification. Mass Spectrum (+ESI): 240 (M+H)+.
E. 5-Chloro-N-[(lS)-(4,4,4-Mfluoiv-l-(hydroxymethyl)-2-(2,2,2-
triftuoroethyl)butyl)]thiophene-2-sulfonamide
5-Chlorothiophene-2-sulfonyl chloride (0.193 g, 0.654 mmol) was
added dropwise (5 min) as a solution in CH2Cl2 (1.0 mL) to a 0° C solution of(2S)-2-
amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentan-l-oI (0.042 g, 0.175 mmol) in
CH2Cl2(1.0 mL) and pyridine (0.1 mL, 1.09 mmol). The solution was allowed to
warm to 25°C overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-hexane)
indicated that reaction was complete. It was diluted with CH2CI2 (10 mL) and the
organic layer was washed with IN HC1 (2x5 mL), saturated aqueous NaCl (5 mL).
The organic layer was dried over MgSO4, filtered and concentrated to obtain a. crude
off white solid (0.014 g). The crude product was purified by the Biotage Flash™ 12
chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-[(lS)-
(4,4,4-trifluoro-l-(hydroxymethyl)-2-C2,2,2-trifluoroethyl)butyl)]thiophene-2-
sulfonamide as a white solid (0.003 g, 4.1 %). Mass Spectrum (+ESI): 420 (M+H)+,

A solution of lithium borohydride (2M THF, 19.8 mL) was added to a
solution of 2-amino-4,4,4-trifluoro-3-trifluoromethyl-buryric acid ethyl ester (5 g,
19.8 mmol), prepared as described (J. Med Chem. 1981,24, 1043-1047), in THF (80

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mL) at 25 °C and was stirred for 4 h. 2M HC1 was added to the reaction mixture very
carefully until a pH less than 2. The organic solvent was removed in vacuo and the
aqueous layer was neutralized with sat NaHCO3 until pH = 7. The aqueous layer was
extracted with EtOAc (2 x 50 mL) and the organic extracts were dried over Na2SO4
and concentrated to provide 3,3,3-trifluoro-2-(trifluoromethyl)-l-
(hydroxymethyl)propylamine as a yellow oil (3.2 g, 77% yield). The crude oil was of
sufficient purity to utilize in the subsequent reaction.
B. 4,5-Dichloro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trijliioromelhyl)propyl]thiophene-2-sulfon amide
A solution of 3,3,3-trifluoro-2-(trifluoromethyl)-l-
(hydroxymethyl)propylamine (0.192 g, 0.9 mraol) in THF (1 mL) was stirred under
nitrogen at 25 CC. Pyridine (0.147 mL, 1,82 mmol) was added followed by 4,5-
dichlorothiophene-2-sulfonyl chloride (0.226 g, 0.391 mmol) in THF (1 mL), and the
resulting solution stirred for 18 h at 25 °C. After concentration, the residue was taken
up in EtOAc (15 mL) and washed with 1 N aq. HCl (10 mL), brine (10 mL), and then
dried (Na2SO4). After concentration, the crude product was purified by preparatory
TLC, eluent: 30:70 EtOAc:hexanes, to provide 4,5-dichloro-N-[3,3,3-trifluoro-l-
(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-2-sulfonamide as a white solid
(0.037 g, 9%yield, racemic mixture). Mass Spectrum(-ESI): 423.9 (M-H)".

(hydroxymethyl)propylamine (prepared according to the method of Example 13,
0.100 g, 0.4 mmol) in CH2C12 (1 mL) was stirred under nitrogen at 25 °C. Pyridine
(0.097 rnL, 1.2 mmol) was added followed tiy 3-thiophenesulfonyl chloride (0.072 g,

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0.4 mmol) in CH2CI2 (0.5 mL), and the resulting solution stirred for 18 h at 25 °C.
The crude reaction mixture was loaded onto the TsOH Syntage™ samplet and after
concentration was purified by the Biotage Flash™ 12 chromatography system, eluent:
30:70 EtOAc:hexanes, to obtain N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophsne-3-sulfonamide as a white solid (0.053 g, 35 %
yield).
Mass Spectrum (-ESI): 355.9 (M-H).
Anal: Calc'd for C9H8ClF6NO3S2 C, 30.25; H, 2.54; N, 3.92;
Found: C, 30.55; H, 2.27; N, 3.77.

The procedure described in example 29 was followed with the exception that
2,5-dichlorothiophene-3-sulfonyI chloride was used to provide 2,5-dichloro-N-[(lS)-
3,3,3-trifIuoro-l-(hydroxyraethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide
as a white solid (0.026 g, 17% yield). Mass Spectrum (-ESI): 423.8 (M-H).


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The procedure described in example 29 was followed with the exception that
2-thiophenesulfonyl chloride was used to provide N-[(lS)-3,3,3-trifluoro-l-
(hydroxymethyl)-2-(trifIuoromethyl)propyl]thiophene-2-sulfonaraide as a white solid
(0.024 g,17%yield). Mass Spectmm(-ESI): 355.9 (M-H)
EXAMPLE 32
4,5-Dichloro-N-r(lS)-3,3,3-trifluoro-l-(hydroxymethyI)-2-

The procedure described in example 29 was followed with the exception that
4,5-dichlorothiophene-2-sulfonyl chloride was used to provide 4,5-dichloro-N-[(l S)-
3,3,3-trifluoro-l-(hydroxyrnethyl)-2~(triflu3romethyl)propyl]thiophene-2-sulfonarnide
as a white solid (0.050 g, 29 % yield). Mass Spectrum (-ESI): 423.8 (M-H).
EXAMPLE 33
Thiophene-2-sulfonic acid (3,3,3-trifluoro-l-hydroxymethyl-2-trifIuoromethyl-

(hydroxymethyl)propylamine (prepared according to the method of Example 28, Part
A, 105 mg, 0.5 mmol) in CH2C12 (1 mL) was added pyridine (100 μL) and 2-
thiophenesulfonyl chloride (90.5 mg, 0.5 mmol) in CH2CI2 (1 mL). The solution was
stirred for about 8 to about 16 h at 25 °C and then concentrated. EtOAc (1 mL) was

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added and the solution was washed with 1M HC1 (1 mL), brine (1 mL), dried over
Na2SO4 and concentrated. The crude solid was purified by the Biotage Flash™ 12
chromatography system, eluting with EtOAc/hexanes (2:3), to give thiophene-2-
sulfonic acid (3,3,3-triiIuoro-I-hydroxymttthyl-2-trifluoromethyl-propyI)-amide (26.5
mg) as a white solid.
The following compounds (Examples 33-35, Table 1) were prepared using 2-
thiophenesulfonyl chloride, 3-thiophenesulfonyl chloride and 2,5-dichlorothiophene-
3-sulfonyl chloride and employing the procedure outlined in Example 33.


RSO2C1 3,3,3-trifluoro-2-(trifluoromethyl)-l-
(hy d roxymethy I)p ropy lamine
2-thiophsnesulfonyl chloride Example 33
(356 M-H); 2.063 min
3-thiophenesulfonyl chloride Example 34
(356 M-H); 2.013 min
2,5-dichlorothiophene-3-sulfonyl chloride Example 35
(424 M-H); 2.564 min
gradient: 40% acetonitrile/water (0.1% HCOOH) to 100 % acetonitrile (0.1%
HCCOH) over 3 minutes at a flow rate of 0.6 mL/min.


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To a solution of 3,3,3-trifluoro-2-(trifluoroinethyl)-l-
(hydroxymethyl)propylamine (prepared according to the method of Example 28, Part
A, 105 mg, 0.5 mmol) inCH2Cl2 (1 mL) was added pyridine (100 μL) and 4,5-
dibromo thiophene-2-sulfonyl chloride (170 mg, 0.5 mmol) in CH2CI2 (1 mL). The
solution was stirred for about 8 to about 16 h at 25 °C and then concentrated. EtOAc
(1 mL) was added and the solution was washed with 1M HC1 (1 mL), brine (1 mL),
dried over Na2SO4 and concentrated. The crude solid was taken up in DMSO (0.5
mL) and purified by reverse phase HPLC (the Gilson® HPLC instrument, the Luna®
Cl8 100 x 30 mm column, elution gradient; 40% acetonitrileftvater (0.075% TFA) to
100 % acetonitrile (0.075% TFA) over 15 min at a flow rate of 20 mL/min) providing
the title compound (13.8 mg) as a white solid.
The following compounds (Examples 36-39, Table 2) were prepared using 4,5
dibromothiophene-2-sulfonyl chloride, 2-bromo-5-chloro thiophene-2-sulfonyl
chloride, 3-bromo-2,5-dichlorothiophene-3-sulfonyl chloride and benzothiophene-2-
sulfonyl chloride and employing the procedure outlined in Example 36.


RSO2CI 3,3,3-trifluoro-2-(trifluoromethyl)-l-
(hydroxymethyl)propylamine
4,5- dibromothiophene-2-sulfonyl chloride Example 36
(514.1 M-H); 1.882 min
3 -bromo-5 -chlorothiophene-2-sulfonyI
chloride Example 37
(470.1 M-H); 1.699 min
4-bromo-2,5-dichlorothiophene-3-sulfonyl
chloride Example 38
(504.0 M-H); 1.916 min
benzothiophene-2-sulfonyl chloride Example 39
(406.2 M-H); 1.508 min
*Hewlett Packard Series 1100 HPLC/MS, jana C18 2x30 mm column, elution
gradient: 40% acetonitrile/water (0.1% HCOOH) to 100 % acetonitrile (0.1%
HCCOH) over 3 minutes at a flow rate of 0.6 mL/min.

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A solution of trimethylsilyl chloride (1.38 g, 12.73 mmol) was added
to a solution of lithium borohydride (3.2 mL, 2.0 M in THF) and THF (5 mL) at 25°C.
After stirring 5 min, 2-armno-4,4,4-trifluoro-butyric acid (0.50 g, 3.18 mraol) was
added portionwise over a 5 min period. The reaction was allowed to stir 48 h. The
reaction was quenched by cautious addition of MeOH (5 mL) dropwise. The solvent
was evaporated and the residue treated with potassium hydroxide (KOH) solution
(20%, 6 mL). The aqueous phase was extracted using dichloromethane, 3 times (10
mL each). The organic phases were combined and dried over anhydrous sodium
sulfate. After filtration the solvent was evaporated to afford the 2-amino-4,4,4-
trifluoro-butan-1-ol as an oil (0.174 g, 38%). This oil was used directly in the next
reaction without further purification.
B. 5-Chloro-(3,33-trifluoro-l-hydroxymethyl-propyl)-thiophene-2-
sulfonamide
To a solution of 2-amino-4,4,4-trifluoro-butan-l-ol (0.161 g, 1.12
mmol) in dry CH2C12 (4 mL) at 25°C under nitrogen was added dropwise Et3N (0.17
mL, 1.23 mmol) followed also by dropwisi; addition of 5-chlorothiophene-2-sulfonyl
chloride (0.243 g, 1.12 mmol) as a solution in dichloromethane (1 mL). The reaction
was stirred for 18 h at 25°C. The reaction was then quenched by pouring it into a
separator/ funnel containing saturated NaHCO3 solution. Additional CH2Cl2 (15 mL)
was added. After extraction, the organic layer was washed with IN HCl solution,
distilled water and brine. The organic phase was then dried over MgSO4 and
concentrated to a crude solid. After concentration, the crude product was purified by
flash chromatography, eluent: hexane: EtOAc, 4:1 to 2:1, to obtain 5-chIoro-(3,3,3-

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trifluoro-l-hydroxymsthyI-propyI)-thiophene-2-sulfonamide as a clear oil that
crystallized under vacuum (0.191 g, 53 %).
Mass Spectrum (-ESI): 321.9 (M-H).
Anal: Calc'd for C8H9CIF3NO3S2 C, 29.68; H, 2.80; N, 4.33;
Found: C, 29.75; H, 2.72; N, 4.10,

(formyl)propyl]thiophene-2-s ulfon am ide
A solution of 5-chloro-N-[3.3.3-trifluoro-2-(tnfluoromethyl)-l-S-
(hydroxymethyl)propyl]thiophene-2-sulfonamide (prepared according to Example 5,
0.200 g, 0.511 mmol) inCH2Cl2(10 mL) was stirred under nitrogen at 0 °C. Dess-
Martin periodinane reagent (0.325 g, 0.767 mmol) was added in one portion, and the
solution stirred for 1 h at 0 °C. After an additional 1 h at 25 °C, the reaction was
complete by TLC (30:70 EtOAc:PE). The solution was diluted with Et2O (100 mL),
and to this solution was addedNa2S2O3 (1.10 g) in sat. aq. NaHCO3 (10 mL). The
resulting mixture was stirred for 0.5 h. The liquid layers were separated, and the
organic layer was washed with additional sat. aq. NaHCO3 (lOmL) and brine (10 mL)
and then dried (Na2SO4). After concentration, the resulting residue (0.190 g, 95%)
was used directly in the next reaction without further purification.

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B. 5-Chloro-N-[(lS)-3,3,3-Mfiuoro-l-[(lR)-l-hydroxyethyl]-2-
(ti-ifiuoromethyl)propyl]thiophene-2-sulfonamide
A solution of 5-chloro-7V-[3,3,3-trifluoro-2-(trifluoromethyl)-I-S-
(formyl)propyl]thiophene-2-sulfonamide(0.1S8 g, 0.482 mmol) inTHF(5 mL) was
stirred under nitrogen at 0 °C. Methyl magnesium bromide (0.482 mL, 3.0 M in Et20)
was added dropwise, and the resulting solution stirred for 2 h at 25°C. After this time
period, the reaction was complete by TLC (30:70 EtOAc:PE). The solution was
quenched with sat. aq. NH4Cl (10 mL) and then extracted with Et2O (100 mL). The
organic layer was washed with brine (10 mL) and then dried (Na2SO4 After
concentration, the crude product was purified by preparatory plate chroraatography,
eluent: 30:70 EtOAc:PE, followed by chiral HPLC [the Chiralcel® OJ column; 2 x 25
cm, 254 nm, 0.6 mL injections; mobile phase: 10 mL/min 10% EtOH in 7200;
product is peak one, Rf = 6.106, 99.9% purity] to obtain the major diastereomer, 5-
chIoro-N-[(lS)-3,3,3-trifluoro-l-E(lR)-l-hydioxyethyI]-2-(trifluoroniethyl)-
propyl]thiophene-2-sulfonamide, as an off-white solid (0.043 g, 22 %).
Mass Spectrum (-ESI): 404 (M-H).
Anal: Calc'd for C10H10C1F6NO3S2 C, 29.60; H, 2,48; N, 3.45.
Found: C, 29.59; H, 2,40; N, 3.41.
EXAMPLE 42
Aβ40/42ELISA Assay
A. Short Description of the Assay:
Compounds are diluted from DMSO stocks to 2 μM and below in a
cell culture medium Compounds are then applied to CHO cells carrying the APP-
REP-NL plasmid [Sudhir et. at, J. Biolog.Chem. 267:25602-25608 (1992)] for a
period of 22 hours. After the conditioning period, medium is collected, diluted in
assay buffer containing protein, and samples, controls, and synthetic peptide standards
are incubated on a prepared ELISA plate. Using a sandwich ELISA with antibodies
specifically directed against the carboxyl terminus of beta amyloid 40 or 42
[analogous to the method reported by Haugabook et al., J. Neurosci. Methods
108:171-179 (2001) but using goat anti-mouse IgGl (source: Southern Biotech) as the
anchor, 6E10 as the capture antibody (Source: SENETEK), rabbit antiAβ40 and

WO 2004/092I55 PCT/US2004/009268
90
antiAβ42 (source: QCB) and APL-donkey anti-rabbit IgG (H+L, source: Southern
Biotech) as the detection antibody], the effect of the compound treatment on the
cellular production of extracellular beta amyloid is quantified. Cells treated with
compound are subsequently incubated in cell culture medium containing MTS-
formazan. After a short incubation period, MTS/medium containing plates are read in
a spectrophotometer to determine the extent to which compound toxicity affected the
cell's metabolism and ability to synthesize beta amyloid.
B. Materials for the Assay:
(i) Test Samples: compound samples are supplied as 20 mM stock
solutions in a 100% DMSO solution.
(ii) APP-REP-NL cells: Qualified cell lines are carried from week
to week using 1:100 dilutions and are cultured in DMEM supplemented with IX
antibiotic/antimycotic, 200 ug/ml of G418 antibiotic, and 10% certified fetal calf
serum. Cells are also banked in liquid nitrogen Periodically, beta amyloid
production is assessed, and cells are either kept in culture or replaced with progenitors
at full expression.
(iii) Antibodies: Are from certified lots that have already been
qualified in this assay. Antibodies are stored in small frozen aliquots at -80°C that are
thawed and used.
(iv) Reagents: ars of the highest quality available. Certain reagents
are "lot specific" and only reagents from that specific manufacturer and lot may be
used.
(v) Plasticware: is of the highest quality available.
C. Criteria for activity
A compound is considered active if it has an EC50 for Aβ40 reduction
of D. Standard beta amyloid inhibitor
The reference gamma secretase inhibitor DAPT (LY374973,
AN37124: Dovey, H.F. et al., J. Neurochem. 76: 173-181 (2001)) was prepared as
outlined in WO 98/22494 and tested in the Ab40/42 ELISA and gave Aβ40EC50=l 71
nM and Aβ42EC50=128 nM.

WO 2004/092155 PCT/US2004/009268
91
EXAMPLE 43
Represser Release Assay (RRA)
The compounds generated as described in the Examples above are tested in the
RRA in accordance with published techniques [Shuey, D.J., Sheiffele, P., Jones, D.?
Cockctt, M.I., and Quinet, E.M. (1999), "Repressor release: a useful tool for
monitoring amyloid precursor protein (APP) proteolysis in mammalian cells", Society
for Neuroscience Absfracts, Vol. 25, 29th Annual Meeting of Society for
Neuroscience, Miami Beach, Florida, October 23-28,1999]. Briefly, this assay is
performed as follows.
A. Cell Culture
CH0-K1 cells are cultured in whole DMEM media (DMEM - High
Glucose with 10% fetal bovine serum, 1% Non-essential Amino Acids, and 1%
Penicillin-Streptomycin) at 37 °C with 5% CO2. Two million cells are plated into 10-
cm dishes 24 hrs prior to transfection,
Transient transfections are completed as recommended by Gibco BRL
using their Lipofectamine Plus® system First, 6 μg of pRSVO-luc and 6 μg of APP-
lacl construct DNA are added to 460 μL Opti-Mem transfection media and incubated
with the 30 μL Plus® reagent for 15 minutes. Then, a lipid mixture of 40 μL
Lipofectamine Plus® reagent and 460 μL Opti-Mem transfection media is incubated
with the DNA-Plus reagent mixture for 15 minutes. During the DNA-lipid
incubation, the CHO-Kl cells are washed once and covered in 5.0 mL DMEM media
without Penicillin-Streptomycin. The DNA-lipid preparation is then layered onto
these cells and incubated at 37°C overnight.
One and one half million transfected cells per well (100 μL total
volume) are plated into sterile, opaque Packard 96-well Cultur-Plates™ in clear
DMEM whole media (DMEM - without phenol red) and incubated at 37 °C with 5%
CO2 for 3-5 hours.
B. Compound Dilution
Compounds are diluted using two different protocols; one protocol is
used for compounds supplied neat (weighed powder in vial) and the other protocol is
used for compounds supplied in solution (20 mM in DMSO in 96-well plates). For
both protocols, 25 mM He-pes and 25 mM Hepes/1 % DMSO are prepared fresh to be

WO 2004/092155 PCT/US2004/009268
92
used as diluent. The Hepes/DMSO is used as the diluent control on all experimental
plates.
The following table depicts the steps for compound dilution (please
note that the last step is the addition of compound to cells/media in tissue culture
plate):
Table 3

Concentration Dilution

Stock Solution 10mg/mL x mg compound (vial)
diluted with 100% DMSO

Dilution 1 1 mg/mL 20 μL stock solution
180μL25mMHepes

Dilution 2 200 μg/mL 60 μL Dilution 1
240 μL 25 mM Hepes

Dilution 3
(in Cell Plate) 20μg/mL 11.3 μL Dilution 2
(in 100 μl cells/well)
Because some compounds arrive in 96-well format at 20 mM, the following
represents the protocol for their dilution (note that an average molecular weight of
these compounds was used to calculate these dilutions and as above, the last step is
the addition of compound to cells/media in tissue culture plate):
Table 4

Concentration Dilution
Stock Solution (original cone.) 20 mM Solution
Dilution 1 about 200 μg/mL 6 μL stock solution
194μL25 mM Hepes
Dilution 2 (in Cell Plate) about 20 μg/mL 11.3 μL Dilution 2
(in 100 μL cells/well)
Once compounds are diluted, they are applied in duplicate on cells in tissue culture
plates (prepared above). Cells are incubated with compound at 37 °C with 5% CO2
for an additional 36-48 hours.
C. Assay Measurement
Luciferase assays (the LucLite® reagent, Packard) are performed and
are read on a Packard TopCount® instrument, Media is removed from each 96-well
plate and replaced with 100 μL PBS per well (with mg2+ and Ca2+). An equal volume

WO 2004/092155 PCT/US2004/009268
93
(100 μL) of the LucLite® lysis/substrate buffer is added to each well and the plates
arc sealed and mixed in the dark on a rotary shaker for about 15 to about 30 minutes
at room temperature. Luciferase readings are then taken on the TopCount®
instrument. Measurements are expressed as relative light units (RLU) and are
calculated and analyzed in the MS Excel© program as follows.
D. Analysis of data
The results of the assay with respect to the compounds exemplified
herein are provided in the following table, A compound is considered active in RRA
if it leads to at least a 1.5 fold increase in luciferase activity at 20 μg/mL and is non-
toxic, as determined by loss of signal ( amount of luciferase activity (measured in relative light units) over diluent control.
SEM represents the standard error of the mean for fold increase (not shown). All
compounds tested were found to be non-toxic.
E. Standard beta amyloid inhibitor
The reference gamma secretase inhibitor DAPT (LY374973,
AN37124: Dovey, H.F. et aL J. Neurochem 76: 173-181 (2001)) was prepared as
outlined in International Patent Publication No. WO 98/22494 and tested in RRA and
exhibited a 18.5-28.1 fold increase in luciferase activity at 20 μg/mL.

WO 2004/092155 PCT/US2004/009268
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Table 5 - Exemplary ComDOunds of the Invention:

Ex# RRA
data* Name
1 3.2
3.7 5-chloro-N-[(lS, 2R)-4,4,4-trifluoro-l-(hydroxymethyl-2-metliylbutyi]thiophene-2-
sulfoaamide
2 3.7
4.3
5.4 5-diloro-N-[(lS, 2R)-2-cthyl-4)4)4-trifluoro-l- ulfonamide
3 4.3 5'-ch]oro-N-[(lS,2R>2-ethyl, 4,4,4-trifluoro-l-Cl-hydroxyetliyl)butyl]thiophene-2'-
sulfonamide
4 3.7 s'-chloro-N-[3,3,3-trifluoro-2-(trifluoromethyl)-1-Chydroxymethy^propyllthiophene-2'-
aulfonamide
5 3.8 5'-cliloro-N-[3,3,3-trifluoro-2-Ctrifluoromethyl-l-S-(Tiydroxym.ethyl)propyl]thiophene-
2'-sulfonamide
6 4.2 5-chioro-N-[(lR, 2S)-2-ethyl-4,4,4-trifluoro-l-Chydroxymethyl)butyl]thiophene-2-
sulfonamide
7 3.9 5-chloro-N-[4,4,4-trifluoro-l-(hydroxyraethyl)butyl]thiopheae-2-sulfonamide
8 2.8 5-chloro-N-{(lS,2R)-4,4,4-trifiuoro-l-[(IS)-l-hydroxyethyl]-2-methylbutyl}thiophcnc-
2-sulfonamide
9 2.8 5-chloro-N-{(lS, 2R)-4,4,4-trifluoro-l-[(lR)-l-hydroxyethyl3-2-methylbutyl}thiophenc-
2-sulfonamide
10 5.2 5-chloro-N-[(lS, 2S)-414,4-trifluoro-l-(hydroxyraethyI)-2-methylbutyl]thiophene-2-
sulfonamide
11 4.2 2S, 3S)-2-(5-chloro-3-methylben20[b]thiophenc-2-suIfonyl)-araido-5,5,5-trifluoro-3-
ethyl-pentEin-1-ol.
12 1.6 (2S, 3R)-2-(5-chloro-l ,3-dimethy[-l H-pyrazole-^sulfonylJ-amido-5.5.5-trifluoro-3-
phenyl-pentan-1 -ol.
14 6.2
5.8 5-chloro-N-[l-(4J4-diiluorocyclohexyl)-2-hydroxyethyl]thiophene-2-sulfonamide.
15 4.7 5-chloro-N-[l-{6,6-difluofobicyclo[3.1.0]hex-3-yl)-2-hydroxyethyl]thiophens-2-
sulfonamide
16 3.9 5-chioro-N-[(lS,2R)-4,4,4-trifluoro-l-formyl-2-meth.y[buityl]thiophene-2-sulfDnaraide
17 3.6 N-[(lS,2R)-l-acetyl-4,4,4-trifluGro-2-methylbutyl]-5-chlorothiophene-2-sulfonaniide
18 2.9 5-chloro-N-[(lS,2R)4,4,4-trifluoro-l-(l-hydroxy-l-methylechyl)2-
m ethyl butyl] thiophcne-2-sul fonamide
19 4-bromo-5-chloro-N-[3,3,3-trifiuoro-l-(hydroxymethyl)-2-
(trifluoromcthyl]propylithiopher e -2 -sulfonamide.
20 4-bromo-5-chloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]ttiiophene-2-sulfonamjde
21 5-chloro4-fluoro-N-[3,3,3-trifluoro-l-Chydroxymethyl)-2-
(trifiuoromethyl)propyl]thiophei] e-2-sulfonamide
22 5-bromo-N-[33,3-trifluoro-l-Chydroxymelhyl)-2-Ctrifluoromethyl)propyl]thiophens-2-
sulfonainide
23 5-fluoro-N-[3,3,3-trifluoro-l-Chydroxymethyl)-2-(trifiuoroniethyl)propyI]thiophenc-2-
sulfonamide
24 5-brorao-N-[(lS)-3,3,3'triQuoro-l-(hydroxymethyl)-2-
(trinuoromethyl)propyl]lhiophene-2-suifonainide
25 5-fluoro-N-[(lS)-3,3,3-trinuoro-l-Cliydroxyinethyl)-2-
CtrifluoromethyI)propyl]thiophene-2-sutfonamide
26 5-chIoro-N-[4,4,4-lrifluoro-l-(hydroxyniethyl)-2-(2,2,2-trifluoroethyl)butyl]thiophene-2-
sulfonamide
27 5-chloro-N-[ClS)-(4,4,4-trifluoro-l-Chydroxyincthy])-2-(2,2,2-
trifluoroethyl )butyl)] thiophene- 2 -sul fonamid e
28 4,5~dichloro-N-[3,3,3-trifluoro-l-(hydroxymcthyl)-2-Ctrifluoromethyl)propyl]thiophene-
2-sulfonamide

WO 2004/092155 PCT/US2004/009268
95

29 N-[(lS>3J3,3-trifluoro-l-(hydroxymethyI)-2-(trinuoroniethyl)propyl]thiophene-3-
sulfonamide
30 2,5-dichloro-N-[(l S)-3,3,3-trifluoro- l-(hydroxymethyl)-2-
trifluoromethyI)propyl]thiophene-3-sulfonamide
31 N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-(trifluororaethyl)propyl]thiophene-2-
sulfonamide
32 4,5-dichloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophene-2-sulfonarnide
33 thiophene-2-sulfonic acid (3,3,3-trifluoro-I -hydroxymethyl-2-trifluoromethyl-propyl)-
amide
34 thiophene-3-sulfonicacid(3,3,3-trif]uoro-l-hydroxymethyl-2-trifluoromethyl-propyl)-
amide
35 2,5-dichloro-thiophene-3-3ulfonicacid (3,3,3-trifluoro-l-hydroxymethyl-2-
trifluoromcthyl-propyl)-amide
36 4,5-dibromo-N-[3,3,3 -trifluoro-1 -(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophcne-
2-sulfonamide
37 3-bromo-5-chloro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
Ctrifluorometb.yl)pro pyl]thiophene-2-sul fonamide
38 4-bromo-2,5-dicWoro-N-[3,3,3-trifluoro-l-(hydroxymethyl)-2-
(trifluoromethyl)propyl]thiophcnc-3-sulfonamide
39 benzo[b]thiophene-2-sulfonic acid (3,3,3-trifluoro-] -hydroxymethyl-2-trifluoromethyl-
propyl)-amide
40 3.8,4.2 5-chloro-(3,3,3-trifluoro-l-hydroxymethyl-prop>rl)-thiophene-2-suIfonamide
41 6.2 5-chloro-N-[(lS)-3,3,3-trifluoro4-[ClR)-l-hydroxyethyl]-2-
(tr ifluoromethyl)propyl] thiophene-2 -sulfonamid e
* fold increase of APPI, all compounds tested at 20 μg/mL.
All publications cited in this specification ars incorporated herein by
reference. While the invention has been described with reference to a particularly
preferred embodiment, it will be appreciated that modifications can be mads without
departing from the spirit of the invention. Such modifications are intended to fell
within the scope of the appended claims.

WO 2004/092155 PCT/US2004/009268
-96-
What is claimed is:
1. A compound of Formula (I), or pharmaceutically acceptable salt
thereof, wherein Formula (1) has the structure:

wherein:
T is selected from the group consisting of CHO, COR8, and C(OH)R1R2;
R1 and R2 are independently selected from the group consisting of hydrogen,
lower alkyl, substituted lower alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl;
R3 is selected from the group consisting of hydrogen, lower alkyl and
substituted lower alkyl;
R1 is selected from the group consisting of (CF3)(,alkyl, (CF3)n
(subslitutedalkyl), (CF.i)nalkylphenyI, (CF.i)nalkyl(substitutedphenyl), and (F)
,,cyeloalkyl;
n=l-3;
R5 is selected from the group consisting of hydrogen, halogen, CF3, diene fused
to Y when Y=C, and substituted dienc fused to Y when Y=C;
W, Y and Z arc independently selected from the group consisting of C, CR
and N with the proviso that at least one of W or Y or Z must be C;
R6 is selected from the group consisting of hydrogen, halogen, lower alkyl, and
substituted lower alkyl;
X is selected from the group consisting of 0, S, S02, and NR7;
R7 is selected from the group consisting of hydrogen, lower alkyl, substituted
lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl; and
96

WO 2004/092155 PCT/US2004/009268
-97-
R8 is selected from the group consisting of lower alkyl, CF3. phenyl, and
substituted phenyl;
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
2. The compound according to claim 1, wherein R5 is halogen.
3. The compound according to claim 2, wherein R5 is chlorine, bromine,
or fluorine.
4. The compound according lo any of claims 1 to 3, wherein R1 and R2 are
each liydrogen.
5. The compound according to any of claims 1 lo 4, wherein W is C and
Z is CR6
6. The compound according to any of claims 1 to 4, wherein X is S, and
W, Y and Z are independently selected from C or CR6, provided that one of W, Y or Z
is C.
7. The compound according to any of claims 1 to 6, wherein R4 is
selected from the group consisting of (CF3)nIowcraIkyl, (CF3)n (subslituledloweralkyl),
(CF3)n lowcralkylphenyl, and (CF3)n,lowcralkyl(substilutedphcnyl) of S-
stercochemistry.
8. The compound according to claim 1, wherein X is S, W is C, Y is CH,
Z is CH, R5 is chlorine, R4 is CF3CH2CHCH3, R3, R1 and R2 arc each hydrogen, which
has IS, 2R stereochemistry.
9. The compound according to claim 1, wherein X is S, W is C, Y is CH.
Z is CH. R5 is chlorine, R1 is CF3CHCF3, R3, R1 and R2 are each hydrogen, which has
IS stereochemistry.

-98-
10. The compound according to claim 1, wherein W is N and X is NR7.
11. The compound according to claim 1, wherein the compound is selected
from the group consisting of:
5-ChIoro-N-[(lS, 2R)-4,4,4-triluoro-l-(hydroxymethyl)-2-melhylbulyl]
thiophene-2-sulfbnamide;
5-Chloro-N-[(lS,2R)-2-cthyl-4,4,4-trilluoro-l-(hydroxymethyl)butyl]
lhiophene-2-sulfonamide;
5'-Chloro-N-[(l S, 2R)-2-cthyI, 4,4,4-triiluoro-l-(l-hydroxycthyl)bulyl]
thiophene-2'-sulfbnamide;
5'-Chloro-N-[3,3,3-triiluoro-2-(triIluoromclhyI)-l-hydroxymethyl)propyl]
thiophene-2'-sulibnamidc;
5'-Chloro-N-[3,3,3-lri^uoro-2-(lrifluoromcihyl)-l-S-(hydroxymelhyI)propyl]
thiophenc-2'-sulibnamidc;
5-Chlofo-N-[(lR,2S)-2-cthyl-4,4,4-lriIluoro-l-(hydroxymcthyl)butyl]
lhiophcnc-2-sulfonaniide;
5-Chloro-N-[4,4,4-tnlluoro-l-(hydroxymethyl)butyl]thiopheno-2-sulfonamide;
5-Ch]oro-N-{(lS,2R)-4,4,4-trifluoro-l-[(lS)-l-hydroxyclhyI]-2-methylbutyl}
thiophcne-2-sulfonamide;
5-Chloro-N-{(lS,2R)-4,4,4-lrifluoro-l-[(lR)-l-hydroxyethyl]-2-mcthylbulylj
thiophcnc-2-sulfonamidc;
5-ChIoro-N-[(lS,2S)-4,4,4-trifluoro-l-(hydroxymethyl)-2-methyIbutylj
thiophcnc-2-sulfonamidc;
(2S, 3S)-2-(5-Chloro-3-methylbcnzo[b]thiophcnc-2-suIfonyl)-amido-5,5,5-
trifluoro-3-clhyl-pcntan-l-ol;
(2S,3R)-2-(5-ChIoro-l,3-dimcthyl-lH-pyrazoIe-4-suIfonyl)-amido-5,5,5-
triiluoro-3-phenyl-pentan-l-ol;
5-Chloro-N-[l-(4,4-difluorocyclohexyl)-2-hydroxycthyl]thiophenc-2-
sulibnamide;
5-Chloro-N-[l-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-hydroxyethyl]thiophene-
2-sulibnamide;

-99-
5-Chloro-N-[(lS,2R)-4,4,4-trifluoro-l-formyl-2-melhylbutyl]thiophene-2-
sulfonamide;
N-[(lS,2R)-l-Acetyl-4,4,4-lrifluoro-2-mclIiylbutyl]-5-chlorothiophcnc-2-
sulfonamide;
5-Chloro-N-[(lS,2R)-4,4,4-trifluoro-l-(l-hydroxy-l-mcthyIethyl)2-
nicthylbutyl]thiophcnc-2-sulfonamidc;
4-Bromo-5-chloro-N-[3,3,3-triIluoro-l-(hydroxymclhyl)-2-(lrifluoromcthyI)
propyl] thiophcnc-2-sulfonamidc;
4-8romo-5-chloro-N-[(lS)-3,3,3-trifluoro-l-(hydroxymeihyI)-2-
(trifluoromclhyI)propyl]thiophcne-2-sulfonainide;
5-Chloro 4-fluoro-N-[3,3,3-triiluoro-l-(hydroxymethyl)-2-(trinuoromethyl)
propyl]lhiophcnc-2-suJlbnamide;
5-Bromo-N-[3,3,3-lrifluoro-l-(hydroxymcthyl)-2-(lrinuoromcthyl)propyl]
thiophcnc-2-sulfonamidc;
5-FIuoro-N-[3,3,3-lriiluoro-l-(hydroxymclhyl)-2-(triiluoromclhyl)propyl]
Lhiophenc-2-sulJbnamidc;
5-Bromo-N-[(lS)-3,3,3-triJluoro-l-(hydroxymethyl)-2-(triiluoromethyl)
propyl]tliiophene-2-sulfonamide;
5-Fluoro-N-[(lS)-3,3,3-lrifluoro-l-(hydroxymcthyJ)-2-(trifluoromcthyl)propyl]
lhiophcnc-2-sulfonamidc;
5-ChIoro-N-[4,4,4-iriiluoro-l-(hydroxymclhyl)-2-(2,2,2-triiluorocthyl)butyl]lhiophcnc-
2-sullbnamidc;
5-Chloro-N-[(lS)-(4,4,4-triiluoro-l-(hydroxymcthyJ)-2-(2)2,2-trifluorocthyl)
bulyl)] thiophcnc-2-sulfonamidc;
4,5-DichIoro-N-[3,3,3-triiluoro-l-(hydroxymcthyI)-2-(trifluoromcthyl)propyl]
thiophcnc-2-sulfonamidc;
N-[(lS)-3,3,3-Trifluoro-l-(hydroxymcthyl)-2-(trifluoromethyl)propyl]
thiophcnc-3-sulfonamide;
2,5-Dichloro-N-[(lS)-3,3,3-tniluoro-l-(hydroxymethyl)-2-(trifluoromethyl)
propyl]thiophcne-3-suJibnamidc;
N-[(lS)-3s3,3-Trifluoro-l-(hydroxymethyl)-2-(trifluoromethyI)propyl]
thiophcnc-2-sulfonamidc;

-100-
4,5-Dichloro-N-[(lS)-3,3,3-lriilLioro-l-(hydruxymethyl)-2-(iriiluoromethyl)
propyl]thiophcnc-2-sulfonamidc;
Thiophcnc-2-sulfonic acid (3,3,3-trifluoro-l-hydroxymcthyl-2-lrifluoromcihyl
propyl)-amidc;
Thiophcnc-3-sulibnic acid (3,3,34rifluoro-l-hydroxymclhyl-2-lrifluoromelhyl
propyl)-amidc;
2,5-Dichloro-Thiophene-3-sulibnic acid (3,3,3-triiluoro-l-hydroxymelhyl-2-
triiluoromethyl-propyl)-amide;
4,5-Dibromo-N-[3,3,3-lrifluoro-l-(hydroxymcthyl)-2-(trifluorometliyl)propyI]
thiophene-2-sulfonamide;
3-Bromo-5-chloro-N-[3,3,3-lriiluoro-l-(hydroxymclhyl)-2-(lnlluoromethyl)
propyl] thiophene-2-sulfonamide;
4-Bromo-2,5-dichloro-N-[3,3,3-lrifluoro-l-(hydroxymethyl)-2-
(trifluoromclhyl)propyl]thiophcnc-2-sulfonamidc;
Benzo|bJthiophene-2-sulfonic acid (3,3,3-triiluoro-l-(hydroxymelhyl)-2-
(lrilluoromclhyl)propyl)-amidc;
5-Chloro-(3,3,3-triiluoro-l-hydroxymcihyl-propyl)-thiophcnc-2-suIfonamidc;
and
5-Chloro-N-[(lS)-3,3,3-irinuoro-14(lR)-l-hydroxyethyl]-2-(triiluoromethyI)
propyl]thiophene-2-sulfonamidc;
or a pharmaccutically acceptable salt, hydrate, or prodrug thereof.
12. The compound according to claim 1, which is 5-chIoro-N-[(lS)-(4,4,4-
trifluoro-l-(hydroxymethyl)-2-(2,2,2-trinuoroclhyl)bulyl)]thiophcnc-2-sulibnamidc;
or a pharmaccutically acceptable salt, hydrate, or prodrug thereof.
13. The compound according to claim I, wherein X is 0, and W, Y and Z
are independently selected from C and CR6, provided that one of W, Y or Z is C.
14. The compound according to claim 13, wherein R5 is halogen, R4 is
selected from the group consisting of (CF3)n[oweralkyl, (CF3)n(substitutedlowcralkyl).

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(CF3)n lowcralkylphcnyl, (CF3),,loweraIkyl(subslitutedphenyl) of S-stereochemistry,
■and R3, R1 and R2 arc all H.
15. The compound according to claim 1, wherein T is C(OH)R1R2, R1, R2,
and R3 arc H, and R1 is (F),,cycloalkyl or (CF3)n alkyl.
16. The compound according to claim 1, wherein T is C(OH)R1R2, or
CHO, R1 is CH3, R2 is H, R3, is H, and R4 is (CF3)n alkyl.
17. The compound according to claim 1, wherein T is C(OH)R1R2, Ri is H
or CM3, R2 and R3 arc M, and R4 is (CF3)2CH of S-stereochemistry.
i 8. The compound according to claim 1, wherein T is CHO or C(O)R8, R8
is CR3 , R3 is H, and R4 is CH(CH3)CH2CF3 of S-stereochemistry.
19. The compound according to claim 1, wherein T is C(OH)R1R2, R1, R2
and R3 are H, and R4, is CH(CH2CF3)2of S-stcreochemistiy or CH(CH3)CR2CF3 of S-
slcreochemistry.
20. The compound according to claim 1, wherein the pharmaceutically
acceptable salt is selected from the group consisting of salts of organic acids,, sails of
inorganic acids, salts of bases, and mixtures thereof.
21. The compound according to claim 20, wherein the salts of organic and
inorganic acids are selected from the group consisting of acetic acid, lactic acid, citric
acid, tarlaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic
acid, malic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,
sulfuric acid, methanesulfonic acid, toluenesulfonic acid, and mixtures thereof; and
the salts of bases are selected from the group consisting of sodium hydroxide, lithium
hydroxide and potassium hydroxide, and mixtures thereof.

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22. A pharmaceutical composition comprising a compound according to
any ofclaims 1 to 21, or aprodrug thereof, and a physiologically compatible carrier.
23. Use of a compound according to any of claims 1 to 21 in the
preparation of a medicament for inhibiting beta amyloid production in a subject.
24. Use according to claim 23, wherein said compound is delivered orally,
by injection or by inhalation.
25. Use of a compound according to any of claims 1 to 21 in the
preparation of a medicament for treating a disease selected from the group consisting
of Alzheimer's Disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic
amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type,
inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome, in
a subject.
26. A method of preparing a trilluoromethylatcd or iluorinatcd hcterocyclic
sulfonamide compound, said method comprising the steps of:
(a) filtering a diaslcrcomeric mixture of an aminocsler, said
aminoester having at least one chiral center and at least one trifluoromethyl or fluoro
group attached to at least one chiral center through an alkyl group;
(b) treating the aminoester with DIBAL-H in toluene to afford N-
benzyl amino alcohol;
(c) hydrogenating the N-benzyl amino alcohol with a catalyst and
affording an amino alcohol;
(d) sulfonylating the amino alcohol of (c) with a heterocyclic
sulibnyl chloride; and
(c) crystallizing the sulfonylated product of (d) to afford to chirally
pure trilluoromethylated or iluorinatcd heterocyclic sulfonamide compound.

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27. The method according to claim 26, wherein the trifluoromelhylated
hcterocyclic sulfonamidc compound is a compound according to claim 1.
28. The method according to claim 27, wherein the crystallizing step is
performing using ethyl acetate and hcxane.
29. A method of preparing a lrilluoromcthylatcd or fluorinatcd helerocyclic
sulfonamidc compound, said method comprising the steps of:
(a) treating a trilluoromethylated or fluorinatcd aldehyde with a
dehydrating agent and a chiral sulfinaraidc to form a trilluoromcthylatcd or
fluorinated chiral sulfinamidc;
(b) treating said trifluoromelhylated or lluorinatcd chiral
sulflnimide with a cyanaling agent to ibrm a trill uoromethylated or iluorinated
diastercomcric D-amino nitrile;
(c) hydrolyzing said trilluoromcthylated or lluorinatcd
diastereomcric D-amino nitrile to atrilluoromelhylatcd D-amino acid;
(d) reducing said trilluoromelliylatcd or lluorinatcd D-amino acid to
a trill uoromethylated or lluorinatcd D-amino alcohol; and
(e) reacting said trilluoromcthylated or lluorinalcd D-amino alcohol
with a hcterocyclic sulfonyl chloride to form said Irifluoromethylated or iluorinated
hcterocyclic sulfonamidc;
and further if desired
(i) extracting said trilluoromcthylated or Iluorinated heterocyclic
sulfonamidc;
and further if desired;
(g) purifying said trilluoromethylated or lluorinatcd heterocyclic
sulfonamidc
30. The method according to claim 29, wherein said trifluoromclhylated or
lluorinalcd heterocyclic sulfonamidc is purified using chromatography.

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31. The method according to claim 29, wherein said dehydrating agent is
titanium ethoxide, magnesium, sulfatc, or 4A molecular sieves.
32. The method according to claim 29, wherein said chiral sulfmamidc is
S-(+)-toluenesuiiinamidc or t-butanesulfinamidc.
33. The method according to claim 29, wherein said cyanaling agent is
ethyl isopropoxy aluminum cyanide.
34. The method according to claim 29, wherein said dehydrating agent is
titanium cthoxidc, said chiral sulfonaniide is S-(+)-toIucncsulimamidc, and said
cyanaiing agent is ethyl isopropoxy aluminum cyanide.

Compounds of Formula (I), are provided where T is CHO, COR8, or C(OH)R1R2; R1 and R2 are hydrogen, optionally substituted lower alkyl, CF3, optionally substituted alkenyl, or optionally substituted alkynyl; R3 is hydrogen or optionally substituted lower alkyl; R4 is (CF3)nalkyl, (CF3)n(substitutedalkyl), (CF3)nalkylphenyl, (CF3)nalkyl(substitutedphenyl), or (F)ncycloalkyl; n=1-3; R5 is hydrogen, halogen, CF3, diene fused to Y when Y=C, or substituted diene fused to Y when Y=C; W, Y and Z are C, CR6 or N where at least one of W, Y or Z are C; R6 is hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO2, or NR7; R7 is hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and R8 is lower alkyl, CF3, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer"s Disease and Down"s syndrome are also described.

Documents:

01845-kolnp-2005-abstract.pdf

01845-kolnp-2005-claims.pdf

01845-kolnp-2005-description complete.pdf

01845-kolnp-2005-form 1.pdf

01845-kolnp-2005-form 13.pdf

01845-kolnp-2005-form 3.pdf

01845-kolnp-2005-form 5.pdf

01845-kolnp-2005-international publication.pdf

1845-KOLNP-2005-CORRESPONDENCE.pdf

1845-KOLNP-2005-FOR ALTERATION OF ENTRY.pdf

1845-kolnp-2005-granted-abstract.pdf

1845-kolnp-2005-granted-assignment.pdf

1845-kolnp-2005-granted-claims.pdf

1845-kolnp-2005-granted-correspondence.pdf

1845-kolnp-2005-granted-description (complete).pdf

1845-kolnp-2005-granted-examination report.pdf

1845-kolnp-2005-granted-form 1.pdf

1845-kolnp-2005-granted-form 13.pdf

1845-kolnp-2005-granted-form 18.pdf

1845-kolnp-2005-granted-form 3.pdf

1845-kolnp-2005-granted-form 5.pdf

1845-kolnp-2005-granted-gpa.pdf

1845-kolnp-2005-granted-reply to examination report.pdf

1845-kolnp-2005-granted-specification.pdf

1845-KOLNP-2005-PA.pdf

abstract-01845-kolnp-2005.jpg


Patent Number 236201
Indian Patent Application Number 1845/KOLNP/2005
PG Journal Number 41/2009
Publication Date 09-Oct-2009
Grant Date 07-Oct-2009
Date of Filing 16-Sep-2005
Name of Patentee WYETH
Applicant Address FIVE GIRALDA FARMS, MADISON, NJ
Inventors:
# Inventor's Name Inventor's Address
1 KREFT ANTHONY FRANK 43 BARLEY COURT, LANGHORNE, PA 19047
2 KREFT ANTHONY FRANK 43 BARLEY COURT, LANGHORNE, PA 19047, U.S.A.
3 RESNICK LYNN 5 BORELLE SQUARE, PARLIN, NJ 08859
4 MAYER SCOTT CHRISTIAN 310 ROLLING KNOLLS WAY, BRIDGEWATER, NJ 08807
5 DIAMANTIDIS GEORGE 106 RADTKE ROAD, RANDOLPH, NJ 07869
6 COLE DEREK CECIL 14 RENFREW ROAD, NEW CITY, NY 10956
7 WANG TINGZHONG 2 MOUNTAIN VIEW COURT, POMONO, NY 10970
8 GALANTE ROCCO JOHN 16 HOPPER STREET, OAKLAND, NJ 07436
9 HOKE MOLLY 26 DENNIS COURT, HIGHTSTOWN, NJ 08520
10 HARRISON BOYD LYNN 9 WHEATSTON COURT, PRINCETON JUNCTION, NJ 08550
11 ZHANG MINSHENG 31 SCHEURMAN TERRACE, WARREN, NJ 07059
PCT International Classification Number C07D 333/34
PCT International Application Number PCT/US2004/009268
PCT International Filing date 2004-03-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/459, 228 2003-03-31 U.S.A.