U.S. patent application number 14/151232 was filed with the patent office on 2014-12-11 for tetrasubstituted benzenes.
This patent application is currently assigned to ENVIVO PHARMACEUTICALS, INC.. The applicant listed for this patent is EnVivo Pharmaceuticals, Inc.. Invention is credited to Richard CHESWORTH, Gideon SHAPIRO.
Application Number | 20140364641 14/151232 |
Document ID | / |
Family ID | 40364509 |
Filed Date | 2014-12-11 |
United States Patent
Application |
20140364641 |
Kind Code |
A1 |
SHAPIRO; Gideon ; et
al. |
December 11, 2014 |
Tetrasubstituted Benzenes
Abstract
Tetrasubstituted benzenes that act as modulators of gamma
secretase and their use in the treatment of one or more symptoms of
treating neurodegenerative disorders, e.g., Alzheimer's disease,
are described.
Inventors: |
SHAPIRO; Gideon;
(Gainesville, FL) ; CHESWORTH; Richard; (Boston,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EnVivo Pharmaceuticals, Inc. |
Watertown |
MA |
US |
|
|
Assignee: |
ENVIVO PHARMACEUTICALS,
INC.
Watertown
MA
|
Family ID: |
40364509 |
Appl. No.: |
14/151232 |
Filed: |
January 9, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13756871 |
Feb 1, 2013 |
8664249 |
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14151232 |
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13486201 |
Jun 1, 2012 |
8367863 |
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13756871 |
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12341201 |
Dec 22, 2008 |
8217064 |
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13486201 |
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61015605 |
Dec 20, 2007 |
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61109665 |
Oct 30, 2008 |
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Current U.S.
Class: |
560/59 ;
562/469 |
Current CPC
Class: |
A61P 43/00 20180101;
C07C 2601/08 20170501; C07C 323/18 20130101; C07C 67/48 20130101;
C07C 67/48 20130101; C07D 277/64 20130101; C07C 51/09 20130101;
C07C 205/37 20130101; C07C 2601/02 20170501; C07C 2601/04 20170501;
C07C 205/55 20130101; C07C 69/757 20130101; C07D 285/14 20130101;
C07C 59/72 20130101; C07C 51/09 20130101; C07D 309/08 20130101;
C07C 229/42 20130101; C07C 69/734 20130101; A61P 25/28 20180101;
C07C 69/734 20130101; C07C 69/734 20130101; C07C 67/343 20130101;
C07C 59/72 20130101; C07C 255/57 20130101; C07C 51/42 20130101;
C07C 205/56 20130101; C07D 271/12 20130101; C07C 67/343
20130101 |
Class at
Publication: |
560/59 ;
562/469 |
International
Class: |
C07C 51/09 20060101
C07C051/09; C07C 67/48 20060101 C07C067/48; C07C 67/343 20060101
C07C067/343 |
Claims
1-62. (canceled)
63. A method for making ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl-
]-3-yl)acetate, the method comprising contacting the compound of
formula ##STR00296## with a 4-trifluoromethylphenyl reagent to
provide a compound of formula ##STR00297##
64. The method of claim 63, wherein the 4-trifluoromethylphenyl
reagent is 4-trifluoromethylphenyl boronic acid.
65. The method of claim 63, wherein the reaction is conducted in
the presence of a catalyst.
66. The method of claim 65, wherein the catalyst is a palladium(0)
catalyst.
67. The method of claim 63, wherein the reaction is conducted in a
presence of a base.
68. The method of claim 67, wherein the base is potassium
carbonate.
69. The method of claim 63, further comprising isolating the
product.
70. A method for making ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl-
]-3-yl)-3-cyclobutylpropanoate, the method comprising contacting
the compound of formula ##STR00298## with a cyclobutylmethyl
reagent to provide the compound of formula ##STR00299##
71. The method of claim 70, wherein the cyclobutylmethyl reagent is
cyclobutylmethyl halide.
72. The method of claim 71, wherein cyclobutylmethyl halide is
cyclobutylmethyl bromide.
73. The method of claim 70, wherein the reaction is conducted in
the presence of a deprotonating base.
74. The method of claim 73, wherein the deprotonating base is
sodium hydride.
75. The method of claim 70, further comprising isolating the
product.
76. A method for making
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)-[1,1'-biphenyl-
]-3-yl)-3-cyclobutylpropanoic acid, the method comprising
contacting the compound of formula ##STR00300## with a hydrolyzing
reagent followed by acidification to provide a compound of formula
##STR00301## or a salt thereof.
77. The method of claim 76, wherein the hydrolyzing reagent is a
hydroxide reagent.
78. The method of claim 77, wherein the hydroxide reagent is
lithium hydroxide.
79. The method of claim 76, wherein the reaction is conducted in
the presence of methanol:tetrahydrofuran:water.
80. The method of claim 76, wherein acidification comprises
addition of an inorganic acid.
81. The method of claim 80, wherein the inorganic acid is
hydrochloric acid.
82. The method of claim 76, further comprising isolating the
product or a salt thereof.
Description
RELATED APPLICATION INFORMATION
[0001] This application claims priority to U.S. provisional
application Ser. No. 61/015,605, filed Dec. 20, 2007, and to U.S.
provisional application Ser. No. 61/109,665, filed Oct. 30, 2008,
both of which are herein incorporated by reference.
BACKGROUND
[0002] Alzheimer's disease (AD) is the most prevalent form of
dementia. It is a neurodegenerative disorder that is associated
(though not exclusively) with aging. The disorder is clinically
characterized by a progressive loss of memory, cognition, reasoning
and judgment that leads to an extreme mental deterioration and
ultimately death. The disorder is pathologically characterized by
the deposition of extracellular plaques and the presence of
neurofibrillary tangles. These plaques are considered to play an
important role in the pathogenesis of the disease.
[0003] These plaques mainly comprise of fibrillar aggregates of
.beta.-amyloid peptide (A.beta.), which are products of the amyloid
precursor protein (APP), a 695 amino-acid protein. APP is initially
processed by .beta.-secretase forming a secreted peptide and a
membrane bound C99 fragment. The C99 fragment is subsequently
processed by the proteolytic activity of .gamma.-secretase.
Multiple sites of proteolysis on the C99 fragment lead to the
production of a range of smaller peptides (A.beta. 37-42 amino
acids). N-terminal truncations can also be found e.g. A.beta.
(4-42, 11-42) for convenience A.beta.40 and A.beta.42 as used
herein incorporates these N-terminal truncated peptides. Upon
secretion, the A.beta. peptides initially form soluble aggregates
which ultimately lead to the formation of insoluble deposits and
plaques. A.beta.42 is believed to be the most neurotoxic, the
shorter peptides have less propensity to aggregate and form
plaques. The A.beta. plaques in the brain are also associated with
cerebral amyloid angiopathy, hereditary cerebral hemorrhage with
amyloidosis, multi infarct dementia, dementia pugilistisca,
inclusion body myositis and Down's Syndrome.
[0004] .gamma.-secretase is an association of four proteins: Aph1,
Nicastrin, Presenillin and Pen-2 (review De Strooper 2003, Neuron
38, 9). A.beta.42 is selectively increased in patients carrying
particular mutations in one of these components, presenilin. These
mutations are correlated with early onset a familial AD. Inhibition
of .gamma.-secretase resulting in the lowering of A.beta.42 is a
desirable activity for the pharmaceutical community and numerous
inhibitors have been found, e.g., Thompson et at (Bio. Org. and
Med. Chem. Letters 2006, 16, 2357-63), Shaw et al (Bio. Org. and
Med. Chem. Letters 2006, 17, 511-16) and Asberom et al (Bio. Org.
and Med. Chem. Letters 2007, 15, 2219-2223). Inhibition of
.gamma.-secretase though is not without side-effects, some of which
are due to the .gamma.-secretase complex processing substrates
other than C99, for e.g. Notch. A more desirable approach is to
modulate the proteolytic activity of the .gamma.-secretase complex
in a manner that lowers A.beta.42 in favor of shorter peptides
without significantly affecting the activity of .gamma.-secretase
on substrates such as Notch.
[0005] Compounds that have shown modulation of .gamma.-secretase
include certain non-steroidal, anti-inflammatory drugs (NSAIDs),
for example Flurbiprofen, (Stock et al Bio. Org. and Med. Chem.
Letters 2006, 16, 2219-2223). Other publications that disclose
agents said to reduce A.beta.42 through the modulation of
.gamma.-secretase include: WO 04/074232, WO 05/054193, Perreto et
al Journal of Medicinal Chemistry 2005, 48 5705-20, WO05/108362, WO
06/008558, WO 06/021441, WO 06/041874, WO 06/045554, WO04110350, WO
06/043964, WO 05/115990, EP1847524, WO 07/116,228, WO 07/110,667,
WO 07/124,394, EP184752, EP 01849762, WO 07/125,364.
SUMMARY
[0006] Described herein are tetrasubstituted benzene compounds of
formulas (I) and (II) and pharmaceutically acceptable salts
thereof
##STR00001##
Wherein:
[0007] A is CO.sub.2H or tetrazole; R.sub.1 and R.sub.2 are
independently selected from: (a) H, (b) F, (c) OH, (d) OR.sub.6,
(e) SR.sub.6, (f) NHR.sub.7, (g) N(R.sub.7).sub.2 (h)
NHC(O)R.sub.6, (i) NHCO.sub.2R.sub.6, (j) (C.sub.2-C.sub.6)alkyl,
(k) (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (l)
C.sub.1-C.sub.6 alkyl that is independently interrupted by one or
more --O--, --S--, --S(O)--, or --S(O).sub.2-- groups, (m)
(C.sub.3-C.sub.7)cycloalkyl, (n)
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (o)
heterocycloalkylalky and (p) (CH.sub.2).sub.nQ wherein n=0-2 and
wherein Q is a mono- or bicyclic aromatic or heteroaromatic ring
system having 5 to 10 ring atoms independently selected from C, N,
O and S, provided that not more than 3 ring atoms in any single
ring are other than C, and wherein Q is optionally independently
substituted with up to 3 groups selected from alkyl, halogen,
CF.sub.3, OH, OCF.sub.3, alkoxy, OCH.sub.2CH.sub.2OCH.sub.3,
NH.sub.2, alkylamino, dialkylamino, morpholino, CN, NO.sub.2,
alkylthio and alkylsulfonyl,
[0008] and wherein each alkyl or cycloalkyl of R.sub.1 and R.sub.2
is optionally independently substituted with one or more halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl,
[0009] provided that both R.sub.1 and R.sub.2 are not H,
or R.sub.1 and R.sub.2 are taken together to form a 3-7 membered
cycloalkyl or heterocycloalkyl ring which is optionally
independently singly or multiply substituted with halo, hydroxy,
oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl or R.sub.1 and R.sub.2
are taken together to form a 3-7 membered cycloalkyl ring
substituted with R.sub.20 and R.sub.21 where R.sub.20 and R.sub.21
are taken together to form a 3-7 membered cycloalkyl ring wherein
each cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl R.sub.6 is selected from:
[0010] (a) C1-C6 alkyl optionally and independently interrupted by
one or more --O--, --S--, --S(O), or --S(O).sub.2-- groups,
[0011] (b) (C.sub.3-C.sub.7)cycloalkyl,
[0012] (c) (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl, (d)
heterocycloalkylalky and
[0013] (e) (CH.sub.2).sub.nQ wherein n=0-2 and wherein Q is a mono-
or bicyclic aromatic or heteroaromatic ring system having 5 to 10
ring atoms independently selected from C, N, O and S, provided that
not more than 3 ring atoms in any single ring are other than C, and
wherein Q is optionally independently substituted with up to 3
groups selected from alkyl, halogen, CF.sub.3, OH, OCF.sub.3,
alkoxy, OCH.sub.2CH.sub.2OCH.sub.3, NH.sub.2, alkylamino,
dialkylamino, morpholino, CN, NO.sub.2, alkylthio and
alkylsulfonyl;
R.sub.7 is independently chosen from alkyl, alkoxyethyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl or
(CH.sub.2).sub.nQ, wherein n=0-2 and wherein Q is a mono or
bicyclic aromatic or heteroaromatic ring system having 5 to 10 ring
atoms independently selected from C, N, O and S, provided that not
more than 3 ring atoms in any single ring are other than C and
wherein Q is optionally substituted with up to 3 groups
independently selected from alkyl, halogen, CF.sub.3, OH,
OCF.sub.3, alkoxy, OCH.sub.2CH.sub.2OCH.sub.3, NH.sub.2,
alkylamino, dialkylamino, morpholino, CN, NO.sub.2, alkylthio,
alkylsulfonyl; or in the case when two R.sub.7 are attached to the
same N and are both alkyl, they can be taken together to form a
5-membered or 6-membered ring optionally containing O, S, N(H) or
N-alkyl; X is a bond or a divalent linking group selected from
--O--, --OCH.sub.2--, --OCH(R.sub.7)--, --OCH.sub.2CH.sub.2--,
--CH.sub.2--, --C(O)--, --CH.dbd.CH--, --CH.sub.2CH.sub.2--,
--CH.sub.2O--, --CH.sub.2OCH.sub.2--, --CH.sub.2CH.sub.2O--, --S--,
--SCH.sub.2--, CH.sub.2S--, --CH.sub.2SCH.sub.2--, --C(O)NH--,
--C(O)N(R.sub.7)--, --NHC(O)--, --N(R.sub.7)C(O)--, --S(O)--,
--S(O.sub.2)--, --S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.7)--,
--N(H)S(O).sub.2--, --N(R.sub.7)S(O).sub.2-- wherein the point of
attachment of divalent linking groups, X, to R.sub.3 in the
Formulas I and II is to the right; Y is a bond or a divalent
linking group selected from --O--, --OCH.sub.2--, --OCH(R.sub.7),
--OCH.sub.2CH.sub.2--, --CH.sub.2--, --C(O)--, --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, --CH.sub.2O--, --CH.sub.2OCH.sub.2--,
--CH.sub.2CH.sub.2O--, --S--, --SCH.sub.2--, CH.sub.2S--,
--CH.sub.2SCH.sub.2--, --C(O)NH--, --C(O)N(R.sub.7)--, --NHC(O)--,
--N(R.sub.7)C(O)--, --S(O)--, --S(O.sub.2)--, --S(O).sub.2N(H)--,
--S(O).sub.2N(R.sub.7)--, --N(H)S(O).sub.2--,
--N(R.sub.7)S(O).sub.2-- wherein the point of attachment of
divalent linking groups, Y, to R.sub.4 in the Formulas I and II is
to the right; R.sub.3 is (a) C.sub.1-C.sub.7 alkyl optionally and
independently interrupted by one or more --O--, --S--, --S(O)--,
and --S(O).sub.2-- groups,
[0014] (b) (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
[0015] (c) heterocycloalkylalkyl, or
[0016] (d) a group Z, wherein Z is a mono- or bi-cyclic ring system
having 3 to 10 ring atoms independently selected from C, N, O and
S, provided that not more than 3 ring atoms in any single ring are
other than C, said ring system optionally bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. In the
case where R.sub.3 is a mono- or bi-cyclic ring system having 5 to
10 ring atoms, the attachment site may be either at a carbon atom
or a nitrogen atom of the mono- or bi-cyclic ring system provided
that only three bonds are made to nitrogen;
R.sub.4 is a (a) C.sub.1-C.sub.7 alkyl group optionally and
independently interrupted by one or more --O--, --S--, --S(O)--, or
--S(O).sub.2-- groups,
[0017] (b) (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
[0018] (c) heterocycloalkylalkyl or
[0019] (d) a group Z, wherein Z is a mono- or bi-cyclic ring system
having 5 to 10 ring atoms independently selected from C, N, O and
S, provided that not more than 3 ring atoms in any single ring are
other than C, said ring system optionally bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. In the
case where R.sub.4 is a mono- or bi-cyclic ring system having 5 to
10 ring atoms, the attachment site may be either at a carbon atom
or a nitrogen atom of the mono- or bi-cyclic ring system provided
that only three bonds are made to nitrogen; and
R.sub.5 is selected from: NO.sub.2, NH.sub.2, aryl, heteroaryl, F,
Cl, Br, CN, OH, C.sub.1-C.sub.4 alkoxy, SR.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2N(R.sub.7).sub.2, (C.sub.1-C.sub.4)
alkyl, (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl,
--O--(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl, and
(C.sub.2-C.sub.4) alkynyl, wherein each alkyl or cycloalkyl is
optionally independently substituted with one or more halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl provided that
one or both of R.sub.3 and R.sub.4 is Z.
[0020] In one embodiment R.sub.1 and R.sub.2 are taken together
form a 3-7 membered cycloalkyl or heterocycloalkyl ring. In another
embodiment R.sub.1 is hydrogen and R.sub.2 is F, R.sub.6, OH,
OR.sub.6, SR.sub.6, NHR.sub.7, N(R.sub.7).sub.2 NHC(O)R.sub.6,
NHCO.sub.2R.sub.6 wherein R.sub.6 and R.sub.7 are as defined
previously. In a further embodiment R.sub.1 is hydrogen and R.sub.2
is R.sub.6, OR.sub.6 or SR.sub.6. In an additional embodiment
R.sub.1 is hydrogen and R.sub.2 is alkyl, alkoxy or thioalkyl. In
another embodiment R.sub.1 is hydrogen and R.sub.2 is R.sub.6. In a
further embodiment R.sub.1 is hydrogen and R.sub.2 is C1-C4
alkyl.
[0021] In one embodiment X is a bond. In another embodiment X is a
divalent linking group selected from --O--, --OCH.sub.2--,
--OCH(R.sub.7)--, --OCH.sub.2CH.sub.2--, --CH.sub.2--, --C(O)--,
--CH.dbd.CH--, --CH.sub.2CH.sub.2--, --CH.sub.2O--,
--CH.sub.2OCH.sub.2--, --CH.sub.2CH.sub.2O--, --S--, --SCH.sub.2--,
CH.sub.2S--, --CH.sub.2SCH.sub.2--, --C(O)NH--, --C(O)N(R.sub.7)--,
--NHC(O)--, --N(R.sub.7)C(O)--, --S(O)--, --S(O.sub.2)--,
--S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.7)--, --N(H)S(O).sub.2--,
--N(R.sub.7)S(O).sub.2-- wherein the point of attachment of
divalent linking groups, X, to R.sub.3 in the Formulas I and II is
to the right. In another embodiment X is --O--, --OCH.sub.2--,
--OCH(R.sub.7)--, CH.sub.2O--, --S--, --S(O).sub.2--,
--S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.7)--, --C(O)NH-- or
--C(O)N(R.sub.7)--. In a further embodiment X is --O--,
--S(O).sub.2--, --S(O).sub.2N(H)-- or --S(O).sub.2N(R.sub.7)--. In
another embodiment X is --O-- or --S(O).sub.2--.
[0022] In one embodiment Y is a bond. In another embodiment Y is a
divalent linking group selected from --O--, --OCH.sub.2--,
--OCH(R.sub.7)--, --OCH.sub.2CH.sub.2--, --CH.sub.2--, --C(O)--,
--CH.dbd.CH--, --CH.sub.2CH.sub.2--, --CH.sub.2O--,
--CH.sub.2OCH.sub.2--, --CH.sub.2CH.sub.2O--, --S--, --SCH.sub.2--,
CH.sub.2S--, --CH.sub.2SCH.sub.2, --C(O)NH--, --C(O)N(R.sub.7)--,
--NHC(O)--, --N(R.sub.7)C(O)--, --S(O)--, --S(O.sub.2)--,
--S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.7)--, --N(H)S(O).sub.2--,
--N(R.sub.7)S(O).sub.2-- wherein the point of attachment of
divalent linking groups, X, to R.sub.3 in the Formulas I and II is
to the right. In another embodiment Y is --O--, --OCH.sub.2--,
--OCH(R.sub.7)--CH.sub.2O--, --S--, --S(O).sub.2--,
--S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.7)--, --C(O)NH-- or
--C(O)N(R.sub.7)--. In a further embodiment Y is --O--,
--S(O).sub.2--, --S(O).sub.2N(H)-- or --S(O).sub.2N(R.sub.7)--. In
another embodiment Y is --O-- or --S(O).sub.2--.
[0023] In one embodiment R.sub.3 is a C1-C7 alkyl group optionally
interrupted by --O--, --S--, --S(O)--, or --S(O).sub.2-- groups. In
another embodiment R.sub.3 is a C1-C7 alkyl group. In a further
embodiment R.sub.3 is a C1-C4 alkyl group examples include but are
not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In
another embodiment R.sub.3 is a cycloalkylalkyl group with examples
including but not limited to cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl and cyclohexylmethyl. In another embodiment
R.sub.3 is heterocycloalkylalkyl. In another embodiment R.sub.3 is
a group Z as defined above wherein Z is a mono- or bi-cyclic ring
system having 5 to 10 ring atoms independently selected from C, N,
O and S, provided that not more than 3 ring atoms in any single
ring are other than C, said ring system optionally bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. In the
latter embodiment Z comprises mono- or bi-cyclic ring system ring
systems that furthermore may be fully saturated, partially
saturated or aromatic. Examples of monocyclic ring systems that are
fully saturated include but are not limited to 5-6 membered ring
systems such as cyclohexyl, cyclopentanyl, piperazinyl,
tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring
systems that are partially saturated include but are not limited to
5-6 membered ring systems such as cyclohexenyl, cyclopentenyl,
dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of
monocyclic ring systems that are aromatic include but are not
limited to 5-6 membered ring systems such as phenyl, pyridyl,
pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl,
thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of
bicyclic ring systems that are fully saturated include but are not
limited to 9-10 membered bicyclic ring systems such as decalinyl,
decahydroquinolinyl and decahydroisoquinolinyl. Examples of
bicyclic ring systems that are partially saturated include but are
not limited to 9-10 membered bicyclic ring systems such as
tetrahydronapthyl, tetrahydroquinolinyl and
tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are
aromatic include but are not limited to 9-10 membered bicyclic ring
systems such as napthyl, indolyl, indazolyl, benzimidazolyl,
benzthiadiazolyl and imidazopyridinyl. In one further embodiment
the mono- or bi-cyclic ring system ring system comprises up to 2
nitrogen atoms and up to 1 sulfur or oxygen atoms.
[0024] In one embodiment R.sub.4 is a C1-C7 alkyl group optionally
interrupted by --O--, --S--, --S(O)--, or --S(O).sub.2-- groups. In
another embodiment R.sub.4 is a C1-C7 alkyl group. In a further
embodiment R.sub.4 is a C1-C4 alkyl group examples include but are
not limited to methyl, ethyl, cyclopropylmethyl, trifluoroethyl. In
another embodiment R.sub.4 is a cycloalkylalkyl group with examples
including but not limited to cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl and cyclohexylmethyl. In another embodiment
R.sub.4 is heterocycloalkylalkyl. In another embodiment R.sub.4 is
a group Z as defined above wherein Z is a mono- or bi-cyclic ring
system having 5 to 10 ring atoms independently selected from C, N,
O and S, provided that not more than 3 ring atoms in any single
ring are other than C, said ring system optionally bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. In the
latter embodiment Z comprises mono- or bi-cyclic ring system ring
systems that furthermore may be fully saturated, partially
saturated or aromatic. Examples of monocyclic ring systems that are
fully saturated include but are not limited to 5-6 membered ring
systems such as cyclohexyl, cyclopentanyl, piperazinyl,
tetrahydrofuranyl and piperidinyl. Examples of monocyclic ring
systems that are partially saturated include but are not limited to
5-6 membered ring systems such as cyclohexenyl, cyclopentenyl,
dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples of
monocyclic ring systems that are aromatic include but are not
limited to 5-6 membered ring systems such as phenyl, pyridyl,
pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl,
thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of
bicyclic ring systems that are fully saturated include but are not
limited to 9-10 membered bicyclic ring systems such as decalinyl,
decahydroquinolinyl and decahydroisoquinolinyl. Examples of
bicyclic ring systems that are partially saturated include but are
not limited to 9-10 membered bicyclic ring systems such as
tetrahydronapthyl, tetrahydroquinolinyl and
tetrahydroisoquinolinyl. Examples of bicyclic ring systems that are
aromatic include but are not limited to 9-10 membered bicyclic ring
systems such as napthyl, indolyl, indazolyl, benzimidazolyl,
benzthiadiazolyl and imidazopyridinyl. In one further embodiment
the mono- or bi-cyclic ring system ring system comprises up to 2
nitrogen atoms and up to 1 sulfur or oxygen atoms.
[0025] Other embodiments include compounds of Formulas III, IV, V,
and VI and pharmaceutically acceptable salts thereof wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as
defined above.
##STR00002##
[0026] Other embodiments include compounds of Formulas VII, VIII,
IX, and X and pharmaceutically acceptable salts thereof wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as
defined above.
##STR00003##
[0027] Other embodiments include compounds of Formulas III, IV, V,
and VI wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are
as defined above and R.sub.1 is hydrogen. Other embodiments include
compounds of Formulas III, IV, V, and VI wherein R.sub.3, R.sub.4,
R.sub.5 and Z are as defined above; R.sub.1 is hydrogen and R.sub.2
is C1-C4 alkyl.
[0028] Other embodiments include compounds of Formulas III, IV, V,
and VI wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, and
Z are as defined above and X and Y are independently chosen from a
bond, --O--, --OCH.sub.2--, --C(O)--, --S--, --S(O).sub.2--,
--S(O).sub.2N(R.sub.7)-- and --N(R.sub.7)S(O).sub.2--. Other
embodiments include compounds of Formulas III, IV, V, and VI
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, and Z are
as defined above and X and Y are independently chosen from a bond,
--O--, --S(O).sub.2-- and --S(O).sub.2N(R.sub.7). Another
embodiment comprises compounds of Formulas III, IV, V, and VI
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, and Z are
as defined above and X and Y are independently chosen from a bond,
--O-- and S(O).sub.2N(R.sub.7). A further embodiment comprises
compounds of Formulas III, IV, V, and VI wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, and Z are as defined above and X and Y
are independently chosen from a bond and --O--.
[0029] Other embodiments include compounds of Formulas III, IV, V,
and VI wherein R.sub.1, R.sub.2, R.sub.5, X, Y and Z are as defined
above and R.sub.3 and R.sub.4 and are independently chosen from a
C1-C7 alkyl optionally and independently interrupted by one or more
--O--, --S--, --S(O)--, and --S(O).sub.2-- groups, cycloalkylalkyl
and heterocycloalkylalkyl. Other embodiments include compounds of
Formulas III, IV, V, and VI wherein R.sub.1, R.sub.2, R.sub.5, X, Y
and Z are as defined above and R.sub.3 and R.sub.4 and are
independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other
embodiments include compounds of Formulas III, IV, V, and VI
wherein R.sub.1, R.sub.2, R.sub.5, Z are as defined above and X, Y
and are independently chosen from a bond, --S--, --SO2- and --O--
and R.sub.3 and R.sub.4 and are independently chosen from C1-C4
alkyl and cyclopropylmethyl. Other embodiments include compounds of
Formulas III, IV, V, and VI wherein R.sub.1, R.sub.2, R.sub.5, X, Y
and Z are as defined above and R.sub.3 and R.sub.4 and are
independently chosen from a group Z wherein Z is as defined
above.
[0030] Other embodiments include compounds of Formulas III, IV, V,
and VI wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, X
and Y are as defined above and Z is a phenyl ring bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. Other
embodiments include compounds of Formulas III, IV, V, and VI
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, X and Y are
as defined above, and Z is a mono- or bi-cyclic ring system having
5 to 10 ring atoms independently selected from C, N, O and S,
provided that not more than 3 ring atoms in any single ring are
other than C, said ring system optionally bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6.
[0031] Other embodiments include compounds of Formulas III, IV, V,
and VI wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 X, Y and Z are as
defined above and R.sub.5 is NO.sub.2, NH.sub.2, F, Cl, Br, CN, OH,
C1-C4 alkoxy, SR.sub.6, S(O).sub.2R.sub.6 or
S(O).sub.2N(R.sub.7).sub.2. Other embodiments include compounds of
Formulas III, IV, V, and VI wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4 X, Y and Z are as defined above and R.sub.5 is aryl or
heteroaryl. Other embodiments include compounds of Formulas III,
IV, V, and VI wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 X, Y and Z
are as defined above and R.sub.5 is chlorine or fluorine.
[0032] Other embodiments include compounds of Formulas VII, VIII,
IX, and X wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z
are as defined above and R.sub.1 is hydrogen. Other embodiments
include compounds of Formulas VII, VIII, IX, and X wherein R.sub.3,
R.sub.4, R.sub.5 and Z are as defined above; R.sub.1 is hydrogen
and R.sub.2 is C1-C4 alkyl.
[0033] Other embodiments include compounds of Formulas VII, VIII,
IX, and X wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5,
and Z are as defined above and X and Y are independently chosen
from a bond, --O--, --OCH.sub.2--, --C(O)--, --S--, --S(O).sub.2--,
--S(O).sub.2N(R.sub.7)-- and --N(R.sub.7)S(O).sub.2--. Other
embodiments include compounds of Formulas VII, VIII, IX, and X
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, and Z are
as defined above and X and Y are independently chosen from a bond,
--O--, --S(O).sub.2-- and --S(O).sub.2N(R.sub.7). Other embodiments
include compounds of Formulas VII, VIII, IX, and X wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5, and Z are as defined above
and X and Y are independently chosen from a bond, --O-- and
S(O).sub.2N(R.sub.7). Other embodiments include compounds of
Formulas VII, VIII, IX, and X wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5, and Z are as defined above and X and Y are
independently chosen from a bond and --O--. Other embodiments
include compounds of Formulas VII, VIII, IX, and X wherein R.sub.1,
R.sub.2, R.sub.5, X, Y and Z are as defined above and R.sub.3 and
R.sub.4 and are independently chosen from a C1-C7 alkyl optionally
and independently interrupted by one or more --O--, --S--,
--S(O)--, and --S(O).sub.2-- groups, cycloalkylalkyl and
heterocycloalkylalkyl. Other embodiments include compounds of
Formulas III, IV, V, and VI wherein R.sub.1, R.sub.2, R.sub.5, X, Y
and Z are as defined above and R.sub.3 and R.sub.4 and are
independently chosen from C1-C4 alkyl and cyclopropylmethyl. Other
embodiments include compounds of Formulas VII, VIII, IX, and X
wherein R.sub.1, R.sub.2, R.sub.5, Z are as defined above and X, Y
and are independently chosen from a bond, --S--, --SO.sub.2-- and
--O-- and R.sub.3 and R.sub.4 and are independently chosen from
C1-C4 alkyl and cyclopropylmethyl. Other embodiments include
compounds of Formulas VII, VIII, IX, and X wherein R.sub.1,
R.sub.2, R.sub.5, X, Y and Z are as defined above and R.sub.3 and
R.sub.4 and are independently chosen from a group Z wherein Z is as
defined above.
[0034] Other embodiments include compounds of Formulas VII, VIII,
IX, and X wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, X
and Y are as defined above and Z is a phenyl ring bearing up to 3
substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6. Other
embodiments include compounds of Formulas VII, VIII, IX, and X
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, X and Y are
as defined above, and Z is a mono- or bi-cyclic ring system having
5 to 10 ring atoms independently selected from C, N, O and S,
provided that not more than 3 ring atoms in any single ring are
other than C, said ring system optionally bearing ring bearing up
to 3 substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6,
OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6, S(O)R.sub.6,
S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7, S(O).sub.2N(R.sub.7).sub.2,
NHR.sub.7, N(R.sub.7).sub.2, NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6,
NHC(O)OR.sub.6, N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6, COR.sub.6.
[0035] Other embodiments include compounds of Formulas VII, VIII,
IX, and X wherein R.sub.1, R.sub.2, R.sub.4 X, Y and Z are as
defined above and R.sub.5 is NO.sub.2, NH.sub.2, F, Cl, Br, CN, OH,
C1-C4 alkoxy, SR.sub.6, S(O).sub.2R.sub.6 or
S(O).sub.2N(R.sub.7).sub.2. Other embodiments include compounds of
Formulas VII, VIII, IX, and X wherein R.sub.1, R.sub.2, R.sub.4 X,
Y and Z are as defined above and R.sub.5 is aryl or heteroaryl.
Other embodiments include compounds of Formulas VII, VIII, IX, and
X wherein R.sub.1, R.sub.2, R.sub.4 X, Y and Z are as defined above
and R.sub.5 is chlorine or fluorine.
[0036] The compounds of formulas I-IX are expected to alter the
activity of .gamma.-secretase and are expected to be useful for the
treatment of Alzheimer's disease and other neurodegenerative
disorders.
[0037] In another embodiment A is CO.sub.2H.
[0038] In another embodiment a compound of formula (I) is
selected.
[0039] In another embodiment a compound of formula (II) is
selected.
[0040] In another embodiment a compound of formula (III) is
selected.
[0041] In another embodiment a compound of formula (IV) is
selected.
[0042] In another embodiment a compound of formula (V) is
selected.
[0043] In another embodiment a compound of formula (VI) is
selected.
[0044] In another embodiment a compound of formula (VII) is
selected.
[0045] In another embodiment a compound of formula (VIII) is
selected.
[0046] In another embodiment a compound of formula (IX) is
selected.
[0047] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, (C.sub.1-C.sub.6)alkyl,
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl, C.sub.1-C.sub.6
alkyl that is independently interrupted by one or more --O--,
--S--, --S(O)--, or --S(O).sub.2-- groups or heterocycloalkylalkyl
wherein each alkyl or cycloalkyl is optionally independently singly
or multiply substituted with halo, hydroxy, cyano, oxo, CF.sub.3,
C.sub.1-C.sub.4 alkyl provided that R.sub.1 and R.sub.2 are not H
simultaneously or
R.sub.1 and R.sub.2 are taken together to form a 3-7 membered
cycloalkyl or heterocycloalkyl ring which are; optionally
independently singly or multiply substituted with halo, hydroxy,
cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl or R.sub.1 and R.sub.2 are
taken together to form a 3-7 membered cycloalkyl ring substituted
with R.sub.20 and R.sub.21 where R.sub.20 and R.sub.21 are taken
together to form a 3-7 membered cycloalkyl ring wherein each
cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl.
[0048] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, (C.sub.1-C.sub.6)alkyl,
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl wherein each
alkyl or cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, cyano, CF.sub.3, C.sub.1-C.sub.4
alkyl provided that R.sub.1 and R.sub.2 are not H
simultaneously.
[0049] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, (C.sub.1-C.sub.6)alkyl, wherein alkyl is
optionally independently singly or multiply substituted with halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl provided that
R.sub.1 and R.sub.2 are not H simultaneously.
[0050] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, (C.sub.3-C.sub.6)alkyl, wherein alkyl is
optionally independently singly or multiply substituted with halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl provided that
R.sub.1 and R.sub.2 are not H simultaneously.
[0051] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, n-propyl, iso-propyl, iso-butyl, n-butyl,
iso-pentyl, and n-pentyl wherein alkyl is optionally independently
singly or multiply substituted with halo, hydroxy, oxo, cyano,
CF.sub.3, C.sub.1-C.sub.4 alkyl provided that R.sub.1 and R.sub.2
are not H simultaneously.
[0052] In another embodiment R.sub.1 is H.
[0053] In another embodiment R.sub.1 is H and R.sub.2 is
n-propyl.
[0054] In another embodiment R.sub.1 is H and R.sub.2 is
iso-butyl.
[0055] In another embodiment R.sub.1 is H and R.sub.2 is
n-butyl.
[0056] In another embodiment R.sub.1 is H and R.sub.2 is
iso-pentyl.
[0057] In another embodiment R.sub.1 is H and R.sub.2 is
n-pentyl.
[0058] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H,
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl wherein
cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl provided that R.sub.1 and R.sub.2 are not H
simultaneously.
[0059] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H,
(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.7)cycloalkyl wherein
cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl provided that R.sub.1 and R.sub.2 are not H
simultaneously.
[0060] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H,
(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.5)cycloalkyl wherein
cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl provided that R.sub.1 and R.sub.2 are not H
simultaneously.
[0061] In another embodiment R.sub.1 is H and R.sub.2 is selected
from cyclopentyl, cyclopropylmethyl and cyclobutylmethyl.
[0062] In another embodiment R.sub.1 is H and R.sub.2 is
cyclopentyl.
[0063] In another embodiment R.sub.1 is H and R.sub.2 is
cyclopropylmethyl.
[0064] In another embodiment R.sub.1 is H and R.sub.2 is
cyclobutylmethyl.
[0065] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which
are; optionally independently singly or multiply substituted with
halo, hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl
or R.sub.1 and R.sub.2 are taken together to form a 3-7 membered
cycloalkyl ring substituted with R.sub.20 and R.sub.21 where
R.sub.20 and R.sub.21 are taken together to form a 3-7 membered
cycloalkyl ring wherein each cycloalkyl is optionally independently
singly or multiply substituted with halo, hydroxy, oxo, cyano,
CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0066] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 3-7 membered cycloalkyl or heterocycloalkyl ring which
are; optionally independently singly or multiply substituted with
halo, hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0067] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 3-7 membered cycloalkyl ring which are; optionally
independently singly or multiply substituted with halo, hydroxy,
oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0068] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a cyclopropyl ring.
[0069] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a cyclobutyl ring.
[0070] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a cyclopentyl ring.
[0071] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a cyclohexyl ring.
[0072] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 3-7 membered cycloalkyl ring substituted with R.sub.20
and R.sub.21 where R.sub.20 and R.sub.21 are taken together to form
a 3-7 membered cycloalkyl ring wherein each cycloalkyl is
optionally independently singly or multiply substituted with halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0073] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 3-7 membered cycloalkyl ring substituted on the same
carbon atom with R.sub.20 and R.sub.21 where R.sub.20 and R.sub.21
are taken together to form a 3-7 membered cycloalkyl ring wherein
each cycloalkyl is optionally independently singly or multiply
substituted with halo, hydroxy, oxo, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl.
[0074] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a spiro[2.3]hexane, a spiro[3.3]heptane or a
spiro[3.4]octane ring system.
[0075] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a spiro[2.3]hexane ring system.
[0076] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a spiro[3.3]heptane ring system.
[0077] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a spiro[3.4]octane ring system.
[0078] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 5,5-disubstituted spiro[2.3]hexane ring system.
[0079] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 2,2-disubstituted spiro[3.3]heptane ring system.
[0080] In another embodiment R.sub.1 and R.sub.2 are taken together
to form a 2,2-disubstituted spiro[3.4]octane ring system.
[0081] In another embodiment R.sub.1 and R.sub.2 are independently
selected from: H, F, OH, OR.sub.6, SR.sub.6, NHR.sub.7,
N(R.sub.7).sub.2 NHC(O)R.sub.6 or NHCO.sub.2R.sub.6 provided that
R.sub.1 and R.sub.2 are not H simultaneously.
[0082] In another embodiment R.sub.1 and R.sub.2 if not H are
unsubstituted, except that when R.sub.1 and R.sub.2 are taken with
the carbon to which they are attached form C.sub.3-C.sub.7 ring,
the ring may be substituted with R.sub.20 and R.sub.21, which
themselves are unsubstituted.
[0083] In another embodiment R.sub.1 and R.sub.2 if not H are
optionally singly or multiply independently substituted with halo,
hydroxy, oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl
[0084] In another embodiment R.sub.1 and R.sub.2 if not H are
singly or multiply independently substituted with halo, hydroxy,
oxo, cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl
[0085] In another embodiment R.sub.6 is C1-C6 alkyl optionally and
independently interrupted by one or more --O--, --S--, --S(O)--, or
--S(O).sub.2-- groups, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.4-C.sub.8) cycloalkylalkyl, heterocycloalkylalkyl.
[0086] In another embodiment R.sub.6 is C.sub.1-C.sub.6 alkyl
optionally and independently interrupted by one or more --O--,
--S--, --S(O)--, or --S(O).sub.2-- groups.
[0087] In another embodiment R.sub.6
(C.sub.3-C.sub.7)cycloalkyl.
[0088] In another embodiment R.sub.6 is a
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl
[0089] In another embodiment R.sub.6 heterocycloalkylalkyl.
[0090] In another embodiment R.sub.6 is (CH.sub.2).sub.nQ.
[0091] In another embodiment R.sub.6 is --CH.sub.2-Q.
[0092] In another embodiment Q is aryl.
[0093] In another embodiment Q is heteroaryl.
[0094] In another embodiment Q is monocyclic heteroaryl.
[0095] In another embodiment Q is bicyclic heteroaryl.
[0096] In another embodiment X is a bond or a divalent linking
group selected from --O--, --OCH.sub.2--, --OCH(R.sub.7)--,
--OCH.sub.2CH.sub.2--, --CH.sub.2--, --C(O)--, --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, --CH.sub.2O--, --CH.sub.2OCH.sub.2,
--CH.sub.2CH.sub.2O--, --S--, --SCH.sub.2--, CH.sub.2S-- or
--CH.sub.2SCH.sub.2--.
[0097] In another embodiment X is a bond or a divalent linking
group selected from --O--, --OCH.sub.2--, --OCH(R.sub.7)--,
--OCH.sub.2CH.sub.2--, --CH.sub.2O--, --CH.sub.2OCH.sub.2-5 or
--CH.sub.2CH.sub.2O.
[0098] In another embodiment X is a bond or a divalent linking
group selected from --CH.sub.2--, --C(O)--, --CH.dbd.CH-- or
--CH.sub.2CH.sub.2--
[0099] In another embodiment X is a bond or a divalent linking
group selected from --S--, --SCH.sub.2-5 CH.sub.2S-- or
--CH.sub.2SCH.sub.2--.
[0100] In another embodiment X is a bond or a divalent linking
group selected from --O-- or --S--.
[0101] In another embodiment X is a bond.
[0102] In another embodiment X is the divalent linking group
--O--.
[0103] In another embodiment X is the divalent linking group
--S--.
[0104] In another embodiment Y is a bond or a divalent linking
group selected from --O--, --OCH.sub.2--, --OCH(R.sub.7)--,
--OCH.sub.2CH.sub.2--, --CH.sub.2--, --C(O)--, --CH.dbd.CH--,
--CH.sub.2CH.sub.2--, --CH.sub.2O--, --CH.sub.2OCH.sub.2--,
--CH.sub.2CH.sub.2O--, --S--, --SCH.sub.2--, CH.sub.2S-- or
--CH.sub.2SCH.sub.2--.
[0105] In another embodiment Y is a bond or a divalent linking
group selected from --O--, --OCH.sub.2--, --OCH(R.sub.7)--,
--OCH.sub.2CH.sub.2--, --CH.sub.2O--, --CH.sub.2OCH.sub.2--, or
--CH.sub.2CH.sub.2O
[0106] In another embodiment Y is a bond or a divalent linking
group selected from --CH.sub.2--, --C(O)--, --CH.dbd.CH-- or
--CH.sub.2CH.sub.2--.
[0107] In another embodiment Y is a bond or a divalent linking
group selected from --S--, --SCH.sub.2--, CH.sub.2S-- or
--CH.sub.2SCH.sub.2--.
[0108] In another embodiment Y is a bond or a divalent linking
group selected from --O-- or --S--.
[0109] In another embodiment Y is a bond.
[0110] In another embodiment Y is the divalent linking group
--O--.
[0111] In another embodiment Y is the divalent linking group
--S--.
[0112] In another embodiment R.sub.3 is a C.sub.1-C.sub.4 alkyl
group.
[0113] In another embodiment R.sub.3 is a C.sub.1-C.sub.3 alkyl
group.
[0114] In another embodiment R.sub.3 is a C.sub.2-C.sub.3 alkyl
group.
[0115] In another embodiment R.sub.3 is selected from ethyl,
n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.
[0116] In another embodiment R.sub.3 is ethyl.
[0117] In another embodiment R.sub.3 is n-propyl.
[0118] In another embodiment R.sub.3 is iso-propyl.
[0119] In another embodiment R.sub.3 is trifluoroethyl.
[0120] In another embodiment R.sub.3 is trifluoropropyl.
[0121] In another embodiment R.sub.3 is a (C.sub.4-C.sub.10)
cycloalkylalkyl group.
[0122] In another embodiment R.sub.3 is a
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0123] In another embodiment R.sub.3 is a (C.sub.3-C.sub.7)
cycloalkyl group.
[0124] In another embodiment R.sub.3 is a
(C.sub.1-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0125] In another embodiment R.sub.3 is a
(C.sub.1)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0126] In another embodiment R.sub.3 is a
(C.sub.1)alkyl-(C.sub.3-C.sub.4) cycloalkyl group.
[0127] In another embodiment R.sub.3 is a cyclopropylmethyl
group.
[0128] In another embodiment R.sub.3 is a cyclobutylmethyl
group.
[0129] In another embodiment R.sub.3 is heterocycloalkylalkyl
group.
[0130] In another embodiment R.sub.3 is represented by the group
Z.
[0131] In another embodiment R.sub.3 is not cyclopropylmethyl
[0132] In another embodiment Z is monocyclic.
[0133] In another embodiment Z is bicyclic
[0134] In another embodiment Z is heteroaryl
[0135] In another embodiment Z is unsubstituted heteroaryl
[0136] In another embodiment Z is benzo[b]thiophenyl,
benzo[c][1,2,5]oxadiazoyl, benzo[c][1,2,5]thiadiazolyl or
benzo[d]thiazolyl
[0137] In another embodiment Z is benzo[b]thiophenyl or
benzo[d]thiazolyl
[0138] In another embodiment Z is benzo[c][1,2,5]oxadiazoyl or
benzo[c][1,2,5]thiadiazolyl
[0139] In another embodiment Z is benzo[b]thiophenyl
[0140] In another embodiment Z is benzo[c][1,2,5]oxadiazoyl
[0141] In another embodiment Z is benzo[c][1,2,5]thiadiazolyl
[0142] In another embodiment Z is benzo[d]thiazolyl
[0143] In another embodiment Z is aryl
[0144] In another embodiment Z is substituted phenyl
[0145] In another embodiment Z is 4-substituted phenyl
[0146] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, OH, C.sub.1-C.sub.4 alkoxy, aryloxy,
heteroaryloxy, OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6,
OC(O)OR.sub.6, OC(O)NHR.sub.7, OC(O)N(R.sub.7).sub.2, SR.sub.6,
S(O)R.sub.6, S(O).sub.2R.sub.6, S(O).sub.2NHR.sub.7,
S(O).sub.2N(R.sub.7).sub.2, NHR.sub.7, N(R.sub.7).sub.2,
NHC(O)R.sub.6, N(R.sub.7)C(O)R.sub.6, NHC(O)OR.sub.6,
N(R.sub.7)C(O)OR.sub.6, N(R.sub.7)C(O)NH(R.sub.7),
N(R.sub.7)C(O)NH(R.sub.7).sub.2, C(O)NH.sub.2, C(O)NHR.sub.7,
C(O)N(R.sub.7).sub.2, CO.sub.2H, CO.sub.2R.sub.6 or COR.sub.6
[0147] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, C.sub.1-C.sub.4 alkoxy, aryloxy,
heteroaryloxy, OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6,
OC(O)OR.sub.6, SR.sub.6, NHR.sub.7, N(R.sub.7).sub.2CO.sub.2H,
CO.sub.2R.sub.6 or COR.sub.6
[0148] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, C.sub.1-C.sub.4 alkoxy, aryloxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6 or
SR.sub.6
[0149] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from halogen, R.sub.6,
CF.sub.3, CN, NO.sub.2, C.sub.1-C.sub.4 alkoxy,
OCH.sub.2CH.sub.2OCH.sub.3, OC(O)R.sub.6, OC(O)OR.sub.6 or
SR.sub.6
[0150] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from halogen, C.sub.1-C.sub.6
alkyl, (C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
CF.sub.3, C.sub.1-C.sub.4 alkoxy, or SR.sub.6
[0151] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from F, Cl, C.sub.1-C.sub.3
alkyl, (C.sub.3-C.sub.6)cycloalkyl, CF.sub.3, C.sub.1-C.sub.4
alkoxy, S--(C.sub.1-C.sub.4)alkyl or
S--(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7)cycloalkyl
[0152] In another embodiment Z is optionally substituted with up to
3 substituents independently selected from F, Cl, C.sub.1-C.sub.3
alkyl, (C.sub.3-C.sub.6)cycloalkyl, CF.sub.3, C.sub.1-C.sub.4
alkoxy, or S--(C.sub.1-C.sub.3)alkyl
[0153] In another embodiment Z is substituted CF.sub.3, OCF.sub.3,
OCH.sub.2CF.sub.3, F, Cl, SMe, Me, Et, iPr
[0154] In another embodiment Z is substituted with F
[0155] In another embodiment Z is substituted with Cl
[0156] In another embodiment Z is substituted with C.sub.1-C.sub.3
alkyl
[0157] In another embodiment Z is substituted with
(C.sub.3-C.sub.6)cycloalkyl
[0158] In another embodiment Z is substituted with CF.sub.3,
[0159] In another embodiment Z is substituted with C.sub.1-C.sub.4
alkoxy
[0160] In another embodiment Z is substituted with
S--(C.sub.1-C.sub.3)alkyl
[0161] In another embodiment R.sub.4 is a C.sub.1-C.sub.7 alkyl
group.
[0162] In another embodiment R.sub.4 is a C.sub.1-C.sub.4 alkyl
group.
[0163] In another embodiment R.sub.4 is a C.sub.1-C.sub.3 alkyl
group.
[0164] In another embodiment R.sub.4 is a C.sub.2-C.sub.3 alkyl
group.
[0165] In another embodiment R.sub.4 is selected from ethyl,
n-propyl, iso-propyl, trifluoroethyl, or trifluoropropyl.
[0166] In another embodiment R.sub.4 is ethyl.
[0167] In another embodiment R.sub.4 is n-propyl.
[0168] In another embodiment R.sub.4 is iso-propyl.
[0169] In another embodiment R.sub.4 is trifluoroethyl.
[0170] In another embodiment R.sub.4 is trifluoropropyl.
[0171] In another embodiment R.sub.4 is a (C.sub.4-C.sub.10)
cycloalkylalkyl group.
[0172] In another embodiment R.sub.4 is a
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0173] In another embodiment R.sub.4 is a (C.sub.3-C.sub.7)
cycloalkyl group.
[0174] In another embodiment R.sub.4 is a
(C.sub.1-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0175] In another embodiment R.sub.4 is a
(C.sub.1)alkyl-(C.sub.3-C.sub.7) cycloalkyl group.
[0176] In another embodiment R.sub.4 is a
(C.sub.1)alkyl-(C.sub.3-C.sub.4) cycloalkyl group.
[0177] In another embodiment R.sub.4 is a cyclopropylmethyl
group.
[0178] In another embodiment R.sub.4 is a cyclobutylmethyl
group.
[0179] In another embodiment R.sub.4 is heterocycloalkylalkyl
group.
[0180] In another embodiment R.sub.4 is represented by the group
Z.
[0181] In another embodiment R.sub.4 is not cyclopropylmethyl
[0182] In another embodiment R.sub.5 is, F, Cl, Br, CN,
C.sub.1-C.sub.4 alkoxy, SR.sub.6, (C.sub.1-C.sub.4) alkyl,
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl,
--(C.sub.3-C.sub.7) cycloalkly or (C.sub.2-C.sub.4) alkynyl, where
each alkyl or cycloalkly is optionally independently singly or
multiply substituted with halo, hydroxy, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl.
[0183] In another embodiment R.sub.5 is, F, Cl, Br, CN,
C.sub.1-C.sub.4 alkoxy, SR.sub.6, (C.sub.1-C.sub.4) alkyl,
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl,
--(C.sub.3-C.sub.7) cycloalkly or (C.sub.2-C.sub.4) alkynyl, where
each alkyl or cycloalkly is optionally independently singly or
multiply substituted with halo, hydroxy, cyano, CF.sub.3,
C.sub.1-C.sub.4 alkyl.
[0184] In another embodiment R.sub.5 is F, Cl, Br, CN,
C.sub.1-C.sub.4 alkoxy, --S--(C.sub.1-C.sub.4)alkyl or
(C.sub.1-C.sub.4) alkyl, where each alkyl is optionally
independently singly or multiply substituted with halo, hydroxy,
cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0185] In another embodiment R.sub.5 is F, Cl, Br, CN,
C.sub.1-C.sub.3 alkoxy --S--(C.sub.1-C.sub.3)alkyl or
(C.sub.1-C.sub.3) alkyl, where each alkyl is optionally
independently singly or multiply substituted with halo, hydroxy,
cyano, CF.sub.3, C.sub.1-C.sub.4 alkyl.
[0186] In another embodiment R.sub.5 is F, Cl, Br or CN.
[0187] In another embodiment R.sub.5 is F or Cl.
[0188] In another embodiment R.sub.5 is F.
[0189] In another embodiment R.sub.5 is Cl.
[0190] In another embodiment R.sub.5 is Br.
[0191] In another embodiment R.sub.5 is CN.
[0192] In another embodiment R.sub.5 is C.sub.1-C.sub.3 alkoxy
--S--(C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3) alkyl.
[0193] In another embodiment R.sub.5 is C.sub.1-C.sub.3 alkoxy.
[0194] In another embodiment R.sub.5 is tri-fluoroethoxy or
tri-fluoropropoxy.
[0195] In another embodiment R.sub.5 is (C.sub.1-C.sub.3)
alkyl.
[0196] In another embodiment R.sub.5 is CF.sub.3.
[0197] In another embodiment R.sub.5 is
--S--(C.sub.1-C.sub.3)alkyl.
[0198] In another embodiment R.sub.5 is --S-Me, --S-Et or
--S--CH.sub.2CF.sub.3.
[0199] In another embodiment R.sub.5 is SR.sub.6.
[0200] In another embodiment R.sub.5 is
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl,
(C.sub.2-C.sub.4) alkynyl, or --(C.sub.3-C.sub.7) cycloalkyl.
[0201] In another embodiment R.sub.5 is
(C.sub.0-C.sub.3)alkyl-(C.sub.3-C.sub.7) cycloalkyl.
[0202] In another embodiment R.sub.5 is (C.sub.2-C.sub.4)
alkynyl.
[0203] In another embodiment R.sub.5 is trifluoroethynyl.
[0204] In another embodiment R.sub.5 is (C.sub.3-C.sub.7)
cycloalkyl.
[0205] In another embodiment R.sub.5 is cyclopropyl.
[0206] In another embodiment R.sub.5 is NO.sub.2 or NH.sub.2.
[0207] In another embodiment R.sub.5 is aryl or heteroaryl.
[0208] In another embodiment the compound is a compound selected
from examples 100-3217.
[0209] In another embodiment a racemic compound described in the
disclosure is selected.
[0210] In another embodiment a single enantiomer of the previous
embodiments is selected.
[0211] In another embodiment a single enantiomer of configuration
(R) of the previous embodiments is selected.
[0212] In another embodiment a single enantiomer of configuration
(S) of the previous embodiments is selected.
[0213] In another embodiment a solvate of a compound of formula
(I-IX) is selected.
[0214] In another embodiment a polymorph of compound of formula
(I-IX) is selected.
[0215] In a separate embodiment, a pharmaceutical composition
comprising of the compound of the previous embodiments and a
pharmaceutically acceptable carrier.
[0216] In a separate embodiment, a method for treating a
neurodegenerative disorder comprising administering to a patient an
effective amount of the pharmaceutical composition of the previous
embodiments.
[0217] In another embodiment a method for treating Alzheimer's
Disease comprising administering to a patient an effective amount
of the pharmaceutical composition of the previous embodiments.
[0218] In the case compounds of Formula (I-IX) may contain
asymmetric centers and exist as different enantiomers or
diastereomers. All enantiomers or diastereomeric forms are embodied
herein.
[0219] Compounds in the disclosure, e.g., compounds of Formulas
I-IX, may be in the form of pharmaceutically acceptable salts. The
phrase "pharmaceutically acceptable" refers to salts prepared from
pharmaceutically acceptable non-toxic bases and acids, including
inorganic and organic bases and inorganic and organic acids. Salts
derived from inorganic bases include lithium, sodium, potassium,
magnesium, calcium and zinc. Salts derived from organic bases
include ammonia, primary (e.g. Tromethamine), secondary and
tertiary amines, and amino acids (e.g. Lysine). Salts derived from
inorganic acids include sulfuric, hydrochloric, phosphoric,
methanesulphonic, hydrobromic. Salts derived from organic acids
include C.sub.1-6 alkyl carboxylic acids, di-carboxylic acids and
tricarboxylic acids such as acetic acid, propionic acid, fumaric
acid, maleic acid, succinic acid, tartaric acid, adipic acid and
citric acid, and alkylsulfonic acids such as methanesulphonic, and
aryl sulfonic acids such as para-tolouene sulfonic acid and benzene
sulfonic acid. For detailed list of slats see P. H. Stahl and C. G.
Wermuth (eds.) "Handbook of Pharmaceutical Salts, Properties,
Selection and Use" Wiley-VCH (ISBN 3-906390-26-8)
[0220] Compounds and pharmaceutically acceptable salts thereof may
be in the form of a solvates. This occurs when a compound of
formula (I-IX)) crystallizes in a manner that it incorporates
solvent molecules into the crystal lattice. Examples of solvents
forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and
acetone. Formulas I-IX cover all solvates of the depicted
compounds.
[0221] Compounds in the disclosure may exist in different crystal
forms known as polymorphs.
[0222] Practitioners of the art will recognize that certain
chemical groups may exist in multiple tautomeric forms. The scope
of this disclosure is meant to include all such tautomeric forms.
For example, a tetrazole may exist in two tautomeric forms, 1-H
tetrazole and a 2-H tetrazole. This is depicted in figure below.
This example is not meant to be limiting in the scope of tautomeric
forms.
##STR00004##
[0223] Practitioners of the art will recognize that certain
electrophilic ketones, may exist in a hydrated form. The scope of
this disclosure is to include all such hydrated forms. For example,
a trifluoromethyl ketone may exist in a hydrated form via addition
of water to the carbonyl group. This is depicted in figure below.
This example is not meant to be limiting in the scope of hydrated
forms.
##STR00005##
Abbreviations used in the following examples and preparations
include: [0224] A.beta. Amyloid-beta [0225] ABL A.beta. lowering
[0226] Ac acyl (Me-C(O)--) [0227] AD Alzheimer's Disease [0228] APP
Amyloid Precursor Protein [0229] Bn Benzyl [0230] b/p brain/plasma
[0231] BSA Bovine serum Albumin [0232] c Cyclo [0233] calcd.
Calculated [0234] cBu Cyclobutyl [0235] c-Bu Cyclobutyl [0236]
c.sub.max Maximal concentration [0237] cPr Cyclopropyl [0238] c-Pr
Cyclopropyl [0239] CHAPS
3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate [0240]
CTF Carboxy Terminal Fragment [0241] CSF Cerebrospinal fluid [0242]
DAPT
N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethy-
l ester [0243] DCC N,N', Dicyclohexylcarbodiimide [0244] DEA
Di-ethylamine [0245] DIEA Di-isopropylethyl amine [0246] DMAP
4-Dimethylamino Pyridine [0247] DMF Dimethylformamide [0248] DMSO
Dimethyl sulfoxide [0249] Dppf 1,4-Bis(diphenylphosphino) ferrocene
[0250] EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
Hydrochloride [0251] EDTA Ethylene Diamine Tetra-acetic Acid [0252]
ELISA Enzyme-Linked Immuno Sorbent Assay [0253] Et.sub.3N
Triethylamine [0254] Eq. Equivalent [0255] g gram(s) [0256] HOBt
1-Hydroxybenzotriazole [0257] HPLC High Pressure Liquid
Chromatography [0258] h Hour(s) [0259] hr Hour(s) [0260] i.v or IV.
Intravenous [0261] KHMDS Potassium Hexamethydisilazide [0262] LC-MS
Liquid Chromatography-Mass Spectrometry [0263] LDA Lithium
Di-isopropylamide [0264] m Multiplet [0265] MeOH Methyl Alcohol or
Methanol [0266] m meta [0267] mcpba meta-chloro perbenzoic acid
[0268] min Minute(s) [0269] mmol millimoles [0270] mmole millimoles
[0271] ul Microliter [0272] .mu.l microliter [0273] Ms Mesylate
[0274] MS Mass Spectrometry [0275] MW Molecular Weight (all values
are .+-.0.05) [0276] n normal [0277] NBS N-Bromosuccinimide [0278]
NCS N-Chlorosuccinimide [0279] NIS N-Iodosuccinimide [0280] NMR
Nuclear Magnetic Resonance [0281] NMM N-Methyl Morpholine [0282]
NSAIDS Non-Steroidal Anti-Inflammatory Drugs [0283] o ortho [0284]
o/n overnight [0285] p para [0286] PBS Phosphate Buffered Saline
[0287] PEPPSI
1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)
palladium(II) dichloride [0288] PhNTf.sub.2
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
[0289] POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp)
palladate (2-) [0290] p.s.i. Pounds per square inch [0291] PPAA
1-Propanephosphonic Acid Cyclic Anhydride [0292] PyBOP.RTM.
Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
[0293] PK Pharmacokinetics [0294] RT (or rt) room temperature
(about 20-25.degree. C.) [0295] s Singlet [0296] sat. Saturated
[0297] sec secondary [0298] t Triplet [0299] tert tertiary [0300]
TBAF Tetra-butyl ammonium fluoride [0301] TFA Trifluoroacetic Acid
[0302] THF Tetrahydrofuran [0303] TMB 3,3' 5,5'
Tetramethylbenzidine [0304] TMS Trimethylsilyl [0305] Tf Triflate
[0306] Ts Tosylate [0307] v/v volume/volume [0308] wt/v
weight/volume
DESCRIPTION OF THE FIGURE
[0309] FIG. 1 demonstrates the desirable effect on A.beta. after
the administration of example 1301
(2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclo-
propylpropanoic acid) to in C57BL/6 mice when give one dose at 30
mg/kg in a Solutol HS 15: Ethanol:Water (15:10:75) formulation
(measuring A.beta. at 3 hours).
DETAILED DESCRIPTION
[0310] Described below are compounds within Formulas I and II as
well as methods for preparing the compounds and using the compounds
to treat one or more symptoms of Alzheimer's disease. The compounds
of the disclosure are gamma secretase modulators (GSMs), i.e.,
compounds that act to shift the relative levels of A.beta. peptides
produced by .gamma.-secretase. In some cases the compounds alter
the relative levels of A.beta. peptides produced by
.gamma.-secretase without significantly changing the total level of
A.beta. peptides produced.
General Reaction Schemes
[0311] The tetrasubstituted benzene compounds of Formulas I and II
may be prepared by multistep organic synthetic routes from known
fluoronitrobenzene and chloronitrobenzene starting materials e.g.
2,4-difluoronitrobenzene, 4-fluoro-2-cyano-nitrobenzene,
3-nitro-4-chlorobenzene, 2,4,5-trifluoronitrobenzene,
2,4,5-trichloronitrobenzene or alternatively from 4-hydroxyphenyl
and 4-aminophenyl acetic acid starting materials by one skilled in
the art of organic synthesis using established organic synthesis
procedures.
[0312] The 1-position acetic acid moiety common to compounds of
Formulas I and II, as the free acid itself or as an ester
derivative thereof, is already present in the case of a
4-hydroxyphenyl acetic acid or 4-hydroxyphenyl acetic acid ester
starting material. In the case of a 4-fluoronitrobenzene starting
materials or intermediates, the acetic acid moiety can be
introduced by standard nucleophilic aromatic substitution of the
4-fluoro group with an unsubstituted malonic ester (eg diethyl
malonate) or a malonic ester derivative already bearing an R.sub.1
group (eg. diethyl 2-isobutylmalonate). Introduction of the
X--R.sub.3 and Y--R.sub.4 groups or intermediate groups that are
further elaborated to X--R.sub.3 and Y--R.sub.4 can be carried out
by substitution or manipulation of suitable 3 or 4-position
functional groups in appropriate starting materials or
intermediates en route to Formulas I and II respectively. In cases
where X or Y is a bond, a 3 or 4-position halogen or triflate group
is replaced with an aryl or heteroaryl group by carbon-carbon bond
forming reaction typically a Suzuki coupling reaction. In cases
where X or Y is O, S or N, a 3 or 4-position halogen (eg the
corresponding 2-fluoro group of a 2,4-difluoronitrobenzene starting
material) substitution reaction is performed using HO--R.sub.3 or
HS--R.sub.3 or H.sub.2N--R.sub.3 and a base (eg NaH,
K.sub.2CO.sub.3) in a suitable solvent (eg DMF). Compounds where X
or Y is --S(O)-- or --S(O.sub.2)-- are prepared by oxidation of
compounds where X or Y is S. Compounds where X or Y is
--S(O).sub.2N(H)--, --S(O).sub.2N(R.sub.5)-- can be prepared by
conversion of a 3 or 4-position nitro group (eg the nitro group of
the nitrobenzene starting material) to a sulfonyl chloride via
Sandmeyer reaction followed by addition of the corresponding amine.
Compounds where X or Y is N(H)S(O).sub.2-- or
--N(R.sub.5)S(O).sub.2-- can be prepared by reduction of a 3 or
4-position nitro group to the corresponding aniline followed by
reaction with the corresponding sulfonylchloride. Compounds where X
or Y is NHC(O)-- or --N(R.sub.5)C(O)-- can be prepared by reduction
of a 3 or 4-position nitro group to the corresponding aniline
followed by reaction with the corresponding carboxylic acid
chloride. Compounds where X or Y is a --C(O)-- can be prepared by
addition of an organometallic reagent (e.g., a Grignard reagent or
organolithium) to a 3 or 4-position cyano group directly or in a
2-step sequence by addition of an organometallic reagent to a 3 or
4-position carboxaldehyde group followed by oxidation. Compounds
where X or Y is --C(O)NH-- or C(O)N(R.sub.5)--)- can be prepared by
addition of a corresponding amine to a 3 or 4-position carboxylic
acid which in turn may be prepared by hydrolysis of a 3 or
4-position cyano group. Either aromatic nucleophilic substitution
of a 2-fluoro-1-nitrobenzene intermediate or alkylation of a 3 or
4-hydroxybenzene intermediate with the corresponding alkyl bromide
or triflate may be used to prepare compounds of Formulas I and II
where the R.sub.4 group is OCH.sub.2CF.sub.3, C2-C4 alkoxy, or
cyclopropyloxymethyl. Compounds wherein the R.sub.4 group is an
alkyl, aryl or heteroaryl group attached by a carbon-carbon bond
may be prepared by a Suzuki coupling reaction. In this process an
aryl or heteroaryl boronic acid or borate ester is reacted with an
intermediate compound having a 3 or 4-position halogen or triflate
group. This method results in replacement of the halogen or
triflate group with an aryl or heteroaryl group which is then
bonded to the intermediate at the carbon atom previously bearing
the boronic acid or ester group. Compounds wherein the R.sub.4
group is a heteroaryl group attached by a carbon-nitrogen bond may
be prepared by reacting a 3 or 4-iodo intermediate with a
heteroaromatic heterocycle having an acidic N--H group under Ulman
reaction or copper catalyzed reaction conditions.
[0313] Compounds of Formulas I and II wherein A=tetrazole may be
prepared from their corresponding nitriles A=CN which are available
via dehydration of the corresponding primary amides A=CONH.sub.2
whose preparation is described above. Thus, treatment of the
nitrile with an azide, such as sodium azide or tributylstanyl azide
(Bu.sub.3SnN.sub.3) at a temperature of 20-100.degree. C.,
optionally with a solvent such as DMF, THF or DMSO.
[0314] Compounds of the disclosure of Formula III in which R.sub.1
is R.sub.8 an alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, R.sub.2 is
R.sub.9 a hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl, or an arylalkyl group, Y is O, X is a
bond, R.sub.3 is Z, R.sub.4 and R.sub.5 are as described previously
and thus having general Formula XXIV may be prepared generally as
depicted in Scheme 1.
##STR00006##
[0315] Thus, as depicted in Scheme 1 an alkyl, cycloalkylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl or arylalkyl
R.sub.8 group is introduced in the first step by treating ethyl
4-benzyloxyphenylacetate one equivalent of a suitable deprotonating
base such as sodium hydride in an appropriate organic solvent
followed by the addition of the corresponding reactive alkyl
bromide R.sub.8Br such as isobutylbromide to yield XX where R.sub.9
is hydrogen. In cases where a second alkyl or aralkyl group is
present this alkylation step is repeated using R.sub.9Br as an
alkylating agent. In cases where a spirocyclic ring is formed by
R.sub.8 and R.sub.9 (e.g. cyclopropyl) then the appropriate
dibromide is used (e.g. dibromoethane in the case of cyclopropyl).
The benzyl group is then removed under standard catalytic
hydrogenation conditions and the resulting phenol is treated with
bromine in acetic acid to give the bromophenol intermediate XXI.
Nitration of XXI then yields nitrophenol intermediate XXII which
then us subjected to a standard base mediated aliphatic or aromatic
nucleophilic substitution reaction with an alkyl or aryl halide
R.sub.4--X to give intermediate XXIII where R.sub.4 is alkyl,
cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, arylalkyl,
heteroarylalkyl, aryl or heteroaryl. This is then followed by
introduction of the Z group by standard reactions. Such reactions
are exemplified by the well established Suzuki coupling of a
substituted aryl or heteroaryl boronic acid derivative
Z--B(OH).sub.2 using a suitable palladium(0) catalyst typically
bearing with phosphine ligands (e.g. Pd(PPh.sub.3).sub.4 or
tetrakistriphenylphosphine) in the case where Z is linked by a
carbon-carbon bond and by copper (eg CuI) mediated Ulman type
coupling of a heteroaryl ring bearing an active N--H group where Z
is a heteroaryl ring linked by a nitrogen-carbon bond.
##STR00007##
[0316] After introduction of the Z group, the nitro group is
converted to the corresponding aniline by any number of standard
reduction conditions (eg SnCl.sub.2 reduction). This is followed by
conversion of the resulting aniline to the diazonium salt which is
then converted "in situ" either directly to R.sub.5 either directly
in the case where R.sub.5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or
SR.sub.6, by using the appropriate copper salt ie CuCl, CuBr, CuCN
or nucleophile ie water, alcohol or thiol or in a subsequent step
e.g. oxidation (eg with MCPBA) of the product of thiol coupling
when R.sub.5 is S(O).sub.2R.sub.6; e.g. Suzuki coupling of the
bromide product when R.sub.5 is heteroaryl e.g. treatment of an
intermediate sulfonylchloride obtained via CuCl/SO.sub.2 conditions
with an amine HN(R.sub.7).sub.2, when R.sub.5 is
S(O).sub.2N(R.sub.7).sub.2, e.g. Burton trifluoromethylation
reaction of the iodide product (Burton, D. J.; Wiemers, D. M. J.
Am. Chem. Soc. 1985, 107, 5014 and 1986, 108, 832; Miller, J. A.,
Coleman, M. C.; Matthews, R. S. J. Org. Chem. 1993, 58, 2637) when
R.sub.5 is CF.sub.3 Standard ester hydrolysis yields compounds of
Formula XXIV.
[0317] Compounds of the disclosure of Formula III in which R.sub.1
is OH, OR.sub.6, SR.sub.6, NHR.sub.7, N(R.sub.7).sub.2
NHC(O)R.sub.6 or NHCO.sub.2R.sub.6; R.sub.2 is H; Y is O, X is a
bond, R.sub.3 is Z, R.sub.4 and R.sub.5 are as described previously
and thus having general Formula XXVII may be prepared generally as
depicted in Scheme 2. Thus, as depicted in Scheme 2 bromination of
intermediates of general Formula XXV, prepared according to Scheme
1, e.g. with N-bromosuccinimide (NBS) yields intermediate XXVI. In
a subsequent step the Br atom is replaced by a suitable alkoxide,
thiolate or masked amine nucleophile (eg azide or N.sub.3). The
product of the latter reaction is either directly subjected to
ester hydrolysis or further processed in optional steps (eg by
conversion the masked amine to an amino group followed by reductive
amination to give mono or dialkylamine derivatives, and optionally
acylation or carbamoylation of such amine derivatives) and then
subjected to final ester hydrolysis to give compounds of Formula
XXVII in which R.sub.10 is OH, OR.sub.6, SR.sub.6, NHR.sub.7,
N(R.sub.7).sub.2 NHC(O)R.sub.6 or NHCO.sub.2R.sub.6
##STR00008##
[0318] Compounds of the disclosure of Formula III and IV in which
R.sub.1 is R.sub.8 an alkyl, cycloalkylalkyl,
heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an
arylalkyl group, R.sub.2 is R.sub.9 a hydrogen, alkyl,
cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, X and Y are a bond, R.sub.3 and R.sub.4 are
respectively Z.sub.1 and Z.sub.2 representing independently chosen
Z groups as defined above and R.sub.5 is as described previously
and thus having general Formula XXX may be prepared generally as
depicted in Scheme 3 starting from compounds of general Formula
XXII which can be prepared as described in Scheme 1.
[0319] Compounds of Formula V in which R.sub.1 is R.sub.8 an alkyl,
cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, or an arylalkyl group, R.sub.2 is R.sub.9 a
hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl; X is Q=O, S, or SO.sub.2; R.sub.5 is
F or Cl; R.sub.3 and Z are as described previously and thus having
general Formula XXXIV may be prepared generally as depicted in
Scheme 4. Accordingly, the 4-halo group of
2,4,5-trifluoronitrobenzene or 2,4,5-trichloronitrobenzene is
selectively displaced by reaction with a 2-substituted
diethylmalonate R.sub.8YCH(CO.sub.2Et).sub.2 under basic conditions
(eg NaH/DMF) followed by hydrolysis and esterification to give
intermediate XXXI. Subsequently the 2-halo group undergoes
nucleophilic aromatic substitution reaction by treatment with a
R.sub.3-J-H compound (wherein J is O, S) under basic conditions (eg
NaH/DMF) followed by reduction and Sandmeyer reaction to give
iodide XXXII.
##STR00009##
[0320] Suzuki coupling then gives intermediates of general formula
XXXIII. Introduction of an R.sub.9 group may be conducted using
alkylation conditions described above. Compounds wherein J is
SO.sub.2 may be prepared by standard oxidation of intermediates
XXXIII wherein J is S. Final products having general Formula XXXIV
are then prepared by standard ester hydrolysis.
[0321] Compounds of Formula IV in which R.sub.1 is R.sub.8 an
alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, or an arylalkyl group, R.sub.2 is R.sub.9 a
hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl; X is O; R.sub.5 is Cl; R.sub.3 and Z
are as described previously and thus having general Formula XXXVIII
may be prepared generally as depicted in Scheme 5. Accordingly, the
4-fluoro group of 2,4-difluoronitrobenzene is selectively displaced
by reaction with a 2-substituted diethylmalonate
R.sub.8CH.sub.2(CO.sub.2Et).sub.2 under basic conditions (eg
NaH/DMF) followed by hydrolysis and esterification to give
intermediate XXXV. Subsequently the 2-halo group undergoes
nucleophilic aromatic substitution reaction by treatment with a
R.sub.3--O--H compound under basic conditions (eg NaH/DMF) followed
by reduction and chlorination reaction (eg with
N-chlorosuccinimide) to give chloroaniline intermediates of general
formula XXXVI. Sandmeyer iodination reaction to followed by Suzuki
coupling then gives intermediates of general formula XXXVII.
Introduction of an R.sub.9 group may be conducted using alkylation
conditions described above. Final products having general Formula
XXXVIII are then prepared by standard ester hydrolysis.
##STR00010##
##STR00011##
[0322] Compounds of Formula IV in which R.sub.1 is R.sub.8 an
alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, or an arylalkyl group, R.sub.2 is R.sub.9 a
hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl; X is J=O, S; R.sub.5 is NO.sub.2,
NH.sub.2, CN, SR.sub.6, SO.sub.2R.sub.6, SO.sub.2N(R.sub.7).sub.2
F, Cl, Br; R.sub.3 and Z are as described previously and thus
having general Formula XLII may be prepared generally as depicted
in Scheme 6. Accordingly, the 2-fluoro group of
2,4-difluoronitrobenzene is selectively displaced by reaction with
a an alcohol or thiol of formula R.sub.3-J-H under basic conditions
(eg NaH/DMF). The 4-fluoro group of the resulting product is
substituted with diethylmalonate under basic conditions (eg
NaH/DMF) followed by hydrolysis and esterification to give
intermediates of Formula XXXIX. Reduction of the nitro group of
XXXIX followed by nitration of the resulting aniline give
nitroaniline intermediates of Formula XL. Sandmeyer iodination
reaction, followed by Suzuki coupling and finally alkylation
reaction to introduce R.sub.8 then gives intermediates of general
Formula XLI. The nitro group of XLI may be optionally reduced via
any number of standard reduction conditions (eg SnCl.sub.2) to an
aniline which may in turn optionally be converted to diverse other
R.sub.5 groups either directly or in multistep procedures. Thus, in
the case where R.sub.5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or
SR.sub.6, diazotization of the aniline is followed by direct "in
situ" conversion to R.sub.5 using the appropriate copper salt ie
CuCl, CuBr, CuCN or nucleophile ie water, alcohol or thiol.
Intermediates where R.sub.5 is S(O).sub.2R.sub.6 may be prepared by
subsequent step oxidation (eg with MCPBA) of the above products of
thiol coupling wherein R.sub.5 is SR.sub.6. Intermediates where
R.sub.5 is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be
prepared by subsequent Suzuki coupling of the above products
wherein R.sub.5 is Br or I. Intermediates where R.sub.5 is CF3 may
be prepared by Burton reaction of the above products wherein
R.sub.5 is I. Intermediates where R.sub.5 is
S(O).sub.2N(R.sub.7).sub.2, may be prepared by subsequent reaction
of above direct sulfonylchloride products (obtained via
CuCl/SO.sub.2 conditions) with an amine HN(R.sub.7).sub.2, Final
products having general Formula XLII are then prepared by optional
alkylation reaction to introduce R.sub.9 followed by standard ester
hydrolysis.
ll
##STR00012##
[0323] Compounds of Formula VII in which R.sub.1 is R.sub.8 an
alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, or an arylalkyl group, R.sub.2 is R.sub.9 a
hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl; X is J=O, S; R.sub.5 is NO.sub.2,
NH.sub.2, CN, SR.sub.6, SO.sub.2R.sub.6, SO.sub.2N(R.sub.7).sub.2
F, Cl, Br; R.sub.3 and Z are as described previously and thus
having general Formula XLV may be prepared generally as depicted in
Scheme 7. Reduction of the nitro group of XXXIX followed by
bromination (eg with NBS) of the resulting aniline and prepared by
1 alkylation reaction to introduce R.sub.9 gives bromoaniline
intermediates of Formula XLIII Suzuki coupling reaction substitutes
Z groups for the Br group to give intermediates of general Formula
XLIV. The aniline group in intermediates of Formula XLIV may in
turn optionally be converted to diverse other R.sub.5 groups either
directly or in multistep procedures. Thus, in the case where
R.sub.5 is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR.sub.6,
diazotization of the aniline is followed by direct "in situ"
conversion to R.sub.5 using the appropriate copper salt ie CuCl,
CuBr, CuCN or nucleophile ie water, alcohol or thiol. Intermediates
where R.sub.5 is S(O).sub.2R.sub.6 may be prepared by subsequent
step oxidation (eg with MCPBA) of the above products of thiol
coupling wherein R.sub.5 is SR.sub.6. Intermediates where R.sub.5
is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be prepared by
subsequent Suzuki coupling of the above products wherein R.sub.5 is
Br or I. Intermediates where R.sub.5 is CF3 may be prepared by
Burton reaction of the above products wherein R.sub.5 is I.
Intermediates where R.sub.5 is S(O).sub.2N(R.sub.7).sub.2, may be
prepared by subsequent reaction of above direct sulfonylchloride
products (obtained via CuCl/SO.sub.2 conditions) with an amine
HN(R.sub.7).sub.2, Final products having general Formula XLII are
then prepared by optional alkylation reaction to introduce R.sub.9
followed by standard ester hydrolysis.
##STR00013##
[0324] Compounds of Formula IV in which R.sub.1 is R.sub.8 an
alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,
heteroarylalkyl, or an arylalkyl group, R.sub.2 is R.sub.9 a
hydrogen, alkyl, cycloalkylalkyl, heterocycloalkylalkyl,
alkoxyalkyl, heteroarylalkyl; X--R.sub.3 and R.sub.5 are identical
(J-R.sub.3 in Scheme 8) and are either C1-C4 alkoxy or SR.sub.6
groups; and Z is as described previously and thus having general
Formula L may be prepared generally as depicted in Scheme 8.
Accordingly, the 2 and 6-fluoro groups of
2,4,6-trifluoronitrobenzene are selectively displaced by reaction
with a an alcohol or thiol of formula R.sub.3-J-H under basic
conditions (eg NaH/DMF). The 4-fluoro group of the resulting
product is substituted with diethylmalonate under basic conditions
(eg NaH/DMF) followed by hydrolysis and esterification to give
intermediates of Formula XLVIII. Reduction of the nitro group of
followed by Sandmeyer iodination reaction of the resulting aniline
gives intermediates of Formula XLVIII. Suzuki coupling and followed
by alkylation reaction to introduce R.sub.8 then gives
intermediates of general Formula XLIX. Final products having
general Formula L are then prepared by optional alkylation reaction
to introduce R.sub.9 followed by standard ester hydrolysis.
Enantioselective Methods
##STR00014##
[0326] Compounds of formulas I-IX may be prepared in an
enantioselectively, this can be accomplished via resolution via
chiral HPLC (CHIRALPAK-AD H (250.times.4.6 mm, 5 .mu.m). Mobile
phase: Hexane (0.1% TFA):IPA (93:7), Flow rate 0.8 mL/min., Diluent
Hexane:IPA (90:10); Column temperature 40.degree. C.) or via
asymmetric synthesis. The phenyl acetic acids of formula (XXXV) are
converted into the corresponding acid chlorides, via treatment with
SOCl.sub.2 or oxalyl chloride with a catalytic amount of DMF. The
reaction is performed in an inert solvent such as CH.sub.2Cl.sub.2,
CHCl.sub.3, THF, or toluene at a temperature of 0-80.degree. C. The
acid chloride is treated with either (R)- or
(S)-4-benzyloxazolidin-2-one to (R isomer depicted-XXXXVI) give the
oxazolidinone (XXXVII). The oxazolidinone ( ) is then subjected to
a base such as NaHMDs, LiHMDS, KHMDS, BuLi or KO.sup.tBu in an
inert solvent such as THF, Me-THF or Et.sub.2O at a temperature of
-78 to 0.degree. C. The subsequent enolate is then treated with the
appropriate electrophile to give the alkylated oxazolidinone
(XXXVIII). The chiral auxillary is removed under conditions such as
LiOH/H.sub.2O.sub.2 followed by a reductive work up with a reagent
such as sodium bi-sulfite to give the desired products of formulas
(I-IX).
[0327] Alternatively the racemic compound of formula (I-IX) may be
coupled to the Evans chiral oxazolidinone via an intermediate such
as the corresponding acid chloride. Upon completion of the
coupling, the reaction produces a mixture of diastereoisomers which
may be separated by methods such as flash chromatography or
crystallization to give single diastereoisomers or enriched
mixtures favouring one diastereoisomer over the other (see scheme
10). The auxillary may be removed as described previously.
##STR00015##
[0328] Examples of enantiomers include but are not limited to;
[0329]
(R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0330]
(S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0331]
(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-2-cyclopentylacetic acid compound
(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclobutylpropanoic acid [0332]
(R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclopropylpropanoic acid [0333]
(S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclopropylpropanoic acid [0334]
(R)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)biphen-
yl-3-yl)pentanoic acid [0335]
(S)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)biphen-
yl-3-yl)pentanoic acid [0336]
(R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0337]
(S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0338]
(R)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4',5-bis(trifluoromethyl)biphen-
yl-3-yl)pentanoic acid [0339]
(S)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4',5-bis(trifluoromethyl)biphen-
yl-3-yl)pentanoic acid [0340]
(R)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4',5-bis(trifluoromethyl)b-
iphenyl-3-yl)propanoic acid [0341]
(S)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4',5-bis(trifluoromethyl)b-
iphenyl-3-yl)propanoic acid [0342]
(R)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)b-
iphenyl-3-yl)propanoic acid [0343]
(S)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)b-
iphenyl-3-yl)propanoic acid [0344]
(R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0345]
(S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0346]
(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclopropylpropanoic acid [0347]
(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclopropylpropanoic acid [0348]
(R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0349]
(S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0350]
(R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4--
yl)-3-cyclopropylpropanoic acid [0351]
(S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4--
yl)-3-cyclopropylpropanoic acid [0352]
(R)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)b-
iphenyl-4-yl)propanoic acid compound [0353]
(S)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)b-
iphenyl-4-yl)propanoic acid compound [0354]
(R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0355]
(S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0356]
(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-4-methylpentanoic acid [0357]
(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-4-methylpentanoic acid [0358]
(R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0359]
(S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tri-
fluoromethyl)phenyl)-4-methylpentanoic acid [0360]
(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-2-cyclopentylacetic acid [0361]
(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclobutylpropanoic acid [0362]
(R)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-
-cyclopentylacetic acid [0363]
(S)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-
-cyclopentylacetic acid [0364]
(R)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-
-cyclobutylpropanoic acid [0365]
(S)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-
-cyclobutylpropanoic acid [0366]
(R)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid [0367]
(S)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid [0368]
(R)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-
-methylpentanoic acid [0369]
(S)-2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-
-methylpentanoic acid [0370]
(R)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cy-
clopentylacetic acid [0371]
(S)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cy-
clopentylacetic acid [0372]
(R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4--
yl)-4-methylpentanoic acid [0373]
(S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4--
yl)-4-methylpentanoic acid [0374]
(R)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cy-
clobutylpropanoic acid [0375]
(S)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cy-
clobutylpropanoic acid [0376]
(R)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid [0377]
(S)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid [0378]
(R)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-me-
thylpentanoic acid [0379]
(S)-2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-me-
thylpentanoic acid [0380]
(R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0381]
(S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0382]
(R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0383]
(S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0384]
(R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-4-methylpentanoic acid [0385]
(S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-4-methylpentanoic acid [0386]
(R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0387]
(S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0388]
(R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0389]
(S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0390]
(R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0391]
(S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-3-cyclopropylpropanoic acid [0392]
(R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0393]
(S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(tr-
ifluoromethyl)phenyl)-4-methylpentanoic acid [0394]
(R)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)biphen-
yl-4-yl)pentanoic acid [0395]
(S)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4',6-bis(trifluoromethyl)biphen-
yl-4-yl)pentanoic acid
[0396] In a further aspect the compounds of the disclosure are
embodied in with distinct examples listed in Tables below.
TABLE-US-00001 TABLE 1 Formula III ##STR00016## Ex R1 R2 Y R4 R5 Z
100 CH3 H O CH2CH3 F 4-fluorophenyl 101 CH2CH3 H O CH2CH3 F
4-fluorophenyl 102 CH2CF3 H O CH2CH3 F 4-fluorophenyl 103 CH2CH2CH3
H O CH2CH3 F 4-fluorophenyl 104 CH2CH(CH3)2 H O CH2CH3 F
4-fluorophenyl 105 cyclopropylmethyl H O CH2CH3 F 4-fluorophenyl
106 SCH(CH3)2 H O CH2CH3 F 4-fluorophenyl 107 OCH2CH3 H O CH2CH3 F
4-fluorophenyl 108 (CH2)2 O CH2CH3 F 4-fluorophenyl 109 (CH2)4 O
CH2CH3 F 4-fluorophenyl 110 CH3 H O CH2CH3 F 4-chlorophenyl 111
CH2CH3 H O CH2CH3 F 4-chlorophenyl 112 CH2CF3 H O CH2CH3 F
4-chlorophenyl 113 CH2CH2CH3 H O CH2CH3 F 4-chlorophenyl 114
CH2CH(CH3)2 H O CH2CH3 F 4-chlorophenyl 115 cyclopropylmethyl H O
CH2CH3 F 4-chlorophenyl 116 SCH(CH3)2 H O CH2CH3 F 4-chlorophenyl
117 OCH2CH3 H O CH2CH3 F 4-chlorophenyl 118 (CH2)2 O CH2CH3 F
4-chlorophenyl 119 (CH2)4 O CH2CH3 F 4-chlorophenyl 120 CH3 H O
CH2CH3 F 4-trifluoromethylphenyl 121 CH2CH3 H O CH2CH3 F
4-trifluoromethylphenyl 122 CH2CF3 H O CH2CH3 F
4-trifluoromethylphenyl 123 CH2CH2CH3 H O CH2CH3 F
4-trifluoromethylphenyl 124 CH2CH(CH3)2 H O CH2CH3 F
4-trifluoromethylphenyl 125 cyclopropylmethyl H O CH2CH3 F
4-trifluoromethylphenyl 126 SCH(CH3)2 H O CH2CH3 F
4-trifluoromethylphenyl 127 OCH2CH3 H O CH2CH3 F
4-trifluoromethylphenyl 128 (CH2)2 O CH2CH3 F
4-trifluoromethylphenyl 129 (CH2)4 O CH2CH3 F
4-trifluoromethylphenyl 130 CH3 H O CH2CH3 F 4-methoxyphenyl 131
CH2CH3 H O CH2CH3 F 4-methoxyphenyl 132 CH2CF3 H O CH2CH3 F
4-methoxyphenyl 133 CH2CH2CH3 H O CH2CH3 F 4-methoxyphenyl 134
CH2CH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 135 cyclopropylmethyl H O
CH2CH3 F 4-methoxyphenyl 136 SCH(CH3)2 H O CH2CH3 F 4-methoxyphenyl
137 OCH2CH3 H O CH2CH3 F 4-methoxyphenyl 138 (CH2)2 O CH2CH3 F
4-methoxyphenyl 139 (CH2)4 O CH2CH3 F 4-methoxyphenyl 140 CH.sub.3
H O CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 141 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 142 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 143 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 144
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 145 cyclopropylmethyl H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 146 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 147 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 148 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 149 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 150 CH.sub.3 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 151 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 152 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 153
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 154 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 155 cyclopropylmethyl H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 156
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 157 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 158 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 159
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 160 CH.sub.3 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 161 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 162 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 163
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 164 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 165 cyclopropylmethyl H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 166
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 167 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 168 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 169
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 170 CH.sub.3 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 171
CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 172
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 173
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 174
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 4-fluorophenyl
175 cyclopropylmethyl H O CH.sub.2CF.sub.3 F 4-fluorophenyl 176
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 177
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-fluorophenyl 178
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 4-fluorophenyl 179
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 4-fluorophenyl 180 CH.sub.3 H
O CH.sub.2CF.sub.3 F 4-chlorophenyl 181 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 182 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 183 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 184 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 F 4-chlorophenyl 185 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 186 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 187 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-chlorophenyl 188 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 4-chlorophenyl 189 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 F 4-chlorophenyl 190 CH.sub.3 H O CH.sub.2CF.sub.3
F 4-trifluoromethylphenyl 191 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3
F 4-trifluoromethylphenyl 192 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3
F 4-trifluoromethylphenyl 193 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 194
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
4-trifluoromethylphenyl 195 cyclopropylmethyl H O CH.sub.2CF.sub.3
F 4-trifluoromethylphenyl 196 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 197 OCH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 198 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 199 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 200 CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 201 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 202 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 203 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 204 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 F 4-methoxyphenyl 205 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 206 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 207 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 208 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 209 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 F 4-methoxyphenyl 210 CH.sub.3 H O
CH.sub.2CF.sub.3 F 3,4 dichloro phenyl 211 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 3,4 dichloro phenyl 212 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 3,4 dichloro phenyl 213 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2CF.sub.3 F 3,4 dichloro phenyl 214
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 215 cyclopropylmethyl H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 216 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 217 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 218 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 219 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 220 CH.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 221 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 222 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 223
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 224 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 225 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 226
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 227 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- oxadiazolyl 228 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- oxadiazolyl 229
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
oxadiazolyl 230 CH.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 231 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 232 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 233
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 234 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 235 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 236
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 237 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]- thiadiazolyl 238 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]- thiadiazolyl 239
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]-
thiadiazolyl 240 CH.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 241
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 242
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 243
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 244
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 4-fluorophenyl 245
cyclopropylmethyl H O CH.sub.2-c-Pr F 4-fluorophenyl 246
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 4-fluorophenyl 247
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 248
(CH.sub.2).sub.2 0 CH.sub.2-c-Pr F 4-fluorophenyl 249
(CH.sub.2).sub.4 0 CH.sub.2-c-Pr F 4-fluorophenyl 250 CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 251 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 252 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 253 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 254 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 4-chlorophenyl 255 cyclopropylmethyl H O
CH.sub.2-c-Pr F 4-chlorophenyl 256 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 4-chlorophenyl 257 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 258 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
F 4-chlorophenyl 259 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F
4-chlorophenyl 260 CH.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 261 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 262 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 263 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 264
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 265 cyclopropylmethyl H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 266 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 267 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 268 (CH.sub.2).sub.2 0 CH.sub.2-c-Pr F
4-trifluoromethylphenyl 269 (CH.sub.2).sub.4 0 CH.sub.2-c-Pr F
4-trifluoromethylphenyl 270 CH.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 271 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 272 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 273 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 274 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-methoxyphenyl 275 cyclopropylmethyl H O CH.sub.2-c-Pr F
4-methoxyphenyl 276 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-methoxyphenyl 277 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 278 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F
4-methoxyphenyl 279 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F
4-methoxyphenyl 280 CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 281 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl
282 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl 283
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl
284 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 285 cyclopropylmethyl H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 286 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 287 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 288 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F 3,4 dichloro phenyl
289 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F 3,4 dichloro phenyl 290
CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 291
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl
292 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]-
oxadiazolyl 293 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]- oxadiazolyl 294 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl
295 cyclopropylmethyl H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]-
oxadiazolyl 296 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]- oxadiazolyl 297 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 298 (CH.sub.2).sub.2
O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl 299
(CH.sub.2).sub.4 O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- oxadiazolyl
300 CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl
301 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]-
thiadiazolyl 302 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]- thiadiazolyl 303 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 304
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]-
thiadiazolyl 305 cyclopropylmethyl H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]- thiadiazolyl 306 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 307
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]-
thiadiazolyl 308 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]- thiadiazolyl 309 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]- thiadiazolyl 310 CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 311 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 312 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 313 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 314 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 Cl 4-fluorophenyl 315 cyclopropylmethyl H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 316 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 317 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 318 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 319 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 Cl 4-fluorophenyl 320 CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 321 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 322 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 323 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 324 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 325 cyclopropylmethyl H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 326 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 327 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 328 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 329 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 Cl 4-chlorophenyl 330 CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 331 CH.sub.2CH.sub.3 H
O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 332 CH.sub.2CF.sub.3
H O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 333
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 334 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 335 cyclopropylmethyl H
O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 336
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl
337 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 338 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 339 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 340 CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-methoxyphenyl 341 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-methoxyphenyl 342 CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl
4-methoxyphenyl 343 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3
Cl 4-methoxyphenyl 344 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 345 cyclopropylmethyl H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 346 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 347 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 348 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 349 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 350 CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 351 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 352 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 353
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 3,4 dichloro
phenyl 354 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 355 cyclopropylmethyl H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 356 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 357 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 358 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 359 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 360 CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 361 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 362
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 363 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 364 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 365
cyclopropylmethyl H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 366 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 367 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 368
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 369 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 370 CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 371 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 372
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 373 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 374 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 375
cyclopropylmethyl H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 376 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 377 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 378
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 379 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 380 CH.sub.3 H O CH.sub.2CF.sub.3
Cl 4-fluorophenyl 381 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 382 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 383 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 384 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
Cl 4-fluorophenyl 385 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 386 SCH(CH.sub.3)2 H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 387 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 388 (CH.sub.2).sub.2 0 O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 389 (CH.sub.2).sub.4 0 O CH.sub.2CF.sub.3 Cl
4-fluorophenyl 400 CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl
401 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 402
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 403
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 404
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl
405 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 406
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 407
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 408
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 409
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 410 CH.sub.3
H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 411
CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
412 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 413 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 414
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 415 cyclopropylmethyl H O CH.sub.2CF.sub.3
Cl 4-trifluoromethylphenyl 416 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 417 OCH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 418 (CH.sub.2).sub.2
O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 419 (CH.sub.2).sub.4
O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 420 CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 421 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 422 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 423 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 424
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl
425 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 426
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 427
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 428
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 429
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 430 CH.sub.3
H O CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 431 CH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 432 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 433
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 3,4 dichloro
phenyl 434 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 435 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 436 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 437 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 438 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 439 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 440 CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 441 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 442
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 443 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 444 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 445
cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 446 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 447 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- oxadiazolyl 448
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
oxadiazolyl 449 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- oxadiazolyl 450 CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 451 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 452
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 453 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 454 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 455
cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 456 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 457 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]- thiadiazolyl 458
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]-
thiadiazolyl 459 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]- thiadiazolyl 460 CH.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 461 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 462 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 463 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 464 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 465 cyclopropylmethyl H O CH.sub.2-c-Pr Cl
4-fluorophenyl 466 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 467 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 468 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl
4-fluorophenyl 469 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl
4-fluorophenyl 470 CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 471
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 472
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 473
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 474
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 475
cyclopropylmethyl H O CH.sub.2-c-Pr Cl 4-chlorophenyl 476
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 477
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 478
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-chlorophenyl 479
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-chlorophenyl 480 CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 481 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 482 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 483
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-trifluoromethylphenyl 484 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 485 cyclopropylmethyl H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 486 SCH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 487 OCH.sub.2CH.sub.3 H
O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 488 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 489 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 490 CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 491 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 492 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 493 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl
494 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-methoxyphenyl
495 cyclopropylmethyl H O CH.sub.2-c-Pr Cl 4-methoxyphenyl 496
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-methoxyphenyl 497
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-methoxyphenyl 498
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-methoxyphenyl 499
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-methoxyphenyl 500 CH.sub.3 H
O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 501 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 502 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 503 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 504
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl
505 cyclopropylmethyl H O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 506
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 507
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 508
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 509
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 3,4 dichloro phenyl 510
CH.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 511
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
oxadiazolyl 512 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- oxadiazolyl 513 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 514
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
oxadiazolyl 515 cyclopropylmethyl H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- oxadiazolyl 516 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- oxadiazolyl 517
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
oxadiazolyl 518 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- oxadiazolyl 519 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
Cl 5-benzo[c][1,2,5]- oxadiazolyl 520 CH.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- thiadiazolyl 521 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 522
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
thiadiazolyl 523 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- thiadiazolyl 524 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 525
cyclopropylmethyl H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
thiadiazolyl 526 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]- thiadiazolyl 527 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl 528
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]- thiadiazolyl
529 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]-
thiadiazolyl 530 CH.sub.3 H O CH.sub.2-c-Pr NO2
4-trifluoromethylphenyl 531 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr NO2
4-trifluoromethylphenyl 532 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr NO2
4-trifluoromethylphenyl 533 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr NO2 4-trifluoromethylphenyl 534
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr NO2
4-trifluoromethylphenyl 535 cyclopropylmethyl H O CH.sub.2-c-Pr NO2
4-trifluoromethylphenyl 536 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
NO2 4-trifluoromethylphenyl 537 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
NO2 4-trifluoromethylphenyl 538 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
NO2 4-trifluoromethylphenyl 539 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
NO2 4-trifluoromethylphenyl 540 CH.sub.3 H O CH.sub.2-c-Pr NO2
5-benzo[c][1,2,5]- oxadiazolyl 541 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 542
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]-
oxadiazolyl 543 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr NO2
5-benzo[c][1,2,5]- oxadiazolyl 544 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 545
cyclopropylmethyl H O CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]-
oxadiazolyl 546 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr NO2
5-benzo[c][1,2,5]- oxadiazolyl 547 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl 548
(CH.sub.2).sub.2 O CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]- oxadiazolyl
549 (CH.sub.2).sub.4 O CH.sub.2-c-Pr NO2 5-benzo[c][1,2,5]-
oxadiazolyl 550 CH.sub.3 H O CH.sub.2-c-Pr NH2
4-trifluoromethylphenyl 551 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr NH2
4-trifluoromethylphenyl 552 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr NH2
4-trifluoromethylphenyl 553 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr NH2 4-trifluoromethylphenyl 554
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr NH2
4-trifluoromethylphenyl 555 cyclopropylmethyl H O CH.sub.2-c-Pr NH2
4-trifluoromethylphenyl 556 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
NH2 4-trifluoromethylphenyl 557 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
NH2 4-trifluoromethylphenyl 558 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
NH2 4-trifluoromethylphenyl 559 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
NH2 4-trifluoromethylphenyl
TABLE-US-00002 TABLE 2 Formula V ##STR00017## EX R1 R2 X R3 R5 Z
560 CH.sub.3 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 561
CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 562
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 563
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 564
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 4-fluorophenyl
565 cyclopropyl- H O CH.sub.2CH.sub.3 F 4-fluorophenyl methyl 566
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 567
OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 4-fluorophenyl 568
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 F 4-fluorophenyl 569
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 4-fluorophenyl 570 CH.sub.3 H
O CH.sub.2CH.sub.3 F 4-chlorophenyl 571 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-chlorophenyl 572 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 4-chlorophenyl 573 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-chlorophenyl 574 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 F 4-chlorophenyl 575 cyclopropyl- H O
CH.sub.2CH.sub.3 F 4-chlorophenyl methyl 576 SCH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 F 4-chlorophenyl 577 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-chlorophenyl 578 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 4-chlorophenyl 579 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 F 4-chlorophenyl 580 CH.sub.3 H O CH.sub.2CH.sub.3
F 4-trifluoromethylphenyl 581 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3
F 4-trifluoromethylphenyl 582 CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3
F 4-trifluoromethylphenyl 583 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-trifluoromethylphenyl 584
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F
4-trifluoromethylphenyl 585 cyclopropyl- H O CH.sub.2CH.sub.3 F
4-trifluoromethylphenyl methyl 586 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 F 4-trifluoromethylphenyl 587 OCH.sub.2CH.sub.3 H
O CH.sub.2CH.sub.3 F 4-trifluoromethylphenyl 588 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 4-trifluoromethylphenyl 589 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 F 4-trifluoromethylphenyl 590 CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 591 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 592 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 593 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 594 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 F 4-methoxyphenyl 595 cyclopropyl- H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl methyl 596 SCH(CH.sub.3).sub.2 H
O CH.sub.2CH.sub.3 F 4-methoxyphenyl 597 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 598 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 599 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 F 4-methoxyphenyl 600 CH.sub.3 H O
CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 601 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 602 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 603 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2CH.sub.3 F 3,4 dichloro phenyl 604
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 605 cyclopropyl- H O CH.sub.2CH.sub.3 F 3,4 dichloro phenyl
methyl 606 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 607 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 608 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 609 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 3,4 dichloro
phenyl 610 CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 611 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 612
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 613 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 614
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 615 cyclopropyl- H O CH.sub.2CH.sub.3
F 5-benzo[c][1,2,5]oxadiazolyl methyl 616 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 617
OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 618 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 619
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl
620 CH.sub.3 H O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl
621 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 622 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 623
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 624 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 625 cyclopropyl- H
O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl methyl 626
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 627 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 628
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl
629 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 630 CH.sub.3 H O CH.sub.2CF.sub.3 F
4-fluorophenyl 631 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-fluorophenyl 632 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F
4-fluorophenyl 633 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-fluorophenyl 634 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 4-fluorophenyl 635 cyclopropyl- H O CH.sub.2CF.sub.3 F
4-fluorophenyl methyl 636 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 4-fluorophenyl 637 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-fluorophenyl 638 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F
4-fluorophenyl 639 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
4-fluorophenyl 640 CH.sub.3 H O CH.sub.2CF.sub.3 F 4-chlorophenyl
641 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-chlorophenyl 642
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F 4-chlorophenyl 643
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-chlorophenyl 644
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 4-chlorophenyl
645 cyclopropyl- H O CH.sub.2CF.sub.3 F 4-chlorophenyl methyl 646
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 4-chlorophenyl 647
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 4-chlorophenyl 648
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 4-chlorophenyl 649
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 4-chlorophenyl 650 CH.sub.3 H
O CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 651 CH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 652 CH.sub.2CF.sub.3 H
O CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 653
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-trifluoromethylphenyl 654 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl 655 cyclopropyl- H O
CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl methyl 656
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F 4-trifluoromethylphenyl
657 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-trifluoromethylphenyl 658 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F
4-trifluoromethylphenyl 659 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
4-trifluoromethylphenyl 660 CH.sub.3 H O CH.sub.2CF.sub.3 F
4-methoxyphenyl 661 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-methoxyphenyl 662 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F
4-methoxyphenyl 663 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-methoxyphenyl 664 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 4-methoxyphenyl 665 cyclopropyl- H O CH.sub.2CF.sub.3 F
4-methoxyphenyl methyl 666 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 4-methoxyphenyl 667 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
4-methoxyphenyl 668 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F
4-methoxyphenyl 669 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
4-methoxyphenyl 670 CH.sub.3 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 671 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 672 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F 3,4 dichloro
phenyl 673 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F 3,4
dichloro phenyl 674 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 3,4 dichloro phenyl 675 cyclopropyl- H O CH.sub.2CF.sub.3 F 3,4
dichloro phenyl methyl 676 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
F 3,4 dichloro phenyl 677 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
3,4 dichloro phenyl 678 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 3,4
dichloro phenyl 679 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 3,4
dichloro phenyl 680 CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 681 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 682
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 683 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 684
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 685 cyclopropyl- H O CH.sub.2CF.sub.3
F 5-benzo[c][1,2,5]oxadiazolyl methyl 686 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 687
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazolyl 688 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl 689
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazolyl
690 CH.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl
691 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 692 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 693
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 694 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 695 cyclopropyl- H
O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl methyl 696
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 697 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl 698
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazolyl
699 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazolyl 700 CH.sub.3 H O CH.sub.2-c-Pr F
4-fluorophenyl 701 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-fluorophenyl 702 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
4-fluorophenyl 703 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-fluorophenyl 704 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-fluorophenyl 705 cyclopropyl- H O CH.sub.2-c-Pr F 4-fluorophenyl
methyl 706 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 4-fluorophenyl
707 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 4-fluorophenyl 708
(CH.sub.2).sub.2 O CH.sub.2-c-Pr F 4-fluorophenyl 709
(CH.sub.2).sub.4 O CH.sub.2-c-Pr F 4-fluorophenyl 710 CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 711 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 712 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 713 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-chlorophenyl 714 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 4-chlorophenyl 715 cyclopropyl- H O CH.sub.2-c-Pr F
4-chlorophenyl methyl 716 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-chlorophenyl 717 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-chlorophenyl 718 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F
4-chlorophenyl 719 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F
4-chlorophenyl 720 CH.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 721 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 722 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 723 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 724
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl 725 cyclopropyl- H O CH.sub.2-c-Pr F
4-trifluoromethylphenyl methyl 726 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 727 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 728 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 729 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr F 4-trifluoromethylphenyl 730 CH.sub.3 H O
CH.sub.2-c-Pr F 4-methoxyphenyl 731 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-methoxyphenyl 732 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr F 4-methoxyphenyl 733 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 4-methoxyphenyl 734 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 4-methoxyphenyl 735 cyclopropyl- H O CH.sub.2-c-Pr
F 4-methoxyphenyl methyl 736 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
F 4-methoxyphenyl 737 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
4-methoxyphenyl 738 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F
4-methoxyphenyl 739 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F
4-methoxyphenyl 740 CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 741 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl
742 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl 743
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro phenyl
744 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 745 cyclopropyl- H O CH.sub.2-c-Pr F 3,4 dichloro phenyl
methyl 746 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 747 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 3,4 dichloro
phenyl 748 (CH.sub.2).sub.2 O CH.sub.2-c-Pr F 3,4 dichloro phenyl
749 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F 3,4 dichloro phenyl 750
CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 751
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl
752 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]oxadiazolyl 753 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 754
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]oxadiazolyl 755 cyclopropyl- H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]oxadiazolyl methyl 756 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 757 OCH.sub.2CH.sub.3
H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 758
(CH.sub.2).sub.2 O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 759
(CH.sub.2).sub.4 O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]oxadiazolyl 760
CH.sub.3 H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 761
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]thiadiazolyl
762 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]thiadiazolyl 763 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 764
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]thiadiazolyl 765 cyclopropyl- H O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]thiadiazolyl methyl 766 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 767 OCH.sub.2CH.sub.3
H O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl 768
(CH.sub.2).sub.2 O CH.sub.2-c-Pr F 5-benzo[c][1,2,5]thiadiazolyl
769 (CH.sub.2).sub.4 O CH.sub.2-c-Pr F
5-benzo[c][1,2,5]thiadiazolyl 770 CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 771 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 772 CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 773 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 774 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3
Cl 4-fluorophenyl 775 cyclopropyl- H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl methyl 776 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3
Cl 4-fluorophenyl 777 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 778 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 779 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl
4-fluorophenyl 780 CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl
781 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 782
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 783
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 784
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl
785 cyclopropyl- H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl methyl 786
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 787
OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 788
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 789
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl 4-chlorophenyl 790 CH.sub.3
H O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 791
CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl
792 CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 793 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 794
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl 795 cyclopropyl- H O CH.sub.2CH.sub.3 Cl
4-trifluoromethylphenyl methyl 796 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 797 OCH.sub.2CH.sub.3 H
O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 798 (CH.sub.2).sub.2
O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 799 (CH.sub.2).sub.4
O CH.sub.2CH.sub.3 Cl 4-trifluoromethylphenyl 800 CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 801 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 802 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 803 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 804
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl
805 cyclopropyl- H O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl methyl 806
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 807
OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 808
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 809
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl 4-methoxyphenyl 810 CH.sub.3
H O CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 811 CH.sub.2CH.sub.3 H
O CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 812 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 3,4 dichloro phenyl 813
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl 3,4 dichloro
phenyl 814 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 815 cyclopropyl- H O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl methyl 816 SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3
Cl 3,4 dichloro phenyl 817 OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3
Cl 3,4 dichloro phenyl 818 (CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl
3,4 dichloro phenyl 819 (CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl 3,4
dichloro phenyl 820 CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 821 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 822
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 823 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 824
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 825 cyclopropyl- H O CH.sub.2CH.sub.3
Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 826 SCH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 827
OCH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 828 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 829
(CH.sub.2).sub.4 O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl
830 CH.sub.3 H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl
831 CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 832 CH.sub.2CF.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 833
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 834 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 835 cyclopropyl-
H O CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl methyl 836
SCH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 837 OCH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 838
(CH.sub.2).sub.2 O CH.sub.2CH.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 839 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 840 CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 841 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 842 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 843 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 844 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 Cl 4-fluorophenyl 845 cyclopropyl- H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl methyl 846 SCH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 Cl 4-fluorophenyl 847 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 848 (CH.sub.2).sub.2 0 O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 849 (CH.sub.2).sub.4 0 O
CH.sub.2CF.sub.3 Cl 4-fluorophenyl 850 CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 851 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 852 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 853 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 854 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 855 cyclopropyl- H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl methyl 856 SCH(CH.sub.3).sub.2 H
O CH.sub.2CF.sub.3 Cl 4-chlorophenyl 857 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 858 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 859 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 Cl 4-chlorophenyl 860 CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 861 CH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 862 CH.sub.2CF.sub.3
H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 863
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 864 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 865 cyclopropyl- H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl methyl 866
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
867 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 868 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 869 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 870 CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-methoxyphenyl 871 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-methoxyphenyl 872 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
4-methoxyphenyl 873 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3
Cl 4-methoxyphenyl 874 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 875 cyclopropyl- H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl methyl 876 SCH(CH.sub.3).sub.2
H O CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 877 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 878 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 879 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 Cl 4-methoxyphenyl 880 CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 881 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 882 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 3,4 dichloro phenyl 883
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 3,4 dichloro
phenyl 884 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 885 cyclopropyl- H O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl methyl 886 SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
Cl 3,4 dichloro phenyl 887 OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3
Cl 3,4 dichloro phenyl 888 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl
3,4 dichloro phenyl 889 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 3,4
dichloro phenyl 890 CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 891 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 892
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 893 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 894
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 895 cyclopropyl- H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 896 SCH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 897
OCH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazolyl 898 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl 899
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazolyl
900 CH.sub.3 H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl
901 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 902 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 903
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 904 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 905 cyclopropyl-
H O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl methyl 906
SCH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 907 OCH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 908
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazolyl 909 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazolyl 910 CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-fluorophenyl 911 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-fluorophenyl 912 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-fluorophenyl 913 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-fluorophenyl 914 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-fluorophenyl 915 cyclopropyl- H O CH.sub.2-c-Pr
Cl 4-fluorophenyl methyl 916 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
Cl 4-fluorophenyl 917 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-fluorophenyl 918 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl
4-fluorophenyl 919 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl
4-fluorophenyl 920 CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 921
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 922
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 923
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 924
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 925
cyclopropyl- H O CH.sub.2-c-Pr Cl 4-chlorophenyl methyl 926
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 927
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-chlorophenyl 928
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-chlorophenyl 929
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-chlorophenyl 930 CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 931 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 932 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 933
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-trifluoromethylphenyl 934 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 935 cyclopropyl- H O
CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl methyl 936
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl
937 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl
938 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 939
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-trifluoromethylphenyl 940
CH.sub.3 H O CH.sub.2-c-Pr Cl 4-methoxyphenyl 941 CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr Cl 4-methoxyphenyl 942 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 943 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 944 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-methoxyphenyl 945 cyclopropyl- H O CH.sub.2-c-Pr
Cl 4-methoxyphenyl methyl 946 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
Cl 4-methoxyphenyl 947 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-methoxyphenyl 948 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl
4-methoxyphenyl 949 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl
4-methoxyphenyl 950 CH.sub.3 H O CH.sub.2-c-Pr Cl 3,4 dichloro
phenyl 951 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 3,4 dichloro
phenyl 952 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 3,4 dichloro
phenyl 953 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 3,4
dichloro phenyl 954 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
3,4 dichloro phenyl 955 cyclopropyl- H O CH.sub.2-c-Pr Cl 3,4
dichloro phenyl methyl 956 SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
3,4 dichloro phenyl 957 OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 3,4
dichloro phenyl 958 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 3,4
dichloro phenyl 959 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 3,4
dichloro phenyl 960 CH.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]oxadiazolyl 961 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
Cl 5-benzo[c][1,2,5]oxadiazolyl 962 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 963
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]oxadiazolyl 964 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 965 cyclopropyl- H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl methyl 966
SCH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]oxadiazolyl 967 OCH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 968 (CH.sub.2).sub.2
O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 969
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl
970 CH.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 971
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl
972 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]thiadiazolyl 973 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 974
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]thiadiazolyl 975 cyclopropyl- H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]thiadiazolyl methyl 976 SCH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl 977
OCH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
5-benzo[c][1,2,5]thiadiazolyl 978 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
Cl 5-benzo[c][1,2,5]thiadiazolyl 979 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr Cl 5-benzo[c][1,2,5]thiadiazolyl
TABLE-US-00003 TABLE 3 Formula III ##STR00018## Compounds of
Formula III Ex R1 R2 Y R4 R5 Z 980 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 981 CH.sub.2CF.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 982
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethyl- phenyl 983 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 984
cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl-
methyl phenyl 985 cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethyl- methyl phenyl 986 (CH.sub.2).sub.2 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 987 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 988
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl-
phenyl 989 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethyl- phenyl 990 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoromethyl- hexane phenyl 991 Cyclopentyl H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethyl- phenyl 992
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 993
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 994
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 995
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
996 cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl methyl 997
cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl methyl 998
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 999
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1000
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1001
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1002
5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl hexane 1003
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1004
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1005
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1006
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl
phenyl 1007 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl 1008 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl methyl 1009 cyclobutyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-ethyl phenyl methyl 1010 (CH.sub.2).sub.2 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1011 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1012 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1013 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1014 5,5-spiro[2.3]- O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl hexane 1015 Cyclopentyl H
O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1016 CH.sub.2CH.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl 1017
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
1018 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 1019 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl 1020 cyclopropyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl methyl 1021 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl methyl 1022
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
1023 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl
phenyl 1024 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 1025 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
CF.sub.3 4-isopropyl phenyl 1026 5,5-spiro[2.3]- O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl hexane 1027 Cyclopentyl H O
CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl 1028 CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl 1029
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl
1030 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethylphenyl 1031 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethylphenyl 1032 cyclopropyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethylphenyl methyl 1033 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl methyl 1034
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl
1035 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethylphenyl 1036 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
CF.sub.3 4-thiomethylphenyl 1037 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethylphenyl 1038 5,5-spiro[2.3]- O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl hexane 1039
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethylphenyl 1040
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy-
phenyl 1041 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethoxy- phenyl 1042 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy- phenyl 1043
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethoxy- phenyl 1044 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoromethoxy- methyl phenyl 1045 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy- methyl phenyl 1046
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy-
phenyl 1047 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethoxy- phenyl 1048 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoromethoxy- phenyl 1049 (CH.sub.2).sub.5
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy- phenyl 1050
5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoromethoxy-
hexane phenyl 1051 Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoromethoxy- phenyl 1052 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoromethyl- phenyl 1053 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- phenyl 1054
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethyl- phenyl 1055 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- phenyl 1056 cyclopropyl-
H O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- methyl phenyl 1057
cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- methyl
phenyl 1058 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethyl- phenyl 1059 (CH.sub.2).sub.3 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoromethyl- phenyl 1060 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- phenyl 1061
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl- phenyl
1062 5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethyl-
hexane phenyl 1063 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethyl- phenyl 1064 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-tolyl 1065 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1066 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1067 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1068 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl
1069 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl 1070
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1071
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1072
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1073
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1074
5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-tolyl hexane 1075
Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1076
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 1077
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 1078
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
1079 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1080 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 1081 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 1082 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1083 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1084 (CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1085 (CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1086 5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
hexane 1087 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
1088 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
1089 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
1090 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-isopropyl phenyl 1091 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1092 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl methyl 1093 cyclobutyl- H
O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl methyl 1094
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1095
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1096
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1097
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1098
5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl hexane
1099 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1100
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1101
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1102
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-thiomethylphenyl 1103 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1104 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl methyl 1105 cyclobutyl- H
O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl methyl 1106
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1107
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1108
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1109
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1110
5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl hexane
1111 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-thiomethylphenyl 1112
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy-
phenyl 1113 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethoxy- phenyl 1114 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy- phenyl 1115
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethoxy- phenyl 1116 cyclopropyl- H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoromethoxy- methyl phenyl 1117 cyclobutyl- H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy- methyl phenyl 1118
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy-
phenyl 1119 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3
4-trifluoromethoxy- phenyl 1120 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoromethoxy- phenyl 1121 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy- phenyl 1122
5,5-spiro[2.3]- O CH.sub.2-c-Pr CF.sub.3 4-trifluoromethoxy- hexane
phenyl 1123 Cyclopentyl H O CH2-c-Pr CF.sub.3 4-trifluoromethoxy-
phenyl 1124 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1125 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1126
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1127 CH.sub.2CH(CH.sub.3).sub.2
H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1128 cyclopropyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 4-trifluoromethyl- methyl CF.sub.3 phenyl 1129
cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethyl-
methyl CF.sub.3 phenyl 1130 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1131 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl
1132 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1133 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1134
5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethyl-
hexane CF.sub.3 phenyl 1135 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1136 CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 4-tolyl CF.sub.3 1137
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 4-tolyl CF.sub.3
1138 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-tolyl CF.sub.3 1139 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 OCH.sub.2 4-tolyl CF.sub.3 1140 cyclopropyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 4-tolyl methyl CF.sub.3 1141 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-tolyl methyl CF.sub.3 1142
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 4-tolyl CF.sub.3
1143 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 4-tolyl
CF.sub.3 1144 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2
4-tolyl CF.sub.3 1145 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
OCH.sub.2 4-tolyl CF.sub.3 1146 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3
OCH.sub.2 4-tolyl hexane CF.sub.3 1147 Cyclopentyl H O CH.sub.2
CF.sub.3 OCH.sub.2 4-tolyl CF.sub.3 1148 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl CF.sub.3 1149
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl
CF.sub.3 1150 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 4-ethyl phenyl CF.sub.3 1151 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl CF.sub.3 1152
cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl methyl
CF.sub.3 1153 cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl
phenyl methyl CF.sub.3 1154 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 4-ethyl phenyl CF.sub.3 1155 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 4-ethyl phenyl CF.sub.3 1156 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl CF.sub.3 1157
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl phenyl
CF.sub.3 1158 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 OCH.sub.2 4-ethyl
phenyl hexane CF.sub.3 1159 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 4-ethyl phenyl CF.sub.3 1160 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-isopropyl phenyl CF.sub.3 1161
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 4-isopropyl phenyl
CF.sub.3 1162 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 4-isopropyl phenyl CF.sub.3 1163
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-isopropyl phenyl CF.sub.3 1164 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 4-isopropyl phenyl methyl CF.sub.3 1165 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-isopropyl phenyl methyl CF.sub.3 1166
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 4-isopropyl phenyl
CF.sub.3 1167 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2
4-isopropyl phenyl CF.sub.3 1168 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 OCH.sub.2 4-isopropyl phenyl CF.sub.3 1169
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 4-isopropyl phenyl
CF.sub.3 1170 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 OCH.sub.2
4-isopropyl phenyl hexane CF.sub.3 1171 Cyclopentyl H O CH.sub.2
CF.sub.3 OCH.sub.2 4-isopropyl phenyl CF.sub.3 1172
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 4-thiomethylphenyl
CF.sub.3 1173 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-thiomethylphenyl CF.sub.3 1174 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-thiomethylphenyl CF.sub.3 1175
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-thiomethylphenyl CF.sub.3 1176 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 4-thiomethylphenyl methyl CF.sub.3 1177 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-thiomethylphenyl methyl CF.sub.3 1178
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 4-thiomethylphenyl
CF.sub.3 1179 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2
4-thiomethylphenyl CF.sub.3 1180 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 OCH.sub.2 4-thiomethylphenyl CF.sub.3 1181
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 4-thiomethylphenyl
CF.sub.3 1182 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 OCH.sub.2
4-thiomethylphenyl hexane CF.sub.3 1183 Cyclopentyl H O CH.sub.2
CF.sub.3 OCH.sub.2 4-thiomethylphenyl CF.sub.3 1184
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1185 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1186 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1187 CH.sub.2CH(CH.sub.3).sub.2
H O CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1188 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- methyl CF.sub.3 phenyl 1189 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethoxy- methyl CF.sub.3
phenyl 1190 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1191 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1192 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1193 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1194 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3 OCH.sub.2
4-trifluoromethoxy- hexane CF.sub.3 phenyl 1195 Cyclopentyl H O CH2
CF3 OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl 1196
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl-
CF.sub.3 phenyl 1197 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1198 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1199
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1200 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl- methyl CF.sub.3 phenyl
1201 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl-
methyl CF.sub.3 phenyl 1202 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1203 (CH.sub.2).sub.3
O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl- CF.sub.3 phenyl 1204
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl-
CF.sub.3 phenyl 1205 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethyl- CF.sub.3 phenyl 1206 5,5-spiro[2.3]- O
CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl- hexane CF.sub.3 phenyl
1207 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethyl-
CF.sub.3 phenyl 1208 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-tolyl CF.sub.3 1209 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-tolyl CF.sub.3 1210 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 4-tolyl CF.sub.3 1211 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1212 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 4-tolyl methyl CF.sub.3 1213 cyclobutyl- H
O CH.sub.2-c-Pr OCH.sub.2 4-tolyl methyl CF.sub.3 1214
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1215
(CH.sub.2)3 O CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1216
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1217
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1218
5,5-spiro[2.3]- O CH.sub.2-c-Pr OCH.sub.2 4-tolyl hexane CF.sub.3
1219 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 4-tolyl CF.sub.3 1220
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl
CF.sub.3 1221 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 4-ethyl
phenyl CF.sub.3 1222 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 4-ethyl phenyl CF.sub.3 1223 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl CF.sub.3 1224 cyclopropyl-
H O CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl methyl CF.sub.3 1225
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl methyl
CF.sub.3 1226 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 4-ethyl
phenyl CF.sub.3 1227 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
4-ethyl phenyl CF.sub.3 1228 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 4-ethyl phenyl CF.sub.3 1229 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl CF.sub.3 1230
5,5-spiro[2.3]- O CH.sub.2-c-Pr OCH.sub.2 4-ethyl phenyl hexane
CF.sub.3 1231 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 4-ethyl
phenyl CF.sub.3 1232 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-isopropyl phenyl CF.sub.3 1233 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 4-isopropyl phenyl CF.sub.3 1234 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 4-isopropyl phenyl CF.sub.3 1235
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 4-isopropyl
phenyl CF.sub.3 1236 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2
4-isopropyl phenyl methyl CF.sub.3 1237 cyclobutyl- H O
CH.sub.2-c-Pr OCH.sub.2 4-isopropyl phenyl methyl CF.sub.3 1238
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 4-isopropyl phenyl
CF.sub.3 1239 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
4-isopropyl phenyl CF.sub.3 1240 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 4-isopropyl phenyl CF.sub.3 1241 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 4-isopropyl phenyl CF.sub.3 1242
5,5-spiro[2.3]- O CH.sub.2-c-Pr OCH.sub.2 4-isopropyl phenyl hexane
CF.sub.3 1243 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 4-isopropyl
phenyl CF.sub.3 1244 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-thiomethylphenyl CF.sub.3
1245 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-thiomethylphenyl CF.sub.3 1246 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr OCH.sub.2 4-thiomethylphenyl CF.sub.3 1247
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2
4-thiomethylphenyl CF.sub.3 1248 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 4-thiomethylphenyl methyl CF.sub.3 1249 cyclobutyl- H O
CH.sub.2-c-Pr OCH.sub.2 4-thiomethylphenyl methyl CF.sub.3 1250
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 4-thiomethylphenyl
CF.sub.3 1251 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
4-thiomethylphenyl CF.sub.3 1252 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 4-thiomethylphenyl CF.sub.3 1253 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 4-thiomethylphenyl CF.sub.3 1254
5,5-spiro[2.3]- O CH.sub.2-c-Pr OCH.sub.2 4-thiomethylphenyl hexane
CF.sub.3 1255 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2
4-thiomethylphenyl CF.sub.3 1256 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl 1257 CH.sub.2CF.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1258 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1259 CH.sub.2CH(CH.sub.3).sub.2
H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl
1260 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy-
methyl CF.sub.3 phenyl 1261 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethoxy- methyl CF.sub.3 phenyl 1262 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl 1263
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy-
CF.sub.3 phenyl 1264 (CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl 1265 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy- CF.sub.3 phenyl 1266
5,5-spiro[2.3]- O CH.sub.2-c-Pr OCH.sub.2 4-trifluoromethoxy-
hexane CF.sub.3 phenyl 1267 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2
4-trifluoromethoxy- CF.sub.3 phenyl
TABLE-US-00004 TABLE 4 Compounds of Formula III Formula III
##STR00019## Ex R1 R2 Y R4 R5 Z 1268 cyclobutyl- H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methyl methylphenyl 1269 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methylphenyl 1270
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methylphenyl
1271 5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl 4-trifluoro- hexane
methylphenyl 1272 Cyclopentyl H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methylphenyl 1273 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl
1274 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1275
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1276
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1277
cyclopropyl- H O CH.sub.2 CF.sub.3 Cl 4-tolyl methyl 1278
cyclobutyl- H O CH.sub.2 CF.sub.3 Cl 4-tolyl methyl 1279
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1280
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1281
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1282
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1283 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 Cl 4-tolyl hexane 1284 Cyclopentyl H O CH.sub.2
CF.sub.3 Cl 4-tolyl 1285 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1286 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1287 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
Cl 4-ethyl phenyl 1288 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 Cl 4-ethyl phenyl 1289 cyclopropyl- H O CH.sub.2 CF.sub.3
Cl 4-ethyl phenyl methyl 1290 cyclobutyl- H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl methyl 1291 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1292 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-ethyl
phenyl 1293 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl
1294 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl 1295
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl hexane 1296
Cyclopentyl H O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl 1297
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl phenyl 1298
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl phenyl 1299
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl
phenyl 1300 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1301 cyclopropyl- H O CH.sub.2 CF.sub.3 Cl
4-isopropyl methyl phenyl 1302 cyclobutyl- H O CH.sub.2 CF.sub.3 Cl
4-isopropyl methyl phenyl 1303 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
Cl 4-isopropyl phenyl 1304 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1305 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1306 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1307 5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl
4-isopropyl hexane phenyl 1308 Cyclopentyl H O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1309 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-thiomethyl- phenyl 1310 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-thiomethyl- phenyl 1311 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 Cl 4-thiomethyl- phenyl 1312 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1313 cyclopropyl- H O
CH.sub.2 CF.sub.3 Cl 4-thiomethyl- methyl phenyl 1314 cyclobutyl- H
O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- methyl phenyl 1315
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1316
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1317
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1318
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1319
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- hexane phenyl
1320 Cyclopentyl H O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1321
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1322 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methoxyphenyl 1323 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1324
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1325 cyclopropyl- H O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methyl methoxyphenyl 1326 cyclobutyl- H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methyl methoxyphenyl 1327 (CH.sub.2).sub.2
O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1328
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl
1329 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1330 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methoxyphenyl 1331 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
Cl 4-trifluoro- hexane methoxyphenyl 1332 Cyclopentyl H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1333 cyclobutyl- H O
CH.sub.2-c-Pr Cl 4-trifluoro- methyl methylphenyl 1334
(CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1335
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1336
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-trifluoro- hexane methylphenyl
1337 Cyclopentyl H O CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl
1338 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-tolyl 1339
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-tolyl 1340
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-tolyl 1341
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-tolyl 1342
cyclopropyl- H O CH.sub.2-c-Pr Cl 4-tolyl methyl 1343 cyclobutyl- H
O CH.sub.2-c-Pr Cl 4-tolyl methyl 1344 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr Cl 4-tolyl 1345 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl
4-tolyl 1346 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-tolyl 1347
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-tolyl 1348 5,5-spiro[2.3] O
CH.sub.2-c-Pr Cl 4-tolyl hexane 1349 Cyclopentyl H O CH.sub.2-c-Pr
Cl 4-tolyl 1350 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-ethyl
phenyl 1351 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-ethyl phenyl
1352 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-ethyl phenyl
1353 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-ethyl phenyl
1354 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-ethyl phenyl methyl 1355
cyclobutyl- H O CH.sub.2-c-Pr Cl 4-ethyl phenyl methyl 1356
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1357
(CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1358
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1359
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1360
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-ethyl phenyl hexane 1361
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1362
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1363
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1364
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl
1365 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-isopropyl
phenyl 1366 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-isopropyl methyl
phenyl 1367 cyclobutyl- H O CH.sub.2-c-Pr Cl 4-isopropyl methyl
phenyl 1368 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl
1369 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1370
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1371
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1372
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-isopropyl hexane phenyl 1373
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1374
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1375
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1376
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl
1377 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1378 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-thiomethyl- methyl
phenyl 1379 cyclobutyl- H O CH.sub.2-c-Pr Cl 4-thiomethyl- methyl
phenyl 1380 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1381 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1382 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1383 (CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1384 5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-thiomethyl- hexane
phenyl 1385 Cyclopentyl H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl
1386 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-trifluoro-
methoxyphenyl 1387 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl
4-trifluoro- methoxyphenyl 1388 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1389
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-trifluoro-
methoxyphenyl 1390 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-trifluoro-
methyl methoxyphenyl 1391 cyclobutyl- H O CH.sub.2-c-Pr Cl
4-trifluoro- methyl methoxyphenyl 1392 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1393 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1394 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1395 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1396 5,5-spiro[2.3] O
CH.sub.2-c-Pr Cl 4-trifluoro- hexane methoxyphenyl 1397 Cyclopentyl
H O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1398
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1399 CH.sub.2CF.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1400
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1401 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1402
cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 1403 cyclobutyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 1404
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro-
methylphenyl 1405 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1406 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1407
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1408 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl 1409
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1410 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl 1411 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 1412 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1413
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 1414 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl methyl 1415 cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl methyl 1416 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 1417 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1418 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1419 (CH.sub.2).sub.5
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1420 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl hexane 1421
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1422
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl
phenyl 1423 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 1424 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 1425
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 1426 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl methyl 1427 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 1428
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl
phenyl 1429 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 1430 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 1431 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1432 5,5-spiro[2.3] O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 1433 Cyclopentyl
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 1434
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1435 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1436 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1437
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1438 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 1439 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 1440
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 1441 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1442 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1443 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1444
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
hexane phenyl 1445 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-isopropyl phenyl 1446 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1447
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1448 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1449
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1450 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 1451 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl
1452 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1453 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1454 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1455
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1456 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- hexane phenyl 1457 Cyclopentyl H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1458
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1459 CH.sub.2CF.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1460
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1461 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
1462 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methyl methoxyphenyl 1463 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 1464
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1465 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1466
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1467 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1468
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 1469 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1470 CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1471
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1472 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1473
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1474 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 1475
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 1476 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1477 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1478
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1479 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1480 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl
1481 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1482 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 1483 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 1484 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-tolyl 1485 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1486 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 1487 cyclobutyl- H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 1488
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1489
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1490
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1491
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1492
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl hexane
1493 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1494
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl
phenyl 1495 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 1496 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1497 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 1498 cyclopropyl-
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 1499
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 1500 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 1501 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-ethyl phenyl 1502 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1503 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 1504 5,5-spiro[2.3]
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 1505
Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
1506 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1507 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1508 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1509
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1510 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl methyl phenyl 1511 cyclobutyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 1512
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 1513 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1514 (CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl phenyl 1515 (CH.sub.2).sub.5 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1516 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl hexane phenyl 1517
Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl
1518 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1519 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1520
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1521 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1522
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
methyl phenyl 1523 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- methyl phenyl
1524 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1525 (CH.sub.2).sub.3 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1526 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1527
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 1528 5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- hexane phenyl 1529 Cyclopentyl H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1530
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 1531 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1532
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1533 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 1534
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methoxyphenyl 1535 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1536 (CH.sub.2).sub.3
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1537
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 1538 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl 1539 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methoxyphenyl
1540 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl
TABLE-US-00005 TABLE 5 Compounds of Formula IV Formula IV
##STR00020## Ex R1 R2 X R3 R5 Z 1541 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1542 CH.sub.2CF.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1543
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methylphenyl 1544 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1545
cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methyl
methylphenyl 1546 cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methyl methylphenyl 1547 (CH.sub.2).sub.2 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1548 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1549
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methylphenyl 1550 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methylphenyl 1551 5,5-spiro[2.3]- O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoro- hexane methylphenyl 1552 Cyclopentyl H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 1553
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1554
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1555
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
1556 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3
4-tolyl 1557 cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
methyl 1558 cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
methyl 1559 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
1560 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1561
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1562
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1563
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl hexane 1564
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 1565
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1566
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1567
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl
phenyl 1568 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl 1569 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl methyl 1570 cyclobutyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-ethyl phenyl methyl 1571 (CH.sub.2).sub.2 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1572 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1573 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1574 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1575 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl hexane 1576 Cyclopentyl H
O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 1577 CH.sub.2CH.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl 1578
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
1579 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 1580 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl 1581 cyclopropyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl methyl phenyl 1582 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl methyl phenyl 1583
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
1584 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl
phenyl 1585 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 1586 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
CF.sub.3 4-isopropyl phenyl 1587 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
CF.sub.3 4-isopropyl hexane phenyl 1588 Cyclopentyl H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl 1589 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 1590
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl-
phenyl 1591 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethyl- phenyl 1592 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 1593 cyclopropyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- methyl phenyl 1594
cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- methyl
phenyl 1595 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethyl- phenyl 1596 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
CF.sub.3 4-thiomethyl- phenyl 1597 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 1598 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 1599 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- hexane phenyl 1600
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl
1601 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methoxyphenyl 1602 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 1603 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 1604
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 1605 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoro- methyl methoxyphenyl 1606 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methyl methoxyphenyl 1607
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methoxyphenyl 1608 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 1609 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 1610 (CH.sub.2).sub.5
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 1611
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- hexane
methoxyphenyl 1612 Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 1613 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 1614 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl 1615
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methylphenyl 1616 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 1617 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl methylphenyl 1618
cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl
methylphenyl 1619 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methylphenyl 1620 (CH.sub.2).sub.3 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 1621 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl 1622
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl
1623 5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- hexane
methylphenyl 1624 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methylphenyl 1625 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-tolyl 1626 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1627 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1628 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 1629 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl
1630 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl 1631
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1632
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1633
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1634
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1635
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-tolyl hexane 1636
Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-tolyl 1637
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 1638
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 1639
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
1640 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1641 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 1642 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 1643 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1644 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1645 (CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1646 (CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 1647 5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
hexane 1648 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
1649 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
1650 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
1651 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-isopropyl phenyl 1652 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1653 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl methyl phenyl 1654 cyclobutyl- H
O CH.sub.2-c-Pr CF.sub.3 4-isopropyl methyl phenyl 1655
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1656
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1657
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1658
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1659
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-isopropyl hexane phenyl
1660 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 1661
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl
1662 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl-
phenyl 1663 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-thiomethyl- phenyl 1664 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 1665 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- methyl phenyl 1666 cyclobutyl-
H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- methyl phenyl 1667
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 1668
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 1669
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 1670
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 1671
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- hexane phenyl
1672 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl
1673 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methoxyphenyl 1674 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 1675 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methoxyphenyl 1676
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro-
methoxyphenyl 1677 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methyl methoxyphenyl 1678 cyclobutyl- H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl methoxyphenyl 1679
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methoxyphenyl 1680 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 1681 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methoxyphenyl 1682 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methoxyphenyl 1683
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- hexane
methoxyphenyl 1684 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 1685 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1686
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1687 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1688
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1689 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 1690
cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 1691 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1692 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl
1693 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1694 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1695 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- hexane
methylphenyl 1696 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1697 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1698 CH.sub.2CF.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1699
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 1700 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 1701 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl methyl 1702 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl methyl 1703 (CH.sub.2).sub.2 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1704 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1705
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl
1706 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 1707 5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl hexane 1708 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl 1709 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1710 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 1711
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 1712 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 1713 cyclopropyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 1714
cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 1715 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 1716 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 1717 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1718 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 1719 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 1720
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl
1721 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1722 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1723 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1724
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1725 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 1726 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 1727
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 1728 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1729 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1730 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1731
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
hexane phenyl 1732 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-isopropyl phenyl 1733 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1734
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1735 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1736
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1737 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 1738 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl
1739 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1740 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1741 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1742
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1743 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- hexane phenyl 1744 Cyclopentyl H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1745
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1746 CH.sub.2CF.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1747
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1748 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
1749 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methyl methoxyphenyl 1750 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 1751
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1752 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1753
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1754 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1755
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 1756 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1757 CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1758
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1759 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1760
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1761 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 1762
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 1763 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1764 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1765
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1766 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1767 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl
1768 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1769 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 1770 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 1771 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-tolyl 1772 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1773 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 1774 cyclobutyl- H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 1775
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1776
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1777
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1778
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1779
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl hexane
1780 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 1781
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl
phenyl 1782 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 1783 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1784 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 1785 cyclopropyl-
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 1786
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 1787 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 1788 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-ethyl phenyl 1789 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 1790 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 1791 5,5-spiro[2.3]
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 1792
Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
1793 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1794 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1795 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1796 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1797
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
methyl phenyl 1798 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl methyl phenyl 1799 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1800 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1801
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 1802 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 1803 5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl hexane phenyl 1804 Cyclopentyl H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 1805
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 1806 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1807 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1808
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1809 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-thiomethyl- methyl phenyl 1810 cyclobutyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 1811
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 1812 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1813 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1814 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 1815
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
hexane phenyl 1816 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 1817 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1818 CH.sub.2CF.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
1819 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 1820 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1821
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methoxyphenyl 1822 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methyl methoxyphenyl 1823 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1824
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 1825 (CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl 1826 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 1827
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 1828 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl
TABLE-US-00006 TABLE 6 Compounds of Formula IV Formula IV
##STR00021## Ex R1 R2 X R3 R5 Z 1829 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methylphenyl 1830 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 Cl 4-trifluoro- methylphenyl 1831
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methylphenyl 1832 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
Cl 4-trifluoro- methylphenyl 1833 cyclopropyl- H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methyl methylphenyl 1834 cyclobutyl- H O
CH.sub.2 CF.sub.3 Cl 4-trifluoro- methyl methylphenyl 1835
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methylphenyl
1836 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methylphenyl 1837 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methylphenyl 1838 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
Cl 4-trifluoro- methylphenyl 1839 5,5-spiro[2.3] O CH.sub.2
CF.sub.3 Cl 4-trifluoro- hexane methylphenyl 1840 Cyclopentyl H O
CH.sub.2 CF.sub.3 Cl 4-trifluoro- methylphenyl 1841
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1842
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1843
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1844
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl 4-tolyl 1845
cyclopropyl- H O CH.sub.2 CF.sub.3 Cl 4-tolyl methyl 1846
cyclobutyl- H O CH.sub.2 CF.sub.3 Cl 4-tolyl methyl 1847
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1848
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1849
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1850
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-tolyl 1851 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 Cl 4-tolyl hexane 1852 Cyclopentyl H O CH.sub.2
CF.sub.3 Cl 4-tolyl 1853 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1854 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1855 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
Cl 4-ethyl phenyl 1856 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 Cl 4-ethyl phenyl 1857 cyclopropyl- H O CH.sub.2 CF.sub.3
Cl 4-ethyl phenyl methyl 1858 cyclobutyl- H O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl methyl 1859 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl
4-ethyl phenyl 1860 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-ethyl
phenyl 1861 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl
1862 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl 1863
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl hexane 1864
Cyclopentyl H O CH.sub.2 CF.sub.3 Cl 4-ethyl phenyl 1865
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl phenyl 1866
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl phenyl 1867
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-isopropyl
phenyl 1868 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1869 cyclopropyl- H O CH.sub.2 CF.sub.3 Cl
4-isopropyl methyl phenyl 1870 cyclobutyl- H O CH.sub.2 CF.sub.3 Cl
4-isopropyl methyl phenyl 1871 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
Cl 4-isopropyl phenyl 1872 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1873 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1874 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1875 5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl
4-isopropyl hexane phenyl 1876 Cyclopentyl H O CH.sub.2 CF.sub.3 Cl
4-isopropyl phenyl 1877 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-thiomethyl- phenyl 1878 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-thiomethyl- phenyl 1879 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 Cl 4-thiomethyl- phenyl 1880 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1881 cyclopropyl- H O
CH.sub.2 CF.sub.3 Cl 4-thiomethyl- methyl phenyl 1882 cyclobutyl- H
O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- methyl phenyl 1883
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1884
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1885
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1886
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1887
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- hexane phenyl
1888 Cyclopentyl H O CH.sub.2 CF.sub.3 Cl 4-thiomethyl- phenyl 1889
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1890 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methoxyphenyl 1891 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1892
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1893 cyclopropyl- H O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methyl methoxyphenyl 1894 cyclobutyl- H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methyl methoxyphenyl 1895 (CH.sub.2).sub.2
O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1896
(CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 Cl 4-trifluoro- methoxyphenyl
1897 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 Cl 4-trifluoro-
methoxyphenyl 1898 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 Cl
4-trifluoro- methoxyphenyl 1899 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
Cl 4-trifluoro- hexane methoxyphenyl 1900 Cyclopentyl H O CH.sub.2
CF.sub.3 Cl 4-trifluoro- methoxyphenyl 1901 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1902 CH.sub.2CF.sub.3 H
O CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1903
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-trifluoro-
methylphenyl 1904 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl
4-trifluoro- methylphenyl 1905 cyclopropyl- H O CH.sub.2-c-Pr Cl
4-trifluoro- methyl methylphenyl 1906 cyclobutyl- H O CH.sub.2-c-Pr
Cl 4-trifluoro- methyl methylphenyl 1907 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1908 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1909 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1910 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1911 5,5-spiro[2.3] O
CH.sub.2-c-Pr Cl 4-trifluoro- hexane methylphenyl 1912 Cyclopentyl
H O CH.sub.2-c-Pr Cl 4-trifluoro- methylphenyl 1913
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-tolyl 1914 CH.sub.2CF.sub.3
H O CH.sub.2-c-Pr Cl 4-tolyl 1915 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-tolyl 1916 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-tolyl 1917 cyclopropyl- H O CH.sub.2-c-Pr Cl
4-tolyl methyl 1918 cyclobutyl- H O CH.sub.2-c-Pr Cl 4-tolyl methyl
1919 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-tolyl 1920
(CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-tolyl 1921 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr Cl 4-tolyl 1922 (CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl
4-tolyl 1923 5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-tolyl hexane 1924
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-tolyl 1925 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-ethyl phenyl 1926 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr Cl 4-ethyl phenyl 1927 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr Cl 4-ethyl phenyl 1928 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-ethyl phenyl 1929 cyclopropyl- H O CH.sub.2-c-Pr
Cl 4-ethyl phenyl methyl 1930 cyclobutyl- H O CH.sub.2-c-Pr Cl
4-ethyl phenyl methyl 1931 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl
4-ethyl phenyl 1932 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-ethyl
phenyl 1933 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1934
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1935
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-ethyl phenyl hexane 1936
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-ethyl phenyl 1937
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1938
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1939
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl
1940 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-isopropyl
phenyl 1941 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-isopropyl methyl
phenyl 1942 cyclobutyl- H O CH.sub.2-c-Pr Cl 4-isopropyl methyl
phenyl 1943 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl
1944 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1945
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1946
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1947
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-isopropyl hexane phenyl 1948
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-isopropyl phenyl 1949
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1950
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1951
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl
1952 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr Cl 4-thiomethyl-
phenyl 1953 cyclopropyl- H O CH.sub.2-c-Pr Cl 4-thiomethyl- methyl
phenyl 1954 cyclobutyl- H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl
1955 (CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1956
(CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1957
(CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1958
(CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1959
5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-thiomethyl- hexane phenyl 1960
Cyclopentyl H O CH.sub.2-c-Pr Cl 4-thiomethyl- phenyl 1961
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl
1962 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr Cl 4-trifluoro-
methoxyphenyl 1963 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr Cl
4-trifluoro- methoxyphenyl 1964 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl 1965 cyclopropyl- H O
CH.sub.2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1966 cyclobutyl-
H O CH.sub.2-c-Pr Cl 4-trifluoro- methyl methoxyphenyl 1967
(CH.sub.2).sub.2 O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl
1968 (CH.sub.2).sub.3 O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl
1969 (CH.sub.2).sub.4 O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl
1970 (CH.sub.2).sub.5 O CH.sub.2-c-Pr Cl 4-trifluoro- methoxyphenyl
1971 5,5-spiro[2.3] O CH.sub.2-c-Pr Cl 4-trifluoro- hexane
methoxyphenyl 1972 Cyclopentyl H O CH.sub.2-c-Pr Cl 4-trifluoro-
methoxyphenyl 1973 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 1974 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1975
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1976 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1977
cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 1978 cyclobutyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 1979
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1980 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 1981 (CH.sub.2).sub.4
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl
1982 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 1983 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl 1984
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 1985 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl 1986 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 1987 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1988
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 1989 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl methyl 1990 cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl methyl 1991 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 1992 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1993 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1994 (CH.sub.2).sub.5
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1995 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl hexane 1996
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 1997
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl
phenyl 1998 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 1999 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 2000
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 2001 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl methyl 2002 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 2003
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl
phenyl 2004 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 2005 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 2006 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2007 5,5-spiro[2.3] O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 2008 Cyclopentyl
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 2009
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2010 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2011 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2012
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2013 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 2014 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 2015
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 2016 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2017 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2018 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2019
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
hexane phenyl 2020 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-isopropyl phenyl 2031 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2032
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2033 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2034
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2035 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 2036 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl
2037 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2038 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2039 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2040
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2041 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- hexane phenyl 2042 Cyclopentyl H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2043
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2044 CH.sub.2CF.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2045
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2046 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
2047 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methyl methoxyphenyl 2048 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 2049
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2050 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2051
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2052 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2053
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 2054 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2055 CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2056
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2057 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2058
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 2059 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 2060
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 2061 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 2062 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2063
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2064 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 2065 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl
2066 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2067 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 2068 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 2069 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-tolyl 2070 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2071 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 2072 cyclobutyl- H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 2073
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2074
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2075
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2076
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2077
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl hexane
2078 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2079
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl
phenyl 2080 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 2081 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2082 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 2083 cyclopropyl-
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 2084
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 2085 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 2086 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-ethyl phenyl 2087 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2088 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 2089 5,5-spiro[2.3]
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 2090
Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
2091 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2092 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2093 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2094
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2095 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl methyl phenyl
2096 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
methyl phenyl 2097 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl phenyl 2098 (CH.sub.2).sub.3 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2099 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2100
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 2101 5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl hexane phenyl 2102 Cyclopentyl H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2103 CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2104
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 2105 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-thiomethyl- phenyl 2106 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2107
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
methyl phenyl 2108 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- methyl phenyl 2109 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2110 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2111
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 2112 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2113 5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-thiomethyl- hexane phenyl 2114 Cyclopentyl H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2115
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 2116 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl 2117 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2118
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2119 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 2120
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methoxyphenyl 2121 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2122 (CH.sub.2).sub.3
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2123
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 2124 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl 2125 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methoxyphenyl
2126 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl
TABLE-US-00007 TABLE 7 Compounds of Formula VII Formula VII
##STR00022## Ex R1 R2 Y R4 R5 Z 2127 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2128 CH.sub.2CF.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2129
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methylphenyl 2130 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2131
cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methyl
methylphenyl 2132 cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methyl methylphenyl 2133 (CH.sub.2).sub.2 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2134 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2135
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methylphenyl 2136 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methylphenyl 2137 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoro- hexane methylphenyl 2138 Cyclopentyl H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methylphenyl 2139
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2140
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2141
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
2142 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3
4-tolyl 2143 cyclopropyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
methyl 2144 cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
methyl 2145 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl
2146 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2147
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2148
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2149
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl hexane 2150
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-tolyl 2151
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2152
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2153
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl
phenyl 2154 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl 2155 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-ethyl phenyl methyl 2156 cyclobutyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-ethyl phenyl methyl 2157 (CH.sub.2).sub.2 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2158 (CH.sub.2).sub.3 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2159 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2160 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2161 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl hexane 2162 Cyclopentyl H
O CH.sub.2 CF.sub.3 CF.sub.3 4-ethyl phenyl 2163 CH.sub.2CH.sub.3 H
O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl 2164
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
2165 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 2166 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl 2167 cyclopropyl- H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl methyl phenyl 2168 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl methyl phenyl 2169
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl phenyl
2170 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3 4-isopropyl
phenyl 2171 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 CF.sub.3
4-isopropyl phenyl 2172 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
CF.sub.3 4-isopropyl phenyl 2173 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
CF.sub.3 4-isopropyl hexane phenyl 2174 Cyclopentyl H O CH.sub.2
CF.sub.3 CF.sub.3 4-isopropyl phenyl 2175 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 2176
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl-
phenyl 2177 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethyl- phenyl 2178 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 2179 cyclopropyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- methyl phenyl 2180
cyclobutyl- H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- methyl
phenyl 2181 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3
4-thiomethyl- phenyl 2182 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
CF.sub.3 4-thiomethyl- phenyl 2183 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 2184 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl 2185 5,5-spiro[2.3]
O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- hexane phenyl 2186
Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3 4-thiomethyl- phenyl
2187 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methoxyphenyl 2188 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 2189 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 2190
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 2191 cyclopropyl- H O CH.sub.2 CF.sub.3
CF.sub.3 4-trifluoro- methyl methoxyphenyl 2192 cyclobutyl- H O
CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methyl methoxyphenyl 2193
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro-
methoxyphenyl 2194 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 2195 (CH.sub.2).sub.4 O CH.sub.2
CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 2196 (CH.sub.2).sub.5
O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- methoxyphenyl 2197
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 CF.sub.3 4-trifluoro- hexane
methoxyphenyl 2198 Cyclopentyl H O CH.sub.2 CF.sub.3 CF.sub.3
4-trifluoro- methoxyphenyl 2199 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 2200 CH.sub.2CF.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl 2201
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methylphenyl 2202 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 2203 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl methylphenyl 2204
cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl
methylphenyl 2205 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methylphenyl 2206 (CH.sub.2).sub.3 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methylphenyl 2207 (CH.sub.2).sub.4 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl 2208
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methylphenyl
2209 5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- hexane
methylphenyl 2210 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methylphenyl 2211 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
CF.sub.3 4-tolyl 2212 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 2213 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 2214 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-tolyl 2215 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl
2216 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-tolyl methyl 2217
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 2218
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 2219
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 2220
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-tolyl 2221
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-tolyl hexane 2222
Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-tolyl 2223
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 2224
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl 2225
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
2226 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 2227 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 2228 cyclobutyl- H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
methyl 2229 (CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 2230 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 2231 (CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 2232 (CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-ethyl
phenyl 2233 5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
hexane 2234 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-ethyl phenyl
2235 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
2236 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl
2237 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-isopropyl phenyl 2238 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2239 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-isopropyl methyl phenyl 2240 cyclobutyl- H
O CH.sub.2-c-Pr CF.sub.3 4-isopropyl methyl phenyl 2241
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2242
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2243
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2244
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2245
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-isopropyl hexane phenyl
2246 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-isopropyl phenyl 2247
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl
2248 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl-
phenyl 2249 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-thiomethyl- phenyl 2250 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 2251 cyclopropyl- H O
CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- methyl phenyl 2252 cyclobutyl-
H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- methyl phenyl 2253
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 2254
(CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 2255
(CH.sub.2).sub.4 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 2256
(CH.sub.2).sub.5 O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl 2257
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- hexane phenyl
2258 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3 4-thiomethyl- phenyl
2259 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methoxyphenyl 2260 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 2261 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methoxyphenyl 2262
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro-
methoxyphenyl 2263 cyclopropyl- H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methyl methoxyphenyl 2264 cyclobutyl- H O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methyl methoxyphenyl 2265
(CH.sub.2).sub.2 O CH.sub.2-c-Pr CF.sub.3 4-trifluoro-
methoxyphenyl 2266 (CH.sub.2).sub.3 O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 2267 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
CF.sub.3 4-trifluoro- methoxyphenyl 2268 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr CF.sub.3 4-trifluoro- methoxyphenyl 2269
5,5-spiro[2.3] O CH.sub.2-c-Pr CF.sub.3 4-trifluoro- hexane
methoxyphenyl 2270 Cyclopentyl H O CH.sub.2-c-Pr CF.sub.3
4-trifluoro- methoxyphenyl 2271 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2272
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 2273 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2274
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 2275 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 2276
cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 2277 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2278 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl
2279 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 2280 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2281 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- hexane
methylphenyl 2282 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 2283 CH.sub.2CH.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 2284 CH.sub.2CF.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 2285
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 2286 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl 2287 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-tolyl methyl 2288 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl methyl 2289 (CH.sub.2).sub.2 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 2290 (CH.sub.2).sub.3
O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl 2291
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-tolyl
2292 (CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl 2293 5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-tolyl hexane 2294 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-tolyl 2295 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2296 CH.sub.2CF.sub.3 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 2297
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 2298 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 2299 cyclopropyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 2300
cyclobutyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 2301 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-ethyl phenyl 2302 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-ethyl phenyl 2303 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2304 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl 2305 5,5-spiro[2.3] O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 2306
Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-ethyl phenyl
2307 CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2308 CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2309 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2310
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2311 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 2312 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl methyl phenyl 2313
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 2314 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2315 (CH.sub.2).sub.4 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2316 (CH.sub.2).sub.5 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2317
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-isopropyl
hexane phenyl 2318 Cyclopentyl H O CH.sub.2 CF.sub.3 OCH.sub.2
CF.sub.3 4-isopropyl phenyl 2319 CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2320
CH.sub.2CF.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2321 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2322
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2323 cyclopropyl- H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 2324 cyclobutyl- H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl
2325 (CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2326 (CH.sub.2).sub.3 O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2327 (CH.sub.2).sub.4 O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2328
(CH.sub.2).sub.5 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2329 5,5-spiro[2.3] O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-thiomethyl- hexane phenyl 2330 Cyclopentyl H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2331
CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2332 CH.sub.2CF.sub.3 H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2333
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2334 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
2335 cyclopropyl- H O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methyl methoxyphenyl 2336 cyclobutyl- H O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methyl methoxyphenyl 2337
(CH.sub.2).sub.2 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2338 (CH.sub.2).sub.3 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2339
(CH.sub.2).sub.4 O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2340 (CH.sub.2).sub.5 O CH.sub.2
CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2341
5,5-spiro[2.3] O CH.sub.2 CF.sub.3 OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 2342 Cyclopentyl H O CH.sub.2 CF.sub.3
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2343 CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2344
CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2345 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2346
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methylphenyl 2347 cyclopropyl- H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methyl methylphenyl 2348
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methylphenyl 2349 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 2350 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methylphenyl 2351
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2352 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methylphenyl 2353 5,5-spiro[2.3] O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- hexane methylphenyl
2354 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methylphenyl 2355 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 2356 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-tolyl 2357 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-tolyl 2358 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2359 cyclopropyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 2360 cyclobutyl- H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl methyl 2361
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2362
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2363
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2364
(CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2365
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl hexane
2366 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-tolyl 2367
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl
phenyl 2368 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 2369 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2370 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 2371 cyclopropyl-
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl methyl 2372
cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
methyl 2373 (CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-ethyl phenyl 2374 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-ethyl phenyl 2375 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-ethyl phenyl 2376 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl 2377 5,5-spiro[2.3]
O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl hexane 2378
Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-ethyl phenyl
2379 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2380 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2381 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2382 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2383
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
methyl phenyl 2384 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl methyl phenyl 2385 (CH.sub.2).sub.2 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2386 (CH.sub.2).sub.3 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2387
(CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl
phenyl 2388 (CH.sub.2).sub.5 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-isopropyl phenyl 2389 5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-isopropyl hexane phenyl 2390 Cyclopentyl H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-isopropyl phenyl 2391
CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 2392 CH.sub.2CF.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2393 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2394
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2395 cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-thiomethyl- methyl phenyl 2396 cyclobutyl- H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- methyl phenyl 2397
(CH.sub.2).sub.2 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
phenyl 2398 (CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2399 (CH.sub.2).sub.4 O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2400 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl- phenyl 2401
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-thiomethyl-
hexane phenyl 2402 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-thiomethyl- phenyl 2403 CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr
OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2404 CH.sub.2CF.sub.3
H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl
2405 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3
4-trifluoro- methoxyphenyl 2406 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2407
cyclopropyl- H O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methyl methoxyphenyl 2408 cyclobutyl- H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methyl methoxyphenyl 2409 (CH.sub.2).sub.2 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2410
(CH.sub.2).sub.3 O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
methoxyphenyl 2411 (CH.sub.2).sub.4 O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl 2412 (CH.sub.2).sub.5 O
CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro- methoxyphenyl 2413
5,5-spiro[2.3] O CH.sub.2-c-Pr OCH.sub.2 CF.sub.3 4-trifluoro-
hexane methoxyphenyl 2414 Cyclopentyl H O CH.sub.2-c-Pr OCH.sub.2
CF.sub.3 4-trifluoro- methoxyphenyl
TABLE-US-00008 TABLE 8 Compounds of Formula VII Formula VII
##STR00023## Ex R1 R2 Y R4 R5 Z 2415 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2416 CH.sub.2CF.sub.3 H
O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2417
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2418 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2419 cyclopropylmethyl
H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2420
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
2421 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
2422 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
2423 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
2424 (CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl
2425 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2426 Cyclopentyl H O CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2427 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3
Cl 4-tolyl 2428 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 4-tolyl
2429 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-tolyl 2430
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-tolyl 2431
cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 4-tolyl 2432
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl 4-tolyl 2433
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-tolyl 2434
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 4-tolyl 2435
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-tolyl 2436
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 4-tolyl 2437
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl 4-tolyl 2438 Cyclopentyl
H O CH.sub.2CF.sub.3 Cl 4-tolyl 2439 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2440 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2441 CH.sub.2CH.sub.2CH.sub.3 H
O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2442
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl
2443 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2444
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2445
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2446
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2447
(CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2448
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2449
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2450
Cyclopentyl H O CH.sub.2CF.sub.3 Cl 4-ethyl phenyl 2451
CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-isopropyl phenyl 2452
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 4-isopropyl phenyl 2453
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-isopropyl phenyl
2454 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2455 cyclopropylmethyl H O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2456 cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2457 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2458 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2459 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2460 (CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2461 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl 4-isopropyl
phenyl 2462 Cyclopentyl H O CH.sub.2CF.sub.3 Cl 4-isopropyl phenyl
2463 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl
2464 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl
2465 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-thiomethylphenyl 2466 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2467 cyclopropylmethyl H O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2468 cyclobutylmethyl H O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2469 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2470 (CH.sub.2).sub.3 O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2471 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2472 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2473 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2474 Cyclopentyl H O
CH.sub.2CF.sub.3 Cl 4-thiomethylphenyl 2475 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2476 CH.sub.2CF.sub.3
H O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2477
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 Cl
4-trifluoromethoxyphenyl 2478 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2479 cyclopropylmethyl
H O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2480
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl
2481 (CH.sub.2).sub.2 O CH.sub.2CF.sub.3 Cl
4-trifluoromethoxyphenyl 2482 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3
Cl 4-trifluoromethoxyphenyl 2483 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2484 (CH.sub.2).sub.5
O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl 2485
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl
2486 Cyclopentyl H O CH.sub.2CF.sub.3 Cl 4-trifluoromethoxyphenyl
2487 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl
2488 CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl
2489 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
4-trifluoromethylphenyl 2490 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2491 cyclopropylmethyl H
O CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2492 cyclobutylmethyl H
O CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2493 (CH.sub.2).sub.2 O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2494 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2495 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2496 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2497 5,5-spiro[2.3]hexane
O CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2498 Cyclopentyl H O
CH.sub.2--c-Pr Cl 4-trifluoromethylphenyl 2499 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 4-tolyl 2500 CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr
Cl 4-tolyl 2501 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
4-tolyl 2502 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr Cl
4-tolyl 2503 cyclopropylmethyl H O CH.sub.2--c-Pr Cl 4-tolyl 2504
cyclobutylmethyl H O CH.sub.2--c-Pr Cl 4-tolyl 2505
(CH.sub.2).sub.2 O CH.sub.2--c-Pr Cl 4-tolyl 2506 (CH.sub.2).sub.3
O CH.sub.2--c-Pr Cl 4-tolyl 2507 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
Cl 4-tolyl 2508 (CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl 4-tolyl 2509
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl 4-tolyl 2510 Cyclopentyl H
O CH.sub.2--c-Pr Cl 4-tolyl 2511 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2512 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2513 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2514 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2--c-Pr Cl 4-ethyl phenyl 2515 cyclopropylmethyl H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2516 cyclobutylmethyl H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2517 (CH.sub.2).sub.2 O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2518 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2519 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2520 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2521 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2522 Cyclopentyl H O
CH.sub.2--c-Pr Cl 4-ethyl phenyl 2523 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2524 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2525 CH.sub.2CH.sub.2CH.sub.3
H O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2526
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr Cl 4-isopropyl phenyl
2527 cyclopropylmethyl H O CH.sub.2--c-Pr Cl 4-isopropyl phenyl
2528 cyclobutylmethyl H O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2529
(CH.sub.2).sub.2 O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2530
(CH.sub.2).sub.3 O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2531
(CH.sub.2).sub.4 O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2532
(CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2533
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2534
Cyclopentyl H O CH.sub.2--c-Pr Cl 4-isopropyl phenyl 2535
CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl 4-thiomethylphenyl 2536
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr Cl 4-thiomethylphenyl 2537
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl 4-thiomethylphenyl
2538 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2539 cyclopropylmethyl H O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2540 cyclobutylmethyl H O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2541 (CH.sub.2).sub.2 O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2542 (CH.sub.2).sub.3 O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2543 (CH.sub.2).sub.4 O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2544 (CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2545 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2546 Cyclopentyl H O CH.sub.2--c-Pr Cl
4-thiomethylphenyl 2547 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
4-trifluoromethoxyphenyl 2548 CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr
Cl 4-trifluoromethoxyphenyl 2549 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2550
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr Cl
4-trifluoromethoxyphenyl 2551 cyclopropylmethyl H O CH.sub.2--c-Pr
Cl 4-trifluoromethoxyphenyl 2552 cyclobutylmethyl H O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2553 (CH.sub.2).sub.2 O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2554 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2555 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2556 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl 2557
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl
2558 Cyclopentyl H O CH.sub.2--c-Pr Cl 4-trifluoromethoxyphenyl
2559 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2560 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2561
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2562 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2563
cyclopropylmethyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2564 cyclobutylmethyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2565 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2566
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2567 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2568 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2569
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2570 Cyclopentyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2571 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2572 CH.sub.2CF.sub.3 H
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2573
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-tolyl 2574 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-tolyl 2575 cyclopropylmethyl H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2576 cyclobutylmethyl H
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2577 (CH.sub.2).sub.2
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2578 (CH.sub.2).sub.3
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2579 (CH.sub.2).sub.4
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2580 (CH.sub.2).sub.5
O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl 2581
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl
2582 Cyclopentyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-tolyl
2583 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-ethyl phenyl 2584 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-ethyl phenyl 2585 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-ethyl phenyl 2586
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-ethyl phenyl 2587 cyclopropylmethyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-ethyl phenyl 2588 cyclobutylmethyl H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-ethyl phenyl 2589
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-ethyl
phenyl 2590 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-ethyl phenyl 2591 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-ethyl phenyl 2592 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-ethyl phenyl 2593
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-ethyl
phenyl 2594 Cyclopentyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-ethyl phenyl 2595 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2596 CH.sub.2CF.sub.3 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl phenyl 2597
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-isopropyl phenyl 2598 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl phenyl 2599
cyclopropylmethyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-isopropyl phenyl 2600 cyclobutylmethyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2601 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl phenyl 2602
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl
phenyl 2603 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-isopropyl phenyl 2604 (CH.sub.2).sub.5 O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2605 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl phenyl 2606
Cyclopentyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-isopropyl
phenyl 2607 CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-thiomethylphenyl 2608 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3
4-thiomethylphenyl 2609 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-thiomethylphenyl 2610
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-thiomethylphenyl 2611 cyclopropylmethyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2612 cyclobutylmethyl H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-thiomethylphenyl 2613
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-thiomethylphenyl 2614 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2615 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-thiomethylphenyl 2616
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-thiomethylphenyl 2617 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2618 Cyclopentyl H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-thiomethylphenyl 2619
CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2620 CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2621
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2622 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2623
cyclopropylmethyl H O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2624 cyclobutylmethyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2625 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2626
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2627 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2628 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2629
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2630 Cyclopentyl H O CH.sub.2CF.sub.3
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2632 CH.sub.2CH.sub.3 H
O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2633
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2634 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2635
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2636 cyclopropylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2637 cyclobutylmethyl H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2638
(CH.sub.2).sub.2 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2639 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2640 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2641
(CH.sub.2).sub.5 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethylphenyl 2642 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2643 Cyclopentyl H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethylphenyl 2644
CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-tolyl 2645
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-tolyl 2646
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-tolyl 2647 CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2648 cyclopropylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2649 cyclobutylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2650 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2651 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2652 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2653 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-tolyl 2654 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-tolyl 2655 Cyclopentyl H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-tolyl 2656 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl phenyl 2657
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl
phenyl 2658 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-ethyl phenyl 2659 CH.sub.2CH(CH.sub.3).sub.2 H
O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl phenyl 2660
cyclopropylmethyl H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl
phenyl 2661 cyclobutylmethyl H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-ethyl phenyl 2662 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-ethyl phenyl 2663 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl phenyl 2664
(CH.sub.2).sub.4 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl phenyl
2665 (CH.sub.2).sub.5 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-ethyl
phenyl 2666 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-ethyl phenyl 2667 Cyclopentyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-ethyl phenyl 2668 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl phenyl 2669
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl
phenyl 2670 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2671
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-isopropyl phenyl 2672 cyclopropylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2673 cyclobutylmethyl H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl phenyl 2674
(CH.sub.2).sub.2 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl
phenyl 2675 (CH.sub.2).sub.3 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-isopropyl phenyl 2676 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-isopropyl phenyl 2677 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl phenyl 2678
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-isopropyl
phenyl 2679 Cyclopentyl H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-isopropyl phenyl 2680 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2681 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-thiomethylphenyl 2682
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-thiomethylphenyl 2683 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-thiomethylphenyl 2684
cyclopropylmethyl H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-thiomethylphenyl 2685 cyclobutylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2686 (CH.sub.2).sub.2 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-thiomethylphenyl 2687
(CH.sub.2).sub.3 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-thiomethylphenyl 2688 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2689 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-thiomethylphenyl 2690
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-thiomethylphenyl 2691 Cyclopentyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-thiomethylphenyl 2692 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2693
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2694 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2695
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2696 cyclopropylmethyl H O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2697 cyclobutylmethyl H
O CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2698
(CH.sub.2).sub.2 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2699 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2700 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2701
(CH.sub.2).sub.5 O CH.sub.2--c-Pr OCH.sub.2CF.sub.3
4-trifluoromethoxyphenyl 2702 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr
OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl 2703 Cyclopentyl H O
CH.sub.2--c-Pr OCH.sub.2CF.sub.3 4-trifluoromethoxyphenyl
TABLE-US-00009 TABLE 9 Compounds of Formula III Formula III
##STR00024## Ex R1 R2 Y R4 R5 Z 2704 CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2705
CH.sub.2CF.sub.3 H O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2706 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2707
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2708 cyclopropylmethyl H O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2709
cyclobutylmethyl H O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2710 (CH.sub.2).sub.2 O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2711
(CH.sub.2).sub.3 O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2712 (CH.sub.2).sub.4 O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2713
(CH.sub.2).sub.5 O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl 2714 5,5-spiro[2.3]hexane O
CH.sub.2CH.sub.2CF.sub.3 Cl 4-trifluoromethylphenyl 2715
Cyclopentyl H O CH.sub.2CH.sub.2CF.sub.3 Cl
4-trifluoromethylphenyl
TABLE-US-00010 TABLE 10 Compounds of Formula III Formula III
##STR00025## Ex R1 R2 Y R4 R5 Z 2716 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2717
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2718 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2719
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2720 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2721
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2722 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2723
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2724 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2725
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2726 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2727
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2733 cyclobutylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2735
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
2737 (CH.sub.2).sub.5 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2738 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2739 Cyclopentyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2745
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2747 (CH.sub.2).sub.3 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2749
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole
2750 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2751 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]oxadiazole 2752 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2753
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2754 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2755
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2756 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2757
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2758 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2759
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2760 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2761
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2762 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2763
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2769 cyclobutylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2771
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole
2773 (CH.sub.2).sub.5 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2774 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2775 Cyclopentyl H
O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2781
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2783 (CH.sub.2).sub.3 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2785
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole
2786 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2787 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]thiadiazole 2788 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2789
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2790 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2791
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2792 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2793
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2794 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2795 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2796
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2797 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2798 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2799
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole
2805 cyclobutylmethyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 2807 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
F 5-benzo[c][1,2,5]oxadiazole 2809 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2810
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
2811 Cyclopentyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
2817 cyclobutylmethyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2819 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
Cl 5-benzo[c][1,2,5]oxadiazole 2821 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2822
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2823 Cyclopentyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2824 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2825
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2826 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2827
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2828 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2829
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2830 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2831 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2832
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2833 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2834 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2835
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2841 cyclobutylmethyl H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2843 (CH.sub.2).sub.3
O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2845
(CH.sub.2).sub.5 O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole
2846 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2847 Cyclopentyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2853 cyclobutylmethyl H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2855
(CH.sub.2).sub.3 O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
2857 (CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 2858 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2859 Cyclopentyl H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
TABLE-US-00011 TABLE 11 Compounds of Formula IV Formula IV
##STR00026## Ex R1 R2 X R3 R5 Z 2860 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2861
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2862 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2863
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2864 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2865
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2866 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2867
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2868 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2869
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2870 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2871
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2872 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2873
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
2874 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2875 CH.sub.2CH(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2876
cyclopropylmethyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2877 cyclobutylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2878
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
2879 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2880 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 2881
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
2882 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2883 Cyclopentyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 2884 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2885
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2886 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2887
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2888 cyclopropylmethyl H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2889
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2890 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2891
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole
2892 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2893 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 2894
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 2895 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]oxadiazole 2896 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2897
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2898 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2899
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2900 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2901
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2902 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2903
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2904 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2905
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2906 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2907
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2908 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2909
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2910 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2911
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2912 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2913
cyclobutylmethyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2914 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2915
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole
2916 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2917 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 2918
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 2919 Cyclopentyl H O CH.sub.2CF.sub.3
F 5-benzo[c][1,2,5]thiadiazole 2920 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2921
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2922 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2923
CH.sub.2CH(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2924 cyclopropylmethyl H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2925
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2926 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2927
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole
2928 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2929 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 2930
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 2931 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]thiadiazole 2932 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2933
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2934 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2935
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2936 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2937
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2938 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2939 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2940
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 2941 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2942 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 2943
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole
2944 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 2945 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2946
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 2947 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2948 cyclopropylmethyl
H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2949
cyclobutylmethyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
2950 (CH.sub.2).sub.2 O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 2951 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
F 5-benzo[c][1,2,5]oxadiazole 2952 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2953 (CH.sub.2).sub.5
O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 2954
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
2955 Cyclopentyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
2956 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2957 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2958
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2959 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2960
cyclopropylmethyl H O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole
2961 cyclobutylmethyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2962 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
Cl 5-benzo[c][1,2,5]oxadiazole 2963 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2964 (CH.sub.2).sub.4
O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 2965
(CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole
2966 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2967 Cyclopentyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 2968 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2969
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2970 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2971
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2972 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2973
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2974 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2975 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2976
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2977 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2978 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 2979
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 2980 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2981 CH.sub.2CF.sub.3
H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2982
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2983 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2984
cyclopropylmethyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole
2985 cyclobutylmethyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2986 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
F 5-benzo[c][1,2,5]thiadiazole 2987 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2988 (CH.sub.2).sub.4
O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 2989
(CH.sub.2).sub.5 O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole
2990 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2991 Cyclopentyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 2992 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2993
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
2994 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 2995 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2996
cyclopropylmethyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 2997 cyclobutylmethyl H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 2998
(CH.sub.2).sub.2 O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
2999 (CH.sub.2).sub.3 O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3000 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
Cl 5-benzo[c][1,2,5]thiadiazole 3001 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3002
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3003 Cyclopentyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole
TABLE-US-00012 TABLE 12 Compounds of Formula VII Formula VII
##STR00027## Ex R1 R2 Y R4 R5 Z 3004 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3005
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3006 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3007
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3008 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3009
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3010 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3011
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3012 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3013
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3014 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3015
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3016 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 3017
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
3018 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 3019 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 3020
cyclopropylmethyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 3021 cyclobutylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 3022
(CH.sub.2).sub.2 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
3023 (CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 3024 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole 3025
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]oxadiazole
3026 5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 3027 Cyclopentyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]oxadiazole 3028 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 3029
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 3030 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 3031
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 3032 cyclopropylmethyl H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 3033
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 3034 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 3035
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole
3036 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 3037 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]oxadiazole 3038
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]oxadiazole 3039 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]oxadiazole 3040 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3041
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3042 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3043
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3044 cyclopropylmethyl H O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3045
cyclobutylmethyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3046 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3047
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3048 (CH.sub.2).sub.4 O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3049
(CH.sub.2).sub.5 O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3050 5,5-spiro[2.3]hexane O
CH.sub.2CF.sub.3 CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3051
Cyclopentyl H O CH.sub.2CF.sub.3 CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3052 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 3053
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 3054 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 3055
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 3056 cyclopropylmethyl H O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 3057
cyclobutylmethyl H O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 3058 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 3059
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole
3060 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 3061 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 F 5-benzo[c][1,2,5]thiadiazole 3062
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 F
5-benzo[c][1,2,5]thiadiazole 3063 Cyclopentyl H O CH.sub.2CF.sub.3
F 5-benzo[c][1,2,5]thiadiazole 3064 CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 3065
CH.sub.2CF.sub.3 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 3066 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 3067
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 3068 cyclopropylmethyl H O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 3069
cyclobutylmethyl H O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 3070 (CH.sub.2).sub.2 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 3071
(CH.sub.2).sub.3 O CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole
3072 (CH.sub.2).sub.4 O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 3073 (CH.sub.2).sub.5 O
CH.sub.2CF.sub.3 Cl 5-benzo[c][1,2,5]thiadiazole 3074
5,5-spiro[2.3]hexane O CH.sub.2CF.sub.3 Cl
5-benzo[c][1,2,5]thiadiazole 3075 Cyclopentyl H O CH.sub.2CF.sub.3
Cl 5-benzo[c][1,2,5]thiadiazole 3076 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3077
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3078 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3079
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3080 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3081
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3082 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3083 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3084
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]oxadiazole 3085 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3086 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole 3087
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]oxadiazole
3088 CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 3089 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 3090
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 3091 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 3092 cyclopropylmethyl
H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 3093
cyclobutylmethyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
3094 (CH.sub.2).sub.2 O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]oxadiazole 3095 (CH.sub.2).sub.3 O CH.sub.2--c-Pr
F 5-benzo[c][1,2,5]oxadiazole 3096 (CH.sub.2).sub.4 O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 3097 (CH.sub.2).sub.5
O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole 3098
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
3099 Cyclopentyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]oxadiazole
310O CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 3101 CH.sub.2CF.sub.3 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3102
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 3103 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3104
cyclopropylmethyl H O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole
3105 cyclobutylmethyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 3106 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
Cl 5-benzo[c][1,2,5]oxadiazole 3107 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3108 (CH.sub.2).sub.4
O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole 3109
(CH.sub.2).sub.5 O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]oxadiazole
3110 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 3111 Cyclopentyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]oxadiazole 3112 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3113
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3114 CH.sub.2CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3115
CH.sub.2(CH.sub.3).sub.2 H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3116 cyclopropylmethyl H O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3117
cyclobutylmethyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3118 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3119 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3120
(CH.sub.2).sub.4 O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3121 (CH.sub.2).sub.5 O CH.sub.2--c-Pr
CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3122 5,5-spiro[2.3]hexane O
CH.sub.2--c-Pr CF.sub.3 5-benzo[c][1,2,5]thiadiazole 3123
Cyclopentyl H O CH.sub.2--c-Pr CF.sub.3
5-benzo[c][1,2,5]thiadiazole 3124 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 3125 CH.sub.2CF.sub.3
H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 3126
CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 3127 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 3128
cyclopropylmethyl H O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole
3129 cyclobutylmethyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 3130 (CH.sub.2).sub.2 O CH.sub.2--c-Pr
F 5-benzo[c][1,2,5]thiadiazole 3131 (CH.sub.2).sub.3 O
CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 3132 (CH.sub.2).sub.4
O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole 3133
(CH.sub.2).sub.5 O CH.sub.2--c-Pr F 5-benzo[c][1,2,5]thiadiazole
3134 5,5-spiro[2.3]hexane O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 3135 Cyclopentyl H O CH.sub.2--c-Pr F
5-benzo[c][1,2,5]thiadiazole 3136 CH.sub.2CH.sub.3 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3137
CH.sub.2CF.sub.3 H O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
3138 CH.sub.2CH.sub.2CH.sub.3 H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3139 CH.sub.2(CH.sub.3).sub.2 H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3140
cyclopropylmethyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3141 cyclobutylmethyl H O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3142
(CH.sub.2).sub.2 O CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole
3143 (CH.sub.2).sub.3 O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3144 (CH.sub.2).sub.4 O CH.sub.2--c-Pr
Cl 5-benzo[c][1,2,5]thiadiazole 3145 (CH.sub.2).sub.5 O
CH.sub.2--c-Pr Cl 5-benzo[c][1,2,5]thiadiazole 3146
5,5-spiro[2.3]hexane O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole 3147 Cyclopentyl H O CH.sub.2--c-Pr Cl
5-benzo[c][1,2,5]thiadiazole
EXPERIMENTAL PROCEDURES
Example 534
2-(6-cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-meth-
ylpentanoic acid
##STR00028##
[0397] Step-1
2-(3-Bromo-4-hydroxyphenyl)-4-methylpentanoate
##STR00029##
[0399] To a stirred solution of ethyl
2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in
100 ml of glacial acetic acid at 0.degree. C., slowly added bromine
(20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h.
After completion the reaction, the reaction mixture was poured into
water and neutralized with saturated sodium carbonate solution and
extracted with ethyl acetate (300 ml.times.3). The organic layer
was washed with water, saturated sodium bicarbonate solution and
brine. The organic layer was then distilled off to yield product
ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g,
80%). .sup.1H NMR (CDCl.sub.3): .delta. 7.20 (m 2H), 6.80 (d, J=7.9
Hz, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m,
1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m,
6H). Mass: (315, M+1, 100%).
Step-2
2-(3-Bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid
##STR00030##
[0401] Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g)
was taken in acetic acid (100 ml) and to it added drop wise 70%
nitric acid (10 ml) below 15.degree. C. The reaction mixture was
stirred for 2 h. After completion of the reaction; it was poured
into 300 ml of ice water and extracted with ethyl acetate (300
ml.times.3). The ethyl acetate layer was washed with bicarbonate
solution, water and finally brine solution. The organic layer was
then distilled off and the crude residue was purified by column
chromatography using Ethyl acetate:hexane (2:3) as eluent provided
12 g of 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid.
The acid was taken in 50 ml of absolute ethanol and 2 ml of
concentrated sulfuric acid and refluxed for 1 h. The ethanol layer
was distilled off, washed it with water and dried gave 13 g of
ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate
intermediate. .sup.1H NMR (CDCl.sub.3): .delta. 8.20 (s 1H), 7.20
(s, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m,
1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m,
6H). Mass: (360, M+1, 100%).
Step 3
Ethyl
2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate
##STR00031##
[0403] A solution of ethyl
2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g,
11.26 mmol) was taken in 50 ml of DMSO and to it added
Cs.sub.2CO.sub.3 (3.02 g, 12.39 mmol). The reaction mixture was
stirred at room temperature for 15 minutes and then added
cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After
completion of addition, the reaction mixture was stirred at
70.degree. C. for 4 h. After completion of the reaction, it was
poured into water (200 ml) and extracted with ethyl acetate (100
ml.times.3). The ethyl acetate layer was washed with 1N HCl, water
and finally brine solution. The organic layer was then distilled
off and the crude residue was purified by column chromatography
using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl
2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate.
.sup.1H NMR (CDCl.sub.3): .delta. 8.20 (s 1H), 7.20 (s, 1H), 4.15
(q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80
(m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25
(m, 5H). Mass: (414, M+1, 100%).
Step 4
Ethyl
2-(6-(cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoate
##STR00032##
[0405] To a solution of ethyl
2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate
(2 g, 4.83 mmol) in 30 ml of DMF/Water (25:5 ml) was added
Pd(PPh.sub.3).sub.4 (558 mg, 0.483 mmol), Cs.sub.2CO.sub.3 (5.5 g,
16.9 mmol) and 4-CF3-PhB(OH).sub.2 (1.01 g, 5.31 mmol) and the
reaction mixture was stirred at 90.degree. C. for 12 h. After
completion of the reaction, it was poured into water (100 ml) and
extracted with ethyl acetate (100 ml.times.3). The ethyl acetate
layer was washed with 1N HCl, water and finally brine solution. The
organic layer was then distilled off and the crude residue was
purified by column chromatography using Ethyl acetate:hexane (2:3)
as eluent provided 1.3 g of ethyl
2-(6-(cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate. .sup.1H NMR (CDCl.sub.3): .delta. 8.20 (s 1H),
7.40-7.20 (m, 5H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H),
1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t,
3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (480, M+1, 100%).
Step 5
2-(6-(Cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00033##
[0407] Ethyl
2-(6-(cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate (100 mg, 0.208 mmol) was taken in a mixture of MeOH;
THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol).
The reaction mixture was stirred at room temperature for 3 h. After
completion of the reaction, it was poured into water (50 ml) and
extracted with ethyl acetate (100 ml.times.2). The ethyl acetate
layer was washed with 1N HCl, water and finally brine solution. The
organic layer was then distilled off and the crude residue was
purified by column chromatography using Ethyl acetate:hexane (1:1)
as eluent provided 70 mg of
2-(6-(cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid. .sup.1H NMR (CDCl.sub.3): .delta. 8.20 (s
1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m,
1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25
(m, 5H). Mass: (452, M+1, 100%).
Example 554
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-4-meth-
ylpentanoic acid
##STR00034##
[0408] Step 1
Ethyl
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoate
##STR00035##
[0410] Ethyl
2-(6-(cyclopropylmethoxy)-5-nitro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate (300 mg, 0.626 mmol) was taken in 30 ml of
Toluene:Water (1:1) and to it added Fe powder (203 mg, 3.62 mmol),
Ammonium formate (228 mg, 3.62 mmol). The reaction mixture was
refluxed for 3 h and then filtered through celite. The toluene was
distilled off under reduced pressure and the crude residue was
purified by column chromatography using Ethyl acetate:hexane (2:3)
as eluent provided 220 mg of ethyl
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate. .sup.1H NMR (CDCl.sub.3): .delta. 7.40-7.20 (m,
5H), 6.90 (s 1H), 4.50 (bs, 2H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45
(d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H),
1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (450, M+1,
100%).
Step 3
2-(5-Amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00036##
[0412] Ethyl
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate. (120 mg, 0.267 mmol) was taken in a mixture of
MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7
mmol). The reaction mixture was stirred at room temperature for 3
h. After completion of the reaction, it was poured into water (50
ml) and extracted with ethyl acetate (100 ml.times.2). The ethyl
acetate layer was washed with 1N HCl, water and finally brine
solution. The organic layer was then distilled off and the crude
residue was purified by column chromatography using Ethyl
acetate:hexane (1:1) as eluent provided 80 mg of
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-4--
methylpentanoic acid
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid. .sup.1H NMR (CDCl.sub.3): .delta. 7.40-7.20 (m,
5H), 7.00 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H),
1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m,
5H). Mass: (422, M+1, 100%).
Example 484
2-(6-cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00037##
[0413] Step 1
Ethyl
2-(6-cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoate
##STR00038##
[0415]
2-(6-Cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoic acid (150 mg, 0.33 mmol) was taken up in 10 ml
of 6N HCl and a solution of sodium nitrite (30 mg, 0.40 mmol, 5 ml
in water) was added at 0.degree. C. The reaction mixture was
stirred for 15 minutes at 0.degree. C. and then poured into a
saturated solution of copper (II) chloride in water (25 ml) The
reaction mixture was then heated at 70.degree. C. for 3 hours. The
mixture was cooled to room temperature and extracted with ethyl
acetate (2.times.100 mL). The combined organic layers were dried
(MgSO.sub.4) and concentrated under reduced pressure. The crude
residue obtained was purified by column chromatography using ethyl
acetate:hexane (2:3) as eluent to yield 120 mg of ethyl
2-(6-cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate. .sup.1H NMR (CDCl.sub.3): .delta. 7.60-7.45 (m,
5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H),
1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t,
3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (470, M+1, 100%).
Step 2
2-(6-Cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00039##
[0417] The ethyl
2-(6-cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate above (120 mg, 0.207 mmol) was taken up in a mixture
of MeOH; THF:Water (30 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was
added. The reaction mixture was stirred at room temperature for 3
h. After completion of the reaction, it was poured into water (50
ml) and extracted with ethyl acetate (2.times.100 ml). The combined
extracts were washed with 1N HCl, water and finally brine solution.
The combined organic layers were dried (MgSO.sub.4) and
concentrated under reduced pressure. The crude residue obtained was
purified by column chromatography using ethyl acetate:hexane (1:1)
as eluent to yield 105 mg of
2-(6-cyclopropylmethoxy)-5-chloro-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid product. .sup.1H NMR (CDCl.sub.3): .delta.
7.65-7.40 (m, 5H), 7.20 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H),
1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m,
6H), 0.35-0.25 (m, 5H). Mass: (442, M+1, 100%). HPLC Purity
(99%).
Example 264
2-(6-cyclopropylmethoxy)-5-fluoro-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00040##
[0418] Step 1
Ethyl
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate
##STR00041##
[0420]
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoic acid (200 mg, 0.53 mmol) was taken up in 5 ml of
1,2-dichlorobenzene and a solution of BF3-etherate (1.5M, 5 ml) was
added at 0.degree. C. The reaction mixture was stirred for 15
minutes at 0.degree. C. and t-butyl nitrite (1.5M, 3 ml) was added
in a dropwise manner. The reaction mixture was then heated at
100.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were dried (MgSO.sub.4) and concentrated
under reduced pressure. The crude residue obtained was purified by
column chromatography using ethyl acetate:hexane (2:3) as eluent to
provide 120 mg of ethyl
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoate. .sup.1H NMR (CDCl.sub.3): .delta. 7.60-7.35 (m, 5H),
7.20 (s 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00
(m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00
(m, 6H), 0.35-0.25 (m, 5H). Mass: (453, M+1, 100%).
Step 2
2-(6-cyclopropylmethoxy)-5-fluoro-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00042##
[0422] The above ethyl
2-(6-cyclopropylmethoxy)-5-amino-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoate (120 mg, 0.267 mmol) was taken up in MeOH; THF:Water
(20 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reaction
mixture was stirred at room temperature for 3 h. After completion,
the reaction was poured into water (50 ml) and extracted with ethyl
acetate (2.times.100 ml). The combined ethyl acetate layers were
washed with 1N HCl, water and finally brine solution. The combined
organic layers were dried (MgSO.sub.4) and concentrated under
reduced pressure. The crude residue obtained was purified by column
chromatography using ethyl acetate:hexane (1:1) as eluent to yield
85 mg of
2-(6-cyclopropylmethoxy)-5-fluoro-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid product. .sup.1H NMR (CDCl.sub.3): .delta.
7.55-7.30 (m, 5H), 7.10 (s, 1H), 3.60 (t, 1H), 3.45 (d, 2H),
1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m,
6H), 0.35-0.25 (m, 5H). Mass: (425, M+1, 100%). HPLC Purity
(97%).
Example 724
2-(2-cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid
##STR00043##
[0423] Step 1
Diethyl 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonate
##STR00044##
[0425] 2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in
DMF (50 mL) was added dropwise to a stirred suspension of sodium
hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200
mL) over 20 min. at 0.degree. C. under nitrogen. The mixture was
stirred for 0.5 h at room temperature, cooled to 0.degree. C. and
1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150
mL) was added dropwise. The resulting reaction mixture was stirred
at room temperature for 16 h, poured into ice water (200 mL) and
extracted with EtOAc (3.times.100 mL). The combined organic phases
were washed with water (3.times.100 mL), brine (100 mL) and dried
(MgSO.sub.4). Evaporation of solvent under reduced pressure gave a
brown oil which was purified by column chromatography over silica
gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of
2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester
as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.87
(dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18
(m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1
Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 168.2, 155.1 (d, .sup.1J.sub.CF=252.3 Hz),
150.9 (d, .sup.1J.sub.CF=263.2 Hz), 135.7, 135.1, 120.0 (dd,
.sup.2J.sub.CF=26.0, .sup.3J.sub.CF=4.0 Hz), 113.0 (d,
.sup.2J.sub.CF=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8.
Step 2
2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid
##STR00045##
[0427] The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic
acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in
AcOH/H.sub.2O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture
was heated under reflux for 96 h. After cooling the solvent was
evaporated under reduced pressure and water (200 mL) was added. The
reaction mixture was extracted with EtOAc (3.times.100 mL), and the
combined extracts were washed with water (3.times.100 mL), brine
(100 mL) and dried (MgSO.sub.4). Evaporation of solvent under
reduced pressure gave a yellow oil which crystallized on standing
to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic
acid. Chromatography of the residual oil (Heptane-EtOAc gradient)
gave an additional 3 g of product (72% combined yield). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 9.63 (br s, 1H), 7.82 (dd,
J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m,
1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H),
0.95-0.92 (m, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta.
177.6, 158.2 (d, .sup.1J.sub.CF=232.5 Hz), 150.9 (d,
.sup.1J.sub.CF=262.5 Hz), 136.0, 134.7, 119.0 (d,
.sup.2J.sub.CF=20.0, Hz), 113.1 (d, .sup.2J.sub.CF=29.4 Hz), 41.7,
41.3, 26.0, 22.6, 21.9.
Step 3
2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl
ester
##STR00046##
[0429] 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid
(29.0 g, 0.11 mol) was dissolved in EtOH (200 mL) and
H.sub.2SO.sub.4 (96%) 10 mL added. The reaction mixture was
refluxed for 3 h and the solvent evaporated to an oil which was
dissolved in EtOAc. Water (150 mL) added and the reaction mixture
was extracted with EtOAc (3.times.100 mL). Organic phases washed
with saturated NaHCO.sub.3 (50 mL), water (100 mL) and brine (100
mL) then dried under MgSO.sub.4. The evaporation of solvent under
reduced pressure gave
2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester
as yellow oil 32.0 g, (97%), which was used for the next step
without purification. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 7.81 (dd, J=8.8, 6.2 Hz, 1H), 7.41 (dd, J=11.1, 5.6 Hz,
1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m, 1H), 1.71-1.62 (m, 1H),
1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.95-0.92 (m, 6H);
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 171.6, 155.0 (d,
.sup.1J.sub.CF=246.0 Hz), 151.5 (d, .sup.1J.sub.CF=261.3 Hz),
145.5, 135.7, 118.8 (dd, .sup.2J.sub.CF=24.0, .sup.3J.sub.CF=4.0
Hz), 113.0 (d, .sup.2J.sub.CF=20.0 Hz), 61.6, 41.8, 26.1, 22.5,
22.0, 14.1.
Step 4
2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00047##
[0431] Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with
n-BuLi (2.5M in hexane 7.4 g, 46 mL, 115.6 mmol) at -15.degree. C.
under nitrogen, and the reaction mixture was stirred 1 h at
25.degree. C. To the mixture was added
2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester
(29 g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at
25.degree. C. and the reaction mixture stirred for an additional 16
h. Water (100 mL) was added and the reaction mixture was extracted
with EtOAc (3.times.100 mL). The combined organic phases washed
with water (3.times.100 mL), brine (100 mL) and dried (MgSO.sub.4).
Evaporation of the solvent under reduced pressure gave a brown oil
which was purified by column chromatography over silica gel
(Heptane-EtOAc gradient) to give 29.5 g, (81%) of
2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester as a yellow oil. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz,
1H), 4.07 (t, J=7.7 Hz, 1H), 4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H),
1.68-1.60 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.20 (m, 1H), 1.19-1.00
(m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65 (d, J=7.7 Hz, 2H), 0.54 (d,
J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25 (d, J=4.4 Hz, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 172.6, 152.7 (d,
.sup.1J.sub.CF=243.4 Hz), 148.8, 138.1, 133.3 (d,
.sup.2J.sub.CF=15.7 Hz), 115.8, 112.6 (d, .sup.2J.sub.CF=29.5 Hz),
75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2, 10.0, 9.8, 3.4.
Step 5
2-(5-Cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00048##
[0433]
2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (10.0 g, 26.4 mmol) was dissolved in
EtOH (200 mL) and hydrogenated at 50 psi, 25.degree. C. for 24 h
over 10% Pd--C (1 g). The mixture was filtered and the solvent
evaporated to give crude a brown oi, which was purified by column
chromatography over silica gel (Heptane-EtOAc gradient) to give 6.7
g, (72%) of
2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester as a yellow oil. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 6.73 (d, J=6.9 Hz, 1H), 6.40 (d, J=11.0
Hz, 1H), 4.00-3.70 (m, 5H), 1.91-1.81 (m, 1H), 1.65-1.56 (m, 1H),
1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.90 (d,
J=6.6 Hz, 6H), 0.63-0.57 (m, 2H), 0.53-047 (m, 2H), 0.35-0.28 (m,
2H), 0.25-0.18 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 174.2, 154.8 (d, .sup.1J.sub.CF=236.0 Hz), 142.6, 136.6 (d,
.sup.3J.sub.CF=11.5 Hz), 114.1 (d, .sup.2J.sub.CF=16.8 Hz), 111.6
(d, .sup.3J.sub.CF=4.8 Hz), 101.6 (d, .sup.2J.sub.CF=28.2 Hz),
73.8, 69.2, 42.1, 40.8, 25.9, 22.7, 22.2, 10.5, 9.8, 3.2.
Step 6
2-(5-Cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00049##
[0435]
2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (2.9 g, 8.3 mmol) was dissolved in a
mixture of EtOH/H.sub.2O/H.sub.2SO.sub.4 (96%) 50 mL/100 mL/2.5 mL
at 0.degree. C. A solution of NaNO.sub.2 (0.63 g, 9.1 mmol) in
water (20 mL) was added dropwise at 0.degree. C. and the reaction
mixture was stirred for 20 min. A solution of KI (4.0 g, 24.1 mmol)
in water (20 mL) was added dropwise at 0.degree. C. and the
reaction mixture was heated 50-60.degree. C. for 2.5 h. The
reaction mixture was extracted with EtOAc (3.times.50 mL). The
combined organic layers were washed with 10% sodium thiosulfate (30
mL) followed by brine (30 mL) and then dried over MgSO.sub.4. and
solvent evaporated to give crude brown oil, which was purified by
column chromatography over silica gel (Heptane-EtOAc gradient) to
give 2.2 g, (57%) of
2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentano-
ic acid cyclopropylmethyl ester as a yellow oil. .sup.1H NMR (300
MHz, CDCl.sub.3/TMS): .delta. 7.46 (d, J=8.8 Hz, 1H), 6.83 (d,
J=6.3 Hz, 1H), 4.01-3.83 (m, 5H), 1.96-1.86 (m, 1H), 1.69-1.58 (m,
1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m, 1H), 1.12-1.00 (m, 1H), 0.91
(d, J=6.3 Hz, 6H), 0.66-0.60 (m, 2H), 0.55-047 (m, 2H), 0.42-0.34
(m, 2H), 0.26-0.18 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 173.2, 154.3 (d, .sup.1J.sub.CF=243.4 Hz), 154.1, 127.1 (d,
.sup.2J.sub.CF=16.2 Hz), 125.5 (d, .sup.2J.sub.CF=26.4 Hz), 112.3
(d, .sup.3J.sub.CF=3.6 Hz), 84.6 (d, .sup.3J.sub.CF=8.4 Hz), 74.5,
69.6, 41.9, 41.5, 26.0, 22.7, 22.2, 10.2, 9.8, 3.3.
Step 7
2-(2-Cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid cyclopropylmethyl ester
##STR00050##
[0437] To a solution of
2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME
(10 mL) under argon was added 4-trifluoromethylphenylboronic acid
(0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and
Pd(PPh.sub.3).sub.4 (0.015 g, 0.013 mmol). The reaction mixture was
refluxed for 18 h, a water/EtOAc 15/15 mL mixture was added and the
organic phase was separated and dried over MgSO.sub.4. The solvent
was then evaporated to give a yellow oil which was purified by
column chromatography over silica gel (Heptane-EtOAc gradient) to
give 0.18 of
2-(2-cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)-4-meth-
yl-pentanoic acid cyclopropylmethyl ester as a light yellow oil.
.sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.70-7.64 (m, 4H),
7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz,
1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H),
1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d,
J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). .sup.13C NMR
(75 MHz, CDCl.sub.3/TMS): .delta. 173.5, 154.3 (d,
.sup.1J.sub.CF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d,
.sup.2J.sub.CF=16.9 Hz), 124.8 (q, .sup.3J.sub.CF=3.7 Hz), 124.0
(q, .sup.1J.sub.CF=271.6 Hz), 117.0 (d, .sup.2J.sub.CF=24.6 Hz),
113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8,
3.2.
Step 8
2-(2-Cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid
##STR00051##
[0439]
2-(2-cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)--
4-methyl-pentanoic acid cyclopropylmethyl ester (0.14 g, 0.29 mmol)
was dissolved in a mixture of EtOH/H.sub.2O (9 ml/1 ml) and KOH 0.3
g added. The reaction mixture was refluxed for 2 h and after
cooling the solvent was evaporated. Water (10 mL) was added and the
reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic extracts were dried over MgSO.sub.4 and evaporated
under reduced pressure to an oil which was purified by column
chromatography over silica gel (Heptane-EtOAc gradient) to give
0.12 g of a white solid. A second chromatography of the solid gave
0.03 g (25%) of pure
2-(2-cyclopropylmethoxy-5-fluoro-4'-trifluoromethyl-biphenyl-4-yl)-4-meth-
yl-pentanoic acid product as a crystalline white solid.
M.P.=110-111.degree. C., .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 8.99 (br s 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H),
6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz,
2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H),
1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H),
0.24 (d, J=3.9 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 179.2, 154.7 (d, .sup.1J.sub.CF=239.8 Hz), 152.0, 140.6,
132.0, 129.9, 129.6, 125.7 (d, .sup.2J.sub.CF=16.2 Hz), 124.8 (q,
.sup.3J.sub.CF=3.6 Hz), 124.0 (q, .sup.1J.sub.CF=270 Hz), 117.2 (d,
.sup.2J.sub.CF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1,
10.3, 3.2.
Example 485
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid
##STR00052##
[0440] Step 1
Ethyl 2-(3-bromo-4-hydroxyphenyl)acetate
##STR00053##
[0442] To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate
(20 g, 0.11 mol) in 200 ml of CCl.sub.4, was slowly added bromine
(18.8 g, 0.11 mol) dissolved in 10 ml of CCl.sub.4 at 0.degree. C.
for 30 min. The reaction mass was stirred for another 30 min at
0.degree. C. After completion of the reaction, the mixture was
poured onto crushed ice and extracted with DCM (.times.2). The
combined organic layers were washed with water, and 10% sodium
bi-sulfite solution, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give ethyl
2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield. (22.4 g).
.sup.1HNMR (CDCl3): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53
(bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).
Step 2
Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate
##STR00054##
[0444] To a stirred solution of ethyl
2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 mol) in 200 ml of
DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed.
Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a
period of 10 min. The reaction mixture was refluxed for a further 5
h. Upon completion of reaction, the mixture was poured onto crushed
ice and extracted with DCM (.times.2). The combined organic layer
were washed with 10% NaHCO.sub.3 solution and water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under vacuum to give
ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield.
(13.6 g). .sup.1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs,
1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).
Step 3
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate
##STR00055##
[0446] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and
K.sub.2CO.sub.3 (2.8 g, 0.02 mol) in 100 ml of DMSO was slowly
added cyclopropyl methylbromide (1.46 ml, 0.017 mol) at room
temperature. Upon completion of the addition, the reaction mixture
was heated at 60.degree. C. for 4 h. Upon completion of the
reaction, the mixture was poured onto water and extracted with
EtOAc (.times.2). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to give ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72%
yield. (93.4 g). .sup.1HNMR (CDCl3): 7.38 (bs, 1H); 7.28 (s, 1H);
4.16 (q, 2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t,
3H); 0.63 (m, 2H); 0.38 (m, 2H).
Step 4
Ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)acetate
##STR00056##
[0448] A mixture of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g,
0.011 mol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012
mol), Palladium Tetrakis(triphenylphosphine) (1.3 g, 0.001 mol),
Cesium carbonate (13.1 g, 0.04 mol) in DMF/water mixture (100 ml/5
ml) was stirred overnight at 100.degree. C. Upon completion of
reaction, the precipitate were removed by filtration. The filtrate
was diluted with water and extracted with EtOAc twice. The combined
organic layers were washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by Flash Column Chromatography to give ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)acet-
ate in 57% yield. (2.7 g). .sup.1HNMR (CDCl3): 7.69 (bs, 4H); 7.36
(s, 1H); 7.17 (s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H);
1.28 (t, 3H); 0.96 (m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).
Step 5
Ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-3-cyclopropylpropanoate
##STR00057##
[0450] To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in
25 ml of DMF was slowly added a mixture of ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)acet-
ate (300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg,
0.782 mmol) in 20 ml of DMF at 0.degree. C. for 15 min under
nitrogen atmosphere. Upon completion of the addition, the mixture
was stirred for 15 min at 0.degree. C. The reaction mixture was
poured onto crushed ice and extracted with EtOAc (.times.2). The
combined organic layers were washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by Flash column Chromatography to give ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-y-
l)-3-cyclopropylpropanoate in 62% yield. (0.210 g). .sup.1HNMR
(CDCl3): 7.69 (s, 4H); 7.41 (s, 1H); 7.21 (s, 1H); 4.19 (q, 2H);
3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78 (m, 1H); 1.27 (t,
3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13 (m, 2H); 0.1
(m, 2H).
Step 6
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid
##STR00058##
[0452] A mixture of ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-c-
yclopropylpropanoate (100 mg, 0.214 mmol) and lithium hydroxide
monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture
(5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon
completion of reaction, the volatiles were removed under reduced
pressure. The residue was diluted with water, acidified with 5% HCl
solution and extracted with EtOAc (.times.2). The combined organic
layers were washed with water, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
Flash Column Chromatography to give
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-c-
yclopropylpropanoic acid in 56% yield. (52.6 mg). .sup.1HNMR
(CDCl3): 7.71 (s, 4H); 7.42 (s, 1H); 7.23 (s, 1H); 3.68 (t, 1H);
3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H); 0.97 (bs, 1H); 0.71 (bs,
1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).
Example 414
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid
##STR00059##
[0453] Step 1
Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate
##STR00060##
[0455] To a stirred solution compound ethyl
2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in
dry methanol (100 mL) was added Pd(OH).sub.2 under an atmosphere of
nitrogen. The reaction mixture was stirred for 5 h under an
atmosphere of hydrogen. The reaction mixture was filtered through
Celite.TM., washed with methanol and concentrated to dryness under
reduced pressure. The crude material was purified by column
chromatography to yield ethyl
2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%).
.sup.1HNMR (CDCl3, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs,
1H); 4.13 (q, 2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H);
1.21 (t, 3H), 0.97 (d, 6H).
Step 2
Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate
##STR00061##
[0457] Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate
1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H.sub.2O/HCl
60 mL/30 mL/8 mL at 0.degree. C. A solution of NaNO.sub.2 (0.919 g,
1.1 eq) in water (10 mL) was added dropwise at 0.degree. C. and the
reaction mixture was stirred for 1 h at 0.degree. C. A solution of
CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the
reaction mixture at 0.degree. C. The reaction mixture was then
heated to 50.degree. C. for 2.5 h. upon which the mixture was
poured into ice water, extracted with ethyl acetate (3.times.100
mL) The combined organic layers were washed with water (200 mL) and
brine (100 mL), dried over NaSO.sub.4 and concentrated in vacuo to
give crude black oil which was purified by chromatography over
silica gel (hexane/EtOAc) to give ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow
oil 2.2 g, (47.3%). .sup.1HNMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4
(s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m,
2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);
Step 3
Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methyl
pentanoate
##STR00062##
[0459] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57
mmol) and K.sub.2CO.sub.3 (1.58 g, 0.011 mol) in dry DMF (20 mL),
slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at
room temperature. Upon completion of the addition, the reaction
mixture was slowly heated to 100.degree. C. for 4 h. Upon
completion, the reaction mixture was poured into water and
extracted with ethyl acetate (2.times.50 mL). The combined organic
layer were washed with water, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography over silica gel (hexane/EtOAc) to give
ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(1.4 g, 60% yield). .sup.1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34
(s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H),
1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Step 4
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-4-methylpentanoate
##STR00063##
[0461] A mixture of ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq),
Pd(PPh.sub.3).sub.4 (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2
eq) in DME (30 ml) was stirred for overnight at 100.degree. C. Upon
completion, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate (2.times.50
mL). The combined organic layers were washed with water followed by
brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuo.
The residue was purified by Flash Column Chromatography to give
ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate in 74% yield (1.08 g). .sup.1HNMR (CDCl3, 400
MHz): 7.68 (m, 5H), 7.43 (s, 1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13
(q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H);
1.24 (t, 3H), 0.92 (d, 6H);
Step 5
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid
##STR00064##
[0463] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate (800 mg, mmol) and lithium hydroxide monohydrate
(27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml
5/ml) was stirred for 3 h at room temperature. Upon completion of
the reaction, the volatiles were removed under reduced pressure.
The residue was diluted with water, acidified with 5% HCl solution
and extracted with ethyl acetate (3.times.50 mL). The combined
organic layers were washed with water, dried over Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure. The residue was
purified by Flash Column Chromatography to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoic acid in 88% yield (670 mg).
[0464] Or alternatively example 414 may be synthesized via the
following procedures:
Step 1
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-4-methylpentanoate
##STR00065##
[0466] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.75 g, 1.70 mmol) was dissolved in anhydrous DMF (20 mL),
NaH (60% wt. in paraffin oil, 0.049 g, 2.04 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature, upon which isobutyl bromide (0.2 mL, 1.87 mmol), was
added in a drop wise manner at 0.degree. C. The reaction mixture
was stirred an additional 1 h at 0.degree. C. and then saturated
NH.sub.4Cl solution (10 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.20 mL) and the combined organic
layers were washed with water (2.times.10 mL) and brine (10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give a colorless oil, witch was purified by
flash column chromatography to give ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate (0.5 g, 59% yield) as a thick liquid.
Step 2
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methyl pentanoic acid
##STR00066##
[0468] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate (0.6 g, 1.21 mmol) and lithium hydroxide
monohydrate (0.509 g, 12.1 mmol) in MeOH/THF/Water a solvent
mixture (10 mL/10 mL/10 mL) was stirred for 4 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. The residue was diluted with water,
acidified with 5% HCl solution and extracted with ethyl acetate
(3.times.20 mL). The combined organic layers washed with water,
dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced
pressure. The residue was purified by Flash Column Chromatography
to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methyl pentanoic acid (0.4 g, 72% yield) as a white solid.
Example 1055
2-(6-Cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-p-
entanoic Acid
Step 1
Diethyl
2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate
##STR00067##
[0470] To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol)
in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%,
11.1 g, 277 mmol) in small portions. After the addition, the
reaction mixture was stirred at 0.degree. C. for 10 min and then at
room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3
g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the
mixture was stirred at room temperature for two days. The DMF was
removed under high vacuum and the residue was diluted with ethyl
acetate (400 mL). Water (400 mL) was added dropwise; ammonium
chloride (25 g) was added and the layers were separated. The
organic layer was washed with brine (400 mL), dried over sodium
sulfate, and concentrated under reduced pressure to give a
red-brown oil, which was purified by silica-gel flash
chromatography eluting with heptane/ethyl acetate (12:1) to give
the desired product diethyl
2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g,
87%) as a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25
(m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2
Hz), 0.84 (d, 6H, J=6.6 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3):
.delta. 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55,
123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16,
24.66, 23.66, 13.89.
Step 2
4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid
##STR00068##
[0472] To a solution of diethyl
2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g,
184 mmol) in acetic acid (500 mL) were added water (157 mL) and
concentrated H.sub.2SO.sub.4 (55 mL) carefully. The reaction
mixture was refluxed for three days and then concentrated under
reduced pressure. The residue was diluted with water (400 mL) and
extracted with ethyl acetate (6.times.100 mL). The combined organic
extracts were washed with water (400 mL), dried over sodium
sulfate, and concentrated under reduced pressure to give a brown
oil. The residue was purified by silica-gel flash chromatography
eluting with heptane/EtOAc (5:1 and then 2:1) to give
4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5
g, 76%) as a yellowish oil: .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 11.51 (s, 1H, br), 7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H),
7.71 (d, 1H, J=8.4 Hz), 3.84 (t, 1H, J=7.8 Hz), 2.06 (m, 1H), 1.72
(m, 1H), 1.49 (m, 1H), 0.95 (d, 3H, J=6.6. Hz), 0.94 (d, 3H, J=6.3
Hz); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 178.76, 147.09,
143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz),
121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.
Step 3
4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl
ester
##STR00069##
[0474] To a solution of
4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.3
g, 139 mmol) in absolute ethanol (300 mL) was added concentrated
sulfuric acid (95-98%, 9.0 mL) and the solution was heated at
reflux overnight. The reaction mixture was concentrated under
reduced pressure; the residue was treated with a solution of sodium
carbonate (5%, 300 mL) and the mixture was extracted with ethyl
acetate (300 mL). The organic layer was washed with brine (300 mL),
dried over sodium sulfate, and concentrated under reduced pressure.
Purification by silica-gel flash chromatography eluting with
heptane/EtOAc (10:1) gave
4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl
ester (38.4 g, 83%) as a yellowish oil: .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.90 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.74
(dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H), 3.83 (t, 1H, J=7.5 Hz), 2.06
(m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 0.97
(d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); .sup.13C NMR (75 MHz,
CDCl.sub.3): .delta. 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5
Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45,
49.45, 42.65, 26.03, 22.41, 22.17, 14.10.
Step 4
2-(4-Amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl
ester
##STR00070##
[0476] A suspension of
4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl
ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460 mmol) and
water (16.6 g, 920 mmol) in ethanol (500 mL) was heated at reflux
for four hours. The reaction mixture was concentrated under reduced
pressure; the residue was treated with ethyl acetate (300 mL) and
aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extracted
with ethyl acetate (3.times.600 mL). The combined organic layers
were washed with brine (1 L), dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by
silica-gel flash chromatography eluting with heptane/ethyl acetate
(10:1) to give
2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl
ester (31.1 g, 89%) as a yellow oil: .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.35 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=8.4,
2.1 Hz), 6.69 (d, 1H, J=8.4 Hz), 4.10 (m, 4H), 3.54 (t, 1H, J=7.8
Hz), 1.91 (m, 1H), 1.58 (m, 1H), 1.44 (m, 1H), 1.21 (t, 3H, J=6.9
Hz), 0.90 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz); .sup.13C NMR
(75 MHz, CDCl.sub.3): .delta. 174.14, 143.45, 132.22, 128.58,
125.91 (q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29
Hz), 60.60, 48.54, 42.35, 25.77, 22.46, 22.18, 14.04.
Step 5
2-(4-Hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid ethyl ester
##STR00071##
[0478] To sulfuric acid (95-98%, 20.0 mL) was added
2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl
ester (6.06 g, 20.0 mmol). The mixture was cooled to 0.degree. C.
and water (30.0 mL) was added dropwise. A solution of NaNO.sub.2
(1.66 g, 24.0 mmol) in water (12 mL) was added dropwise and the
mixture was stirred for additional 20 min. A few crystals of urea
were added to decompose any excess NaNO.sub.2. A solution of cupric
nitrate (466 g, 2.00 mol) in water (880 mL) was added, followed by
addition of Cu.sub.2O (2.86 g, 20.0 mmol). The mixture was stirred
for 5 min and diethyl ether (1 L) was added. The organic extract
was washed with brine (500 mL), dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by
silica-gel flash chromatography eluting with heptane/ethyl acetate
(20:1) to give
2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid ethyl ester (2.20 g, 31%) as a yellow oil: HRMS (DIP-CI-MS):
calcd for C.sub.15H.sub.19NO.sub.5F.sub.3 (M+H).sup.+: 350.1215.
found 350.1240; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 11.13
(s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 4.15 (m, 2H), 3.69 (t, 1H,
J=7.8 Hz), 2.00 (m, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.25 (t, 3H,
J=7.2 Hz), 0.94 (d, 3H, J=6.3 Hz), 0.93 (d, 3H, J=6.6 Hz); .sup.13C
NMR (75 MHz, CDCl.sub.3): .delta. 172.75, 152.45, 134.67 (q, J=5
Hz), 134.29, 131.40, 127.90, 122.35, (q, J=271 Hz), 121.42 (q, J=32
Hz), 61.51, 48.76, 42.76, 26.23, 22.60, 22.42, 14.32.
Step 6
2-(4-Cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentano-
ic acid ethyl ester
##STR00072##
[0480] To a solution of
2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid ethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g,
8.38 mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous
THF (32 mL) was added diethyl azodicarboxylate (40 wt % solution in
toluene, 3.98 g, 9.14 mmol) dropwise. The reaction mixture was
stirred at room temperature for two days and then concentrated
under reduced pressure. The residue was triturated with THF/hexane
(1:5, 3.times.15 mL). The combined extracts were concentrated under
reduced pressure to give a yellow solid, which was purified by
silica-gel flash chromatography eluting with heptane/ethyl acetate
(60:1 and then 10:1) to give
2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentan-
oic acid ethyl ester (1.89 g, 61%) as a colorless oil: .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m,
2H), 3.79 (d, 2H, J=7.2 Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H),
1.55 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz),
0.86 (m, 6H), 0.56 (d, 2H, J=6.6 Hz), 0.27 (m, 2H); .sup.13C NMR
(75 MHz, CDCl.sub.3): .delta. 172.49, 149.98, 144.40, 135.55,
130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q, J=272
Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14, 10.66,
3.39.
Step 7
2-(3-Amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentano-
ic acid ethyl ester
##STR00073##
[0482] A mixture of
2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentan-
oic acid ethyl ester (1.85 g, 4.59 mmol) and Pd/C (1.85 g) in
ethanol and 1 N HCl (4.60 mL) was hydrogenated under 36 psi H.sub.2
in a Parr apparatus. After 4 h, the reaction mixture was filtered
through Celite 521.RTM.. The filtrate was concentrated under
reduced pressure to give a yellow oil. The residue was treated with
an aqueous solution of sodium carbonate (3 g in 100 mL of water)
and the resulting solution was extracted with ethyl acetate (100
mL). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure to give a brown oil, which was
purified by silica-gel flash chromatography eluting with a gradient
of heptane/ethyl acetate (from 10:1 to 2:1) to give
2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentan-
oic acid ethyl ester (0.88 g, 51%) as a light pink oil: .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 6.83 (s, 1H), 6.80 (s, 1H), 4.04 (m,
2H), 3.85 (s, 2H), 3.66 (d, 2H, J=6.9 Hz), 3.45 (t, 1H, J=7.8 Hz),
1.84 (m, 1H), 1.49 (m, 1H), 1.39 (m, 1H), 1.22 (m, 1H), 1.14 (t,
3H, J=7.2 Hz), 0.82 (m, 6H), 0.56 (d, 2H, J=7.5 Hz), 0.27 (d, 2H,
J=4.5 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 173.61,
142.71, 141.25, 135.51, 123.75 (q, J=30 Hz), 123.52 (q, J=271 Hz),
118.46, 115.52 (q, J=5 Hz), 77.88, 60.70, 49.03, 42.53, 25.86,
22.40, 22.31, 14.07, 10.98, 3.19.
Step 8
2-(4-Cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoi-
c acid ethyl ester
##STR00074##
[0484] To a solution of p-toluenesulfonic acid monohydrate (0.308
g, 1.62 mmol) in acetonitrile (2.3 mL) was added
2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentan-
oic acid ethyl ester (0.20 g, 0.54 mmol). The resulting suspension
of the amine salt was cooled in an ice bath. A solution of sodium
nitrite (0.0745 g, 1.08 mmol) in water (0.32 mL) was added
dropwise, followed by addition of a solution of KI (1.79 g, 10.8
mmol) in water (2.0 mL). The reaction mixture was stirred in the
ice bath for one hour and then at room temperature for one hour.
TLC showed that the reaction was completed. Water (20 mL) was added
and then an aqueous solution of sodium bicarbonate (1 M) to adjust
the pH to 8. Ethyl acetate (20 mL) was added for extraction. The
organic layer was washed with aqueous Na.sub.2S.sub.2O.sub.4
solution (10%, 20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure to give a
brown oil, which was purified by silica-gel flash chromatography
eluting with heptane/ethyl acetate (30:1) to give
2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentano-
ic acid ethyl ester (0.15 g, 57%) as a yellowish oil: .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 7.93 (s, 1H), 7.52 (s, 1H), 4.11 (m,
2H), 3.83 (d, 2H, J=7.2 Hz), 3.59 (t, 1H, J=7.5 Hz), 1.95 (m, 1H),
1.50 (m, 3H), 1.22 (t, 3H, J=6.9 Hz), 0.91 (d, 3H, J=6.3 Hz), 0.90
(d, 3H, J=6.3 Hz), 0.64 (m, 2H), 0.43 (m, 2H); .sup.13C NMR (75
MHz, CDCl.sub.3): .delta. 172.96, 155.55, 142.66, 136.98, 126.94
(q, J=5 Hz), 124.87 (q, J=30 Hz), 122.64 (q, J=272 Hz), 93.73,
79.79, 61.06, 48.53, 42.65, 26.01, 22.39, 14.16, 10.75, 3.36.
Step 9
2-(6-Cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-p-
entanoic acid ethyl ester
##STR00075##
[0486] A mixture of
2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentano-
ic acid ethyl ester (0.14 g, 0.29 mmol),
4-(trifluoromethyl)benzeneboronic acid (0.089 g, 0.47 mmol),
Pd(dppf)Cl.sub.2 (0.023 g, 0.031 mmol) and a solution of aqueous
sodium carbonate (2 M, 0.31 mL, 0.62 mmol) in 1,4-dioxane (4 mL)
was degassed and heated at 100.degree. C. for ten days. The
reaction mixture was concentrated under reduced pressure; the
residue was treated with water (30 mL) and ethyl acetate (30 mL).
The organic layer was washed with brine (30 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography eluting with
heptane/ethyl acetate (100:1) to give a colorless oil (0.11 g),
which was further purified by flash chromatography on silica gel
100 C.sub.18-reversed phase eluting with MeOH/H.sub.2O (5:1 to
20:3) to give
2-(6-cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl--
pentanoic acid ethyl ester (0.05 g, 34%) as a white solid: .sup.1H
NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.73 (m, 4H), 7.58 (s, 1H),
7.48 (s, 1H), 4.13 (m, 2H), 3.70 (t, 1H, J=7.5 Hz), 3.27 (d, 2H,
J=7.2 Hz), 2.00 (m, 1H), 1.67 (m, 2H), 1.51 (m, 1H), 1.25 (t, 3H,
J=7.2 Hz), 0.93 (m, 8H), 0.45 (d, 2H, J=7.5 Hz); .sup.13C NMR (75
MHz, CDCl.sub.3/TMS): .delta. 173.35, 153.80, 140.99, 135.48,
135.40, 134.05, 130.05 (q, J=32 Hz), 129.88 (q, J=32 Hz), 129.42,
126.41 (q, J=5 Hz), 125.33 (q, J=4 Hz), 124.06 (q, J=270 Hz),
123.48 (q, J=270 Hz), 79.47, 60.98, 49.21, 42.87, 26.19, 22.46,
14.22, 10.56, 3.13.
Step 10
2-(6-Cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-p-
entanoic acid
##STR00076##
[0488] A mixture of
2-(6-cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl--
pentanoic acid ethyl ester (0.04 g, 0.08 mmol) and aqueous KOH (1.4
M, 0.4 mL) in ethanol (5 mL) was stirred at room temperature for
two days. After the solvent was removed under reduced pressure, the
residue was diluted with water (30 mL), acidified with 1 N HCl to
pH 1, and then extracted with ethyl acetate (30 mL). The organic
layer was dried over sodium sulfate, concentrated under reduced
pressure and freeze-dried overnight to give the desired carboxylic
acid
2-(6-cyclopropylmethoxy-5,4'-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl--
pentanoic acid (0.04 g, 100%) as a white solid: mp 148-149.degree.
C.; HRMS (ESI-TOF): calcd for
C.sub.24H.sub.23O.sub.3F.sub.6Na.sub.2 (M-H+2 Na).sup.+: 519.1341.
found 519.1366; .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.72
(m, 4H), 7.59 (s, 1H), 7.48 (s, 1H), 3.73 (m, 1H), 3.27 (d, 2H,
J=6.9 Hz), 2.02 (m, 1H), 1.69 (m, 1H), 1.56 (m, 1H), 1.28 (m, 1H),
0.94 (m, 8H), 0.46 (m, 2H); the proton of COOH was not observed;
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 178.95, 154.12,
140.82, 135.61, 134.49, 134.24, 130.18 (q, J=32 Hz), 129.44 (q,
J=32 Hz), 129.40, 126.50 (q, J=5 Hz), 125.39 (q, J=4 Hz), 124.04
(q, J=270 Hz), 123.40 (q, J=271 Hz), 79.55, 48.91, 42.35, 26.07,
22.49, 22.35, 10.58, 3.15; HPLC purity: 95.2%, retention time=11.78
min.
Example 754
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl-
)-4-methylpentanoic acid
##STR00077##
[0489] Step 1
Cyclopropylmethyl
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluoropheny-
l)-4-methylpentanoate
##STR00078##
[0491] To a solution of
2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in DME (anhydrous,
10 mL) under argon atmosphere was added
4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16
g, 1.05 mmol), and Pd(PPh.sub.3).sub.4 (0.015 g, 0.013 mmol). The
reaction mixture was refluxed for 18 h (oil bath, 100.degree. C.).
A mixture of water and EtOAc (15 mL/15 mL) was added and the layers
were separated. The organic phase was dried over MgSO.sub.4 and
evaporated to give a crude yellow oil, which was purified by silica
gel gradient column chromatograph using Heptane-EtOAc (60:1-9:1) to
give cyclopropylmethyl
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluoropheny-
l)-4-methylpentanoate as a yellowish oil (0.18 g, 90%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 7.70-7.64 (m, 4H), 7.05 (d,
J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H),
4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H),
1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d,
J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). .sup.13C NMR
(75 MHz, CDCl.sub.3/TMS): .delta. 173.5, 154.3 (d,
.sup.1J.sub.CF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d,
.sup.2J.sub.CF=16.9 Hz), 124.8 (q, .sup.3J.sub.CF=3.7 Hz), 124.0
(q, .sup.1J.sub.CF=271.6 Hz), 117.0 (d, .sup.2J.sub.CF=24.6 Hz),
113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8,
3.2.
Step 2
2-(4-benzo[1,2,5]oxadiazol-5-yl-5-cyclopropylmethoxy-2-fluoro-phenyl)-4-me-
thylpentanoic acid
##STR00079##
[0493] Cyclopropylmethyl
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluoropheny-
l)-4-methylpentanoate (0.14 g, 0.29 mmol) was dissolved in a
mixture of EtOH/H.sub.2O (9 mL/1 mL) and KOH (0.3 g) was added. The
reaction mixture was refluxed for 2 h and after cooling the solvent
was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and
the reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic phases were dried over MgSO.sub.4 and evaporated
under reduced pressure to give a colorless oil. Purification by
gradient column chromatography on silica gel Heptane-EtOAc
(50:1-9:1) gave
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluoropheny-
l)-4-methylpentanoic acid as a white solid (0.12 g, quantitative);
pure portion (0.03 g, 25%); white microcrystals,
M.P.=110-111.degree. C., .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H),
6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz,
2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H),
1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H),
0.24 (d, J=3.9 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 179.2, 154.7 (d, .sup.1J.sub.CF=239.8 Hz), 152.0, 140.6,
132.0, 129.9, 129.6, 125.7 (d, .sup.2J.sub.CF=16.2 Hz), 124.8 (q,
.sup.3J.sub.CF=3.6 Hz), 124.0 (q, .sup.1J.sub.CF=270 Hz), 117.2 (d,
.sup.2J.sub.CF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1,
10.3, 3.2.
Example 2959
2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-me-
thyl-pentanoic acid
##STR00080##
[0494] Step 1
2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl
ester
##STR00081##
[0496] To a solution of 2-isobutylmalonic acid diethyl ester (75.0
g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in
mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 0.5 h, then warmed
to 25.degree. C. The reaction mixture was cooled down to 0.degree.
C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31
mol) in DMF (150 mL) was added dropwise at 0.degree. C. The
reaction mixture was stirred at 25.degree. C. for 16 h. After
cooling, the reaction mixture was poured into ice water (200 mL)
and extracted with EtOAc (3.times.100 mL). The combined organic
phases washed with water (3.times.100 mL), brine (100 mL), and
dried (MgSO.sub.4). Evaporation of the solvent under reduced
pressure gave a brown oil. The crude product (92.0 g, 82%) was used
for the next step without purification. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9,
1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d,
J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d,
J=7.0 Hz, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta.
169.2, 154.5 (d, .sup.1J.sub.CF=263.1 Hz), 146.9 (d, unresolved),
125.3, 124.1 (d, .sup.3J.sub.CF=3.6 Hz), 118.6 (d,
.sup.2J.sub.CF=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.
Step 2
2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid
##STR00082##
[0498] 2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl
ester (92.0 g, 0.26 mol) was dissolved in
AcOH/H.sub.2O/H.sub.2SO.sub.4 (96%) (500 mL/200 mL/70 mL) and the
reaction mixture was refluxed for 24 h. After cooling and
evaporation, water (300 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.100 mL). The combined organic phases
were washed with water (3.times.100 mL), brine (100 mL) and dried
(MgSO.sub.4). The evaporation of solvent under reduced pressure
gave a brown oil (61 g, quantitative), which was used for the next
step without purification. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H),
2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92
(m, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 178.3,
156.0 (d, .sup.1J.sub.CF=232.5 Hz), 147.0, 136.0, 126.2, 124.3,
118.1 (d, .sup.2J.sub.CF=30 Hz), 49.3, 42.0, 25.8, 22.4, 22.0.
Step 3
2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester
##STR00083##
[0500] 2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g,
0.12 mmol) was dissolved in EtOH (100 mL) and H.sub.2SO.sub.4 (96%,
5 mL) was added. The reaction mixture was refluxed for 3 h and the
solvent evaporated. Water (100 mL) was added and the reaction
mixture was extracted with EtOAc (3.times.100 mL). The combined
organic phases were washed with saturated NaHCO.sub.3 solution (50
mL), water (100 mL) and brine (100 mL), and then dried over
MgSO.sub.4. Evaporation of the solvent under reduced pressure gave
a brown oil (31.0 g, 97%), which was used for the next step without
purification. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 8.03
(t, J=8.4 Hz, 1H), 7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t,
J=7.6 Hz, 1H), 2.10-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m,
1H), 1.25 (t, J=7.0 Hz, 3H), 0.95-0.92 (m, 6H); .sup.13C NMR (75
MHz, CDCl.sub.3/TMS): .delta. 172.2, 155.3 (d, .sup.1J.sub.CF=265.0
Hz), 148.3 (d, .sup.3J.sub.CF=8.4 Hz), 136.5, 126.1, 124.1 (d,
.sup.3J.sub.CF=3.6 Hz), 117.8 (d, .sup.2J.sub.CF=21.6 Hz), 61.3,
49.4, 42.3, 25.9, 22.5, 22.1, 14.1.
Step 4
2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid
cyclopropylmethyl ester
##STR00084##
[0502] Cyclopropylmethanol (80.0 g, 1.11 mol) was treated with
n-BuLi (2.5 M in hexane, 9.1 g, 57 mL, 0.14 mol) at a temperature
ranging from -15 to 0.degree. C. The reaction mixture was stirred
for 1 h at 25.degree. C. Then, a solution of
2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester in
cyclopropylmethanol (30 mL) was added at 25.degree. C. and the
reaction mixture was stirred for 16 h. Water (100 mL) was added and
the reaction mixture was extracted with EtOAc (3.times.100 mL). The
combined organic phases were washed with water (3.times.100 mL),
brine (100 mL), and dried (MgSO.sub.4). Evaporation of the solvent
under reduced pressure gave a brown oil, which was purified by
silica gel gradient column chromatography by use of Heptane-EtOAc
(9:1-4:1) to give
2-(3-cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid
cyclopropylmethyl ester as a yellow oil (34.0 g, 93%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 7.78 (d, J=8.4 Hz, 1H), 7.06 (s,
1H), 6.97 (d, J=8.4 Hz, 1H), 4.00-3.83 (m, 4H), 3.69 (t, J=8.0 Hz,
1H), 2.07-1.92 (m, 1H), 1.69-1.60 (m, 1H), 1.52-1.42 (m, 1H),
1.32-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.92 (d, J=6.3 Hz, 6H),
0.68-0.62 (m, 2H), 0.56-0.48 (m, 2H), 0.42-0.38 (m, 2H), 0.26-0.21
(m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 172.9,
152.3, 146.2, 138.8, 125.6, 119.8, 114.4, 74.2, 69.8, 49.8, 42.6,
26.0, 22.5, 22.2, 10.0, 9.7, 3.3.
Step 5
2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid
cyclopropylmethyl ester
##STR00085##
[0504] 2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (34.0 g, 94.2 mmol) was dissolved in
AcOH (300 mL) and water (20 mL). Then, Zn powder (60.0 g, 923 mmol)
was added in portions. The reaction mixture was refluxed for 1 h
and after cooling the precipitate was filtered. The solvent was
evaporated and water (150 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.100 mL) and the combined organic
phases were washed with water (3.times.100 mL) and brine (100 mL).
Drying of the organic phase was performed with magnesium sulfate.
The evaporation of the solvent gave crude product as a brown oil,
which was purified by silica gel gradient column chromatography by
use of Heptane-EtOAc to give
2-(4-amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid
cyclopropylmethyl ester as a yellow oil (23 g, 75%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 6.73-6.61 (m, 3H), 3.94-3.78 (m,
6H), 3.53 (t, J=7.7 Hz, 1H), 1.94-1.85 (m, 1H), 1.65-1.56 (m, 1H),
1.52-1.43 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d,
J=6.6 Hz, 6H), 0.64-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.36-0.33 (m,
2H), 0.24-0.21 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 174.6, 146.4, 135.3, 129.3, 120.5, 114.6, 111.2, 73.1,
69.0, 49.2, 42.7, 25.8, 22.6, 22.4, 10.4, 9.8, 3.2.
Step 6
2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00086##
[0506] 2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in
chloroform (200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv,
39.6 mmol) was added. The reaction mixture was refluxed for 1 h and
after cooling treated with 10% potassium carbonate solution (100
mL). The reaction mixture was extracted with EtOAc (3.times.50 mL)
and the combined organic phases were dried over magnesium sulfate.
Evaporation of the solvent gave the crude product as a brown oil,
which was purified by silica gel gradient column chromatography by
use of Heptane-EtOAc to give
2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester as a yellow oil (5 g, 36%). .sup.1H
NMR (300 MHz, CDCl.sub.3/TMS): .delta. 6.85 (s, 1H), 6.66 (s, 1H),
3.95-3.80 (m, 4H), 3.49 (t, J=7.7 Hz, 1H), 1.94-1.82 (m, 1H),
1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03
(m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58 (m, 2H), 0.53-0.47 (m,
2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 174.2, 146.8, 132.6, 128.7, 120.6, 118.3,
109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8,
3.3.
Step 7
2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00087##
[0508]
2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (5.0 g, 13.7 mmol) was dissolved in a
mixture of EtOH/H.sub.2O/H.sub.2SO.sub.4 (96%) (65 mL/100 mL/2.5
mL) and the reaction mixture was cooled down to 0.degree. C. A
solution of NaNO.sub.2 (0.95 g, 13.7 mmol) in water (5 mL) was
added dropwise at 0.degree. C. and the reaction mixture was stirred
for 30 min. A solution of KI (7.0 g, 42.2 mmol) in water (20 mL)
was added dropwise at 0.degree. C. The reaction mixture was heated
to 50-60.degree. C. for 2.5 h. The reaction mixture was extracted
with EtOAc (3.times.50 mL). The organic layers were combined and
washed with 10% sodium thiosulfate solution (30 mL) followed by
brine (30 mL). The organic phase was dried over MgSO.sub.4 and the
solvent evaporated to give a crude brown oil, which was purified by
silica gel gradient column chromatography by use of Heptane-EtOAc
(20:1-9:1) to give
2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester as a yellow oil (4.0 g, 62%). .sup.1H
NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.07 (s, 1H), 6.66 (s, 1H),
3.95-3.80 (m, 4H), 3.58 (t, J=7.7 Hz, 1H), 1.96-1.89 (m, 1H),
1.66-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03
(m, 1H), 0.91 (d, J=6.6 Hz, 6H), 0.67-0.61 (m, 2H), 0.56-0.50 (m,
2H), 0.45-0.40 (m, 2H), 0.26-0.21 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 173.2, 159.2, 141.6, 139.4, 121.4, 109.8,
90.4, 74.0, 69.7, 49.4, 42.5, 26.0, 22.6, 22.3, 10.2, 9.8, 3.3.
Step 8
2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-me-
thyl-pentanoic acid cyclopropylmethyl ester
##STR00088##
[0510] To a solution of
2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.27 g, 0.57 mmol) in DME (anhydrous,
10 mL) under argon atmosphere were added
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]oxadiazole
(0.15 g, 0.61 mmol), CsF (0.2 g, 1.32 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.021
g, 0.029 mmol, need 0.06 mmol to complete the reaction!). The
reaction mixture was refluxed for 18 h (oil bath, 100.degree. C.).
A mixture water/EtOAc (15 mL/15 mL) was added and the layers were
separated. The organic phase was dried over MgSO.sub.4, then
evaporated to give a crude yellow oil, which was purified by silica
gel gradient column chromatography using Heptane-EtOAc (20:1-9:1)
to give
2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-m-
ethyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 41%) of as a
yellowish oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.83
(d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H),
6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96
(m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H),
0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19
(br s, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 173.4,
157.0, 149.2, 148.3, 142.0, 138.7, 135.4, 133.5, 126.4, 121.6,
117.4, 114.9, 110.6, 73.4, 69.8, 49.8, 42.8, 26.1, 22.5, 22.4,
10.0, 9.8, 3.3, 3.1
Step 9
2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-me-
thyl-pentanoic acid
##STR00089##
[0512]
2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-pheny-
l)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 0.23
mmol) was dissolved in a mixture of EtOH/H.sub.2O (9 mL/1 mL) and
KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed
for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl
was added to adjust the pH to 5, and the reaction mixture was
extracted with EtOAc (3.times.10 mL). The combined organic phases
were dried over MgSO.sub.4 and evaporated under reduced pressure to
give
2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-m-
ethyl-pentanoic acid as a yellow oil (0.068 g, 70%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 8.40 (br s, 1H), 7.70 (d, J=9.3
Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 6.97 (s, 1H), 6.73
(s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7 Hz, 1H), 1.90-1.81
(m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H), 0.98-0.68 (m, 1H),
0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10 (m, 2H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 179.1, 157.1, 149.1,
148.3, 141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0,
110.9, 73.4, 49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.
Example 2995
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-m-
ethyl-pentanoic acid
##STR00090##
[0513] Step 1
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-m-
ethyl-pentanoic acid cyclopropylmethyl ester
##STR00091##
[0515] To a solution of
2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.18 g, 0.38 mmol) in DME (anhydrous,
10 mL) under argon atmosphere were added
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]thiodiazole
(0.15 g, 0.57 mmol), CsF (0.14 g, 0.92 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.02
g, 0.027 mmol). The reaction mixture was refluxed for 18 h (oil
bath, 100.degree. C.). A mixture of water and EtOAc (15 mL/15 mL)
was added and the layers were separated. The combined organic
phases were dried over MgSO.sub.4 and evaporated to give a crude
yellow oil, which was purified by silica gel gradient column
chromatography by use of Heptane-EtOAc (20:1-9:1) to give
2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4--
methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 50%) as a
yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.83 (d,
J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91
(s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m,
1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96
(d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s,
2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 173.5, 157.1,
154.7, 154.0, 141.4, 136.8, 133.7, 132.9, 126.9, 122.8, 121.6,
120.0, 110.8, 73.3, 69.7, 49.7, 42.7, 26.1, 22.5, 22.5, 10.0, 9.8,
3.3, 3.1.
Step 2
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-m-
ethyl-pentanoic acid
##STR00092##
[0517]
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phen-
yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19
mmol) was dissolved in a mixture of EtOH and H.sub.2O (9 mL/1 mL)
and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was
refluxed for 2 h and after cooling the solvent was evaporated.
Then, 6 N HCl was added to adjust the pH to 5, and the reaction
mixture was extracted with EtOAc (3.times.10 mL). The combined
organic phases were dried over MgSO.sub.4 and evaporated under
reduced pressure to give
2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4--
methyl-pentanoic acid as a yellow oil (0.038 g, 55%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 8.02 (d, J=9.0 Hz, 1H), 7.96 (s,
1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d,
J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69
(m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz,
6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 179.1, 157.2, 154.6, 154.0, 140.5, 136.7,
134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0,
25.9, 22.6, 22.3, 10.0, 3.1.
Example 1904
2-(2-Chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid
##STR00093##
[0518] Step 1
2-(2-Chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid cyclopropylmethyl ester
##STR00094##
[0520] To a solution of
2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.09 g, 0.19 mmol) in DME (anhydrous,
10 mL) under argon atmosphere were added
4-trifluoromethylphenylboronic acid (0.04 g, 0.2 mmol), CsF (0.07
g, 0.46 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.06
g, 0.08 mmol). The reaction mixture was refluxed for 18 h (oil
bath, 100.degree. C.). A mixture of water and EtOAc (15 mL/15 mL)
was added and the layers were separated. The organic phase was
dried over MgSO.sub.4, then evaporated to give a crude yellow oil,
which was purified by silica gel gradient column chromatography by
use of Heptane-EtOAc (20:1-9:1) to give
2-(2-chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)-4-
-methyl-pentanoic acid cyclopropylmethyl ester (0.063 g, 70%) as a
yellowish oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.66
(d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.88 (s,
1H), 4.01-3.86 (m, 2H), 3.77 (d, J=6.6 Hz, 2H), 3.65 (t, J=7.9 Hz,
1H), 2.04-1.95 (m, 1H), 1.71-1.62 (m, 1H), 1.59-1.48 (m, 1H),
1.20-1.02 (m, 2H), 0.96-0.94 (m, 6H), 0.56-0.46 (m, 4H), 0.27-0.25
(m, 2H), 0.16-0.15 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 173.5, 157.0, 141.2, 138.9, 133.6, 130.8 (two signals),
127.8, 124.5 (q), 124.3 (q, .sup.1J.sub.CF=271.0 Hz), 121.6, 111.0,
73.3, 69.7, 49.6, 42.7, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.
Step 2
2-(2-Chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)-4-methy-
l-pentanoic acid
##STR00095##
[0522]
2-(2-Chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)--
4-methyl-pentanoic acid cyclopropylmethyl ester (0.06 g, 0.12 mmol)
was dissolved in a mixture of EtOH and H.sub.2O (9 mL/1 mL) and KOH
(0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for
2 h and after cooling the solvent was evaporated. Then, 6 N HCl was
added to adjust the pH to 5 and the reaction mixture was extracted
with EtOAc (3.times.10 mL). The combined organic phases were dried
over MgSO.sub.4 and evaporated under reduced pressure to give
2-(2-chloro-6-cyclopropylmethoxy-4'-trifluoromethyl-biphenyl-4-yl)-4-meth-
yl-pentanoic acid as a yellowish solid (0.046 g, 85%).
M.p.=115-116.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08 (s,
1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H),
2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89
(m, 1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m,
2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 179.0, 157.1,
140.3, 138.8, 133.8, 130.8, 129.3 (q), 128.2, 124.6, 124.3 (q,
.sup.1J.sub.CF=271.0 Hz), 121.6, 111.2, 73.4, 49.4, 42.0, 25.9,
22.6, 22.3, 10.0, 3.0.
Example 3200
2-(2,4'-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic
acid
##STR00096##
[0523] Step 1
2-(2,4'-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic
acid cyclopropylmethyl ester
##STR00097##
[0525] To a solution of
2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.32 g, 0.67 mmol) in DME (anhydrous,
20 mL) under argon atmosphere were added 4-chlorophenylboronic acid
(0.13 g, 0.83 mmol), CsF (0.24 g, 1.58 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05
g, 0.07 mmol). The reaction mixture was refluxed for 18 h (oil
bath, 100.degree. C.). A mixture of water and EtOAc (15 mL/15 mL)
was added and the layers were separated. The organic phase was
dried over MgSO.sub.4 and evaporated to give a crude yellow oil,
which was purified by silica gel gradient column chromatography by
use of Heptane-EtOAc (20:1-9:1) to give
2-(2,4'-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentan-
oic acid cyclopropylmethyl ester (0.26 g, 87%) as a yellowish oil.
.sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.37 (d, J=8.0 Hz,
2H), 7.24 (d, J=8.2 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 3.96-3.89
(m, 2H), 3.76 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.7 Hz, 1H), 2.04-1.95
(m, 1H), 1.71-1.48 (m, 2H), 1.21-1.00 (m, 2H), 0.94 (d, J=6.3 Hz,
6H), 0.55-0.48 (m, 4H), 0.27-0.15 (m, 4H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 173.5, 157.1, 140.8, 133.7, 133.5, 133.0,
131.8, 128.1, 127.8, 121.5, 111.1, 73.2, 69.6, 49.6, 42.6, 26.1,
22.6, 22.5, 10.0, 9.8, 3.3, 3.0.
Step 2
2-(2,4'-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic
acid
##STR00098##
[0527]
2-(2,4'-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-penta-
noic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved
in a mixture of EtOH and H.sub.2O (9 mL/1 mL) and KOH (0.2 g, 3.6
mmol) was added. The reaction mixture was refluxed for 2 h and
after cooling the solvent was evaporated. Then, 6 N HCl was added
to adjust the pH to 5 and the reaction mixture was extracted with
EtOAc (3.times.10 mL). The organic phase was dried over MgSO.sub.4
and evaporated under reduced pressure to give
2-(2,4'-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic
acid as a yellowish solid (0.15 g, 93%). M.p.=52-53.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 10.60 (br s, 1H),
7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83
(s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93
(m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H),
0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 179.7, 157.2, 139.7,
134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4,
42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Example 3201
4-Methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoi-
c acid
##STR00099##
[0528] Step 1
4-Methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoi-
c acid cyclopropylmethyl ester
##STR00100##
[0530] To a solution of
2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic
acid cyclopropylmethyl ester (0.53 g, 1.11 mmol) in DME (anhydrous,
20 mL) under argon atmosphere were added 4-chlorophenylboronic acid
(0.25 g, 1.30 mmol), CsF (0.41 g, 2.70 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.24
g, 0.33 mmol). The reaction mixture was refluxed for 18 h (oil
bath, 100.degree. C.). A mixture water and EtOAc (15 mL/15 mL) was
added and the layers were separated. The organic phase was dried
over MgSO.sub.4 and evaporated to give a crude yellow oil, which
was purified by silica gel gradient column chromatography by use of
Heptane-EtOAc (20:1-9:1) to give
4-methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pe-
ntanoic acid cyclopropylmethyl ester (0.37 g, 70%) as a yellowish
oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.48-7.42 (m,
2H), 7.17-7.14 (m, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 4.07-3.87 (m,
2H), 3.78 (d, J=6.3 Hz, 2H), 3.64 (t, J=7.7 Hz, 1H), 2.03-1.93 (m,
1H), 1.70-1.49 (m, 2H), 1.21-1.00 (m, 2H), 0.95-0.93 (m, 6H),
0.56-0.49 (m, 4H), 0.27-0.19 (m, 4H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 173.4, 156.9, 141.3, 134.9, 133.6, 132.5,
131.6, 131.2, 129.9, 129.5, 126.6, 121.5, 110.8, 73.2, 69.6, 49.6,
42.6, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.
Step 2
4-Methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoi-
c acid
##STR00101##
[0532]
4-Methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-p-
entanoic acid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was
dissolved in a mixture of EtOH and H.sub.2O (9 mL/1 mL) and KOH
(0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for
2 h and after cooling the solvent was evaporated. Then, 6 N HCl was
added to adjust the pH to 5, and the reaction mixture was extracted
with EtOAc (3.times.10 mL). The organic phase was dried over
MgSO.sub.4 and evaporated under reduced pressure to give
4-methyl-2-(2,3',4'-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentano-
ic acid as a white solid (0.30 g, 90%). M.p.=118-119.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 9.70 (br s, 1H),
7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.53 (dd, J=8.2,
1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78 (d, J=6.3 Hz, 2H),
3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65 (m, 1H),
1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H),
0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 179.4, 157.0, 140.3, 134.8, 133.9, 132.5,
131.6, 131.3, 129.9, 129.6, 127.0, 121.5, 111.1, 73.3, 49.4, 42.0,
25.9, 22.6, 22.3, 10.0, 3.1.
Example 1976
2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-4-me-
thyl-pentanoic acid
##STR00102##
[0533] Step 1
5-Fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene
##STR00103##
[0535] To a solution of 2,2,2-trifluoroethanol (28.2 g, 282.0 mmol)
in toluene (120 mL) n-BuLi (1.6 M in hexane, 8.0 g, 80 mL, 125.0
mmol) was added at 0.degree. C. and the reaction mixture warmed up
to 25.degree. C. A solution of 1,3,5-trifluoronitrobenzene (10.0 g,
56.5 mmol) in toluene (50 mL) was added dropwise. The reaction
mixture was refluxed for 30 h and then poured into water (100 mL).
The reaction mixture was extracted with EtOAc (3.times.100 mL). The
organic layers were combined and dried over MgSO.sub.4. The solvent
was evaporated under reduced pressure to give
5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene as a
brown oil (18.0 g, 95%). The product was used for the next step
without purification. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 6.47 (d, J=9.4 Hz, 2H), 4.40 (q, J=8.0 Hz, 4H).
Step 2
2-[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid
diethyl ester
##STR00104##
[0537] To a solution of diethyl malonate (18.0 g, 114.9 mmol) in
DMF (50 mL) was added sodium hydride (60% in mineral oil, 3.0 g,
125.0 mmol) at 0.degree. C. The reaction mixture was stirred at
25.degree. C. for 0.5 h and a solution of
5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene (18.0 g,
53.4 mmol) in DMF (30 mL) was added dropwise. The reaction mixture
was heated 100.degree. C. for 24 h. After cooling the reaction
mixture was poured into water (300 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic phases were washed with water
(3.times.100 mL), brine (100 mL) and dried (MgSO.sub.4).
Evaporation of the solvent under reduced pressure gave
2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid
diethyl ester as a brown oil (20.8 g, 80%). The crude product was
used for the next step without purification. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 6.91 (s, 2H), 4.62 (s, 1H), 4.48 (q, J=8.0
Hz, 4H), 4.28-4.16 (m, 4H), 1.31-1.25 (m, 6H). .sup.13C NMR (75
MHz, CDCl.sub.3/TMS): .delta. 166.4, 149.2, 136.7, 132.3, 122.3 (q,
.sup.1J.sub.CF=276.6 Hz), 109.5 (two signals), 67.0 (q,
.sup.2J.sub.CF=36.7 Hz), 61.4, 41.6, 14.0.
Step 3
[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl
ester
##STR00105##
[0539] Crude
2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid
diethyl ester (20.8 g, 43.6 mmol) was dissolved in a mixture of
AcOH/12 N HCl (150 mL/150 mL) and the reaction mixture was refluxed
for 16 h. The solvent was evaporated and water (100 mL) was added.
The reaction mixture was extracted with EtOAc (3.times.100 mL). The
organic layers were combined, washed with water (3.times.100 mL),
and dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure to give a brown solid, which was washed with a mixture of
Heptane/Et.sub.2O (100 mL/100 mL) to give
[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl
ester as a solid (10.0 g, 57%). .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 6.71 (s, 2H), 4.45 (q, J=7.7 Hz, 4H), 4.18
(q, J=7.2 Hz, 2H), 3.63 (s, 2H), 1.28 (t, J=7.1 Hz, 6H). .sup.13C
NMR (75 MHz, CDCl.sub.3/TMS): .delta. 169.7, 149.6, 138.5, 132.4,
122.4 (q, .sup.1J.sub.CF=277.6 Hz), 109.4 (two signals), 67.0 (q,
.sup.2J.sub.CF=37.2 Hz), 61.6, 41.4, 14.2.
Step 4
[4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl
ester
##STR00106##
[0541] [4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic
acid ethyl ester (10.0 g, 24.7 mmol) was dissolved in EtOH (200 mL)
and hydrogenated at 50 psi, 25.degree. C. for 16 h in the presence
of Pd--C catalyst (10%, 1 g). The catalyst was filtered off and the
solvent evaporated to give a crude brown oil, which was purified by
silica gel gradient column chromatography by use of Heptane-EtOAc
to give [4-amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic
acid ethyl ester as a yellow oil (8.3 g, 90%). .sup.1H NMR (300
MHz, CDCl.sub.3/TMS): .delta. 6.52 (s, 2H), 4.37 (q, J=8.0 Hz, 4H),
4.14 (q, J=7.2 Hz, 2H), 3.90 (br s, 2H), 3.48 (s, 2H), 1.25 (t,
J=7.2 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta.
171.4, 145.0, 126.3, 123.2, (q, .sup.1J.sub.CF=277.6 Hz), 122.6,
110.0, 109.8 (two signals), 66.8 (q, .sup.2J.sub.CF=35.5 Hz), 61.0,
41.0, 14.2.
Step 5
[4-Iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl
ester
##STR00107##
[0543] [4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic
acid ethyl ester (7.1 g, 18.9 mmol) was dissolved in MeCN (50 mL)
and p-TsOH.times.H.sub.2O (11.0 g, 57.9 mmol) was added. The
reaction mixture was cooled down to -15.degree. C. and NaNO.sub.2
(1.6 g, 23.2 mmol) in water (1 mL) was added. The reaction mixture
was stirred at -15.degree. C. for 0.5 h; then a solution of KI
(15.0 g, 93.8 mmol) in water (10 mL) was added. The reaction
mixture was stirred at -15.degree. C. for additional 0.5 h and
quenched with 1 N NaHCO.sub.3 solution to pH 9-10. After addition
of 10% NaHSO.sub.3 solution (20 mL), the reaction mixture was
extracted with EtOAc (3.times.50 mL). The combined organic phases
were washed with saturated NaCl solution, dried (MgSO.sub.4) and
evaporated to give crude a brown oil (9.0 g), which was purified by
gradient column chromatography on silica gel eluting with
Heptane-EtOAc (9:1-3:1) to give
[4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl
ester as a white solid (3.8 g, 41%). .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): .delta. 6.53 (s, 2H), 4.40 (q, J=8.0 Hz, 4H), 4.16
(q, J=7.1 Hz, 2H), 3.56 (s, 2H), 1.26 (t, J=7.2 Hz, 3H). .sup.13C
NMR (75 MHz, CDCl.sub.3/TMS): .delta. 170.3, 157.7, 136.7, 122.8
(q, .sup.1J.sub.CF=277.6 Hz), 108.9 (two signals), 78.3, 67.0 (q,
.sup.2J.sub.CF=36.0 Hz), 61.3, 41.2, 14.2.
Step 6
[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-acetic
acid ethyl ester
##STR00108##
[0545] To a solution of
[4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl
ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) under argon
atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g,
2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh.sub.3).sub.4 (0.3 g,
0.26 mmol). The reaction mixture was refluxed for 18 h (oil bath,
100.degree. C.). A mixture of water and EtOAc (15 mL/15 mL) was
added and the layers were separated. The organic phase was dried
over MgSO.sub.4 and evaporated to give a crude yellow oil, which
was purified by silica gel gradient column chromatography by use of
Heptane-EtOAc (20:1-9:1) to give
[2,6-bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-aceti-
c acid ethyl ester (0.54 g, 70%) as a yellowish oil. .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 7.64 (d, J=8.2 Hz, 2H), 7.46 (d,
J=8.0 Hz, 2H), 6.68 (s, 2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t,
J=7.2 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta.
170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0, 124.4 (q,
.sup.3J.sub.CF=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals),
66.5 (q, .sup.2J.sub.CF=35.5 Hz), 61.3, 41.5, 14.2.
Step 7
2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-4-me-
thyl-pentanoic acid
##STR00109##
[0547]
[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-
-acetic acid ethyl ester (0.52 g, 1.03 mmol) was dissolved in
anhydrous DMF (5 mL) and sodium hydride (60% in oil, 0.05 g, 2.08
mmol) was added at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 20 min and isobutyl bromide (0.15 g, 1.09 mmol)
was added. The reaction mixture was stirred for 1 h at the same
temperature and at 25.degree. C. for 15 min., followed by addition
of saturated ammonium chloride solution (10 mL). The reaction
mixture was extracted with ethyl acetate (2.times.20 mL) and the
combined organic phases were washed with water (3.times.20 mL),
saturated sodium chloride solution (10 mL) and dried over magnesium
sulfate. Evaporation gave the crude yellow oil (0.56 g), which was
purified by silica gel column chromatography with Heptane/EtOAc to
give a white solid (0.24 g). The resulting solid was dissolved in
EtOH (10 mL), and H.sub.2O (1 mL) and potassium hydroxide (0.2 g)
were added. The reaction mixture was refluxed for 2 h and solvent
evaporated. Then, 6 N HCl was added to adjust the pH to 3-5 and the
mixture was extracted with EtOAc (3.times.10 mL). The combined
organic phases were dried over MgSO.sub.4 and evaporated to give
2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-4-yl]-4-m-
ethyl-pentanoic acid as a white solid (0.2 g, 40%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 7.65 (d, J=8.1 Hz, 2H), 7.46 (d,
J=8.1 Hz, 2H), 6.72 (s, 2H), 4.24 (q, J=8.0 Hz, 4H), 3.69 (t, J=7.7
Hz, 1H), 2.03-1.96 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.52 (m, 1H),
0.96 (d, J=6.3 Hz, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 179.3, 155.4, 140.6, 135.3, 130.9, 129.6, 129.1, 124.5 (q,
.sup.3J.sub.CF=4 Hz), 124.2 (q, .sup.1J.sub.CF=272 Hz), 122.9 (q,
.sup.1J.sub.CF=278 Hz), 119.8, 107.9, 66.5 (q, .sup.2J.sub.CF=36
Hz), 49.7, 42.2, 25.9, 22.6, 22.3.
Example 2420
2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-
-cyclobutyl-propionic acid
##STR00110##
[0548] Step 1
4-Fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene
##STR00111##
[0550] To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89
mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600
mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over
30 min to keep the temperature between 30 and 40.degree. C. After
the temperature had dropped to 30.degree. C., the reaction mixture
was heated to 45-50.degree. C. using an oil bath for additional 16
h. After cooling, water (500 mL) and 2.5 N H.sub.2SO.sub.4 (200-300
mL, for adjustment of pH to 5) were added and the organic layer was
separated. The water layer was extracted with EtOAc (2.times.300
mL). The combined organic layers were washed with saturated sodium
chloride solution (100 mL) and dried over magnesium sulfate. The
solvent was evaporated to give a yellow oil, which solidified after
30 min to give a yellowish solid (450.0 g, quantitative). The crude
product was used in the next step without purification. .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 8.03-7.98 (m, 1H), 6.93-6.82 (m,
2H), 4.49 (q, J=7.7 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 165.0 (d, .sup.1J.sub.CF=259.6 Hz), 152.3 (d,
.sup.3J.sub.CF=13.1 Hz), 128.2 (d, .sup.3J.sub.CF=11.9 Hz), 122.4
(d, .sup.1J.sub.CF=273.4 Hz), 110.1 (d, .sup.2J.sub.CF=22.5 Hz),
105.9 (q, .sup.1J.sub.CF=242.6 Hz), 104.3 (d, .sup.2J.sub.CF=26.1
Hz), 67.6 (q, .sup.1J.sub.CF=36.7 Hz).
Step 2
[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid
##STR00112##
[0552] Potassium hydroxide (.gtoreq.85%, 176 g, .gtoreq.2.67 mmol)
was added to a solution of
4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene (412 g,
.about.90% purity, 1.56 mmol) and diethyl malonate (503.0 g, 3.14
mmol) in DMSO (700 mL) in portions to keep the temperature at
.about.40.degree. C. The reaction mixture became deep red in color.
The reaction mixture was stirred at 40.degree. C. overnight.
Monitoring was performed by TLC (EtOAc:Hept., 1:3).
[0553] Acetic acid (1 L) was added to the warm reaction mixture
followed by a mixture of concentrated sulfuric acid (325 mL) in
water (1 L) in one portion. A precipitate, which was formed
initially, dissolved at the end of the addition. Effective stirring
was required for this reaction. The reaction mixture was heated at
reflux overnight. The reaction mixture was cooled to room
temperature and EtOAc (1000 mL) and water (1000 mL) were added. The
organic layer (bottom layer!) was separated. The aqueous solution
was extracted with EtOAc (500 mL), the organic phases were
combined, washed with water (3.times.2000 mL), brine (500 mL), and
dried over MgSO.sub.4 with charcoal. The solvent was evaporated and
the solid residue was washed by stirring with heptane/EtOAc (20:1,
500 mL). The solid was filtered and dried in vacuum. The yield of
2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid was 256 g
(65%). .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.80 (d,
J=8.3 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 5.07 (s, 1H),
4.67 (q, J=8.2 Hz, 2H), 3.70 (s, 2H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): .delta. 175.0, 151.5, 144.0, 140.3, 126.4, 125.0,
122.2 (d, .sup.1J.sub.CF=273.0 Hz), 118.0, 67.6 (q,
.sup.1J.sub.CF=36.0 Hz), 42.5.
Step 3
[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid methyl
ester
##STR00113##
[0555] Concentrated sulfuric acid (50 mL) was added slowly to a
solution of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid
(180 g, 0.64 mol) in MeOH (500 mL). The reaction mixture was
stirred at room temperature overnight. The methanol was evaporated
and EtOAc (500 mL) was added. The solution was washed with water
(2.times.200 mL) and brine and dried over MgSO.sub.4. The solvent
was evaporated, the solid residue was stirred with heptane (200
mL), and the solid was filtered. Yield 182.2 g (96%). .sup.1H NMR
(300 MHz, CDCl.sub.3/TMS): .delta. 7.82 (d, J=8.7 Hz, 1H),
7.07-7.05 (m, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s,
2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 170.1, 150.4,
141.2, 139.4, 125.9, 123.9, 122.6 (d, .sup.1J.sub.CF=277.6 Hz),
117.5, 67.6 (q, .sup.1J.sub.CF=36.7 Hz), 52.4, 41.0.
Step 4
3-Cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic
acid methyl ester
##STR00114##
[0557] [4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid
methyl ester (33 g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g,
114.1 mmol) were mixed in DMSO (50 mL) and KOH (6.4 g, 114.1 mmol)
was added in portions over 15 min. The reaction mixture was stirred
for 16 h and water (100 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.50 mL). The combined organic phases
were dried over MgSO.sub.4 and evaporated to give a crude yellow
oil, which was purified by silica gel gradient column
chromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of
the product as a yellow oil. (The synthesis was repeated with
temperature kept at 40.degree. C. over 16 h to give the product in
quantitative yield). .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta.
7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.50 (q, J=7.7 Hz, 2H),
3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10 (m, 2H), 2.03-1.75
(m, 5H), 1.70-1.55 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d,
.sup.1J.sub.CF=277.6 Hz), 116.0, 67.5 (q, .sup.1J.sub.CF=36.7 Hz),
52.3, 49.6, 40.7, 33.9, 28.2, 27.9, 18.4.
Step 5
2-[4-Amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic
acid methyl ester
##STR00115##
[0559] A solution of the
3-cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic
acid methyl ester (15 g, 36.0 mmol) in EtOH (150 mL) was
hydrogenated at 50 psi and 25.degree. C. for 16 h in the presence
of Pd--C catalyst (10%, 1.5 g). On the next day, the catalyst was
filtered off and the solvent evaporated to give the crude product
(12.3 g, 88%) as a yellow oil, which was used without purification
for the next step. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta.
6.79-6.73 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 4.36 (q, J=8.3 Hz, 2H),
3.80 (br s, 2H), 3.63 (s, 3H), 3.35 (t, J=7.7 Hz, 1H), 2.20-1.86
(m, 4H), 1.85-1.70 (m, 3H), 1.67-1.51 (m, 2H). .sup.13C NMR (75
MHz, CDCl.sub.3/TMS): .delta. 174.7, 146.7, 135.7, 129.1, 123.3 (d,
.sup.1J.sub.CF=277.6 Hz), 122.7, 115.4, 112.2, 66.4 (q,
.sup.1J.sub.CF=35.4 Hz), 51.9, 48.9, 40.8, 34.0, 28.3, 28.1,
18.5.
Step 6
2-[4-Amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propion-
ic acid methyl ester
##STR00116##
[0561] To a solution of the
2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic
acid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was
added N-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was
stirred at 25.degree. C. for 16 h and a mixture of water and
methylene chloride (100 mL/100 mL) was added. The reaction mixture
was extracted with methylene chloride (2.times.50 mL) and the
organic phases were separated. The combined organic phases were
dried over MgSO.sub.4 and evaporated to give a crude yellow oil,
which was purified by a short silica gel column chromatography
eluting with heptane-EtOAc (4:1) to give the product (13.9 g, 94%)
as a yellowish oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta.
7.06 (d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz,
2H), 4.21 (br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H),
2.20-1.89 (m, 4H), 1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). .sup.13C
NMR (75 MHz, CDCl.sub.3/TMS): .delta. 174.2, 144.6, 134.4, 128.9,
125.7, 123.0 (d, .sup.1J.sub.CF=277.6 Hz), 110.9, 108.7, 66.5 (q,
.sup.1J.sub.CF=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0,
18.5.
Step 7
2-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3--
cyclobutyl-propionic acid methyl ester
##STR00117##
[0563] To a solution of
2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propio-
nic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100
mL) under argon atmosphere were added
4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g,
72.3 mmol), and Pd(PPh.sub.3).sub.4 (3.4 g, 2.94 mmol). The
reaction mixture was refluxed for 18 h (oil bath, 100.degree. C.).
On the next day, a mixture water and EtOAc (100 mL/100 mL) was
added and the layers were separated. The organic phase was dried
over MgSO.sub.4 and evaporated to give a crude yellow oil, which
was purified by a short silica gel column chromatography by use of
Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a
yellowish oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.70
(d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz,
2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39
(t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75
(m, 3H), 1.69-1.52 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS):
.delta. 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q,
.sup.3J.sub.CF=3.6 Hz), 123.8, 123.3 (q, .sup.1J.sub.CF=277.6 Hz),
111.4, 66.5 (q, .sup.1J.sub.CF=35.4 Hz), 52.0, 49.0, 40.9, 34.1,
28.3, 28.1, 18.5.
Step 8
2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-
-cyclobutyl-propionic acid methyl ester
##STR00118##
[0565] To a solution of
2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-
-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a
mixture of MeCN and H.sub.2O (120 mL/120 mL), concentrated HCl (25
mL) was added. The reaction mixture was cooled down to 0-5.degree.
C. and a solution of NaNO.sub.2 (2.9 g, 42.0 mmol) in water (3 mL)
was added dropwise. The reaction mixture was stirred at 0-5.degree.
C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once.
The reaction mixture was heated at 50.degree. C. for additional 3 h
and the solvent was evaporated. The reaction mixture was extracted
with EtOAc (3.times.50 mL) and the combined organic phases were
washed with water (200 mL) and brine (100 mL). The organic phase
was dried over MgSO.sub.4 and evaporated to give the product (14.5
g, 95%) as a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
.delta. 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd,
J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t,
J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m,
2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 173.6, 153.5,
142.2, 141.0, 138.9, 129.7, 125.0 (q, .sup.3J.sub.CF=3.6 Hz),
124.8, 124.0 (q, .sup.1J.sub.CF=271.6 Hz), 126.6 (q,
.sup.1J.sub.CF=278.8 Hz), 121.4, 114.0, 67.3 (q,
.sup.1J.sub.CF=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0,
18.5.
Step 9
2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-
-cyclobutyl-propionic acid
##STR00119##
[0567] To a solution of the
2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]--
3-cyclobutyl-propionic acid methyl ester (8.0 g, 14.5 mmol) in a
mixture of the EtOH (100 mL) and H.sub.2O (15 mL) was added
potassium hydroxide (10 g, 178.5 mmol). The reaction mixture was
refluxed for 3 h and the solvent evaporated. Then, 6 N HCl was
added to adjust the pH to 3-5 and the mixture was extracted with
EtOAc (3.times.50 mL). The combined organic phases were dried over
MgSO.sub.4 and evaporated to give
2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]--
3-cyclobutyl-propionic acid as a white solid (7.0 g, 90%). .sup.1H
NMR (300 MHz, CDCl.sub.3/TMS): .delta. 7.70 (d, J=8.2 Hz, 2H), 7.53
(d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.49 (t,
J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H), 1.71-1.52 (m,
2H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. 179.1, 153.6,
142.1, 141.2, 138.0, 129.7, 125.0 (q, .sup.3J.sub.CF=3.6 Hz),
124.9, 124.0 (q, .sup.1J.sub.CF=262.5 Hz), 123.0 (q,
.sup.1J.sub.CF=277.6 Hz), 121.8, 114.3, 67.3 (q,
.sup.1J.sub.CF=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.
Example 415
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid
##STR00120##
[0568] Step 1
Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate
##STR00121##
[0570] To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate
(20 g, 0.076 mol) in 200 ml of DCM was added MeOH (3.4 ml, 0.84
mol). The mixture was brought to reflux and sulfuryl chloride (6.8
ml 0.846 mol) dissolved in DCM (50 mL) was slowly added under over
10 min. The reaction mixture was refluxed further for 5 h, upon
which the reaction mixture was poured onto crushed ice and
extracted with DCM (.times.2). The combined organic layers were
washed with 10% NaHCO.sub.3 solution and water. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and evaporated under
vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate
in 60% yield. (13.6 g).
Step 2
Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate
##STR00122##
[0572] To a stirred solution of compound ethyl
2-(3-chloro-4-hydroxyphenyl)acetate (11 g, 51 mmol) in 200 ml of
CCl.sub.4, was slowly added bromine (8.22 g, 51 mmol) as a solution
CCl.sub.4 (100 ml) at 0.degree. C. over a period of 30 min. The
reaction mixture was stirred for a further 30 min at 0.degree. C.
Upon which the reaction mixture was poured onto crushed ice and
extracted with DCM (2.times.100 mL). The combined organic layers
were washed with water followed by 10% sodium bisulfite solution,
dried over Na.sub.2SO.sub.4 filtered and evaporated under reduced
pressure to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate
(12.2 g) as a white solid in 80% yield. .sup.1HNMR (CDCl.sub.3):
7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s,
2H); 1.29 (t, 3H).
Step 3
Ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate
##STR00123##
[0574] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol),
potassium carbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was
slowly added trifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at
room temperature, the reaction mixture was slowly heated to
100.degree. C. and heating was continued for 4 h. Upon which the
reaction mixture was poured onto water and extracted with ethyl
acetate (2.times.50 mL). The combined organic layers were washed
with water, dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure. Purification by column chromatography over silica
gel (hexane/EtOAc) to gave compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750
g, 30% yield). .sup.1HNMR (CDCl.sub.3, 400 MHz): 7.43 (s, 1H); 7.34
(s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H),
1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Step 4
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)acetate
##STR00124##
[0576] A mixture of
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750
g, 2.0 mmol), 4-trifluoromethyl phenylboronic acid (0.567 g, 3.0
mmol), Pd (PPh.sub.3).sub.4 (0.231 g, 0.2 mmol), cesium fluoride
(0.604 g, 4.0 mmol) in DME (10 ml) was stirred overnight at
100.degree. C., upon which the precipitates were removed by
filtration. The filtrate was diluted with water and extracted with
ethyl acetate (2.times.50 mL). The combined organic layers were
washed with water followed by brine and dried over
Na.sub.2SO.sub.4. The crude residue was purified by flash column
chromatography to give ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.525 g, 73.6%) as an off white solid.
Step 5
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-3-cyclopropylpropanoate
##STR00125##
[0578] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (1.0 g, 2.27 mmol) was dissolved in anhydrous DMF (80 mL),
NaH (60% wt. in paraffin oil, 0.109 g, 2.72 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature, upon which cyclopropyl methyl bromide (0.24 mL, 2.5
mmol) was added in a dropwise manner at 0.degree. C. The reaction
mixture was stirred an additional 1 h at 0.degree. C. upon which
saturated NH.sub.4Cl solution (10 mL) was added. The reaction
mixture was extracted with EtOAc (3.times.50 mL) and the combined
organic phases were washed with water (3.times.20 mL) and brine (20
mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure to give colorless oil, which was purified by flash
column chromatography to yield compound ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclopropylpropanoate (0.68 g).
Step 6
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid
##STR00126##
[0580] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclopropylpropanoate (0.68 g, 0.4 mmol) and lithium hydroxide
monohydrate (100 mg, 4.6 mmol) in a MeOH/THF/Water solvent mixture
(15 ml/15 ml/15/ml) was stirred for 3 h at room temperature. After
completion of reaction, the volatiles were removed under reduced
pressure. The residue was diluted with water, acidified with 5% HCl
solution and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclopropylpropanoic acid in 88% yield (0.4 g). .sup.1H-NMR
(CDCl.sub.3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.43 (s, 1H);
7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94 (m, 1H), 1.78 (m,
1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).
Example 1269
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclobutane carboxylic acid
Step 1
Ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(Trifluoromethyl)biphenyl-3-
-yl)-cyclo butane carboxylate
##STR00127##
[0582] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (1.5 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 1,3-dibromopropane (0.757 g, 3.7 mmol) was added
drop wise at 0.degree. C. The reaction mixture was stirred for an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield compound
ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-cyclo butane carboxylate (400 mg).
Step 2
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclobutane carboxylic acid
##STR00128##
[0584] A mixture of
ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-cyclo butane carboxylate (400 mg, 0.83 mmol) and lithium
hydroxide monohydrate (0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent
mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room
temperature. Upon completion of the reaction, the volatiles were
removed under reduced pressure. The residue was diluted with water,
acidified with 5% HCl solution and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
to give
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
cyclobutane carboxylic acid in 88% yield (0.21 g). .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.39 (s, 1H);
7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m, 2H); 2.52 (m, 2H); 2.16 (m,
1H), 1.91 (m, 1H).
Example 419
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclopentane carboxylic acid
Step 1
Ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-cyclo pentane carboxylate
##STR00129##
[0586] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.8 g, 1.81 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.109 g, 4.5 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 1,4-dibromobutane (0.432 g, 1.99 mmol) was added
drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. upon which saturated NH.sub.4Cl
solution (10 mL) was added. The reaction mixture was extracted with
EtOAc (3.times.20 mL) and the combined organic phases were washed
with water (3.times.20 mL) and brine (20 mL), and dried over
MgSO.sub.4. The volatiles were removed under reduced pressure and
the residue was purified by flash column chromatography to yield
compound ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
cyclo pentane carboxylate (400 mg) as a thick liquid.
Step 2
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclopentane carboxylic acid
##STR00130##
[0588] A mixture of compound ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
cyclo pentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxide
monohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture
(5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. After
completion of reaction, the volatiles were removed under reduced
pressure. The residue was diluted with water, acidified with 5% HCl
solution and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny-
l-3-yl)-cyclopentane carboxylic acid (0.05 g). .sup.1H-NMR
(CDCl.sub.3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H);
7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94 (m, 2H); 1.78 (m,
4H).
Example 3202
445-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)tet-
rahydro-2H-pyran-4-carboxylic acid
Step 1
Ethyl
4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)tetrahydro-2H-pyran-4-carboxylate
##STR00131##
[0590] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was
added drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield ethyl
4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)t-
etrahydro-2H-pyran-4-carboxylate (400 mg).
Step 2
4-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)te-
trahydro-2H-pyran-4-carboxylic acid
##STR00132##
[0592] A mixture of ethyl
4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)t-
etrahydro-2H-pyran-4-carboxylate (400 mg, 0.78 mmol) and lithium
hydroxide monohydrate (0.188 g, 7.8 mmol) in a MeOH/THF/Water
solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. Residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (3.times.50
mL). Combined organic layer was washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)t-
etrahydro-2H-pyran-4-carboxylic acid (100 mg). .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H);
7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99 (m,
2H).
Example 3203
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
,4-dimethylcyclohexanecarboxylic acid
Step 1
Ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-4,4-dimethylcyclohexanecarboxylate
##STR00133##
[0594] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 3,3-dimethyl-1,5-dibromopentane (0.322 g, 1.25
mmol) was added drop wise at 0.degree. C. The reaction mixture was
stirred an additional 1 h at 0.degree. C. and saturated NH.sub.4Cl
solution (10 mL) was added. The reaction mixture was extracted with
EtOAc (3.times.20 mL) and the combined organic phases were washed
with water (3.times.20 mL) and brine (20 mL), and dried over
MgSO.sub.4. The volatiles were removed under reduced pressure and
the residue was purified by flash column chromatography to yield
compound ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4,4-dimethylcyclohexanecarboxylate (230 mg).
Step 2
1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
,4-dimethylcyclohexanecarboxylic acid
##STR00134##
[0596] A mixture of compound ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4,4-dimethylcyclohexanecarboxylate (200 mg, 0.37 mmol) and lithium
hydroxide monohydrate (88 mg, 3.7 mmol) in a MeOH/THF/Water solvent
mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature.
After completion of the reaction, the volatiles were removed under
reduced pressure. The residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (3.times.50
mL). The combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4,4-dimethylcyclohexanecarboxylic acid in 67% yield (150 mg).
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56
(s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88 (m, 2H);
1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).
Example 1270
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclohexane carboxylic acid
Step 1
Ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-cyclohexanecarboxylate
##STR00135##
[0598] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 1,5-dibromopentane (0.19 g, 1.24 mmol) was added
drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield compound ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-cyclohexanecarboxylate (0.37 g) as a thick liquid.
Step 2
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-c-
yclohexane carboxylic acid
##STR00136##
[0600] A mixture of ethyl
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
cyclohexanecarboxylate (0.37 g, 0.72 mmol) and lithium hydroxide
monohydrate (0.174 g, 7.28 mmol) in a MeOH/THF/Water solvent
mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. The residue was diluted with water,
acidified with 5% HCl solution and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure. The residue was purified by Flash Column
Chromatography to give
1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny-
l-3-yl)-cyclohexane carboxylic acid (0.25 g) as a white solid.
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.55
(s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.52-1.81 (m,
6H); 1.33 (m, 2H).
Example 1271
5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-s-
piro[2,3]hexane-5-carboxylic acid
Step 1
Ethyl
5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-Spiro[2,3]hexane-5-carboxylate
##STR00137##
[0602] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.136 g, 3.4 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and 1,1-bis(bromomethyl)cyclopropane (0.482 g, 1.4
mmol, for preparation see J. Org. Chem 1993, 58, 4122-26) was added
drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield compound ethyl
5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-spiro[2,3]hexane-5-carboxylate (150 mg) as a low melting
solid.
Step 2
5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-s-
piro[2,3]hexane-5-carboxylic acid
##STR00138##
[0604] A mixture of ethyl
5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
spiro[2,3]hexane-5-carboxylate (0.5 g, 0.9 mmol) and lithium
hydroxide monohydrate (0.415 g, 9.88 mmol) in a MeOH/THF/Water
solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. Residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (3.times.50
mL). The combined organic layer was washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
spiro[2,3]hexane-5-carboxylic acid (0.29 g). .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H);
7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58 (t,
2H), 0.48 (t, 2H).
Example 1268
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclobutylpropanoic acid
Step 1
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-3-cyclobutylpropanoate
##STR00139##
[0606] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.6 g, 0.49 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.039 g, 1.69 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and cyclobutylmethyl bromide (0.223 g, 1.49 mmol) was
added drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclobutylpropanoate (0.25 g) as a colorless liquid.
Step 2
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclobutylpropanoic acid
##STR00140##
[0608] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclobutylpropanoate (0.25 g, 0.49 mmol) and lithium hydroxide
monohydrate (0.206 g, 4.9 mmol) in a MeOH/THF/Water solvent mixture
(10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After
completion of reaction volatiles were removed under reduced
pressure. Residue was diluted with water, acidified with 5% HCl
solution and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny-
l-3-yl)-3-cyclobutylpropanoic acid (0.106 g) as a white solid.
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41
(s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H); 2.15-2.28 (m,
2H); 1.55-2.15 (m, 7H).
Example 1272
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-2-
-cyclopentylacetic acid
Step 1
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-2-cyclopentylacetate
##STR00141##
[0610] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.8 g, 1.8 mmol) was dissolved in anhydrous DMF (40 mL),
NaH (60% wt. in paraffin oil, 0.052 g, 2.18 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and cyclopentyl bromide (0.298 g, 1.99 mmol) was added
drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.50 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield compound ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-2-cyclopentylacetate (0.4 mg) as a thick liquid.
Step 2
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-2-
-cyclopentylacetic acid
##STR00142##
[0612] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
2-cyclopentylacetate (400 mg, 0.78 mmol) and lithium hydroxide
monohydrate (0.330 g, 7.87 mmol) in a MeOH/THF/Water solvent
mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. The residue was diluted with water,
acidified with 5% HCl solution and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure. The residue was purified by Flash Column
Chromatography to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
2-cyclopentylacetic acid (0.08 g). .sup.1H-NMR (CDCl.sub.3, 400
MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70 (d, 2H), 7.55 (s, 1H); 7.35
(s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82 (m, 1H); 1.18-1.68 (m,
7H); 1.08 (m, 1H).
Example 3204
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-(4-fluorophenyl)propanoic acid
Step 1
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-3-(4-fluorophenyl)propanoate
##STR00143##
[0614] Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)a-
cetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL),
NaH (60% wt. in paraffin oil, 0.039 g, 1.36 mmol) was added at
0.degree. C. The reaction mixture was stirred for 30 min at room
temperature and cyclopentyl bromide (0.283 g, 1.49 mmol) was added
drop wise at 0.degree. C. The reaction mixture was stirred an
additional 1 h at 0.degree. C. and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4.
The volatiles were removed under reduced pressure and the residue
was purified by flash column chromatography to yield compound ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
3-yl)-3-(4-fluorophenyl)propanoate (0.29 g) as a colorless
liquid.
Step 2
2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-(4-fluorophenyl)propanoic acid
##STR00144##
[0616] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-(4-fluorophenyl)propanoate (400 mg, 0.719 mmol) and lithium
hydroxide monohydrate (0.306 g, 7.29 mmol) in a MeOH/THF/Water
solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room
temperature. After completion of reaction volatiles were removed
under reduced pressure. The residue was diluted with water,
acidified with 5% HCl solution and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4, filtered and evaporated under
reduced pressure. The residue was purified by Flash Column
Chromatography to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny-
l-3-yl)-3-(4-fluorophenyl)propanoic acid (0.1 g). .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H), 7.18 (s,
1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd, 1H),
3.02 (dd, 1H).
Example 1905
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-3-cy-
clopropylpropanoic acid
##STR00145##
[0617] Step 1
2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene
##STR00146##
[0619] Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred
suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a
period of 15 min at 0.degree. C. under an atmosphere of nitrogen.
The reaction mixture was allowed to warm to room temperature and
stirred for 1 h at RT. The mixture was cooled to 0.degree. C. and a
solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL
THF was added in a drop wise manner. The reaction mixture was
stirred at 0.degree. C. for 2 h and then poured onto ice water. The
mixture was extracted with ethyl acetate (3.times.100 mL). The
combined organic layers were dried over MgSO.sub.4 and concentrated
under reduced pressure to give 22.0 g of
2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil
(86%).
Step 2
Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate
##STR00147##
[0621] Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred
suspension of sodium hydride
[0622] (60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min. at
0.degree. C. under nitrogen. The reaction mixture was allowed to
warm to room temperature and stirred for 1 h. A solution of
2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF
(88 mL) was added drop wise at 0.degree. C., and the reaction
mixture was heated to 100.degree. C. for 3 h. The reaction mixture
was allowed to cool to room temperature, poured into ice water and
extracted with EtOAc (3.times.100 mL). The combined organic phases
were washed with water (3.times.100 mL) and brine (100 mL), dried
(MgSO.sub.4) and filtered. Evaporation of the volatiles under
reduced pressure gave 10.0 g of crude product which was purified by
chromatography over silica gel (hexane/EtOAc) gave of diethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g).
.sup.1H-NMR (CDCl.sub.3, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3
(m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02
(d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).
Step 3
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid
##STR00148##
[0624] Compound diethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (10 g) was
dissolved in 100 mL ethanol and cooled to 0.degree. C., NaOH
solution (4 eq) was added slowly to the reaction mixture for about
15 min. The reaction mixture was heated gently up to 60.degree. C.
for 5 h. Progress of the reaction was monitored by TLC analysis.
After complete conversion of starting material solvent was
evaporated under reduced pressure, residue dissolved in H.sub.2O,
acidified with 6N HCl to pH-2. Filtered the solid material washed
with water, dried under reduced pressure to give
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, 200 MHz): 0.36 (m, 2H), 0.58
(m, 2H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H),
7.23 (s, 1H), 7.81 (d, 1H).
Step 4
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate
##STR00149##
[0626] 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g,
143 mmol) was dissolved in 20% EtOH-HCl solution (200 ml) and
refluxed for 3 h to convert the starting material to ester. The
volatiles were removed under reduced pressure and the residue was
extracted with ethyl acetate (.times.2). The combined organic
extracts were washed with water, dried (Na.sub.2SO.sub.4), filtered
and concentrated under reduced pressure. The crude material was
purified by re crystallization to ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale
yellow solid.
Step 5
Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate
##STR00150##
[0628] To a stirred solution of compound ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH
(100 mL), Pd(OH).sub.2 (2 g) was added and the mixture was reduced
under an H.sub.2 atmosphere for 6 h at room temperature. The
mixture was filtered a pad of Celite.TM. washing with MeOH. The
combined filtrates were concentrated under reduced pressure to
yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (7.5 g)
as a thick liquid. .sup.1H-NMR (CDCl.sub.3, 200 MHz): 0.38 (m, 2H),
0.61 (m, 2H), 1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d,
2H), 4.16 (q, 2H), 6.72 (m, 3H).
Step 6
Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate
##STR00151##
[0630] To a stirred solution of ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol)
in dry CCl.sub.4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at
0.degree. C. The reaction mixture was allowed to stir for 3 h at
room temperature. The reaction mixture was diluted with water and
extracted with DCM (2.times.50 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and the volatiles
removed in vacuo. The crude reaction mixture was purified by column
chromatography to give ethyl
2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg)
as a yellow solid.
Step 7
Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate
##STR00152##
[0632]
Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate
(2.5 g, 10.0 mmol) was dissolved in a mixture of
EtOH/H.sub.2O/H.sub.2SO.sub.4 (96%) 200 mL/400 mL/10 mL at
0.degree. C. A solution of NaNO.sub.2 (3.2 g, 1.16 eq) in water (40
mL) was added drop wise at 0.degree. C., and the reaction mixture
was stirred for 40 min at the same temperature. A solution of KI
(30 g, 30.1 mmol) in water (80 mL) was added drop wise at 0.degree.
C. The reaction mixture was heated to 50.degree. C. for 2.5 h upon
which the volatiles were removed under reduced pressure. The
reaction mixture was extracted with EtOAc (3.times.50 mL), and the
combined organic layers were washed with 10% sodium thiosulfate
(2.times.50 mL), water (300 mL) and brine (300 mL). The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to give a crude black oil which was purified by
chromatography over silica gel (hexane/EtOAc) to give the product
ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate as a
yellow oil (8.7 g).
Step 8
Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl-
)acetate
##STR00153##
[0634] A mixture of compound ethyl
2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14
mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF
(0.28 g, 1.84 mmol) and Pd (PPh.sub.3).sub.4 (0.410 g, 0.4 mmol) in
75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under
argon. The reaction mixture was cooled to RT and 75 mL of EtOAc and
75 mL of water were added. The organic phase was separated, dried
over NaSO.sub.4, filtered and concentrated under reduced pressure
to give a yellow oil. The oil was purified by chromatography over
silica gel (hexane/EtOAc) to give ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (4.6 g) as a yellow oil. .sup.1H-NMR (CDCl.sub.3, 200 MHz):
0.41 (m, 2H), 0.62 (m, 2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s,
2H), 3.89 (d, 2H), 4.17 (q, 2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64
(m, 4H).
Step 9
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-3-cy-
clopropylpropanoic acid
##STR00154##
[0636] Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (1.1 g, 2.4 mmol) was dissolved in 10 mL anhydrous DMF and NaH
(60% wt. in oil, 0.9 g) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and cyclopropyl
methyl bromide (1.25 mL) was added drop wise at 0.degree. C. The
reaction mixture was stirred for an additional 1 h at 0.degree. C.
upon which saturated NH.sub.4Cl solution (10 mL) was added. The
reaction mixture was extracted with EtOAc (3.times.20 mL) and the
combined organic phases were washed with water (3.times.20 mL) and
brine (20 mL), and dried over MgSO.sub.4, filtered and the
volatiles removed under reduced pressure to give 0.85 g of a
colorless oil. The oil was dissolved in 10 mL of EtOH/H.sub.2O
(9:1, v/v) and (1.0 g) LiOH added. The reaction mixture was
refluxed for 5 h and concentrated under reduced pressure. Water (10
mL) was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
MgSO.sub.4 and evaporated under reduced pressure. Purification by
column chromatography over silica gel (hexane/EtOAc 9:1) gave
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-3
cyclopropylpropanoic acid (0.42 g) as a white solid, L-21-1 (56%).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.65 (d, 2H), 7.38 (d,
2H), 7.08 (s, 1H), 6.83 (s, 1H), 3.75 (d, 2H), 3.62 (t, 1H), 1.96
(m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m,
4H).
Example 1908
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-cycl-
obutanecarboxylic acid
##STR00155##
[0638] Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt.
in oil, 0.13 g, mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,3-dibromopropane (1.5 mL) was added drop wise at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h and upon which
saturated NH.sub.4Cl solution (10 mL) was added. The reaction
mixture was extracted with EtOAc (3.times.20 mL) and the combined
organic phases were washed with water (3.times.20 mL) and brine (20
mL), and dried over MgSO.sub.4, filtered and concentrated under
reduced pressure to give 240 mg of a colorless oil. The oil was
dissolved in 10 mL of EtOH/H.sub.2O (9:1, v/v) and 0.42 g LiOH
added. The reaction mixture was refluxed for 5 h and concentrated
under reduced pressure. Water (10 mL) was added and the reaction
mixture was extracted with EtOAc (3.times.10 mL). The combined
organic phases were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified via
column chromatography over silica gel (hexane/EtOAc 9:1) to give
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl-
)-cyclobutanecarboxylic acid (0.210 g) as a white solid (52%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.68 (d, 2H),
7.41 (d, 2H), 7.06 (s, 1H), 6.89 (s, 1H), 3.78 (d, 2H), 2.88 (m,
2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.97 (m, 1H), 1.03 (m, 1H), 0.46
(m, 2H), 0.18 (m, 2H).
Example 1909
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-cycl-
opentanecarboxylic acid
##STR00156##
[0640] Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt.
in oil, 0.13 g, mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,4-dibromobutane (0.24 g) was added drop wise at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h and saturated
NH.sub.4Cl solution (10 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.20 mL) and the combined organic
phases were washed with water (3.times.20 mL) and brine (20 mL),
and dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give 380 mg of colorless oil. The oil was dissolved in
10 mL of EtOH/H.sub.2O (9:1, vvl) and 1.0 g LiOH added. The
reaction mixture was refluxed for 5 h and concentrated under
reduced pressure. Water (10 mL) was added and the reaction mixture
was extracted with EtOAc (3.times.10 mL). The combined organic
phases were dried over MgSO.sub.4 filtered and concentrated under
reduced pressure. Purification by column chromatography over silica
gel (hexane/EtOAc 9:1) gave
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-cyc-
lopentanecarboxylic acid (0.210 g) as a white solid (60%). .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 7.68 (d, 2H), 7.41 (d, 2H), 7.16
(s, 1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66 (m, 2H), 1.97 (m, 2H),
1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18 (d, 2H).
Example 2491
2-(6-Chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid
##STR00157##
[0641] Step 1
Ethyl
3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate
##STR00158##
[0643] Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g,
17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in
oil, 0.475 g, 19.7 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
cyclopropylmethyl bromide (2.67 g, 19.7 mmol) was added drop wise
at 0.degree. C. The reaction mixture was stirred at 0.degree. C.
for 1 h and saturated NH.sub.4Cl solution (10 mL) was added. The
reaction mixture was extracted with EtOAc (3.times.20 mL) and the
combined organic phases were washed with water (3.times.20 mL) and
brine (20 mL), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure to give ethyl
3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4
g) as a colorless oil.
Step 2
Ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate
##STR00159##
[0645] To a stirred solution of ethyl
3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate
(4.0 g), in dry MeOH (100 mL), Pd(OH).sub.2 (2 g) was added and the
mixture was reduced under an atmosphere of H.sub.2 for 6 h at room
temperature. The reaction mixture was filtered through a pad of
Celite.TM. washing with MeOH. The combined filtrates were
concentrated under reduced pressure to yield ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate
(3.5 g) as a thick liquid.
Step 3
Ethyl
2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl
propanoate
##STR00160##
[0647] To a stirred solution of ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate
(3.0 g, 9.8 mmol) in dry CHCl.sub.3 (50 mL), NBS (1.4 g, 7.8 mmol)
was added at 0.degree. C. The reaction mixture was allowed to stir
for 3 h at room temperature. The reaction mixture was diluted with
water and extracted with DCM (2.times.50 mL). The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography to yield the ethyl
2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl
propanoate (1.5 g) as a yellow solid.
Step 4
Ethyl
2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
-3-cyclopropylpropanoate
##STR00161##
[0649] A mixture of ethyl
2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropyl
propanoate (2.8 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid
(2.05 g, 18.8 mmol), CsF (2.19 g, 14.5 mmol) and Pd
(PPh.sub.3).sub.4 (0.837 g, 0.72 mmol) in 30 mL anhydrous
1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction
mixture was cooled to RT, and 75 mL of EtOAc and 75 mL of water
were added. The organic phase was separated, dried over NaSO.sub.4,
filtered and concentrated under reduced pressure to give a yellow
oil. The oil was purified by chromatography over silica gel
(hexane/EtOAc) to give ethyl
2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoate (2.5 g) as a yellow oil.
Step 5
Ethyl
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-3-cyclopropylpropanoate
##STR00162##
[0651] Ethyl
2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoate (1 g, 2.2 mmol) was dissolved in a mixture of
MeCN/H.sub.2O/HCl 30 mL/30 mL/2 mL at 0.degree. C. A solution of
NaNO.sub.2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise
at 0.degree. C., and the reaction mixture was stirred for 40 min,
at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in
water (10 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 90.degree. C. for 2.0 h and the mixture was
concentrated under reduced pressure. The reaction mixture was
extracted with EtOAc (3.times.50 mL), the combined organic layers
were washed with water (50 mL) followed by brine (50 mL), was dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a crude black oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-c-
yclopropylpropanoate (1.1 g) as a yellow oil.
Step 6
2-(6-Chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid
##STR00163##
[0653]
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-y-
l)-3-cyclopropylpropanoate (80 mg) was dissolved in 10 mL of
MeOH/THF/H.sub.2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The
reaction mixture was stirred at room temperature for 5 h and then
concentrated under reduced pressure. Water (10 mL) was added and
the reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic phases were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. Purification by column
chromatography over silica gel (hexane/EtOAc 9:1) gave compound
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-c-
yclopropylpropanoic acid (45 mg) as a white solid. .sup.1H-NMR (500
MHz, CDCl.sub.3): 7.71 (d, 2H), 7.54 (d, 2H), 6.95 (d, 1H), 6.87
(s, 1H), 3.97 (d, 2H), 3.64 (t, 1H), 2.55 (m, 2H), 1.96 (m, 1H),
1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).
Example 2494
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
butanecarboxylic acid
##STR00164##
[0654] Step 1
Ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate
##STR00165##
[0656] Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g,
17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in
oil, 1.43 g, 35.9 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,3-dibromopropane (1.91 mL, 17.9 mmol) was added drop wise at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 1
h and saturated NH.sub.4Cl solution (10 mL) was added. The reaction
mixture was extracted with EtOAc (3.times.20 mL) and the combined
organic phases were washed with water (3.times.20 mL) and brine (20
mL), dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8
g) as a colorless oil.
Step 2
Ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate
##STR00166##
[0658] To a stirred solution of ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8
g), in dry MeOH (100 mL), Pd(OH).sub.2 (1.2 g) was added and the
reaction mixture was reduced under an atmosphere of H.sub.2 for 6 h
at room temperature. The reaction mixture was filtered through a
pad of Celite.TM. washing with MeOH. The combined filtrates were
concentrated under reduced pressure to yield ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4
g) as a thick liquid.
Step 3
Ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxyla-
te
##STR00167##
[0660] To a stirred solution of ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4
g, 8.3 mmol) in dry CHCl.sub.3 (50 mL), NBS (1.4 g, 7.8 mmol) was
added at 0.degree. C. The reaction mixture was allowed to stir for
3 h at room temperature. The reaction mixture was diluted with
water, extracted with DCM (2.times.50 mL), the combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography to yield ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxyl-
ate (1.5 g) as a yellow solid.
Step 4
Ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
cyclobutanecarboxylate
##STR00168##
[0662] A mixture of ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate
(0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g,
1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh.sub.3).sub.4 (0.1 g,
0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled to RT and 25 mL of
EtOAc and 75 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a yellow oil. The oil was purified
by chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
butanecarboxylate (0.290 g) as a yellow oil.
Step 5
Ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)cyclobutanecarboxylate
##STR00169##
[0664] Ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
butanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture
of MeCN/H.sub.2O/HCl 10 mL/10 mL/4 mL at 0.degree. C. A solution of
NaNO.sub.2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise
at 0.degree. C., and the reaction mixture was stirred for 40 min,
at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in
water (2 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 70.degree. C. for 1 h and the solvent was
evaporated under reduced pressure. The reaction mixture was
extracted with EtOAc (3.times.50 mL), and the combined organic
layers were washed with water (50 mL) followed by brine (50 mL).
The solution was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give crude black oil which was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
obutanecarboxylate (0.110 g) as yellow oil.
Step 6
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
butanecarboxylic acid
##STR00170##
[0666] Ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
obutanecarboxylate (0.1 g) dissolved in MeOH/THF/H.sub.2O (10 mL/10
mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at
room temperature for 5 h and concentrated under reduced pressure.
Water (10 mL) was added and the reaction mixture was extracted with
EtOAc (3.times.10 mL). The combined organic extracts were dried
over MgSO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (hexane/EtOAc
9:1) gave
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
obutanecarboxylic acid (75 mg) as a white solid. .sup.1H-NMR (500
MHz, CDCl.sub.3): 7.71 (d, 2H), 7.54 (d, 2H), 6.86 (s, 1H), 6.85
(s, 1H), 3.97 (d, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 2.13 (m, 1H),
1.92 (m, 1H), 1.35 (t, 1H), 0.47 (m, 2H), 0.41 (m, 2H).
Example 2495
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
pentanecarboxylic acid
##STR00171##
[0667] Step 1
Ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate
##STR00172##
[0669] Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (0.5
g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil,
0.13 g, mmol) was added at 0.degree. C. The reaction mixture was
stirred for 0.5 h at 25.degree. C. and 1,4-dibromobutane (0.24 g,
mmol) was added drop wise at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 1 h and saturated NH.sub.4Cl solution
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3.times.20 mL) and the combined organic phases were washed with
water (3.times.20 mL) and brine (20 mL), and dried over MgSO.sub.4,
filtered and concentrated under reduced pressure to give ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate
(380 mg) as a colorless oil.
Step 2
Ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate
##STR00173##
[0671] To a stirred solution of ethyl
1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (10
g), in dry MeOH (100 mL) Pd (OH).sub.2 (2 g) was added and the
mixture was reduced under an atmosphere of H.sub.2 for 6 h at room
temperature. The mixture was filtered through a pad of Celite.TM.,
washing with MeOH. The combined filtrates were concentrated under
reduced pressure to yield ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate
(7.5 g) as a thick liquid.
Step 3
Ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxyl-
ate
##STR00174##
[0673] To a stirred solution of ethyl
1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate
(1.2 g, 4.0 mmol) in dry CCl.sub.4 (60 mL), NBS (0.427 g, 3.2 mmol)
was added at 0.degree. C. The reaction mixture was allowed to stir
for 3 at room temperature to complete the reaction. The reaction
mixture was diluted with water, extracted with DCM (2.times.50 mL),
the combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The crude
reaction mixture was purified by column chromatography to yield
ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate
(920 mg) as a yellow solid.
Step 4
Ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
cyclopentanecarboxylate
##STR00175##
[0675] A mixture of ethyl
1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate
(5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17
mmol), CsF (0.28 g, 1.84 mmol) and Pd (PPh.sub.3).sub.4 (0.410 g,
0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 75 mL of
EtOAc and 75 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Step 5
Ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)cyclopentanecarboxylate
##STR00176##
[0677] Ethyl
1-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
pentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of
MeCN/H.sub.2O/HCl 30 mL/30 mL/2 mL at 0.degree. C. A solution of
NaNO.sub.2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise
at 0.degree. C., and the reaction mixture was stirred for 40 min,
at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in
water (10 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 90.degree. C. for 2.0 h and the solvent was
evaporated. The reaction mixture was extracted with EtOAc
(3.times.50 mL), and the combined organic layers were washed with
water (50 mL) followed by brine (50 mL). The solution was dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a crude black oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
opentanecarboxylate as yellow oil (1.1 g).
Step 6
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cyclo-
pentanecarboxylic acid
##STR00177##
[0679] Ethyl
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
opentanecarboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H.sub.2O
(10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was
stirred at room temperature for 5 h and concentrated under reduced
pressure. Water (10 mL) was added and the reaction mixture was
extracted with EtOAc (3.times.10 mL). The combined organic phases
were dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. Purification by column chromatography over silica gel
(hexane/EtOAc 9:1) gave
1-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cycl-
opentane carboxylic acid (45 mg) as a white solid. .sup.1H-NMR (500
MHz, CDCl.sub.3): 7.68 (d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97
(s, 1H), 3.97 (d, 2H), 2.64 (m, 2H), 1.95 (m, 2H), 1.77 (m, 4H),
1.21 (m, 1H), 0.45 (m, 2H), 0.18 (m, 2H);
Example 2419
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid
##STR00178##
[0680] Step 1
Ethyl
3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate
##STR00179##
[0682] Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (2
g, 6.5 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in
oil, 0.171 g, 7.1 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
cyclopropylmethyl bromide (0.967 g, 7.16 mmol) was added drop wise
at 0.degree. C. The reaction mixture was stirred at 0.degree. C.
for 1 h and saturated NH.sub.4Cl solution (10 mL) was added. The
reaction mixture was extracted with EtOAc (3.times.20 mL) and the
combined organic phases were washed with water (3.times.20 mL) and
brine (20 mL), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure to give ethyl
3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate
(1.05 g) as a colorless oil.
Step 2
Ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate
##STR00180##
[0684] To a stirred solution of ethyl
3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate
(1.0 g), in dry MeOH (100 mL) Pd(OH).sub.2 (500 mg) was added and
the mixture was reduced under an atmosphere of H.sub.2 for 6 h at
room temperature. The mixture was filtered off through a pad of
Celite.TM., washing with MeOH. The combined filtrates were
concentrated under reduced pressure to give ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate
(0.9 g) as a thick liquid.
Step 3
Ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpro-
panoate
##STR00181##
[0686] To a stirred solution of ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate
(0.9 g, 2.7 mmol) in dry CHCl.sub.3 (50 mL), NBS (0.412 g, 2.3
mmol) was added at 0.degree. C. The reaction mixture was allowed to
stir for 3 h at room temperature to complete the reaction. The
reaction mixture was diluted with water, extracted with DCM
(2.times.50 mL), the combined organic solvents was dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude reaction mixture was purified by column chromatography to
give ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoa-
te (1.02 g) as a yellow solid.
Step 4
Ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-3-cyclopropylpropanoate
##STR00182##
[0688] A mixture of ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoa-
te (1.1, 3.3 mmol), 4-trifluoromethylphenylboronic acid (1.26 g,
6.7 mmol), CsF (1.26 g, 8.3 mmol) and Pd (PPh.sub.3).sub.4 (0.38 g,
0.33 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 50 mL of
EtOAc and 50 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a yellow oil. The oil was purified
by chromatography over silica gel (hexane/EtOAc) to give ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoate (0.85 g, 82% yield) as a white solid.
Step 5
Ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-3-cyclopropylpropanoate
##STR00183##
[0690] Ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a
mixture of MeCN/H.sub.2O/HCl 15 mL/15 mL/2 mL at 0.degree. C. A
solution of NaNO.sub.2 (0.185 g, 2.68 mmol) in water (2 mL) was
added drop wise at 0.degree. C., and the reaction mixture was
stirred for 40 min, at the same temperature. A solution of CuCl
(1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at
0.degree. C. The reaction mixture was heated to 90.degree. C. for 2
h. The reaction mixture was extracted with EtOAc (3.times.50 mL),
and the combined organic layers were washed with water (50 mL)
followed by brine (50 mL). The solution was dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give an oil. The oil was purified by chromatography over silica
gel (hexane/EtOAc) to give ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclopropylpropanoate (0.528 g) as a yellow oil.
Step 6
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-
-cyclopropylpropanoic acid
##STR00184##
[0692] The ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
3-cyclopropylpropanoate (500 mg, 1.01 mmol) dissolved in 20 mL of
MeOH/THF/H.sub.2O (10 mL/10 mL/5 mL) and LiOH (57 mg) was added.
The reaction mixture was stirred at room temperature for 5 h and
concentrated under reduced pressure. Water (10 mL) was added and
the reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic phases were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. Purification by column
chromatography over silica gel (hexane/EtOAc 9:1) gave
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
cyclopropylpropanoic acid (250 mg) as a white solid. .sup.1H-NMR
(500 MHz, CDCl.sub.3): 7.72 (d, 2H), 7.54 (d, 2H), 7.02 (d, 2H),
4.44 (q, 2H), 3.72 (t, 1H), 1.92 (m, 1H), 1.79 (m, 1H), 1.08 (m,
1H), 0.66 (m, 1H), 0.44 (m, 2H), 0.16 (m, 2H).
Example 2422
Ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)cyclobutanecarboxylate
##STR00185##
[0693] Step 1
Ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
##STR00186##
[0695] Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (3
g, 9.7 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in
oil, 0.514 g, 10.7 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,3-dibromopropane (1.03 mL, 9.7 mmol) was added drop wise at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 1
h and saturated NH.sub.4Cl solution (10 mL) was added. The reaction
mixture was extracted with EtOAc (3.times.20 mL) and the combined
organic phases were washed with water (3.times.20 mL) and brine (20
mL), dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(900 mg) as a colorless oil.
Step 2
Ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
##STR00187##
[0697] To a stirred solution of ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(900 mg), in dry MeOH (50 mL), Pd(OH).sub.2 (400 mg) was added and
the mixture reduced under an atmosphere of H.sub.2 for 6 h at room
temperature. The mixture was filtered through a pad of Celite.TM.
washing with MeOH, the combined filtrates were concentrated under
reduced pressure to yield ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(800 mg) as a thick liquid.
Step 3
Ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarbox-
ylate
##STR00188##
[0699] To a stirred solution of ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(2.4 g, 8.3 mmol) in dry CHCl.sub.3 (50 mL), NBS (1.4 g, 7.8 mmol)
was added at 0.degree. C. The reaction mixture was allowed to stir
for 3 h at room temperature to complete the reaction. The reaction
mixture was diluted with water, extracted with DCM (2.times.50 mL),
the combined organic solvents were dried over Na.sub.2SO.sub.4,
filtered and concentrated under educed pressure. The crude reaction
mixture was purified by column chromatography to give ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(1.5 g) as a yellow solid.
Step 4
Ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)cyclobutanecarboxylate
##STR00189##
[0701] A mixture of ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g,
1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh.sub.3).sub.4 (0.1 g,
0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 25 mL of
EtOAc and 75 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a yellow oil. The oil was purified
by chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clobutanecarboxylate (0.290 g) as a yellow oil.
Step 5
Ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)cyclobutanecarboxylate
##STR00190##
[0703] Ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a
mixture of MeCN/H.sub.2O/HCl 10 mL/10 mL/4 mL at 0.degree. C. A
solution of NaNO.sub.2 (0.066 g, 0.96 mmol) in water (2 mL) was
added drop wise at 0.degree. C., and the reaction mixture was
stirred for 40 min, at the same temperature. A solution of CuCl
(0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0.degree.
C. The reaction mixture was heated to 70.degree. C. for 1 h and the
solvent was evaporated. The reaction mixture was extracted with
EtOAc (3.times.50 mL), and the combined organic layers were washed
with water (50 mL) followed by brine (50 mL). The solution was
dried over Na.sub.2SO.sub.4, filtered and concentrated to give oil.
The oil was purified by chromatography over silica gel
(hexane/EtOAc) to give ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclobutanecarboxylate as a yellow oil (0.110 g).
Step 6
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clobutanecarboxylic acid
##STR00191##
[0705] Ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H.sub.2O (10
mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was
stirred at room temperature for 5 h and concentrated under reduced
pressure. Water (10 mL) was added and the reaction mixture was
extracted with EtOAc (3.times.10 mL). The combined organic phases
were dried over MgSO.sub.4, filtered and evaporated under reduced
pressure. Purification by column chromatography over silica gel
(hexane/EtOAc 9:1) gave
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclobutanecarboxylic acid (75 mg) of the product as a white solid.
.sup.1H-NMR (500 MHz, CDCl.sub.3): 7.74 (d, 2H), 7.53 (d, 2H), 6.99
(s, 1H), 6.97 (s, 1H), 4.43 (q, 2H), 2.88 (m, 2H), 2.54 (m, 2H),
2.15 (m, 1H), 1.93 (m, 1H)
Example 2423
1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clopentanecarboxylic acid
##STR00192##
[0706] Step 1
Ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate
##STR00193##
[0708] Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate
(0.5 g, mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt.
in oil, 0.13 g, mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0.degree.
C. The reaction mixture was stirred at 0.degree. C. for 1 h and
saturated NH.sub.4Cl solution (10 mL) was added. The reaction
mixture was extracted with EtOAc (3.times.20 mL) and the combined
organic phases were washed with water (3.times.20 mL) and brine (20
mL), dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate
(380 mg) as a colorless oil.
Step 2
Ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate
##STR00194##
[0710] To a stirred solution of ethyl
1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate
(10 g), in dry MeOH (100 mL) Pd(OH).sub.2 (2 g) was added and
reduced under an atmosphere of H.sub.2 for 6 h at room temperature.
The mixture was filtered through a pad of Celite.TM. washing with
MeOH. The combined filtrates were concentrated under reduced
pressure to yield ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate
(7.5 g) as a thick liquid.
Step 3
Ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarbo-
xylate
##STR00195##
[0712] To a stirred solution of ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate
(1.2 g, 4.0 mmol) in dry CCl.sub.4 (60 mL), NBS (0.427 g, 3.2 mmol)
was added at 0.degree. C. The reaction mixture was allowed to stir
for 3 h at room temperature. The reaction mixture was diluted with
water, extracted with DCM (2.times.50 mL), the combined organic
solvents was dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude reaction mixture was purified by
column chromatography to give ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarb-
oxylate (920 mg) as a yellow solid.
Step 4
Ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)cyclopentanecarboxylate
##STR00196##
[0714] A mixture of ethyl
1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylat-
e (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17
mmol), CsF (0.28 g, 1.84 mmol) and Pd(PPh.sub.3).sub.4 (0.410 g,
0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 75 mL of
EtOAc and 75 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Step 5
Ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)cyclopentanecarboxylate
##STR00197##
[0716] Ethyl
1-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of
MeCN/H.sub.2O/HCl 30 mL/30 mL/2 mL at 0.degree. C. A solution of
NaNO.sub.2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise
at 0.degree. C., and the reaction mixture was stirred for 40 min,
at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in
water (10 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 90.degree. C. for 2.0 h and the solvent was
evaporated. The reaction mixture was extracted with EtOAc
(3.times.50 mL), and the combined organic layers were washed with
water (50 mL) followed by brine (50 mL). The solution was dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give an oil. The oil was purified by chromatography
over silica gel (hexane/EtOAc) to give the ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclopentane carboxylate (1.1 g) as yellow oil.
Step 6
1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)cy-
clopentanecarboxylic acid
##STR00198##
[0718] The ethyl
1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclopentane carboxylate (80 mg) dissolved in 10 mL of
MeOH/THF/H.sub.2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The
reaction mixture was stirred at room temperature for 5 h and
concentrated under reduced pressure. Water (10 mL) was added and
the reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic phases were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. Purification by column
chromatography over silica gel (hexane/EtOAc 9:1) gave
1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)c-
yclopentane carboxylic acid (45 mg) as a white solid. .sup.1H-NMR
(500 MHz, CDCl.sub.3): 7.74 (d, 2H), 7.55 (d, 2H), 7.08 (s, 1H),
4.44 (q, 2H), 2.66 (m, 2H), 1.98 (m, 2H), 1.78 (m, 4H).
Example 2418
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid
##STR00199##
[0719] Step 1
Ethyl
4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate
##STR00200##
[0721] Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (4
g, 16.2 mmol) was dissolved in 50 mL anhydrous DMF and NaH (60% wt.
in oil, 0.846 g, 21.1 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and isobutyl bromide
(2.12 mL, 19.5 mmol) was added drop wise at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h and saturated
NH.sub.4Cl solution was added. The reaction mixture was extracted
with EtOAc (3.times.20 mL) and the combined organic phases were
washed with water (3.times.20 mL) and brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
give ethyl
4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5
g) as a colorless oil.
Step 2
Ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
##STR00201##
[0723] To a stirred solution of ethyl
4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5
g), in dry MeOH (100 mL), Pd(OH).sub.2 (500 mg) was added and the
mixture reduced under an atmosphere of H.sub.2 for 6 h at room
temperature. The mixture was filtered through a pad of Celite.TM.
washing with MeOH. The combined filtrates were concentrated under
reduced pressure to give ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.2
g) as a thick liquid.
Step 3
Ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoa-
te
##STR00202##
[0725] To a stirred solution of ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(0.750 g, 2.2 mmol) in dry CHCl.sub.3 (100 mL), NBS (0.320 g, 1.8
mmol) was added at 0.degree. C. The reaction mixture was allowed to
stir for 3 h at room temperature. The reaction mixture was diluted
with water, extracted with DCM (2.times.50 mL), the combined
organic solvents was dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude reaction mixture was
purified by column chromatography to give ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentano-
ate (700 mg) as a yellow solid.
Step 4
Ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3--
yl)-4-methylpentanoate
##STR00203##
[0727] A mixture of ethyl
2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g,
3.39 mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh.sub.3).sub.4 (0.196
g, 0.16 mmol) in 40 mL anhydrous 1,2-dimethoxy ethane was refluxed
for 8 h under argon. The reaction mixture was cooled, and 35 mL of
EtOAc and 35 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoate (650 mg) as a colorless liquid.
Step 5
Ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-
-yl)-4-methylpentanoate
##STR00204##
[0729] Ethyl
2-(6-amino-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoate (640 mg, 1.3 mmol) was dissolved in a mixture of
MeCN/H.sub.2O/HCl 15 mL/15 mL/1 mL at 0.degree. C. A solution of
NaNO.sub.2 (0.138 g, 2.0 mmol) in water (2 mL) was added drop wise
at 0.degree. C., and the reaction mixture was stirred for 40 min,
at the same temperature. A solution of CuCl (1.32 g, 13.4 mmol) in
water (5 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 80.degree. C. for 2 h and the mixture was
concentrated under reduced pressure. The reaction mixture was
extracted with EtOAc (3.times.50 mL), and the combined organic
layers were washed with water (50 mL) followed by brine (50 mL).
The solution was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give crude black oil which was purified by
chromatography over silica gel (hexane/EtOAc) to give the ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate (380 mg) as a yellow solid.
Step 6
2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-
-methylpentanoic acid
##STR00205##
[0731] Ethyl
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate (320 mg, 0.647 mmol) was dissolved in a
MeOH/THF/H.sub.2O (10 mL/10 mL/5 mL) mixture, LiOH (163 mg, 3.88
mmol) was added. The reaction mixture was stirred at room
temperature for 5 h and then concentrated under reduced pressure.
Water (10 mL) was added and the reaction mixture was extracted with
EtOAc (3.times.10 mL). The combined organic phases were dried over
MgSO.sub.4, filtered and evaporated under reduced pressure.
Purification was achieved by re-crystallization in hexane/ether
mixture to give
2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoic acid (220 mg) as a white solid. .sup.1H-NMR (500
MHz, CDCl.sub.3): 7.74 (d, 2H), 7.55 (d, 2H), 7.01 (s, 2H), 4.44
(q, 2H), 3.68 (t, 1H), 1.98 (m, 2H), 1.61 (m, 1H), 1.54 (m, 1H),
0.95 (d, 6H)
Example 1277
2-(5-Chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropy-
l propanoic acid
##STR00206##
[0732] Step 1
Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate
##STR00207##
[0734] To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate
(25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118
mmol) was slowly added at 0.degree. C. over a period of 30 min.
Diethyl ether (19.6 mL) was slowly added reaction mixture at
0.degree. C. and stirring was continued for 30 min at 0.degree. C.
The reaction mixture was slowly warmed to 15.degree. C. for 1 h.
After completion of reaction, the mixture was poured onto crushed
ice and extracted with DCM (.times.2). The combined organic layers
were washed with 10% NaHCO.sub.3 solution followed by water. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated under vacuum to give compound ethyl
2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.
Step 2
Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate
##STR00208##
[0736] To a stirred solution of ethyl
2-(3-chloro-4-hydroxyphenyl)acetate (15 g, 69 mmol) in CCl.sub.4
(270 mL), bromine (11.1 g, 69 mmol) was added slowly (dissolved in
140 mL of CCl.sub.4) at -10.degree. C. over a period of 30 min. The
reaction mixture was stirred for another 1 h at -10.degree. C. Upon
completion of the reaction, the mixture was poured onto crushed ice
and extracted with DCM (.times.2). The combined organic layers were
washed with saturated Na.sub.2S.sub.2O.sub.3 solution, water, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The crude compound was purified by re-crystallization
using hexane to yield compound ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (7 g, 7 g starting
material recovered) as a white solid.
Step 3
Ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate
##STR00209##
[0738] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (6.5 g, 22 mmol), in
DMF (100 mL), K.sub.2CO.sub.3 (7.67 g, 55.6 mmol) was added.
Trifluoroethyl iodide (13.16 mL, 133 mmol) was added in a drop wise
manner to the reaction mixture at RT. The mixture was then heated
at 60.degree. C. for 4 h. After completion of reaction, the mixture
was poured into water and extracted with ethyl acetate (2.times.100
mL). The combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
compound was purified by column chromatography to give compound
ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate
(6.5 g) as a white solid.
Step 4
Ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpr-
opanoate
##STR00210##
[0740] To a suspension of NaH (0.327 g, 60% in paraffin oil, 8.1
mmol) in DMF (100 mL), slowly added a mixture of ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g,
6.8 mmol) and cyclopropyl methylbromide (0.718 mL, 7.5 mmol)
dissolved in DMF (20 mL) at 0.degree. C. for 15 min under an
atmosphere of nitrogen. The reaction mixture was allowed stir at
0.degree. C. for 15 min, upon which the mixture was poured onto
crushed ice and extracted with ethyl acetate (2.times.50 mL). The
combined organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4 and evaporated. The residue was purified by Flash
column chromatography to give compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (2.35 g) as a thick syrup.
Step 5
Ethyl
2-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cycl-
opropylpropanoate
##STR00211##
[0742] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74
mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116
mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was
stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
2-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cycloprop-
ylpropanoate (375 mg,) as a thick oil.
Step 7
2-(5-Chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropy-
lpropanoic acid
##STR00212##
[0744] A mixture of ethyl
2-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cycloprop-
ylpropanoate (370 mg, 0.84 mmol) and lithium hydroxide monohydrate
(282 mg, 6.7 mmol) in MeOH/THF/Water solvent mixture (10 ml/10
ml/10/ml) was stirred for 3 h at room temperature. After completion
of the reaction, the volatiles were removed under reduced pressure.
The residue was diluted with water, acidified with 5% HCl solution
and extracted with ethyl acetate (2.times.25 mL). The combined
organic layers were washed with water, dried with Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by Flash Column Chromatography to give
2-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-c-
yclopropylpropanoic acid (200 mg) as a white solid. .sup.1HNMR
(CDCl.sub.3): 7.21-7.42 (m, 6H); 3.87 (q, 2H); 3.65 (t, 1H); 2.39
(s, 3H), 1.93 (m, 1H); 1.88 (m, 1H); 0.66 (m, 1H); 0.42 (m, 2H);
0.12 (m, 1H); 0.1 (m, 1H).
Example 1289
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl-
propanoic acid
Step 1
Ethyl
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclo-
propyl propanoate
##STR00213##
[0746] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (500 mg, 1.15 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74
mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116
mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was
stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropy-
l propanoate (400 mg) as a thick oil.
Step 2
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropyl-
propanoic acid
##STR00214##
[0748] A mixture of ethyl
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropy-
l propanoate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate
(222 mg, 5.2 mmol) in MeOH/THF/Water solvent mixture (10 ml/10
ml/10/ml) was stirred for 3 h at room temperature. After completion
of the reaction, the volatiles were removed under reduced pressure.
The residue was diluted with water, acidified with 5% HCl solution
and extracted with ethyl acetate (2.times.25 mL). The combined
organic layers were washed with water, dried with Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by Flash Column Chromatography to give
2-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cy-
clopropylpropanoic acid (200 mg) as a white solid. .sup.1HNMR
(CDCl.sub.3): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s,
1H), 3.85 (q, 2H); 3.66 (t, 1H); 2.73 (q, 2H), 1.93 (m, 1H); 1.88
(m, 1H); 1.29 (t, 3H), 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H);
0.05 (m, 1H).
Example 1313
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cycl-
opropyl propanoic acid
Step 1
Ethyl
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)--
3-cyclopropyl propanoate
##STR00215##
[0750] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (500 mg, 1.15 mmol), 4-thiomethyl phenylboronic acid (293 mg,
1.7 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116
mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was
stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyc-
lopropyl propanoate (360 mg) as a thick oil.
Step 2
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cycl-
opropyl propanoic acid
##STR00216##
[0752] A mixture of ethyl
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyc-
lopropyl propanoate (350 mg, 0.74 mmol) and lithium hydroxide
monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture
(10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After
completion of the reaction, the volatiles were removed under
reduced pressure. Residue was diluted with water, acidified with 5%
HCl solution and extracted with ethyl acetate (2.times.25 mL). The
combined organic layers were washed with water, dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
2-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-y-
l)-3-cyclopropyl propanoic acid (310 mg) as a white solid.
.sup.1HNMR (CDCl.sub.3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H),
7.22 (s, 1H), 3.93 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.93 (m,
1H); 1.78 (m, 1H); 1.29 (t, 3H), 0.65 (m, 1H); 0.42 (m, 2H); 0.12
(m, 1H); 0.05 (m, 1H).
Example 1325
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl-3-yl)--
3-cyclopropyl propanoic acid
Step 1
Ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl--
3-yl)-3-cyclopropyl propanoate
##STR00217##
[0754] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (500 mg, 1.15 mmol), 4-trifluoromethoxy phenylboronic acid (310
mg, 1.65 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g,
0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml)
was stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl-3-yl)-
-3-cyclopropyl propanoate (260 mg) as a thick oil.
Step 2
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl-3-yl)--
3-cyclopropyl propanoic acid
##STR00218##
[0756] A mixture of ethyl
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl-3-yl)-
-3-cyclopropyl propanoate (260 mg, 0.50 mmol) and lithium hydroxide
monohydrate (186 mg, 4.44 mmol) in a MeOH/THF/Water solvent mixture
(10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After
completion of the reaction, the volatiles were removed under
reduced pressure. The residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (2.times.25
mL). The combined organic layers were washed with water, dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethoxy)biphenyl-3-yl)-
-3-cyclopropyl propanoic acid (180 mg) as white solid. .sup.1HNMR
(CDCl.sub.3): 7.56 (d, 2H), 7.40 (s, 1H), 7.25 (m, 3H), 3.98 (q,
2H); 3.68 (t, 1H); 2.56 (s, 3H), 1.913 (m, 1H); 1.76 (m, 1H); 1.29
(t, 3H), 0.62 (m, 1H); 0.41 (m, 2H); 0.12 (m, 1H); 0.05 (m,
1H).
Example 1301
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopr-
opyl propanoic acid
Step 1
Ethyl
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-c-
yclopropyl propanoate
##STR00219##
[0758] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropano-
ate (500 mg, 1.15 mmol), 4-isopropyl phenylboronic acid (225 mg,
1.74 mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116
mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was
stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclop-
ropyl propanoate (400 mg) as thick oil.
Step 2
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopr-
opyl propanoic acid
##STR00220##
[0760] A mixture of ethyl
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclop-
ropyl propanoate (400 mg, 0.85 mmol) and lithium hydroxide
monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture
(10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After
completion of the reaction, the volatiles were removed under
reduced pressure. The residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (2.times.25
mL). The combined organic layers were washed with water, dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)--
3-cyclopropyl propanoic acid (180 mg) as white solid. .sup.1HNMR
(CDCl.sub.3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s,
1H), 3.86 (q, 2H); 3.67 (t, 1H); 2.98 (m, 1H), 1.93 (m, 1H); 1.78
(m, 1H); 1.28 (d, 6H), 0.66 (m, 1H); 0.43 (m, 2H); 0.12 (m, 1H);
0.05 (m, 1H).
Example 1280
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane
carboxylic acid
##STR00221##
[0761] Step 1
Ethyl
1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarbo-
xylate
##STR00222##
[0763] To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF
(100 mL), slowly added a mixture of ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g,
6.8 mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in
DMF (20 mL) at 0.degree. C. for 15 min under an atmosphere of
nitrogen. The reaction mixture was allowed stir at 0.degree. C. for
15 min, upon which the reaction mixture was poured onto crushed ice
and extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by Flash column chromatography to give ethyl
1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylat-
e (2.12 g) as a thick syrup.
Step 2
Ethyl
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobu-
tanecarboxylate
##STR00223##
[0765] A mixture of compound ethyl
1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylat-
e (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68
mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116
mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was
stirred for overnight at 100.degree. C. After completion of the
reaction, the precipitate was removed by filtration. The filtrate
was diluted with water and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude material was
purified by column chromatography to yield ethyl
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanec-
arboxylate (325 mg) as thick oil.
Step 3
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane
carboxylic acid
##STR00224##
[0767] A mixture of ethyl
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanec-
arboxylate (300 mg, 0.70 mmol) and lithium hydroxide monohydrate
(280 mg, 11.6 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10
ml/10/ml) was stirred for 3 h at room temperature. After completion
of the reaction, the volatiles were removed under reduced pressure.
The residue was diluted with water, acidified with 5% HCl solution
and extracted with ethyl acetate (2.times.25 mL). The combined
organic layers were washed with water, dried with Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by Flash Column Chromatography to give
1-(5-chloro-4'-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cycl-
obutane carboxylic acid (185 mg, 66%) as white solid. .sup.1HNMR
(CDCl.sub.3): 7.42 (m, 2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s,
1H), 3.87 (q, 2H); 2.85 (m, 2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12
(m, 1H); 1.83 (m, 1H).
Step 4
Ethyl
1-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobut-
ane carboxylate
##STR00225##
[0769] A mixture of compound ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500
mg, 1.2 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol),
Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol),
Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for
overnight at 100.degree. C. After completion of the reaction, the
precipitate was removed by filtration. The filtrate was diluted
with water and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to yield
ethyl
1-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane
carboxylate (360 mg) as a thick oil.
Step 5
1-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane
carboxylic acid
##STR00226##
[0771] A mixture of ethyl
1-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane
carboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate
(222 mg, 9.2 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10
ml/10/ml) was stirred for 3 h at room temperature. After completion
of the reaction, the volatiles were removed under reduced pressure.
The residue was diluted with water, acidified with 5% HCl solution
and extracted with ethyl acetate (2.times.25 mL). The combined
organic layers were washed with water, dried with Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by Flash Column Chromatography to give
1-(5-chloro-4'-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclo-
butane carboxylic acid (260 mg) as white solid. .sup.1HNMR (CDCl3,
500 MHz): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H),
3.85 (q, 2H); 2.82 (m, 2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m,
1H), 1.91 (m, 1H); 1.27 (t, 3H).
Example 1316
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobu-
tane carboxylic acid
Step 1
Ethyl
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)c-
yclobutane carboxylate
##STR00227##
[0773] A mixture of ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500
mg, 1.2 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol),
Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol),
Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for
overnight at 100.degree. C. After completion of the reaction, the
precipitate was removed by filtration. The filtrate was diluted
with water and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to yield
ethyl
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclob-
utane carboxylate (342 mg) as thick oil.
Step 2
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobu-
tane carboxylic acid
##STR00228##
[0775] A mixture of ethyl
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclob-
utane carboxylate (325 mg, 0.70 mmol) and lithium hydroxide
monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture
(10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After
completion of the reaction, the volatiles were removed under
reduced pressure. The residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (2.times.25
mL). The combined organic layers were washed with water, dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
1-(5-chloro-4'-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-y-
l)cyclobutane carboxylic acid (265 mg) as a white solid. .sup.1HNMR
(CDCl.sub.3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s,
1H), 3.93 (q, 2H); 2.83 (m, 2H), 2.53 (s, 3H), 2.32 (m, 2H), 2.13
(m, 1H), 1.93 (m, 1H).
Example 1304
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)
cyclobutane carboxylic acid
Step 1
Ethyl
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cycl-
obutane carboxylate
##STR00229##
[0777] A mixture of ethyl
2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500
mg, 1.2 mmol), 4-isopropyl phenylboronic acid (245 mg, 1.68 mmol),
Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol),
Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for
overnight at 100.degree. C. After completion of the reaction, the
precipitate was removed by filtration. The filtrate was diluted
with water and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to yield
ethyl
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobuta-
ne carboxylate (425 mg) as thick oil.
Step 2
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutan-
e carboxylic acid
##STR00230##
[0779] A mixture of ethyl
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobuta-
ne carboxylate (400 mg, 0.88 mmol) and lithium hydroxide
monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture
(10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After
completion of the reaction, the volatiles were removed under
reduced pressure. The residue was diluted with water, acidified
with 5% HCl solution and extracted with ethyl acetate (2.times.25
mL). The combined organic layers were washed with water, dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by Flash Column Chromatography to give
1-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)c-
yclobutane carboxylic acid (289 mg) as white solid. .sup.1HNMR
(CDCl.sub.3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s,
1H), 3.86 (q, 2H); 2.99 (m, 1H), 2.86 (m, 2H), 2.52 (m, 2H), 2.13
(m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).
Example 1833
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-3-
-cyclopropylpropanoic acid
##STR00231##
[0780] Step 1
Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl
propanoate
##STR00232##
[0782] To a stirred solution of ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate
(1.2 g, 4.0 mmol) in dry CCl.sub.4 (60 mL), NCS (0.427 g, 3.2 mmol)
was added at 0.degree. C. The reaction mixture was allowed to stir
for 3 h at room temperature to complete the reaction. The reaction
mixture was diluted with water, extracted with DCM (2.times.50 mL),
the combined organic solvents was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude reaction mixture was
purified by column chromatography to yield compound
ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropyl
propanoate (0.920 g) as a yellow solid.
Step 2
Ethyl
2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpro-
panoate
##STR00233##
[0784]
Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclop-
ropyl propanoate (0.9 g, 2.6 mmol) was dissolved in a mixture of
AcCN/H.sub.2O/HCl (96%) 25 mL/25 mL/1 mL at 0.degree. C. A solution
of NaNO.sub.2 (0.277 g, 4.02 mmol) in water (2 mL) was added drop
wise at 0.degree. C., and the reaction mixture was stirred for 40
min, at the same temperature. A solution of KI (4.5 g, 26.8 mmol)
in water (10 mL) was added drop wise at 0.degree. C. The reaction
mixture was heated to 70.degree. C. for 1 h. The reaction mixture
was extracted with EtOAc (3.times.50 mL), and the combined organic
layers were washed with 10% sodium thiosulfate (2.times.50 mL),
water (100 mL) followed by brine (100 mL). The solution was dried
over Na.sub.2SO.sub.4, filtered and concentrated to give crude
black oil which was purified by column chromatography over silica
gel (hexane/EtOAc, 95:5) to give ethyl
2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoa-
te (1.1 g, 90.9%) as yellow oil.
Step 3
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-
-yl)-3-cyclopropyl propanoate
##STR00234##
[0786] A mixture of ethyl
2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoa-
te (1.1 g, 2.4 mmol), 4-trifluoromethylphenylboronic acid (0.928 g,
4.9 mmol), CsF (0.926 g, 6.1 mmol) and Pd (PPh.sub.3).sub.4 (0.283
g, 0.245 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed
for 8 h under argon. The reaction mixture was cooled, and 40 mL of
EtOAc and 40 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a yellow oil. The oil was purified
by column chromatography over silica gel (hexane/EtOAc, 95:5) to
give
ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
4-yl)-3-cyclopropyl propanoate (0.650 g) as a yellow oil.
Step 4
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-3-
-cyclopropylpropanoic acid
##STR00235##
[0788]
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bip-
henyl-4-yl)-3-cyclopropyl propanoate (0.65 g, 1.31 mmol) was
dissolved in 25 mL of MeOH/THF/H.sub.2O (10:10:5, vvl), LiOH (0.252
g, 10.5 mmol) was added. The reaction mixture was stirred for 5 h
at room temperature and concentrated under reduced pressure. Water
(10 mL) was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (DCM/MeOH,
95:5) gave the
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)--
3-cyclopropylpropanoic acid (0.585 g) as a white solid. .sup.1H NMR
(500 MHz, CDCl.sub.3/TMS): .delta. 7.71 (d, 2H), 7.39 (d, 2H), 7.22
(s, 1H), 6.91 (s, 1H), 4.23 (q, 2H), 3.72 (t, 1H), 1.93 (m, 1H),
1.82 (m, 1H), 0.81 (m, 1H), 0.52 (m, 2H), 0.15 (m, 2H).
Example 1836
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cy-
clobutane carboxylic acid
##STR00236##
[0789] Step 1
Ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarbo-
xylate
##STR00237##
[0791] To a stirred solution of ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(2.0 g, 6.3 mmol) in dry CHCl.sub.3 (30 mL), NCS (0.842 g, 6.3
mmol) was added at 0.degree. C. The reaction mixture was allowed to
stir for 3 at room temperature to complete the reaction. The
reaction mixture was diluted with water, extracted with DCM
(2.times.100 mL), the combined organic solvents was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
reaction mixture was purified by Flash column chromatography to
yield ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylat-
e (0.4 g) as thick syrup.
Step 2
Ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarbox-
ylate
##STR00238##
[0793] Ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylat-
e (0.45 g, 1.27 mmol) was dissolved in a mixture of
AcCN/H.sub.2O/HCl (96%) 15 mL/10 mL/3.1 mL at 0.degree. C. A
solution of NaNO.sub.2 (0.132 g, 1.91 mmol) in water (1 mL) was
added drop wise at 0.degree. C., and the reaction mixture was
stirred for 40 min, at the same temperature. A solution of KI (2.11
g, 12.7 mmol) in water (10 mL) was added drop wise at 0.degree. C.
The reaction mixture was heated to 80.degree. C. for 1 h. The
reaction mixture was extracted with EtOAc (3.times.50 mL), and the
combined organic layers were washed with 10% sodium thiosulfate
(2.times.50 mL), water (100 mL) followed by brine (100 mL). The
solution was dried over Na.sub.2SO.sub.4, filtered and concentrated
to give crude black oil which was purified by column chromatography
over silica gel (hexane/EtOAc, 95:5) to give ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(0.350 g) as yellow oil.
Step 3
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-
-yl)cyclobutanecarboxylate
##STR00239##
[0795] A mixture of ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate
(0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g,
1.47 mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh.sub.3).sub.4
(0.084 g, 0.36 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was
refluxed for 8 h under argon. The reaction mixture was cooled, and
20 mL of EtOAc and 20 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
column chromatography over silica gel (hexane/EtOAc, 95:5) to give
ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
4-yl)cyclobutanecarboxylate (0.182 g) as a colorless oil.
Step 4
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cy-
clobutanecarboxylic acid
##STR00240##
[0797]
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bip-
henyl-4-yl)cyclobutanecarboxylate (0.2 g, 0.41 mmol) was dissolved
in 25 mL of MeOH/THF/H.sub.2O (10:10:5, vvl), LiOH (0.10 g, 4.1
mmol) was added. The reaction mixture was stirred for 5 h at room
temperature and concentrated under reduced pressure. Water (10 mL)
was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (DCM/MeOH,
95:5) gave the compound
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)c-
yclobutanecarboxylic acid (0.06 g) as a white solid. .sup.1H NMR
(500 MHz, CDCl.sub.3/TMS): .delta. 7.72 (d, 2H), 7.41 (d, 2H), 7.19
(s, 1H), 6.79 (s, 1H), 4.23 (q, 2H), 3.92 (m, 2H), 2.58 (m, 2H),
2.19 (m, 1H), 1.97 (m, 1H);
Example 1837
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-
-yl)cyclopentanecarboxylate
##STR00241##
[0798] Step 1
Ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarb-
oxylate
##STR00242##
[0800] To a stirred solution of ethyl
1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate
(1.2 g, 3.6 mmol) in dry CHCl.sub.3 (60 mL), NCS (0.411 g, 3.08
mmol) was added at 0.degree. C. The reaction mixture was allowed to
stir for 3 at room temperature to complete the reaction. The
reaction mixture was diluted with water, extracted with DCM
(2.times.100 mL), the combined organic solvents was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
reaction mixture was purified by Flash column chromatography to
yield ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxyla-
te (0.860 g) as a thick syrup.
Step 2
Ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarbo-
xylate
##STR00243##
[0802] Ethyl
1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxyla-
te (0.86 g, 2.3 mmol) was dissolved in a mixture of
AcCN/H.sub.2O/HCl (96%) 10 mL/8 mL/2.1 mL at 0.degree. C. A
solution of NaNO.sub.2 (0.243 g, 3.5 mmol) in water (1 mL) was
added drop wise at 0.degree. C., and the reaction mixture was
stirred for 40 min, at the same temperature. A solution of KI (3.9
g, 23.5 mmol) in water (10 mL) was added drop wise at 0.degree. C.
The reaction mixture was heated to 80.degree. C. for 1 h. The
reaction mixture was extracted with EtOAc (3.times.50 mL), and the
combined organic layers were washed with 10% sodium thiosulfate
(2.times.50 mL), water (100 mL) followed by brine (100 mL). The
solution was dried over Na.sub.2SO.sub.4, filtered and concentrated
to give crude black oil which was purified by column chromatography
over silica gel (hexane/EtOAc, 95:5) to give ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylat-
e (0.580 g) as pale yellow oil.
Step 3
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-
-yl)cyclopentanecarboxylate
##STR00244##
[0804] A mixture of ethyl
1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylat-
e (0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g,
2.4 mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh.sub.3).sub.4 (0.14 g,
0.12 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 25 mL of
EtOAc and 25 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
column chromatography over silica gel (hexane/EtOAc, 95:5) to give
ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
4-yl)cyclopentanecarboxylate (0.480 g) as a color less oil.
Step 4
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cy-
clopentanecarboxylic acid
##STR00245##
[0806]
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bip-
henyl-4-yl)cyclopentane carboxylate (0.32 g, 0.64 mmol) was
dissolved in 25 mL of MeOH/THF/H.sub.2O (10:10:5, vvl), LiOH (0.163
g, 3.88 mmol) was added. The reaction mixture was stirred for 5 h
at room temperature and concentrated under reduced pressure. Water
(10 mL) was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (DCM/MeOH,
95:5) gave the
1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)c-
yclopentanecarboxylic acid (0.220 g, 73%) as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 7.69 (d, 2H), 7.41 (d, 2H), 7.26
(s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71 (m, 2H), 1.98 (m, 2H),
1.81 (m, 4H).
Example 1832
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-4-
-methylpentanoic acid
##STR00246##
[0807] Step 1
Ethyl
2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentano-
ate
##STR00247##
[0809] To a stirred solution of ethyl
2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(0.25 g, 0.75 mmol) in dry CHCl.sub.3 (20 mL), NCS (0.08 g, 0.6
mmol) was added at 0.degree. C. The reaction mixture was allowed to
stir for 3 at room temperature to complete the reaction. The
reaction mixture was diluted with water, extracted with DCM
(2.times.100 mL), the combined organic solvents was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
reaction mixture was purified by Flash column chromatography to
yield ethyl
2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(0.15 g) as thick syrup.
Step 2
Ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoa-
te
##STR00248##
[0811] Ethyl
2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate
(0.7 g, 1.9 mmol) was dissolved in a mixture of AcCN/H.sub.2O/HCl
(96%) 20 mL/20 mL/1.3 mL at 0.degree. C. A solution of NaNO.sub.2
(0.197 g, 2.8 mmol) in water (2 mL) was added drop wise at
0.degree. C., and the reaction mixture was stirred for 40 min, at
the same temperature. A solution of KI (3.16 g, 19.0 mmol) in water
(10 mL) was added drop wise at 0.degree. C. The reaction mixture
was heated to 80.degree. C. for 1 h. The reaction mixture was
extracted with EtOAc (3.times.100 mL), and the combined organic
layers were washed with 10% sodium thiosulfate (2.times.50 mL),
water (100 mL) followed by brine (100 mL). The solution was dried
over Na.sub.2SO.sub.4, filtered and concentrated to give crude
black oil which was purified by column chromatography over silica
gel (hexane/EtOAc, 95:5) to give
ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentano-
ate (0.35 g) as pale yellow oil.
Step 3
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-
-yl)-4-methylpentanoate
##STR00249##
[0813] A mixture of
ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentano-
ate (0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g,
2.09 mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh.sub.3).sub.4 (0.121
g, 0.104 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed
for 8 h under argon. The reaction mixture was cooled, and 25 mL of
EtOAc and 25 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
column chromatography over silica gel (hexane/EtOAc, 95:5) to give
ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl--
4-yl)-4-methylpentanoate (0.265 g,) as a colorless oil.
Step 4
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)-4-
-methylpentanoic acid
##STR00250##
[0815]
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bip-
henyl-4-yl)-4-methylpentanoate (0.35 g, 0.733 mmol) was dissolved
in 25 mL of MeOH/THF/H.sub.2O (10:10:5, vvl), LiOH (0.176 g, 7.33
mmol) was added. The reaction mixture was stirred for 5 h at room
temperature and concentrated under reduced pressure. Water (10 mL)
was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (DCM/MeOH,
95:5) gave the compound
2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)--
4-methylpentanoic acid (0.085 g) as a white solid. .sup.1H NMR (500
MHz, CDCl.sub.3): .delta. 7.69 (d, 2H), 7.41 (d, 2H), 7.20 (s, 1H),
6.86 (s, 1H), 4.23 (q, 2H), 3.71 (t, 1H), 2.01 (m, 1H), 1.73 (m,
1H), 1.58 (m, 1H), 0.98 (d, 6H).
Example 1908
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cyclo-
butane carboxylic acid
##STR00251##
[0816] 2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene
##STR00252##
[0818] Cyclopropylmethanol (15 g, 207 mmol) was added to a stirred
suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over
15 min at 0.degree. C. under nitrogen. The reaction mixture was
allowed to warm to room temperature and stirred for 1 h. A solution
of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was
added drop wise at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 2 h and then poured into ice water. The reaction
mixture was extracted with ethyl acetate (3.times.100 mL). The
combined organic layers were dried over MgSO.sub.4 and concentrated
under reduced pressure to give 22.0 g of product as orange oil
(86%).
Step 2
Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl) malonate
##STR00253##
[0820] Diethyl malonate (9.8 g, 1.1 eq.) was added to a stirred
suspension of sodium hydride (60% in mineral oil, 2.09 g) in 88 mL
DMF over 15 min. at 0.degree. C. under nitrogen. The reaction
mixture was allowed to warm to room temperature and stirred for 1
h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10
g, 1 eq.) in DMF (88 mL) was added drop wise at 0.degree. C., and
the reaction mixture was heated to 100.degree. C. for 3 h. The
reaction mixture was allowed to cool to room temperature, poured
into ice water and extracted with EtOAc (3.times.100 mL). The
combined organic phases were washed with water (3.times.100 mL),
brine (100 mL) and dried (MgSO.sub.4). Evaporation of solvent under
reduced pressure gave 10.0 g of crude product which was purified by
silica gel chromatography (hexane/EtOAc) gave 7.0 g of the desired
product (42%)
[0821] .sup.1H-NMR (CDCl.sub.3, 200 MHz): 0.4 (m, 2H), 0.71 (m,
2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s,
1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).
Step 3
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate
##STR00254##
[0823] i) Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate
(10 g) was dissolved in 100 mL ethanol and cooled to 0.degree. C.,
NaOH solution (4 eq) was added slowly to the reaction mixture for
about 15 min. The reaction mixture was heated gently up to
60.degree. C. for 5 h. Progress of the reaction was monitored by
TLC analysis. After complete conversion of starting material
solvent was evaporated under reduced pressure, the residue
dissolved in H.sub.2O, acidified with 6N HCl to pH-2. The solid
material was collected via filtration, washed with water, dried
under reduced pressure to yield 6.5 g (90%) of
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid as a yellow
solid.
[0824] .sup.1H-NMR (CDCl3, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H),
1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s,
1H), 7.81 (d, 1H).
[0825] ii) 2-(3-(Cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5
g) was taken up in an ethanolic HCl solution (50 mL, 25%) and
refluxed for 4 h, monitored by TLC. The reaction mixture was
concentrated in vacuo to dryness and dissolved in ethyl acetate.
The mixture was washed with NaHCO.sub.3 solution, dried over
NaSO.sub.4 and concentrated in vacuo to give crude yellow solid
which was purified by recrystallization to give the desired product
(4.2 g).
[0826] .sup.1H-NMR (CDCl3, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H),
1.12 (t, 3H), 1.28 (m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 4.21 (q,
2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).
Step 4
Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate
##STR00255##
[0828] To a stirred solution of ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH
(100 mL) was added Pd(OH).sub.2 (2 g). The mixture was hydrogenated
under a H.sub.2 atmosphere for 6 h at room temperature. The
reaction mixture was filtered through a pad of Celite.TM., washing
with MeOH. The combined filtrates were concentrated under reduced
pressure to yield 7.5 g of the desired product as an oil.
[0829] .sup.1H-NMR (CDCl3, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H),
1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q,
2H), 6.72 (m, 3H).
Step 5
Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate
##STR00256##
[0831] To a stirred solution of ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol)
in dry CCl.sub.4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at
0.degree. C. The reaction mixture was allowed to stir for 3 h at
room temperature to complete the reaction. The reaction mixture was
diluted with water, extracted with DCM (2.times.50 mL), the
combined organic solvents was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The crude reaction mixture was purified
by column chromatography to yield Ethyl
2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg)
as a yellow solid.
Step 6
Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate
##STR00257##
[0833]
Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate
(2.5 g, 10.0 mmol) was dissolved in a mixture of AcCN/H.sub.2O/HCl
(96%) 50 mL/50 mL/25 mL at 0.degree. C. A solution of NaNO.sub.2
(3.2 g, 1.16 eq) in water (40 mL) was added drop wise at 0.degree.
C., and the reaction mixture was stirred for 40 min, at the same
temperature. A solution of KI (30 g, 30.1 mmol) in water (80 mL)
was added drop wise at 0.degree. C. The reaction mixture was heated
to 50.degree. C. for 2.5 h and the solvent was evaporated. The
reaction mixture was extracted with EtOAc (3.times.50 mL), and the
combined organic layers were washed with 10% sodium thiosulfate
(2.times.50 mL), water (300 mL) followed by brine (300 mL). The
solution was dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo to give crude black oil which was purified by
chromatography over silica gel (hexane/EtOAc) to give the ethyl
2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (1.2 g)
Step 7
Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl-
)acetate
##STR00258##
[0835] A mixture of compound ethyl
2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g,
12.9 mmol), 4-trifluoromethylphenylboronic acid (3.66 g, 19 mmol),
CsF (3.9 g, 25.8 mmol) and Pd (PPh.sub.3).sub.4 (1.5 g, 1.3 mmol)
in 100 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under
argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75
mL of water were added. The organic phase was separated, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yellow oil. The oil was purified by column chromatography over
silica gel (hexane/EtOAc) to give ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (3.2 g) as yellow oil.
Step 8
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cyclo-
butane carboxylic acid
##STR00259##
[0837] Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (0.5 g, 1.2 mmol) was dissolved in 10 mL anhydrous DMF, NaH
(60% wt. in oil, 0.058 g, 2.4 mmol) was added at 0.degree. C. The
reaction mixture was stirred for 0.5 h at 25.degree. C. and
1,3-dibromopropane (1.5 mL) was added drop wise at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h and saturated
NH.sub.4Cl solution (10 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.20 mL) and the combined organic
phases were washed with water (3.times.20 mL) and brine (20 mL),
and dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give a (320 mg) of colorless oil. The oil was dissolved
in 10 mL of EtOH/H.sub.2O (9:1, vvl) and 0.163 g LiOH added. The
reaction mixture was refluxed for 5 h and concentrated under
reduced pressure. Water (10 mL) was added and the reaction mixture
was extracted with EtOAc (3.times.10 mL). The combined organic
phases were dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. Purification by column chromatography over silica
gel (hexane/EtOAc 9:1) gave
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl-
)cyclobutane carboxylic acid (0.210 g) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 7.68 (d, 2H), 7.41 (d, 2H), 7.06
(s, 1H), 6.78 (s, 1H), 3.78 (d, 2H), 2.86 (m, 2H), 2.58 (m, 2H),
2.16 (m, 1H), 1.95 (m, 1H), 1.03 (m, 1H), 0.46 (m, 2H), 0.18 (m,
2H).
Example 1909
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cyclo-
pentane carboxylic acid
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cyclo-
pentane carboxylic acid
##STR00260##
[0839] Ethyl
2-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)acet-
ate (0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt.
in oil, 0.058 g, 2.4 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and
1,4-dibromobutane (0.24 g) was added drop wise at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h and saturated
NH.sub.4Cl solution (10 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.20 mL) and the combined organic
phases were washed with water (3.times.20 mL) and brine (20 mL),
and dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give a (320 mg, 0.64 mmol) of colorless oil. The oil
was dissolved in 10 mL of EtOH/H.sub.2O (9:1, vvl) and LiOH (0.163
g, 3.88 mmol) added. The reaction mixture was refluxed for 5 h and
concentrated under reduced pressure. Water (10 mL) was added and
the reaction mixture was extracted with EtOAc (3.times.10 mL). The
combined organic phases were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. Purification by column
chromatography over silica gel (hexane/EtOAc 9:1) to give
1-(2-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-4-yl)cycl-
opentane carboxylic acid (220 mg) as a white solid. .sup.1H NMR
(500 MHz, CDCl.sub.3): .delta. 7.68 (d, 2H), 7.41 (d, 2H), 7.16 (s,
1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66 (m, 2H), 1.97 (m, 2H), 1.79
(m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18 (d, 2H);
Example 2418
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid
##STR00261##
[0840] Step 1
Ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate
##STR00262##
[0842] Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (2.2
g, 7.8 mmol) was dissolved in 20 mL anhydrous DMF and NaH (60% wt.
in oil, 0.189 g, 7.8 mmol) was added at 0.degree. C. The reaction
mixture was stirred for 0.5 h at 25.degree. C. and isobutyl bromide
(1.08 g, 7.8 mmol) was added drop wise at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 1 h and saturated
NH.sub.4Cl solution (10 mL) was added. The reaction mixture was
extracted with EtOAc (3.times.20 mL) and the combined organic
phases were washed with water (3.times.20 mL) and brine (20 mL),
and dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.06
g) of colorless oil.
Step 2
Ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
##STR00263##
[0844] To a stirred solution of ethyl
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.0 g,
5.9 mmol), in dry MeOH (50 mL) Pd(OH).sub.2 (1.1 g) was added. The
mixture was reduced under an atmosphere of H.sub.2 for 6 h at room
temperature. The reaction mixture was filtered off through a pad of
Celite.TM., washing with MeOH. The combined filtrates were
concentrated under reduced pressure to yield ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.69
g) as a thick liquid.
Step 3
Ethyl
2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
##STR00264##
[0846] To a stirred solution of ethyl
2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65
g, 5.4 mmol) in dry CCl.sub.4 (60 mL), NBS (0.96 g, 5.4 mmol) was
added at 0.degree. C. The reaction mixture was allowed to stir for
3 at room temperature to complete the reaction. The reaction
mixture was diluted with water, extracted with DCM (2.times.50 mL),
the combined organic solvents was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude reaction mixture was
purified by column chromatography to yield ethyl
2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
(1.5 g) as a yellow solid.
Step 4
Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoate
##STR00265##
[0848] A mixture of ethyl
2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
(1.5 g, 3.9 mmol), 4-trifluoromethylphenylboronic acid (1.1 g, 5.8
mmol), CsF (1.47 g, 7.8 mmol) and Pd (PPh.sub.3).sub.4 (0.45 g,
0.39 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for
8 h under argon. The reaction mixture was cooled, and 75 mL of
EtOAc and 75 mL of water were added. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yellow oil. The oil was purified by
chromatography over silica gel (hexane/EtOAc) to give
ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4-methyl pentanoate (1.2 g) as a yellow oil.
Step 5
Ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4-methylpentanoate
##STR00266##
[0850]
Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)bipheny-
l-3-yl)-4-methyl pentanoate (0.2 g, 0.44 mmol) was dissolved in a
mixture of AcCN/H.sub.2O/HCl 10 mL/10 mL/1 mL at 0.degree. C. A
solution of NaNO.sub.2 (0.039 g, 0.53 mmol) in water (1 mL) was
added drop wise at 0.degree. C., and the reaction mixture was
stirred for 40 min, at the same temperature. A solution of CuCl
(0.22 g, 2.2 mmol) in water (5 mL) was added drop wise at 0.degree.
C. The reaction mixture was heated to 40.degree. C. for 2.0 h and
the solvent was evaporated. The reaction mixture was extracted with
EtOAc (3.times.50 mL), and the combined organic layers were washed
with water (30 mL) followed by brine (20 mL). The solution was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give crude black oil which was purified by chromatography over
silica gel (hexane/EtOAc) to give
ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-y-
l)-4-methylpentanoate (0.12 g) as a thick oil.
Step 6
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid
##STR00267##
[0852] The
ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)bi-
phenyl-3-yl)-4-methylpentanoate (120 mg, 0.255 mmol) dissolved in
10 mL of MeOH/THF/H.sub.2O (10 mL/10 mL/5 mL) and LiOH (30 mg, 1.2
mmol) was added. The reaction mixture was stirred at room
temperature for 5 h and concentrated under reduced pressure. Water
(10 mL) was added and the reaction mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phases were dried over
MgSO.sub.4, filtered and evaporated under reduced pressure.
Purification by column chromatography over silica gel (DCM:MeOH
9:1) gave
2-(6-chloro-5-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-m-
ethylpentanoic acid (89 mg) as a white solid. .sup.1H-NMR (500 MHz,
CDCl.sub.3): 7.68 (d, 2H), 7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s,
1H), 3.96 (d, 2H), 3.64 (t, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.55
(m, 1H), 1.32 (m, 1H), 0.91 (d, 6H), 0.64 (m, 2H), 0.42 (m,
2H);
Example 3205
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thoxybutanoic acid
##STR00268##
[0853] Step 1
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate
##STR00269##
[0855] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12 g, 40.816 mmol) in
DMSO (80 mL) were added K.sub.2CO.sub.3 (14.08 g, 102.020 mmol) and
cyclopropylmethylbromide (5 mL, 4.880 mmol) at RT under inert
atmosphere. The reaction mixture was stirred at 80.degree. C.
temperature over a period of 14 h. After completion of starting
material (by TLC), the reaction mixture was cooled to RT and
quenched with water and extracted with EtOAc (3.times.100 mL).
Combined organic layers were washed with water (3.times.75 mL),
brine and dried over Na.sub.2SO.sub.4. After filtration and
concentration under reduced pressure, the crude material was
purified by column chromatography to afford ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (10 g)
yellow solid.
Step 2
Ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoat-
e
##STR00270##
[0857] To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10
mL) was added ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g,
5.70 mmol) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. over a period of 30 min. To the reaction mixture was
added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at
0.degree. C. for 30 min. After completion of starting material (by
TLC), the reaction mixture was diluted with water (20 mL),
acidified with 1N HCl (pH=5) and extracted with EtOAc (3.times.50
mL). Combined organic layers were washed with water (3.times.25
mL), brine and dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration under reduced pressure, the crude
material was purified by column chromatography to afford ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate
(560 mg) as an off white solid.
Step 3
Ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4-methoxybutanoate
##STR00271##
[0859] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate
(2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL)
were added Cs.sub.2CO.sub.3 (6.4 g, 19.815 mmol), Pd(TPP).sub.4
(1.3 g, 1.120 mmol) and 4-(trifluoromethyl)phenyl boronic acid
(1.29 g, 6.780 mmol) at RT under N.sub.2 atmosphere and the
resulting mixture was stirred at 80.degree. C. for 14 h. After
completion of starting material (by TLC), filtered off the catalyst
and celite bed was washed with EtOAc and extracted with EtOAc
(3.times.100 mL). Combined organic layers were washed with water
(3.times.50 mL), brine and dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration under reduced pressure, the
crude material was purified by column chromatography to afford
ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-m-
ethoxybutanoate (1.2 g) as an off white solid.
Step 4
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thoxybutanoic acid
##STR00272##
[0861] To a stirred solution of ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-m-
ethoxybutanoate (0.3 g, 0.638 mmol) in a mixture of THF (10 mL),
methanol (10 mL) and water (5 mL) was added LiOH.H.sub.2O (53 mg,
12.030 mmol) at room temperature and the mixture was stirred at RT
for 2 h. After complete consumption of starting material as
monitored by TLC, the reaction mixture was diluted with water (10
mL) and acidified using 1 N HCl at 0.degree. C. The aqueous layer
was extracted with EtOAc (2.times.20 mL); combined organic extracts
were washed with water (20 mL), brine (30 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was
purified by column chromatography to afford
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-m-
ethoxybutanoic acid (100 mg) as an off white solid. .sup.1HNMR (500
MHz) (CDCl.sub.3): .delta. ppm 7.68 (m, 4H), 7.40 (s, 1H), 7.20 (s,
1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25 (m, 5H), 2.39 (m, 1H), 1.99
(m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m, 2H).
Example 3206
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methy-
lpentanoic acid
##STR00273##
[0862] Step 1
Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl
pentanoate
##STR00274##
[0864] To a stirred solution of NaH (0.76 g, 15.82 mmol) in DMF (50
mL) was added compound
2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoic acid (5.0 g,
14.4 mmol) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. over a period of 30 min. To the reaction mixture was
added isobutyl bromide (2.93 g, 21.57 mmol) and stirred at
0.degree. C. for 1 h. After completion of starting material (by
TLC), diluted with water (40 mL), acidified with 1N HCl (pH=5) and
extracted with EtOAc (3.times.100 mL). Combined organic layers were
washed with water (3.times.50 mL), brine and dried over anhydrous
Na.sub.2SO.sub.4. After filtration and concentration under reduced
pressure, the crude material was purified by column chromatography
to afford ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl
pentanoate (5.0 g) as a liquid.
Step 2
Ethyl
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-
-methylpentanoate
##STR00275##
[0866] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl
pentanoate (0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and
water (5 mL) were added Cs.sub.2CO.sub.3 (1.4 g, 4.325 mmol), Pd
(TPP).sub.4 (286 mg, 2.475 mmol) and
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole
(355 mg, 1.363 mmol) at RT under N.sub.2 atmosphere and the
resulting mixture was stirred at 80.degree. C. for 14 h. After
completion of starting material (by TLC), the solids were removed
via filtration through a bed of Celite.TM. was washing with EtOAc
(3.times.100 mL). The combined organic layers were washed with
water (3.times.50 mL), brine and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to afford
ethyl
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-meth-
ylpentanoate (100 mg) as an off white solid.
Step 3
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methy-
lpentanoic acid
##STR00276##
[0868] To a stirred solution of ethyl
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-meth-
ylpentanoate (0.1 g, 0.218 mmol) in a mixture of THF (10 mL),
methanol (10 mL) and water (5 mL) was added LiOH.H.sub.2O (45 mg,
1.090 mmol) at room temperature and the mixture was stirred at RT
for 2 h. After complete consumption of starting material as
monitored by TLC, the reaction mixture was diluted with water (10
mL) and acidified using 1 N HCl at 0.degree. C. The aqueous layer
was extracted with EtOAc (2.times.20 mL); combined organic extracts
were washed with water (10 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
material was purified by column chromatography to afford
2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-meth-
ylpentanoic acid (39 mg) as an off white solid. .sup.1HNMR (500
MHz) (CDCl.sub.3): .delta. (ppm) 9.05 (s, 1H), 8.2 (m, 2H), 7.73
(m, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.63 (t, 1H), 3.40 (d, 2H),
1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 0.93 (m, 7H), 0.38 (d,
2H), -0.5 (d, 2H).
Example 514
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl-
)-4-methylpentanoic acid
Step 1
Ethyl
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)-
phenyl)-4-methylpentanoate
##STR00277##
[0870] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
(0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL)
were added Cs.sub.2CO.sub.3 (1.4 g, 4.342 mmol), Pd(TPP).sub.4 (286
mg, 2.480 mmol) and
5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2yl)benzo[c][1,2,5]oxadiaz-
ole (355 mg, 1.364 mmol) at RT under N.sub.2 atmosphere and the
resulting mixture was stirred at 80.degree. C. for 14 h. After
completion of starting material (by TLC), the solids were removed
via filtration through a bed of Celite.TM. was washing with EtOAc
(3.times.100 mL). The combined organic layers were washed with
water (3.times.50 mL), brine and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to afford
ethyl
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)pheny-
l)-4-methylpentanoate (250 mg) as an off white solid.
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl-
)-4-methylpentanoic acid
##STR00278##
[0872] To a stirred solution of ethyl
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)pheny-
l)-4-methylpentanoate (0.25 g, 0.565 mmol) in a mixture of THF (10
mL), methanol (10 mL) and water (5 mL) was added LiOH.H.sub.2O
(118.7 mg, 2.828 mmol) at room temperature and the mixture was
stirred at RT for 2 h. After complete consumption of starting
material as monitored by TLC, the reaction mixture was diluted with
water (10 mL) and acidified using 1 N HCl at 0.degree. C. The
aqueous layer was extracted with EtOAc (2.times.20 mL); combined
organic extracts were washed with water (10 mL), brine (20 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude material was purified by column chromatography to
afford compound
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)pheny-
l)-4-methylpentanoic acid (152 mg) as an off white solid.
.sup.1HNMR (500 MHz) (CDCl.sub.3): .delta. (ppm) 7.92 (s, 1H), 7.85
(m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 3.65 (t, 1H),
3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.22 (m,
1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).
Example 524
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)pheny-
l)-4-methylpentanoic acid
Step 1
Ethyl
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy-
)phenyl)-4-methylpentanoate
##STR00279##
[0874] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate
(0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL)
were added Cs.sub.2CO.sub.3 (1.4 g, 4.325 mmol), Pd(TPP).sub.4 (286
mg, 2.475 mmol) and
5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2yl)benzo[c][1,2,5]thiazdi-
azole (355 mg, 1.363 mmol) at RT under N.sub.2 atmosphere and the
resulting mixture was stirred at 80.degree. C. for 14 h. After
completion of starting material (by TLC), the solids were removed
via filtration through a bed of Celite.TM. was washing with EtOAc
(3.times.100 mL). The combined organic layers were washed with
water (3.times.50 mL), brine and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude material was purified by column chromatography to afford
ethyl
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phen-
yl)-4-methylpentanoate (222 mg) as an off white solid.
Step 2
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)pheny-
l)-4-methylpentanoic acid
##STR00280##
[0876] To a stirred solution of ethyl
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phen-
yl)-4-methylpentanoate (0.22 g, 0.479 mmol) in a mixture of THF (5
mL), methanol (5 mL) and water (2 mL) was added LiOH.H.sub.2O (60.3
mg, 1.438 mmol) at room temperature and the mixture was stirred at
RT for 2 h. After complete consumption of starting material as
monitored by TLC, the reaction mixture was diluted with water (10
mL) and acidified using 1 N HCl at 0.degree. C. The aqueous layer
was extracted with EtOAc (2.times.20 mL); combined organic extracts
were washed with water (10 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was
purified by column chromatography to afford
2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phen-
yl)-4-methyl pentanoic acid (105 mg, 50.0%) as an off white solid.
.sup.1HNMR (500 MHz) (CDCl.sub.3): .delta. (ppm) 8.18 (s, 1H), 8.03
(d, 1H), 7.96 (d, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 3.68 (t, 1H),
3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 0.98 (d,
6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).
Example 3207
2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4'-(trifluoromethyl)bi-
phenyl-3-yl)-4-methylpentanoic acid
##STR00281##
[0877] Step 1
Ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl
pentanoate
##STR00282##
[0879] To a stirred compound ethyl
2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (1.0 g, 3.174 mmol)
in DCM (15 ml) chlorosulfonic acid (2 mL, 28.571 mmol) was added.
The reaction mixture was stirred for 14 h at 80.degree. C. under
N.sub.2 atmosphere. After completion of starting material (by TLC),
the reaction mixture was quenched with NaHCO.sub.3 solution and
extracted with DCM (3.times.100 mL). Combined organic layers were
washed with water (3.times.75 mL), brine and dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give ethyl
2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate
(0.5 g) as a liquid.
Step 2
Ethyl
2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentan-
oate
##STR00283##
[0881] To a stirred solution of ethyl
2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate
(0.73 g, 1.765 mmol) in THF (20 mL) was added N,N-dimethylamine
solution (5.2 mL, 10.592 mmol) at RT under inert atmosphere. The
reaction mixture was stirred at RT over a period of 14 h. After
completion of starting material (by TLC), the reaction mixture was
quenched with water and extracted with EtOAc (3.times.100 mL). The
combined organic layers were washed with water (3.times.75 mL),
brine and dried over Na.sub.2SO.sub.4. After filtration and
concentration under reduced pressure, the crude material was
purified by column chromatography to afford ethyl
2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate
(0.6 g) as a pale yellow liquid.
Step 3
Ethyl
2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-
-methylpentanoate
##STR00284##
[0883] To a stirred solution of ethyl
2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate
(0.75 g, 1.77 mmol) in DMSO (25 mL) were added K.sub.2CO.sub.3 (367
mg, 2.106 mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at
RT under inert atmosphere. The reaction mixture was stirred at
80.degree. C. temperature over a period of 14 h. After completion
of starting material (by TLC), the reaction mixture was cooled to
RT and quenched with water and extracted with EtOAc (3.times.100
mL). Combined organic layers were washed with water (3.times.75
mL), brine and dried over Na.sub.2SO.sub.4. After filtration and
evaporation, the crude material was purified by column
chromatography to afford ethyl
2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-meth-
ylpentanoate (350 mg) as a liquid.
Step 4
2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4'-(trifluoromethyl)bi-
phenyl-3-yl)-4-methylpentanoic acid
##STR00285##
[0885] To a stirred solution of
2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-meth-
ylpentanoate (0.5 g, 1.049 mmol) in a mixture of DMF (10 mL) and
water (5 mL) were added Cs.sub.2CO.sub.3 (1.19 g, 3.670 mmol),
Pd(TPP).sub.4 (243 mg, 0.209 mmol) and
4-(trifluoromethyl)phenylbornate (220 mg, 1.150 mmol) at RT under
N.sub.2 atmosphere and the resulting mixture was stirred at
80.degree. C. for 14 h. After completion of starting material (by
TLC), filtered off the catalyst and celite bed was washed with
EtOAc and extracted with EtOAc (3.times.100 mL). The combined
organic layers were washed with water (3.times.50 mL), brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration in vacuo, the crude material was purified by column
chromatography to afford
2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4'-(trifluoromethyl)b-
iphenyl-3-yl)-4-methylpentanoic acid (100 mg) as an off white
solid. .sup.1HNMR (500 MHz) (CDCl.sub.3): .delta. (ppm) 7.83 (s,
1H), 7.72 (m, 4H), 7.51 (s, 1H), 3.73 (m, 1H), 3.38 (d, 2H), 2.95
(s, 3H), 2.87 (s, 3H), 2.01 (m, 1H), 1.65 (m, 1H), 1.51 (m, 1H),
0.91 (m, 7H), 0.40 (d, 2H), 0.00 (m, 2H).
Step 5
Ethyl
2-(6-(cyclopropylmethoxy)-5-iodo-4'-(trifluoromethyl)biphenyl-3-yl)--
4-methylpentanoate
##STR00286##
[0887] To a stirred solution of ethyl
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate (1.0 g, 2.227 mmol) in a mixture of HCl: H2O (0.81
mL, 6.681 mmol) was added NaNO.sub.2 (0.180 g, 2.672 mmol). After
being stirred for 1 h at 0.degree. C. then added KI (3.69 g, 22.271
mmol) at 0.degree. C. under inert atmosphere. The reaction mixture
was stirred at 100.degree. C. temperature over a period of 2 h.
After completion of starting material (by TLC), the reaction
mixture was cooled to RT and extracted with EtOAc (3.times.100 mL).
The combined organic layers were washed with water (3.times.75 mL),
brine and dried over Na.sub.2SO.sub.4. After filtration and
concentration in vacuo, the crude material was purified by column
chromatography to afford ethyl
2-(6-(cyclopropylmethoxy)-5-iodo-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoate (0.93 g) as a solid.
Example 3210
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
Step 1
Ethyl
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-
-4-methylpentanoate
##STR00287##
[0889] To a stirred solution of ethyl
2-(6-(cyclopropylmethoxy)-5-iodo-4'-(trifluoromethyl)
biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10
mL) was added CuCN (50 mg, 0.536 mmol) at RT under inert
atmosphere. The reaction mixture was stirred at 200.degree. C.
temperature over a period of 2 h. After completion of starting
material (by TLC), the reaction mixture was cooled to RT and
extracted with EtOAc (3.times.20 mL). Combined organic layers were
washed with water (3.times.15 mL), brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation, the crude
material was purified by column chromatography to afford ethyl
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)
biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.
Step 2
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
##STR00288##
[0891] To a stirred solution of ethyl
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)
biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a
mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added
LiOH.H.sub.2O (34 mg, 0.816 mmol) at room temperature and the
mixture was stirred at RT for 2 h. After complete consumption of
starting material as monitored by TLC, the reaction mixture was
diluted with water (10 mL) and acidified using 1 N HCl at 0.degree.
C. The aqueous layer was extracted with EtOAc (2.times.20 mL);
combined organic extracts were washed with water (10 mL), brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The crude material was purified by column
chromatography to afford
2-(5-cyano-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid (50 mg) as an off white solid. .sup.1HNMR (500
MHz) (CDCl.sub.3): .delta. (ppm) 7.70 (m, 4H), 7.61 (s, 1H), 7.51
(s, 1H), 3.71 (t, 1H), 3.55 (m, 2H), 2.00 (m, 1H), 1.67 (m, 1H),
1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H), 0.45 (m, 2H), 0.05 (m,
2H).
Example 3208
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4-methylpentanoic acid
##STR00289##
[0892] Step 1
Ethyl
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)bipheny-
l-3-yl)-4-methylpentanoate
##STR00290##
[0894] To a stirred solution of ethyl
2-(5-amino-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoate (1.0 g, 2.604 mmol) in a mixture of HCl:H.sub.2O
(0.86 mL, 10.4 mmol) and THF (10 mL) was added NaNO.sub.2 (0.215 g,
3.92 mmol). After being stirred for 1 h at 0.degree. C. then added
NaSMe (368 mg, 0.260 mmol) at 0.degree. C. under an inert
atmosphere. The reaction mixture was stirred at RT over a period of
14 h. After complete consumption of starting material (by TLC), the
reaction mixture was extracted with EtOAc (3.times.100 mL). The
combined organic layers were washed with water (3.times.75 mL),
brine and dried over Na.sub.2SO.sub.4. After filtration and
concentration under vacuo, the crude material was purified by
column chromatography to afford ethyl
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)biphenyl-3-y-
l)-4-methylpentanoate (0.93 g) as a solid.
Step 2
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4-methylpentanoic acid
##STR00291##
[0896] To a stirred solution of ethyl
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)biphenyl-3-y-
l)-4-methylpentanoate (80 mg, 0.166 mmol) in a mixture of THF (10
mL), methanol (10 mL) and water (5 mL) was added LiOH.H.sub.2O (20
mg, 0.832 mmol) at room temperature and the mixture was stirred at
RT for 2 h. After complete consumption of starting material as
monitored by TLC, the reaction mixture was diluted with water (10
mL) and acidified using 1 N HCl at 0.degree. C. The aqueous layer
was extracted with EtOAc (2.times.20 mL); combined organic extracts
were washed with water (10 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under vacuo. The crude
material was purified by column chromatography to afford
2-(6-(cyclopropylmethoxy)-5-(methylthio)-4'-(trifluoromethyl)biphenyl-3-y-
l)-4-methylpentanoic acid (38 mg) as an off white solid. .sup.1HNMR
(500 MHz) (CDCl.sub.3): .delta. (ppm) 7.75 (d, 2H), 7.65 (d, 2H),
7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H), 3.60 (d, 2H), 2.82 (s,
3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H), 1.22 (m, 1H), 0.9 (d,
6H), 0.38 (d, 2H), 0.01 (d, 2H).
Example 3209
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-me-
thylbutanoic acid
Step 1
Ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate
##STR00292##
[0898] To a stirred solution of NaH (40 mg, 0.830 mmol) in DMF (5
mL) was added compound ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)acet-
ate (300 mg, 0.728 mmol) and stirred at 0.degree. C. for 1 h. To
the reaction mixture at 0.degree. C. was added isopropyl bromide
(0.08 mL, 0.880 mmol) and continued stirring at 0.degree. C. over a
period of 30 min. After complete consumption of the starting
material (by TLC), the reaction mixture was diluted with water (20
mL), acidified with 1N Hcl (pH=5) and extracted with EtOAc
(3.times.30 mL). The combined organic layers were washed with water
(3.times.15 mL), brine and dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration under educed pressure, the crude
material was purified by column chromatography to afford ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate
(120 mg) as a liquid.
Step 2
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-me-
thylbutanoic acid
##STR00293##
[0900] To a stirred solution of ethyl
2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate
(0.12 g, 0.260 mmol) in a mixture of THF (5 mL), methanol (5 mL)
and water (2 mL) was added LiOH.H.sub.2O (75 mg, 1.320 mmol) at
room temperature and the mixture was stirred at RT for 2 h. After
complete consumption of the starting material, as monitored by TLC,
the reaction mixture was diluted with water (10 mL) and acidified
using 1 N HCl at 0.degree. C. The aqueous layer was extracted with
EtOAc (2.times.20 mL); combined organic extracts were washed with
water (10 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4
and concentrated in vacuo. The crude material was purified by
column chromatography to afford
ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-3-methylbutanoate (100 mg) as an off white solid. .sup.1HNMR (500
MHz) (CDCl.sub.3): .delta. (ppm) 7.66 (m, 4H), 7.41 (s, 1H), 7.20
(s, 1H), 3.41 (d, 2H), 3.15 (d, 1H), 2.3 (m, 1H), 1.12 (d, 3H),
0.97 (m, 1H), 0.72 (d, 3H), 0.40 (d, 2H), 0.00 (d, 2H).
Example 482
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4,
4,4-trifluorobutanoic acid
Step 1
Ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl-
)-4,4,4-trifluorobutanoate
##STR00294##
[0902] To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15
mL) was added ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)acet-
ate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL,
0.15 mmol) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. over a period of 30 min. After completion of starting
material (by TLC), diluted with water (20 mL), acidified with 1N
HCl (pH=5) and extracted with EtOAc (3.times.30 mL). Combined
organic layers were washed with water (3.times.15 mL), brine and
dried over anhydrous Na.sub.2SO.sub.4. After filtration and
evaporation, the crude material was purified by column
chromatography to afford ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4,4-
,4-trifluorobutanoate (300 mg) as liquid.
Step 2
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4,4,-
4-trifluorobutanoic acid
##STR00295##
[0904] To a stirred solution of ethyl
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)
biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a
mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added
LiOH.H.sub.2O (85 mg, 2.024 mmol) at room temperature and the
mixture was stirred at RT for 2 h. After complete consumption of
the starting material as monitored by TLC, the reaction mixture was
diluted with water (10 mL) and acidified using 1 N HCl at 0.degree.
C. The aqueous layer was extracted with EtOAc (2.times.20 mL) the
combined organic extracts were washed with water (10 mL), brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under
vacuum. The crude material was purified by column chromatography to
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4,4-
,4-trifluorobutanoic acid (38 mg) as sticky syrup. .sup.1HNMR (500
MHz) (CDCl.sub.3): .delta. (ppm) 7.71 (m, 4H), 7.39 (s, 1H), 7.19
(s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m, 1H), 2.54 (m, 1H),
0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).
[0905] The following examples can also be made using analogous
procedures as described previously, substituting the appropriate
reagents known to those of ordinary skill in the art.
Example 3211
2-(5-chloro-6-(cyclopropylmethoxy)biphenyl-3-yl)-4-methylpentanoic
acid
Example 3212
2-(5-chloro-6-(2-methoxyethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-methy-
lpentanoic acid
Example 3213
2-(5-chloro-6-(cyclopropylmethoxy)-3'-(trifluoromethyl)biphenyl-3-yl)-4-me-
thylpentanoic acid
Example 3214
2-(5-bromo-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-4-met-
hylpentanoic acid
Example 3215
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-me-
thylpentanoic acid
Example 3216
2-(5-chloro-6-(cyclopropylmethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-ph-
enylpropanoic acid
Example 3217
2-(3-(benzo[d]thiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methy-
lpentanoic acid
[0906] The following examples can also be made using analogous
procedures as described previously, substituting the appropriate
reagents known to those of ordinary skill in the art.
[0907] Examples 464, 474, 480, 481, 483, 485, 488, 489, 494, 504,
1292, 1334, 2490, 2708, 3211, 3212, 3213, 3214, 3215, 3216 and
3217
Pharmacology Experimental
Measurement of A.beta. In Vitro
[0908] The A.beta. peptide is proteolytically derived from a larger
integral membrane amyloid precursor protein (APP). The production
of A.beta. is derived from proteolytic cleavages at its N- and
C-termini within .beta.-APP by the .beta. and .gamma.-secretase
activities, respectively. Transfected cells overexpressing
.beta.-APP or its equivalent producing the A.beta. peptide can be
used to monitor the effects of synthetic compounds on the
production of A.beta.
[0909] To analyze a compound's effects on the concentrations of the
various products of the .gamma.-secretase cleavage activity, the
A.beta. peptides, various methods known to a person skilled in the
art are available. Examples of such methods, but not limited to,
include mass-spectrometric identification as described by Wang et
al, 1996, J. Biol. Chem. 271:31894-31902) or detection by specific
antibodies using, for example, ELISA's.
[0910] Examples of such assays for measuring the production of
A.beta..sub.total, A.beta..sub.40 and A.beta..sub.42 by ELISA
include but are not limited to those described by Vassar et al.,
1999, Science 286:735-741. Suitable kits containing the necessary
antibodies and reagents for such an analysis are available, for
example, but not limited to the Genetics Company, Wako, Covance,
and Innogenetics. The kits are essentially used according to the
manufacturers recommendations similar to the assay that is
described by Citron et al., (1997) Nature Medicine 3:67-72 and the
original assay described by Seubert et al., (1992) Nature
359:325-327.
[0911] Screening was carried out using the human embryonic kidney
cell line HEK-293 overexpressing an amyloid precursor protein (APP)
transgene grown in Pro-293a CDM media (BioWhittaker). Cells were
grown to approximately 70-80% confluency subsequent to the addition
of test compounds. The growth media was aspirated or removed, the
cells washed, and replaced with 100 .mu.l of compound,
appropriately diluted in serum free media. The plates are then
incubated for 16-18 hours at 37.degree. C.
[0912] Conditioned Medium samples are removed for
analysis/quantitation of the various A.beta. peptide levels by
differential ELISA's as described in accompanying instructions to
the kits. Those compounds examined which do not demonstrate any
overt toxicity or non-specific inhibitory properties are
investigated further for their A.beta. inhibitory effects and form
the basis of medicinal chemistry efforts and to study the effect of
the compounds in different experimental conditions and
configurations.
[0913] Table 14 shows representative in vitro data (HEK 293)
EC.sub.50 data for compounds of the disclosure where:
A indicates a compound has an EC.sub.50 for lowering A.beta.42 of
<1 .mu.M B indicates a compound has an EC.sub.50 for lowering
A.beta.42 of >1 .mu.M but <5 .mu.M C indicates a compound has
an EC.sub.50 for lowering A.beta.42 of >5 .mu.M
TABLE-US-00013 TABLE 14 Example # Activity 264 A 414 A 415 A 419 A
464 A 474 A 480 A 481 A 482 A 483 A 484 A 485 A 488 A 489 A 494 A
504 A 514 A 524 A 534 A 554 A 724 A 754 B 1055 A 1268 A 1269 A 1270
A 1271 A 1272 A 1277 A 1280 A 1289 A 1292 A 1301 A 1304 A 1313 A
1316 A 1325 A 1334 A 1832 A 1833 A 1836 A 1837 A 1904 A 1905 A 1908
A 1909 A 1976 A 2418 A 2419 A 2422 A 2423 A 2490 A 2491 A 2494 A
2495 A 2708 A 2959 A 2995 A 3200 A 3201 A 3202 B 3203 A 3204 A 3205
A 3206 A 3207 B 3208 A 3209 A 3210 A 3211 A 3212 A 3213 A 3214 A
3215 A 3216 A 3217 B
[0914] Table 15 shows individual EC.sub.50 values for
representative compounds of the disclosure.
TABLE-US-00014 TABLE 15 EC.sub.50 (A.beta.42) HEK 293 Example #
Compounds Name (.mu.M) 484 2-(5-chloro-6-(cyclopropylmethoxy)-4'-
0.069 (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid 514
2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4- 0.274
(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid 2959
2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-chloro-5- 0.298
(2-cyclopropylethyl)phenyl)-4-methylpentanoic acid 2995
2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-chloro-5- 0.220
(2-cyclopropylethyl)phenyl)-4-methylpentanoic acid 3210
2-(5-cyano-6-(cyclopropylmethoxy)-4'- 0.275
(trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid
Experimental Procedures for Rat Primary Cortical Culture-Based
Abeta.sub.1.fwdarw.42/1.fwdarw.x ELISAs
[0915] Rat primary neocortical cultures are established through the
dissection of the neocortices from 10-12 E17 embryos harvested from
time-pregnant SD (Sprague Dawley) rats (Charles River
Laboratories). Following dissection, the combined neocortical
tissue specimen volume is brought up to 5 mL with dissection medium
(DM; 1.times.HBSS (Invitrogen Corp., cat#14185-052)/10 mM HEPES
(Invitrogen Corp., cat#15630-080)/1 mM Sodium Pyruvate (Invitrogen
Corp., cat#11360-070)) supplemented with 100 uL Trypsin (0.25%;
Invitrogen Corp., cat#15090-046) and 100 uL DNase I (0.1% stock
solution in DM, Roche Diagnostics Corp., cat#0104159), undergoing
digestion via incubation at 37.degree. C. for 10 minutes. Digested
tissue is washed once in plating medium (PM; NeuroBasal (Invitrogen
Corp., cat#21103-049)/10% Horse Serum (Sigma-Aldrich Co.,
cat#H1138)/0.5 mM L-Glutamine (Invitrogen Corp., cat#25030-081)),
then resuspended in a fresh 10 mL PM volume for trituration.
Trituration consists of 18 cycles with a 5 mL-serological pipet,
followed by 18 cycles with a flame-polished glass Pasteur pipet.
The volume is elevated to 50 mL with PM, the contents then passed
over a 70 um cell-strainer (BD Biosciences, cat#352350) and
transferred directly to a wet-ice bath. The cell-density is
quantified using a hemacytometer, and diluted to allow for the
plating of 50000 cells/well/100 uL in pre-coated 96-well PDL-coated
plates (Corning, Inc., cat#3665). Cells are incubated for 4-5 hours
at 37.degree. C./5% CO.sub.2, after which time the entire volume is
exchanged to feeding medium (FM; NeuroBasal/2% B-27 Serum-free
supplement (Invitrogen Corp., cat#17504-044)/0.5 mM L-Glutamine/1%
Penicillin-Streptomycin (Invitrogen Corp., cat#15140-122)). The
cultures undergo two 50% fresh FM exchanges, after 3 days in vitro
(DIV3), and again at DIV7.
[0916] Human C-terminal recognition-site Abeta.sub.1.fwdarw.42 and
Rat N-terminal recognition-site Abeta.sub.1.fwdarw.x
capture-antibodies, diluted 1:300 in 0.05M Carbonate-Bicarbonate
buffer (Sigma-Aldrich Co., C-3041), are use to coat (100 uL/well)
flat-bottomed F96 MicroWell.TM. (MaxiSorp.TM. surface) plates
(Nalge Nunc International, cat#439454), and incubated overnight at
4.degree. C. for eventual use in the ELISA assay. Compounds to be
screened are solubilized in dimethyl sulphoxide (DMSO,
Sigma-Aldrich Co., cat#15493-8), and further diluted in DMSO in an
eight-point dose-response format. Into 96-well plates,
dose-response compound dilutions (1000.times. the desired final
concentration) are stamped out at 2 uL/well, in duplicate (up to 3
compounds/plate), as a daughter plate. In addition, DMSO and
N--[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl
ester (DAPT), a gamma-secretase inhibitor (GSI), are incorporated
as solvent and positive controls, respectively. With the assistance
of liquid-handling automation, the compound daughter plate is
diluted 1:500 with warmed FM, and two DIV8 culture plates are
leveled to 60 uL/well, and immediately overlaid with 60 uL/well of
the 2.times. diluted daughter plate. The plates are returned to the
37.degree. C./5% CO.sub.2-incubator for 24 hours.
[0917] Each coated capture-antibody ELISA plate undergoes
4.times.250 uL/well Phosphate-buffered saline with 0.05%
Tween.RTM.-20 SigmaUltra (PBS-T; Fluka, cat#79383/Sigma-Aldrich
Co., cat#P7949) washes. The ELISA plates are then overlaid with 120
uL/well PBS-T supplemented with 1% Bovine Serum Albumin
Diluent/Blocking solution (BSA; Kirkegaard & Perry Laboratories
(KPL), Inc., cat#50-61-01) and incubate at room-temperature on an
orbital shaker for a minimum of 2 hours.
[0918] Rat Abeta.sub.1.fwdarw.42 and rat Abeta.sub.1.fwdarw.40
peptide (American Peptide Co., cat#62-0-84/62-0-86A) DMSO stock
solutions are serially-diluted 1:2 in FM yielding a final
concentration range of 0-500 pg/mL, to be plated on the respective
ELISA plates for determination of the corresponding standard curve,
from which concentrations of specific or total Abeta peptides in
the presence of a particular drug concentration can be calculated.
The conditioned medium from the duplicate culture plates are
collected and combined into one round-bottom 96-well transfer plate
which is incubated on wet-ice. The culture plates are rinsed once
with 120 ul/well FM, and replenished immediately with 100 uL/well
FM, being returned to the incubator for 10 minutes. Cell-viability
is evaluated by adding 20 uL/well of warmed CellTiter 96.RTM.
Aq.sub.ueous One Solution (MTS/PES; Promega Corp., cat#G3581), and
returning the plates to the incubator for 30-90 minutes. Plate
absorbance at 492 nm is read on a spectrophotometer, and from
which, the ratio of absorbance of compound-treated cells to
absorbance of solvent (DMSO)-treated control cells is calculated.
The calculation of the corresponding EC.sub.50 values is performed
following non-linear curve-fitting using GraphPad Prism.RTM.
software.
[0919] For each ELISA plate, a corresponding transfer-plate is
created containing 120 uL/well of either the rat
Abeta.sub.1.fwdarw.42 or rat Abeta.sub.1.fwdarw.40 peptide standard
solutions, in duplicate, and 110-115 uL/well of the collected
conditioned-medium plate, half designated for the
Abeta.sub.1.fwdarw.42 ELISA, and the other half for the
Abeta.sub.1.fwdarw.x ELISA. The ELISA plates undergo a second set
of 4.times.250 uL/well PBS-T washes, immediately followed by being
overlaid with their designated transfer-plate. The ELISA plates
incubate on an orbital-shaker for 16-18 hours at 4.degree. C.
[0920] Detection antibody solution is prepared by diluting
beta-Amyloid 17-24 (4G8) biotinylated monoclonal antibody (Covance,
Inc., cat#SIG-39240-200) 1:1500 in PBS-T supplemented with 0.67%
BSA. The ELISA plates undergo 4.times.250 uL/well PBS-T washes, and
are overlaid with 100 uL/well of 4G8 diluted detection-antibody
solution. The Abeta.sub.1.fwdarw.42 ELISA plates are incubated on
an orbital-shaker at room-temperature for 90 minutes, the
Abeta.sub.1.fwdarw.x ELISA plates for 60 minutes.
[0921] In order to conjugate the biotinylated monoclonal 4G8
antibody, following 4.times.250 uL/well PBS-T washes, the ELISA
plates undergo a one-hour incubation at 100 ul/well with a 1:15000
dilution of Streptavidin-HRP conjugate (Jackson ImmunoResearch
Laboratories, Inc., cat#016-030-0840) on an orbital-shaker at room
temperature.
[0922] Following a final set of 4.times.250 uL/well PBS-T washes,
the ELISA plates are overlaid with 100 ul/well SureBlue
3,3',5,5'-Tetramethylbenzidine (TMB) Microwell Peroxidase substrate
solution (Kirkegaard & Perry Laboratories, Inc., cat#52-00-02),
protected from light, and incubate for 20-45 minutes at room
temperature. At the point the desired level of development is
attained, 100 ul/well of TMB Stop solution (Kirkegaard & Perry
Laboratories, Inc., cat#50-85-05) is added, and the plate
thoroughly shaken in preparation for reading on a
spectrophotometer. SureBlue TMB Microwell Substrate develops a deep
blue color in the presence of a peroxidase-labeled conjugate, and
turns yellow when stopped by acidification, allowing for plate
absorbance at 450 nm to be read. From the calculation of the
standard curve, the compound dose-response curves, normalized to
DAPT performance, are plotted as % DMSO using GraphPad Prism.RTM.
software, and the corresponding EC.sub.50 values calculated.
Measurement of A.beta.42 In Vivo
[0923] Compounds of the invention can be used to treat AD in mammal
such as a human or alternatively in a validated animal model such
as the mouse, rat, or guinea pig. The mammal may not be diagnosed
with AD, or may not have a genetic predisposition for AD, but may
be transgenic such that it overproduces and eventually deposits
A.beta. in a manner similar to that seen in the human.
Additionally, non-transgenic animals may also be used to determine
the biochemical efficacy of the compound, with an appropriate
assay.
[0924] Compounds can be administered in any standard form using any
standard method. For example, but not limited to, compounds can be
in the form of liquid, tablets or capsules that are taken orally or
by injection. Compounds can be administered at any dose that is
sufficient to significantly reduce, for example, levels of
A.beta..sub.total or more specifically A.beta..sub.42 in the blood
plasma, cerebrospinal fluid (CSF), or brain.
[0925] To determine whether acute administration of the compound
would reduce A.beta..sub.42 levels in-vivo, two-three month old
Tg2576 transgenic mice expressing APP.sub.695 containing the
"Swedish" variant could be used or any other appropriately
validated transgenic model. This transgenic mouse displays
spontaneous, progressive accumulation of .beta.-amyloid (A.beta.)
in brain, eventually resulting in amyloid plaques within the
subiculum, hippocampus and cortex. Animals of this age have high
levels of A.beta. in the brain but no detectable A.beta.
deposition. Mice treated with the compound would be examined and
compared to those untreated or treated with vehicle and brain
levels of soluble A.beta.42 and total A.beta. would be quantitated
by standard techniques, for example, using ELISA. Treatments may be
acute or sub-chronic and treatment periods may vary from hours to
days or longer and can be adjusted based on the results of the
biochemical endpoint once a time course of onset of effect can be
established.
[0926] A typical protocol for measuring A.beta. or A.beta..sub.42
levels from in-vivo samples is shown but it is only one of many
variations that could used to detect the levels of A.beta.. For
example, aliquots of compounds can be dissolved in DMSO (volume
equal to 1/10th of the final formulation volume), vortexed and
further diluted (1:10) with a 10% (w/v) hydroxypropyl 13
cyclodextrin (HBC, Aldrich, Ref N.sup.o 33, 260-7) solution in PBS,
where after they are sonicated for 20 seconds.
[0927] Compounds may be administered as a single oral dose given
three to four hours before sacrifice and subsequent analysis or
alternatively could be given over a course of days and the animals
sacrificed three to four hours after the administration of the
final dose
[0928] Tg2576 mice can be anesthetized with a mixture of
ketamine/xylazine (80/16 mg/kg intraperitoneally). When a deep
level of anesthesia is reached, the mouse's head is secured in a
stereotaxic frame. The skin on the back of the neck is retracted
and the muscles on the back of the neck are removed to expose the
cisterna magna. CSF is collected from the cisterna magna using a
pulled 10 .mu.l micropipette taking care not to contaminate the CSF
with blood. The CSF is immediately diluted 1:10 in 1%
3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate (CHAPS)
[weight per volume in phosphate buffered saline (w/v in
PBS)]containing protease inhibitors (PI's) (Complete, Mini protease
inhibitor cocktail tablets-Roche), quick frozen in liquid nitrogen
and stored at -80.degree. C. until ready for biochemical
analysis.
[0929] Blood is collected via cardiac puncture using a 25 gauge
needle attached to a 1 ml syringe and was dispensed into a 0.6 ml
microtainer tube containing ethylenediaminetetraacetic acid (EDTA).
The blood was centrifuged immediately at 4.degree. C. for 5 minutes
at 1500.times.G. The resulting plasma was aliquoted into 0.5 ml
microcentrifuge tubes, the aliquots are quick frozen in liquid
nitrogen and are stored at -80.degree. C.
[0930] The brain is removed after removing the skull and is rinsed
with PBS. The cerebellum/brain-stem is removed, frozen, and
retained for drug exposure analysis; the remaining brain section
was quartered. The rear right quarter, which contained cortex and
hippocampus, is weighed, frozen in liquid nitrogen and stored at
-80.degree. C. until ELISA analysis. The remaining brain tissue is
frozen in liquid nitrogen and stored at -80.degree. C.
[0931] For total A.beta. or A.beta..sub.40 analysis brain tissue is
homogenized at a volume of 24 ml/g in cold 1% CHAPS containing
protease inhibitors and the resulting homogenates are centrifuged
for 1 hour at 100,000.times.g at 4.degree. C. The supernatant is
removed and transferred to a fresh tube and further diluted to 240
ml/g in CHAPS with protease inhibitors.
[0932] For A.beta..sub.42 analysis brain tissue is homogenized at a
volume of 50 ml/g in cold 1% CHAPS containing PI's. Homogenates
were spun for 1 hour at 100,000.times.g at 4.degree. C. The
supernatant is removed and transferred to a fresh tube and further
to diluted to a final volume 66.7 ml/g in 1% CHAPS with protease
inhibitors.
[0933] To quantify the amount of human A.beta..sub.42 in the
soluble fraction of the brain homogenates, commercially available
Enzyme-Linked-Immunosorbent-Assay (ELISA) kits can be used (h
Amyloid A.beta.42 ELISA high sensitive, The Genetics Company,
Zurich, Switzerland is just one of many examples). The ELISA is
performed according to the manufacturer's protocol. Briefly, the
standard (a dilution of synthetic A.beta.1-42) and samples are
prepared in a 96-well polypropylene plate without protein binding
capacity (Greiner bio-one, Frickenhausen, Germany). The standard
dilutions with final concentrations of 1000, 500, 250, 125, 62.5,
31.3 and 15.6 pg/ml and the samples are prepared in the sample
diluent, furnished with the ELISA kit, to a final volume of 60
.mu.l. Samples, standards and blanks (50 .mu.l) are added to the
anti-A.beta.-coated polystyrol plate (capture antibody selectively
recognizes the C-terminal end of the antigen) in addition with a
selective anti-A.beta.-antibody conjugate (biotinylated detection
antibody) and incubated overnight at 4.degree. C. in order to allow
formation of the antibody-Amyloid-antibody-complex. The following
day, a Streptavidine-Peroxidase-Conjugate is added, followed 30
minutes later by an addition of TMB/peroxide mixture, resulting in
the conversion of the substrate into a colored product. This
reaction is stopped by the addition of sulfuric acid (1M) and the
color intensity is measured by means of photometry with an
ELISA-reader with a 450 nm filter. Quantification of the A.beta.
content of the samples is obtained by comparing absorbance to a
standard curve made with synthetic A.beta.1-42.
[0934] Similar analysis, with minor modification, can be carried
out with CSF (Diluted 1:10 (for a final loading dilution of 1:100)
in 1% CHAPS containing PI and plasma samples (Diluted 1:15 in 0.1%
CHAPS [w/v in PBS]).
[0935] Certain compounds of the disclosure may lower A.beta.42 by
>15%, in some cases certain compounds may lower A.beta.42
>25% and in further cases certain compounds may lower A.beta.42
>40% relative to basal levels.
In Vivo Studies (Rats)
[0936] Male Sprague Dawley rats from Harlan, 230-350 g, were used
for studies. Fasted rats were dosed via oral gavage, with vehicle
(15% Solutol HS 15, 10% EtOH, 75% Water) or compound, at a volume
of 10 ml/kg. For PK studies, at fixed time points after dosing, the
rats were euthanized with an excess of CO.sub.2. Terminal blood was
collected through cardiac puncture, mixed in EDTA tubes,
immediately spun (3 min at 11,000 rpm at 4.degree. C.), and snap
frozen for plasma collection. A piece of frontal cortex was
collected and snap frozen for compound level determination. For
A-beta lowering studies, at a determined time point after dosing
(Cmax if it is .gtoreq.3 hr), rats were euthanized as in the PK
studies and plasma was collected as described above. Cerebellum was
removed and saved for compound level determination, and the
remaining brain was divided into 4 quadrants, snap frozen and saved
to examine A-beta peptide levels. Solutol HS 15 was purchased from
Mutchler Inc.
[0937] Practitioners will also know that similar methods can also
be applied to other species such as mice (including transgenic
strains such as Tg2576), guinea pig, dog and monkey.
Analysis of In Vivo A.beta. Lowering Studies
[0938] Compounds of the invention can be used to treat AD in mammal
such as a human or alternatively in a validated animal model such
as the mouse, rat, or guinea pig. The mammal may not be diagnosed
with AD, or may not have a genetic predisposition for AD, but may
be transgenic such that it overproduces and eventually deposits
A.beta. in a manner similar to that seen in the human.
Alternatively, non-transgenic animals may also be used to determine
the biochemical efficacy of the compound, that is, the effect on
the A.beta. biomarker, with an appropriate assay.
[0939] Compounds can be administered in any standard form using any
standard method. For example, but not limited to, compounds can be
in the form of liquid, tablets or capsules that are taken orally or
by injection. Compounds can be administered at any dose that is
sufficient to significantly reduce, for example, levels of
A.beta..sub.total or more specifically A.beta..sub.42 in the blood
plasma, cerebrospinal fluid (CSF), or brain.
[0940] To determine whether acute administration of the compound
would reduce A.beta..sub.42 levels in-vivo, two-three month old
non-transgenic Sprague-Dawley rats were used. Rats treated with the
compound would be examined and compared to those untreated or
treated with vehicle and brain levels of soluble A.beta..sub.42 and
A.beta..sub.total would be quantitated by standard techniques, for
example, using an immunoassay such as an ELISA. Treatments may be
acute or sub-chronic and treatment periods may vary from hours to
days or longer and can be adjusted based on the results of the
biochemical endpoint once a time course of onset of effect can be
established.
[0941] A typical protocol for measuring A.beta. or A.beta..sub.42
levels from in-vivo samples is shown but it is only one of many
variations that could used to detect the levels of A.beta..
[0942] Compounds may be administered as a single oral dose given
three to four hours before sacrifice and subsequent analysis or
alternatively could be given over a course of days and the animals
sacrificed three to four hours after the administration of the
final dose.
[0943] For total A.beta. or A.beta..sub.42 analysis brain tissue is
homogenized in ten volumes of ice cold 0.4% DEA/50 mM NaCl
containing protease inhibitors, e.g., for 0.1 g of brain 1 ml of
homogenization buffer is added. Homogenization is achieved either
by sonciation for 30 seconds at 3-4W of power or with a polytron
homogenizer at three-quarters speed for 10-15 seconds. Homogenates
(1.2 ml) are transferred to pre-chilled centrifuge tubes (Beckman
343778 polycarbonate tubes) are placed into a Beckman TLA120.2
rotor. Homogenates are centrifuged for 1 hour at 100,000 rpm
(355,040.times.g) at 4.degree. C. The resulting supernatants are
transferred to fresh sample tubes and placed on ice (the pellets
are discarded).
[0944] The samples are further concentrated and purified by passage
over Waters 60 mg HLB Oasis columns according to the methods
described (Lanz and Schachter (2006) J. Neurosci Methods.
157(1):71-81; Lanz and Schachter (2008). J. Neurosci Methods.
169(1):16-22). Briefly, using a vacuum manifold (Waters#WAT200607)
the columns are attached and conditioned with 1 ml of methanol at a
flow rate of 1 ml/minute. Columns are then equilibrated with 1 ml
of water. Samples are loaded (800 .mu.l) into individual columns
(the A.beta. will attach to the column resin).
[0945] The columns are washed sequentially with 1 ml of 5% methanol
followed by 1 ml of 30% methanol. After the final wash the eluates
are collected in 13.times.100 mm tubes by passing 800 .mu.l of
solution of 90% methanol/2% ammonium hydroxide) over the columns at
1 ml/minute. The samples are transferred to 1.5 ml non-siliconized
sample tubes are dried in a speed-vac concentrator at medium heat
for at least 2 hours or until dry.
[0946] The dried samples are either stored at -80.degree. C. or are
used immediately by resuspending the pellets in 80 .mu.l of
Ultra-Culture serum-free media (Lonza) supplemented with protease
inhibitors by vortexing for 10 seconds. Sixty microliters of each
sample is transferred to a pre-coated immunoassay plate coated with
an affinity purified rabbit polyclonal antibody specific to
A.beta..sub.42 (x-42). Sixty microliters of fresh supplemented
ultraculture is added to the remaining sample and 60 microliters is
transferred to a pre-coated and BSA blocked immunoassay plate
coated with an affinity purified rabbit polyclonal antibody
specific to total rodent A.beta. (1-x). Additional standard samples
of rodent A.beta./rodent A.beta..sub.42 are also added to the
plates with final concentrations of 1000, 500, 250, 125, 62.5, 31.3
and 15.6 pg/ml. The samples are incubated overnight at 4.degree. C.
in order to allow formation of the
antibody-Amyloid-antibody-complex. The following day the plates are
washed 3-4 times with 150 microliters of phosphate buffered saline
containing 0.05% Tween 20. After removal of the final wash 100
.mu.l of the monoclonal antibody 4G8 conjugated to biotin (Covance)
diluted 1:1000 in PBS-T containing 0.67% BSA was added and the
plates incubated at room temperature for 1-2 hours. The plates are
again washed 3-4 times with PBS-T and 100 .mu.l of a
Streptavidin-Peroxidase-Conjugate diluted 1:10,000 from a 0.5 mg/ml
stock in PBS-T contained 0.67% BSA is added and the plates
incubated for at least 30 minutes. Following a final set of washes
in PBS-T, a TMB/peroxide mixture is added, resulting in the
conversion of the substrate into a colored product. This reaction
is stopped by the addition of sulfuric acid (1M) and the color
intensity is measured by means of photometry with an microplate
reader with a 450 nm filter. Quantification of the A.beta. content
of the samples is obtained by comparing absorbance to a standard
curve made with synthetic A.beta.. This is one example of a number
of possible measurable endpoints for the immunoassay which would
give similar results.
[0947] FIG. 1 demonstrates the desirable effect on A.beta. after
the administration of example 1301
(2-(5-chloro-4'-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclo-
propylpropanoic acid) to in C57BL/6 mice when give one dose at 30
mg/kg in a Solutol HS 15:Ethanol:Water (15:10:75) formulation
(measuring A.beta. at 3 hours).
Pharmacokinetic Analysis
Sample Preparation
[0948] Plasma samples and standards were prepared for analysis by
treating with a 3.times. volume of acetonitrile containing 500
ng/mL of internal standard (a selected aryl propionic acid).
Typically 150 .mu.L of acetonitrile with internal standard was
added to 50 .mu.L of plasma. Acetonitrile was added first to each
well of a 96-well Phenomenex Strata Impact protein precipitation
filter plate followed by the addition of the plasma sample or
standard. The filter plate was allowed to sit for at least 15
minutes at room temperature before a vacuum was applied to filter
the samples into a clean 96-well plate.
[0949] If sample concentrations were observed or predicted to be
greater than 1000 ng/mL, plasma samples were diluted with blank
plasma 10-150 fold depending on the anticipated concentration and
upper limit of quantitation of the analytical method.
[0950] Samples of frontal cortex or cerebellum were homogenized
then treated in similar manner. To each brain sample, a 4.times.
volume of PBS (pH 7.4) buffer was added along with a 15.times.
volume of acetonitrile (containing internal standard) in a 2 mL
screw-cap plastic tube. The tubes were then filled one third of the
way with 1 mm zirconia/silica beads (Biospec) and placed in a Mini
Bead Beater for 3 minutes. The samples were inspected and if any
visible pieces of brain remained, they were returned to the Bead
Beater for another 2-3 minutes of shaking. The resulting suspension
was considered to be a 5-fold dilution treated with a 3.times.
volume of acetonitrile (with internal standard). Calibration
standards were prepared in 5-fold diluted blank brain homogenate
and precipitated with a 3.times. volume of acetonitrile immediately
after the addition of the appropriate spiking solution (see below).
All brain standards and samples were allowed to sit for at least 15
minutes prior to filtering them through a Phenomenex Strata Impact
protein precipitation filter plate into a clean 96-well plate.
[0951] Spiking solutions for plasma and brain calibration standards
were prepared at concentrations of 0.02, 0.1, 0.2, 1, 2, 10, 20,
100 and 200 .mu.g/mL in 50:50 acetonitrile/water. Calibration
standards were prepared by taking 190 .mu.L of blank matrix (plasma
or brain homogenate) and adding 10 .mu.L of spiking solution
resulting in final concentrations of 1, 5, 10, 50, 100, 500, 1000,
5000 and 10,000 ng/mL.
LC-MS/MS Analysis
[0952] Precipitated plasma and brain samples were analyzed by
LC-MS/MS using a Shimadzu LC system consisting of two LC-10AD pumps
and a SIL-HTc autosampler connected to an Applied Biosystems
MDS/Sciex API 3200 QTRAP mass spectrometer.
[0953] For chromatographic separation, a Phenomenex Luna C-18 3
.mu.M (2.times.20 mm) column was used with an acetonitrile-based
gradient mobile phase. The two mobile phase components were:
[0954] Mobile phase A: water with 0.05% (v/v) formic acid and 0.05%
(v/v) 5 N ammonium hydroxide.
[0955] Mobile phase B: 95:5 acetonitrile/water with 0.05% (v/v)
formic acid and 0.05% (v/v) 5 N ammonium hydroxide.
[0956] The gradient for each analysis was optimized for the
specific compound, but generally, the run started with between 0%
and 40% of mobile phase B, ramped up to 100% of mobile phase B over
1-2 minutes, then held there for 2-3 minutes before returning to
the initial conditions for 4 minutes to re-equilibrate.
[0957] The API 3200 QTRAP mass spectrometer was used in MRM mode
with negative electrospray ionization. MRM transitions and mass
spec settings were optimized for each compound.
[0958] Standard curves were created by quadratic or linear
regression with 1/x*x weighting. Calibration standards were
prepared 1-10,000 ng/mL, but the highest (and sometimes lowest)
standards were often not acceptable for quantitation and only those
standards with reasonable back-calculated accuracies were included
in the calibration curve. Ideally, only standards with +/-15% of
nominal concentration would be included in the fitted standard
curve, but occasionally larger deviations were accepted after
careful consideration. Sample concentrations below the quantitation
range were reported as "BQL". Concentrations above the curve were
usually re-run with larger sample dilutions
Glucuronidation Protocols
[0959] Microsomal glucuronidation reactions were conducted using
the UGT Reaction Mix solutions (A and B) from BD Biosciences and
following the vendor's protocol. 10 .mu.M of test article or
control compound was incubated with 0.5 mg/mL of human or rat liver
microsomes. Samples were taken at 0 and 60 minutes and acetonitrile
was added to terminate the reactions. Samples were analyzed by
LC/MS, monitoring for the loss of parent compound and the
appearance of glucuronide. Control reactions were run for each
compound substituting water for the glucuronic acid solution to
monitor for any loss of parent compound due to degradation or
unanticipated microsomal reactions.
[0960] Hepatocyte experiments were run using cryopreserved human
hepatocytes (single donor) obtained from Celsis/In Vitro
Technologies. Cells were thawed and counted according to the
vendor's protocols using the trypan blue exclusion method to obtain
the count of live cells. Test article and control compounds were
incubated at a concentration of 5 uM in KHB buffer (Celsis/In Vitro
Technologies) containing 1 million cells per mL. Samples were taken
at 0, 60 and 120 minutes. The reactions were terminated with
addition of acetonitrile. Samples were analyzed by LC/MS,
monitoring for the loss of parent compound and the appearance of
glucuronide.
Pharmacology
[0961] Compounds of the disclosure are gamma secretase modulators
(GSMs), i.e., compounds that act to shift the relative levels of
A.beta. peptides produced by .gamma.-secretase. In some cases the
compounds alter the relative levels of A.beta. peptides produced by
.gamma.-secretase without significantly changing the total level of
A.beta. peptides produced. Certain compounds of the disclosure
modulate .gamma.-secretase activity with respect to APP proteolytic
processing and in so doing lower the production of A.beta..sub.42
both in vitro in cells and in vivo in animals. In some cases this
effect occurs at concentrations that do not significantly impair
the viability of cells in vitro and at doses that are well
tolerated in vivo. Certain compounds of the disclosure lower
A.beta..sub.42 secretion in native neuronal and cellular construct
assay systems with EC.sub.50 values that are below 1 micromolar
(Class A compounds, Table 14) while others have EC.sub.50 values
from 1-5 micromolar (Class B compounds, Table 14) and others have
EC.sub.50 values greater than 5 micromolar (Class C compounds).
Certain compounds of the disclosure do not appear to significantly
interfere with .gamma.-secretase related Notch processing activity.
Compounds that significantly interfere with .gamma.-secretase
related Notch processing activity have been associated with toxic
side-effects. Certain compounds of the disclosure have favorable
pharmacokinetic (PK) properties in animals. Thus, certain of the
compounds are orally bioavailable, penetrate into the brain and
have favorable PK parameters including half-life and clearance
supporting pharmaceutical application in humans. In turn, certain
compounds of the disclosure significantly lower A.beta..sub.42
production in the brains of non-transgenic and transgenic animals
after single dose and multi-dose oral administration with no overt
side effects. For certain compounds of the disclosure single oral
doses of <30 milligrams/kilogram are efficacious at lowering
A.beta..sub.42 production in the brains of rats (e.g.
Sprague-Dawley) and wild type mice (e.g. C57BL/6). Certain
compounds of the disclosure which lower A.beta..sub.42 at doses of
<30 milligrams/kilogram appear to be well tolerated and show no
overt or clinical chemical toxicity after subchronic 14-day
administration at doses >30 milligrams/kilogram/day. Certain
compounds of the disclosure have favorable
absorption-distribution-metabolism and excretion (ADME) properties.
Moreover, certain compounds of the disclosure do not appear to
significantly bio-accumulate in tissues especially in the brain.
Compounds of Formulas I-IX wherein A=CO.sub.2H show favorable
profiles with respect to acylglucoronide (A=CO.sub.2Glu) metabolite
formation. The potential for acylglucoronide metabolites to cause
of toxicity has been described particularly for non-steroidal
anti-inflammatory drugs (NSAIDs) containing carboxylic acid groups
(Ebner et al Drug Metabolism and Disposition 1999, 27(10),
1143-49). Several such NSAIDs have been removed from the market due
to idiosyncratic toxicity in humans and it has been speculated that
NSAID idiosyncratic toxicity is related to the relative load and
relative reactivity of acylglucoronide metabolites. Therefore,
carboxylic acid compounds which are less prone to acylgluconoride
formation are expected to be less toxic. As measured using
established in vitro assay systems, certain desirable compounds of
the disclosure are less prone to acylglucoronidation than NSAID
compounds that remain on the market are regarded as safe (e.g.,
flurbiprofen).
Dosage and Administration
[0962] The present disclosure includes pharmaceutical composition
for treating a subject having a neurological disorder comprising a
therapeutically effective amount of a compound of Formulas I-IX, a
derivative or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient, carrier or diluent.
[0963] The pharmaceutical compositions can be administered in a
variety of dosage forms including, but not limited to, a solid
dosage form or in a liquid dosage form, an oral dosage form, a
parenteral dosage form, an intranasal dosage form, a suppository, a
lozenge, a troche, buccal, a controlled release dosage form, a
pulsed release dosage form, an immediate release dosage form, an
intravenous solution, a suspension or combinations thereof. The
dosage can be an oral dosage form that is a controlled release
dosage form. The oral dosage form can be a tablet or a caplet. The
compounds can be administered, for example, by oral or parenteral
routes, including intravenous, intramuscular, intraperitoneal,
subcutaneous, transdermal, airway (aerosol), rectal, vaginal and
topical (including buccal and sublingual) administration. In one
embodiment, the compounds or pharmaceutical compositions comprising
the compounds are delivered to a desired site, such as the brain,
by continuous injection via a shunt.
[0964] In another embodiment, the compound can be administered
parenterally, such as intravenous (i.v.) administration. The
formulations for administration will commonly comprise a solution
of the compound of the Formulas I-IX dissolved in a
pharmaceutically acceptable carrier. Among the acceptable vehicles
and solvents that can be employed are water and Ringer's solution,
an isotonic sodium chloride. In addition, sterile fixed oils can
conventionally be employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid can likewise be used in the preparation of injectables.
These solutions are sterile and generally free of undesirable
matter. These formulations may be sterilized by conventional, well
known sterilization techniques. The formulations may contain
pharmaceutically acceptable auxiliary substances as required to
approximate physiological conditions such as pH adjusting and
buffering agents, toxicity adjusting agents, e.g., sodium acetate,
sodium chloride, potassium chloride, calcium chloride, sodium
lactate and the like. The concentration of compound of Formulas
I-IX in these formulations can vary widely, and will be selected
primarily based on fluid volumes, viscosities, body weight, and the
like, in accordance with the particular mode of administration
selected and the patient's needs. For i.v. administration, the
formulation can be a sterile injectable preparation, such as a
sterile injectable aqueous or oleaginous suspension. This
suspension can be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparation can also be a sterile injectable
solution or suspension in a nontoxic parenterally-acceptable
diluent or solvent, such as a solution of 1,3-butanediol.
[0965] In one embodiment, a compound of Formulas I-IX can be
administered by introduction into the central nervous system of the
subject, e.g., into the cerbrospinal fluid of the subject. The
formulations for administration will commonly comprise a solution
of the compound of Formulas I-IX dissolved in a pharmaceutically
acceptable carrier. In certain aspects, the compound of Formulas
I-IX is introduced intrathecally, e.g., into a cerebral ventricle,
the lumbar area, or the cisterna magna. In another aspect, the
compound of Formulas I-IX is introduced intraocullarly, to thereby
contact retinal ganglion cells.
[0966] The pharmaceutically acceptable formulations can easily be
suspended in aqueous vehicles and introduced through conventional
hypodermic needles or using infusion pumps. Prior to introduction,
the formulations can be sterilized with, preferably, gamma
radiation or electron beam sterilization.
[0967] In one embodiment, the pharmaceutical composition comprising
a compound of Formulas I-IX is administered into a subject
intrathecally. As used herein, the term "intrathecal
administration" is intended to include delivering a pharmaceutical
composition comprising a compound of Formulas I-IX directly into
the cerebrospinal fluid of a subject, by techniques including
lateral cerebroventricular injection through a burrhole or
cisternal or lumbar puncture or the like (described in Lazorthes et
al. Advances in Drug Delivery Systems and Applications in
Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1:
169-179, the contents of which are incorporated herein by
reference). The term "lumbar region" is intended to include the
area between the third and fourth lumbar (lower back) vertebrae.
The term "cisterna magna" is intended to include the area where the
skull ends and the spinal cord begins at the back of the head. The
term "cerebral ventricle" is intended to include the cavities in
the brain that are continuous with the central canal of the spinal
cord. Administration of a compound of Formulas I-IX to any of the
above mentioned sites can be achieved by direct injection of the
pharmaceutical composition comprising the compound of Formulas I-IX
or by the use of infusion pumps. For injection, the pharmaceutical
compositions can be formulated in liquid solutions, preferably in
physiologically compatible buffers such as Hank's solution or
Ringer's solution. In addition, the pharmaceutical compositions may
be formulated in solid form and re-dissolved or suspended
immediately prior to use. Lyophilized forms are also included. The
injection can be, for example, in the form of a bolus injection or
continuous infusion (e.g., using infusion pumps) of pharmaceutical
composition.
[0968] In one embodiment, the pharmaceutical composition comprising
a compound of Formulas I-IX is administered by lateral cerebro
ventricular injection into the brain of a subject. The injection
can be made, for example, through a burr hole made in the subject's
skull. In another embodiment, the encapsulated therapeutic agent is
administered through a surgically inserted shunt into the cerebral
ventricle of a subject. For example, the injection can be made into
the lateral ventricles, which are larger, even though injection
into the third and fourth smaller ventricles can also be made.
[0969] In yet another embodiment, the pharmaceutical composition is
administered by injection into the cisterna magna, or lumbar area
of a subject.
[0970] For oral administration, the compounds will generally be
provided in unit dosage forms of a tablet, pill, dragee, lozenge or
capsule; as a powder or granules; or as an aqueous solution,
suspension, liquid, gels, syrup, slurry, etc. suitable for
ingestion by the patient. Tablets for oral use may include the
active ingredients mixed with pharmaceutically acceptable
excipients such as inert diluents, disintegrating agents, binding
agents, lubricating agents, sweetening agents, flavoring agents,
coloring agents and preservatives. Suitable inert diluents include
sodium and calcium carbonate, sodium and calcium phosphate, and
lactose, while corn starch and alginic acid are suitable
disintegrating agents. Binding agents may include starch and
gelatin, while the lubricating agent, if present, will generally be
magnesium stearate, stearic acid or talc. If desired, the tablets
may be coated with a material such as glyceryl monostearate or
glyceryl distearate, to delay absorption in the gastrointestinal
tract.
[0971] Pharmaceutical preparations for oral use can be obtained
through combination of a compound of Formulas I-IX with a solid
excipient, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable additional
compounds, if desired, to obtain tablets or dragee cores. Suitable
solid excipients in addition to those previously mentioned are
carbohydrate or protein fillers that include, but are not limited
to, sugars, including lactose, sucrose, mannitol, or sorbitol;
starch from corn, wheat, rice, potato, or other plants; cellulose
such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium
carboxymethylcellulose; and gums including arabic and tragacanth;
as well as proteins such as gelatin and collagen. If desired,
disintegrating or solubilizing agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt
thereof, such as sodium alginate.
[0972] Capsules for oral use include hard gelatin capsules in which
the active ingredient is mixed with a solid diluent, and soft
gelatin capsules wherein the active ingredients is mixed with water
or an oil such as peanut oil, liquid paraffin or olive oil.
[0973] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0974] For transmucosal administration (e.g., buccal, rectal,
nasal, ocular, etc.), penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0975] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate. Formulations suitable for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing in addition to
the active ingredient such carriers as are known in the art to be
appropriate. For intramuscular, intraperitoneal, subcutaneous and
intravenous use, the compounds will generally be provided in
sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Aqueous suspensions
may include suspending agents such as cellulose derivatives, sodium
alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting
agent such as lecithin. Suitable preservatives for aqueous
suspensions include ethyl and n-propyl p-hydroxybenzoate.
[0976] The suppositories for rectal administration of the drug can
be prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid at the
rectal temperatures and will therefore melt in the rectum to
release the drug. Such materials are cocoa butter and polyethylene
glycols.
[0977] The compounds can be delivered transdermally, by a topical
route, formulated as applicator sticks, solutions, suspensions,
emulsions, gels, creams, ointments, pastes, jellies, paints,
powders, or aerosols.
[0978] The compounds may also be presented as aqueous or liposome
formulations. Aqueous suspensions can contain a compound of
Formulas I-IX in admixture with excipients suitable for the
manufacture of aqueous suspensions. Such excipients include a
suspending agent, such as sodium carboxymethylcellulose,
methylcellulose, hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
monooleate). The aqueous suspension can also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for osmolarity.
[0979] Oil suspensions can be formulated by suspending a compound
of Formulas I-IX in a vegetable oil, such as arachis oil, olive
oil, sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin; or a mixture of these. The oil suspensions can contain a
thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
Sweetening agents can be added to provide a palatable oral
preparation, such as glycerol, sorbitol or sucrose. These
formulations can be preserved by the addition of an antioxidant
such as ascorbic acid. As an example of an injectable oil vehicle,
see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The
pharmaceutical formulations can also be in the form of oil-in-water
emulsions. The oily phase can be a vegetable oil or a mineral oil,
described above, or a mixture of these. Suitable emulsifying agents
include naturally-occurring gums, such as gum acacia and gum
tragacanth, naturally occurring phosphatides, such as soybean
lecithin, esters or partial esters derived from fatty acids and
hexitol anhydrides, such as sorbitan mono-oleate, and condensation
products of these partial esters with ethylene oxide, such as
polyoxyethylene sorbitan mono-oleate. The emulsion can also contain
sweetening agents and flavoring agents, as in the formulation of
syrups and elixirs. Such formulations can also contain a demulcent,
a preservative, or a coloring agent.
[0980] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation or
transcutaneous delivery (e.g., subcutaneously or intramuscularly),
intramuscular injection or a transdermal patch. Thus, for example,
the compounds may be formulated with suitable polymeric or
hydrophobic materials (e.g., as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble derivatives, for
example, as a sparingly soluble salt.
[0981] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0982] For administration by inhalation, the compounds are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g., gelatin for use in an inhaler or insufflator
may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0983] In general a suitable dose will be in the range of 0.01 to
100 mg per kilogram body weight of the recipient per day,
preferably in the range of 0.2 to 10 mg per kilogram body weight
per day. The desired dose is preferably presented once daily, but
may be dosed as two, three, four, five, six or more sub-doses
administered at appropriate intervals throughout the day.
[0984] The compounds can be administered as the sole active agent,
or in combination with other known therapeutics to be beneficial in
the treatment of neurological disorders. In any event, the
administering physician can provide a method of treatment that is
prophylactic or therapeutic by adjusting the amount and timing of
drug administration on the basis of observations of one or more
symptoms (e.g., motor or cognitive function as measured by standard
clinical scales or assessments) of the disorder being treated.
[0985] Details on techniques for formulation and administration are
well described in the scientific and patent literature, see, e.g.,
the latest edition of Remington's Pharmaceutical Sciences, Maack
Publishing Co, Easton Pa. ("Remington's After a pharmaceutical
composition has been formulated in an acceptable carrier, it can be
placed in an appropriate container and labeled for treatment of an
indicated condition. For administration of the compounds of
Formulas I-IX, such labeling would include, e.g., instructions
concerning the amount, frequency and method of administration.
* * * * *