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AU734928B2 - 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors - Google Patents
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AU734928B2 - 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors - Google Patents

4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors Download PDF

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AU734928B2
AU734928B2 AU67960/98A AU6796098A AU734928B2 AU 734928 B2 AU734928 B2 AU 734928B2 AU 67960/98 A AU67960/98 A AU 67960/98A AU 6796098 A AU6796098 A AU 6796098A AU 734928 B2 AU734928 B2 AU 734928B2
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dihydro
pyridyl
quinazolinone
trifluoromethyl
compound
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AU6796098A (en
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Jeffrey W. Corbett
Soo Sung Ko
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms

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Description

WO 98/45276 PCT/US98/06733
TITLE
4,4-DISUBSTITUTED-3,4-DIHYDRO-2(1H)-QUINAZOLINONES USEFUL AS HIV REVERSE TRANSCRIPTASE INHIBITORS FIELD OF THE INVENTION This invention relates generally to 4,4-disubstituted- 3,4-dihydro-2(1H)-quinazolinones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.
BACKGROUND OF THE INVENTION Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.
WO 98/45276 PCT/US98/06733 At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: the initial attachment of the virion to the T-4 lymphocyte or macrophage site, the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and the processing of gag-pol protein by HIV protease.
Inhibition .of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that WO 98/45276 PCT/US98/06733 block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxythymidinene (d4T), 2',3'-dideoxyinosine (ddl), and 2',3'-dideoxy-3'-thiacytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
An active area of research is in the discovery of nonnucleoside HIV reverse transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.
U.S. 5,519,021 describe reverse transcriptase inhibitors which are benzoxazinones of the formula:
X
1
R
X
H
wherein X is a halogen, Z may be O.
EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula A:
R
1
R
2
R
3
A
wherein G is a variety of groups, R 3 and R 4 may be H, Z may be 0, R 2 may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R 1 may be a variety of groups including substituted alkyl.
WO 98/45276 PCT/US98/06733 WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R 3 and R 4 may be H, Z may be 0, R 2 is substituted alkenyl or substituted alkynyl, and R 1 is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, chloro-4-cyclopropyl-3,4-dihydro-4 (2-pyridy)ethynyl)-2 (IH)quinazolinone.
Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al, Tetr. Lett. 1994, 35(37), 6811- 6814; Tucker et al, J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al, J. Org. Chem. 1995, 60, 1590-1594.
DE 4,320,347 illustrates quinazolinones of the formula: R
R
3
H
wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.
SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises WO 98/45276 PCT/US98/06733 administering to a host in need thereof a therapeutically effective combination of one of the compounds of the present invention and one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula 12
RR
H
I
wherein R1, R 2
R
3 and R 8 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Thus, in a first embodiment, the present invention provides a novel compound of formula I: .t.
WO 98/45276 PCT/US98/06733 R' R 2
SR
8
R
3 NL 0
H
I
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R
1 is C 1 -3 alkyl substituted with 1-7 halogen;
R
2 is selected from C 1 -5 alkyl substituted with 1-2 R 4 alkenyl substituted with 1-2 R 4 and C2- 5 alkynyl substituted with 1 R 4
R
3 at each occurrence, is independently selected from C 1 -4 alkyl, OH, C1- 4 alkoxy, F, Cl, Br, I, NR5R 5 a, NO 2
CN,
C(O)R
6
NHC(O)R
7 and alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form
R
4 is selected from C 3 5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-5 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R 3
R
5 and R 5a are independently selected from H and C1- 3 alkyl;
R
6 is selected from H, OH, C1- 4 alkyl, C1- 4 alkoxy, and
R
7 is selected from Ci-3 alkyl and C1- 3 alkoxy;
R
8 is selected from H, C 3 -5 cycloalkyl, and C1- 3 alkyl; and, n is selected from 0, 1, 2, 3, and 4.
WO 98/45276 PCT/US98/06733 In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R
1 is C1-3 alkyl substituted with 1-7 halogen;
R
2 is selected from C 1 -5 alkyl substituted with 1 R 4
C
2 alkenyl substituted with 1 R 4 and C2- 5 alkynyl substituted with 1 R 4
R
3 at each occurrence, is independently selected from C1-4 alkyl, OH, C1- 4 alkoxy, F, Cl, Br, I, NR5R 5a
NO
2
CN,
C(O)R
6
NHC(O)R
7 and alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form
R
4 is selected from C3- 5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3
R
5 and R 5 a are independently selected from H, CH 3 and C 2
H
5
R
6 is selected from H, OH, CH 3
C
2
H
5
OCH
3
OC
2
H
5 and
R
7 is selected from CH 3
C
2 H5, OCH 3 and OC 2
H
5
R
8 is selected from H, cyclopropyl, CH 3 and C 2
H
5 and, n is selected from 0, 1, 2, and 3.
In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R
1 is selected from CF 3 and C 2
F
5 WO 98/45276 PCT/US98/06733
R
2 is selected from C1- 3 alkyl substituted with 1 R 4
C
2 -3 alkenyl substituted with 1 R 4 and C 2 -3 alkynyl substituted with 1 R 4
R
3 at each occurrence, is independently selected from CI_3 alkyl, OH, C1- 3 alkoxy, F, Cl, Br, I, NR5R 5 a, N02, CN,
C(O)R
6
NHC(O)R
7 and alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form -OCH 2 0-;
R
4 is selected from C3- 5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3
R
5 and R 5a are independently selected from H, CH 3 and C 2
H
5
R
6 is selected from H, OH, CH 3
C
2
H
5
OCH
3
OC
2
H
5 and NRSR 5 a;
R
7 is selected from CH3, C 2
H
5
OCH
3 and OC 2
H
5
R
8 is selected from H, CH3 and C 2 H5; and, n is selected from 0, 1, and 2.
In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R
1 is CF 3
R
2 is selected from C 1 -3 alkyl substituted with 1 R 4
C
2 -3 alkenyl substituted with 1 R 4 and C2- 3 alkynyl substituted with 1 R 4 WO 98/45276 PCT/US98/06733
R
3 at each occurrence, is independently selected from C1- 3 alkyl, OH, C1- 3 alkoxy, F, Cl, NR 5
R
5 a, NO 2 CN, C(O)R 6
NHC(O)R
7 and NHC(O)NR 5
R
5 a; alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form
R
4 is selected from cyclopropyl substituted with 0-1 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 wherein the heterocyclic system is selected from 2-pyridyl, 3pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2imidazolyl;
R
5 and R 5a are independently selected from H, CH 3 and C 2
H
5
R
6 is selected from H, OH, CH 3
C
2
H
5
OCH
3
OC
2
H
5 and NR 5
R
5 a;
R
7 is selected from CH 3
C
2
H
5
OCH
3 and OC 2
H
5
R
8 is selected from H, CH3 and C 2
H
5 and, n is selected from 1 and 2.
In a further preferred embodiment, wherein the compound is of formula Ia R2
R
8 R N O
H
Ia.
In a further preferred embodiment, wherein the compound is of formula Ib: WO 98/45276 WO 9845276PCTIUS98/06733
H
lb.
In a further preferred embodiment, the compound of formula I is selected from: -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3 ,4dihydro-2 (1H) -quinazolinone; -6-Chloro-4- (2-pyridyl) ethynyl-4-trifluoronethyl-3 .4dihydro-2 (1H) -quinazolinone; -6-Chloro-4-phenylethynyl-4-trifluoromethyl-3, 4-dihydro- 2 (21) -quinazolinone; -4-Cyclopropylethynyl-6-methoxy--4-trifluoromethyl-3 .4dihydro-2 (lH) -quinazolinone; -6-Methoxy-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3 .4dihydro-2 (lH) -quinazolinone; -6-Methoxy-4-phenylethynyl-4-trifluoromethyl-3, 4dihydro-2 (1H) -quinazolinone; -4-Cyclopropylethynyl-5, 6-difluoro-4-trifluoromethyl- 3, 4-dihydro-2 (lH) -quinazolinone; 6-Difluo~ro-4- (2-pyridyl) ethynyl-4-trifluoromethyl- 3, 4-dihydro-2 (1H) -quinazolinone; 6-Difluoro-4-phenylethynyl--4-trifluoromethyl-3 .4dihydro-2 (lH) -quinazolinone; -4-CycloprOPYlethynyl-6-fluoro-4-trifluoromethyl-3 .4dihydro-2 (1H) -quinazolinone; -6-Fluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3, 4dihydro-2 (lH) -quinazolinone; -6-Fluoro-4-phenylethynyl-4-trifluoromethyl-3, 4-dihydro- 2 (li) -quinazolinone; -6-Fl'uoro-4- -2-pyridyl)ethyl--4-trifluoromethyl-3, 4dihydro-2 (1H) -quinatolinone; -6-Fluoro-4-phenylethyl-4-trifluoromethyl-3. 4-dihydro- 2 (1H) -quinazolinone; -6-Chloro-4-cyclopropylethynyl-4 -trifluoromethyl-3 .4dihydro-2 (1H) -quinazolinone; -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4- 40*20dihydro-2(1H)-quinazolinone; -4-Cyclopropylethynyl-5, 6-difluoro-4-trifluoromethyl-3, 4dihydro-2 (1H) -quinazolinone; -4-Cyclopropylethynyl-5, 6-difluoro-4-trifluoromethyl-3, 4dihydro-2 (1H) -quinazolinone; or-4-E-yclopropylethenyldfu-4-trif luoromethyl-4 3, 4didr o-2 (1H) -quazinoone; ad or a0hraetclyacpal atteef 12 Preferably the compound is: (+/-)-6-chloro-4-cyclopropylethynyl-4trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-chloro-4-(2-pyridyl)ethynylA...
trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-chloro-4-phenylethynyl-4trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-4-cyclopropylethynyl-6-methoxy-4trifluoromethyl-3,4-dihydro-2( I H)-qui nazoli none, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+I-)-6-methoxy-4-(2-pyridyl) ethynyl-4trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-methoxy-4-phenylethynyl-4trifl uorom ethyl -3,4-d ihyd ro-2 (1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-4-cyclopropylethynyl-5,6-difluoro-4trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
-13- Preferably the compound is: (+/-)-5,6-difluoro-4-phenylethynyl.4trifluoromethyl-3,4-dihydro-2(1 H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-4-cyclop ropy lethynyl -6-fl uoro-4trifluoromethyl-3,4-dihydro-2( I H)-quinazoli none, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-fluoro-4-(2-pyridyl)ethynyl-4trifl uorom ethyl -3,4-di hydro-2 (1 H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-fluoro-4-phenylethynyl-4trifluoromethyl-3,4-dihydro-2( I H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-fluoro-4-(2'-2-pyridyl)ethyl-4trifluoromethyl-3,4-dihydro-2(1 H)-quinazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+/-)-6-fluoro-4-phenylethyl-4trifluoromethyl-3,4-dihydro-2( I H)-qui nazoli none, or a pharmaceutically acceptable salt form thereof.
25Preferably the compound is: (-)-6-chloro-4-cyclopropylethynyl-4trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
1 3a Preferably the compound is: (+)-4-cyclopropylethynyl-5,6-difluoro4trifiuoromethyl-3,4-dihydro-2( 1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (-)-4-cyclopropylethynyl-5,6-difluoro-4trifluoromethyl-3,4-dihydro-2( I H)-quinazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (+)-E-4-cyclopropylethenyi-5,6-difluoro-4trifluoromethyl-3,4-dihydro-2( 1 H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof.
Preferably the compound is: (-)-6-chloro-4-E-cyclopropylethenyl-4trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
In another more preferred embodiment, the compound is selected from: **(+/-)-6-Chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1
H)
quinazolinone; (+/-)-6-Chloro-4-ethylethynyl.4-rifluoromethyl..3,4-di hydro-2( 1 H)-qui nazol inone; WO 98/45276 PCTIUS98/06733 -4-Isopropylethynyl-6-rnethoxy-4-trifluoromethyl-3 ,4dihydro-2 (li) -quinazolinone; 6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3, 4dihydro-2 (1H) -quinazolinone; 6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3 ,4dihydro-2 (iN)-quinazolinone; (+/-)-5,6-Difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro- 2 (iN)-qtiinazolinone; -6-Fluoro-4-isopropylethynyl-4-trifluoromethyl-3 ,4dihydro-2 (1H) -quinazolinone; -6-Fluoro-4-ethylethynyl-4-trifluoromethyl-3, 4-dihydro- 2 (1H) -quinazolinone; 6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3 ,4dihydro-2 (iN)-quinazolinone; 6-Difluoro-4-isopropylethynyl-4-trifiuoromethyl-3 ,4dihydro-2 (iN)-quiinazolinone; (-)-5,6-Difluoro-4-ethylethynyl-4-trifiuoromethyl-3,4dihydro-2 (1H) -quinazolinone; and, 6-Difluoro-4-ethylethynyl-4-trifluoromethyi-3, 4dihydro-2 (iN)-quinazolinone; or a pharmaceutically acceptable salt thereof.
In a third embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or Ii or pharmaceutically acceptable salt form thereof.
WO 98/45276 PCT/US98/06733 In a fourth embodiment, the present invention provides a novel method for treating HIV-infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.
In a fifth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: a compound of formula I or II; and, at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another preferred embodiment, the reverse transcriptase inhibitor is selected from AZT, 3TC, ddl, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L- 697,661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI- 272, CGP-61755, U-140690, and ABT-378.
In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and .indinavir.
In a still further preferred ebodiment, the reverse transcriptase inhibitor is AZT.
WO 98/45276 PCT/US98/06733 In another still further preferred embodiment, the protease inhibitor is indinavir.
In a sixth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: a compound of formula I or II; and, at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In a seventh embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I or II.
In a eighth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula I or II in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
DEFINITIONS
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
WO 98/45276 PCT/US98/06733 The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, npropyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and spentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v 1 to 3 and w 1 to Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and spentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable WO 98/45276 PCT/US98/06733 point along the chain, such as ethynyl, propynyl and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo. "Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 5- membered monocyclic ring, which may be saturated or partially unsaturated. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 6- membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S. The nitrogen and sulfur heteroatoms may optionally be oxidized.
The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and .0 atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 6- membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total WO 98/45276 PCT/US98/06733 number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not.limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddl, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine (Boehringer Ingelheim), L-697,661, LY 73497, Ro 18,893 (Roche), loviride (Janssen), trovirdine (Lilly), MKC- 442 (Triangle), .and HBY 097 (Hoechst).
As used herein, "HIV protease inhibitor" is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX- 478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), U-140690 WO 98/45276 PCT/US98/06733 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in W093/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
WO 98/45276 PCT/US98/06733 The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in thecompounds of the present invention, and the like.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.
"Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto =O) group, then 2 hydrogens on the atom are replaced.
WO 98/45276 PCTIUS98/06733 "Therapeutically effective amount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is t preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
SYNTHESIS
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.
WO 98/45276 PCT/US98/06733 SCHEME 1
R
3 3 R COOH HN(CH 3 OCH3 R N OCH 3 to2
'CH
3 NH2
NH
2 j TMSC1, base
R
1 IMgX R3
O
R1
NH
2 Scheme 1 illustrates a method of preparing keto-anilines from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R 1 -substituted ketone. The keto-anilines are useful intermediates for the presently claimed compounds.
SCHEME 2 R3 I NaHC03 R Me 3 CCOC1 NaHCO3
NH
NH2 NH2 R3 0
R
3
O
n-BuLi
C
F
3 6N-HC1
CF
3
CF
3
CO
2 Et
NH
2 Scheme 2 describes another method of preparing ketoanilines, this time from an appropriately substituted aniline. After iodination and amine protection, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides the ketoaniline. Additional means of preparing keto-anilines are known to one of skill in the art, e.g, Houpis et al, Tetr.
Lett. 1994, 35(37), 6811-6814, the contents of which are hereby incorporated herein by reference.
WO 98/45276 WO 9845276PCTfUS98/06733 SCHEME 3
R
3
CO
"ZCOO HN (CH 3
OCH
3
NH
2 TrBr, DIPEA IkCN(C3
CH
2 C1 2 Ka N(H)Tr
CF
3 TMS, TBAF OH F THF N(H)Tr
R
3 CON
(OCH
3
CH
3 H3reduction R3 CkCHO N Tr
R
3 0 oxidation
CF
3 N(H)Tr Another method of making 2-trifluoroacetylanilines is shown in Scheme 3. After forming the protected aniline, the amide is then reduced and the trifluoromethyl group added.
Oxidation with an oxidant, such as MnO 2 provides the useful intermediate.
SCHEME 4 a) TMSNCO
DMAP/THF
R1b) TBAF/TWtF 4 A mol.
sieves a. n-BuLi/HCCR 4
/TH-F
b. BF 3 'OEt 2
H
2 Pd/C N
H
4 Using the general method detailed in Scheme 4, one can prepare compounds of the present invention. Keto-aniline 1, WO 98/45276 PCT/US98/06733 which may be prepared by the methods desribed in Schemes 1 and 2, is treated with trimethylsilyl isocyanate in dry tetrahydofuran in the presence of dimethylaminopyridine followed by tetrabutylammonium fluoride to give the hydroxyurea 2. The hydroxy-urea 2 is then dehydrated with a dehydrating agent such as 4A molecular sieves in refluxing toluene or xylenes to give the ketimine 3. A substituted acetylenic R 2 group is added by treating the ketimine 3 with a lithium acetylide, which is prepared in a separate vessel by reacting the corresponding substituted acetylene with nbutyllithium in dry tetrahydrofuran, to give the 4,4disubstituted 3,4-dihydro-2(1H)-quinazolinone A, a compound of formula I. The acetylenic bond of the compound 4 may be reduced, by catalytic hydrogenation, to give the corresponding alkenyl group (not shown) or the saturated compound Other R 2 groups may also be introduced by directly reacting the imine 3 with a lithiate R 2 Li or a.Grignard reagent R 2 MgX in the presence or absence of Lewis acid catalyst, such as BF 3 etherate. See also Huffman et al, J.
Org. Chem. 1995, 60, 1590-1594, the contents of which are hereby incorporated herein by reference.
In certain instances, one enantiomer of a compound of Formula I or II may display superior activity compared with the other. When required, separation of the racemic material can be achieved by HPLC using a chiral column as exemplified in Examples 27-34 (Scheme 4) or by a resolution using a resolving agent such as camphonic chloride as in Thomas J.
Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
WO 98/45276 PCT/US98/06733 Examples Abbreviations used in the Examples are defined as follows: for degrees Celsius, for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, for hydrogen or hydrogens, "hr" for hour or hours, for multiplet, for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, for triplet, "TLC" for thin layer chromatography, "EDAC" for 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride, "DIPEA" for diisopropylethylamine, "TBAF" for tetrabutylammonium fluoride, "LAH" for lithium aluminium hydride, and "TEA" for triethylamine.
Example 1 Prepration of (+/-)-6-Chloro-4-cyclopropylethynyl-4trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone (R 4 Cyclopropyl) O a) TMSNCO CF3 OH Cl DMAP/THF C1 PhCH 3 11 I CF3 b) TBAF/THF 4 A mol. sieves
NH
2 W 0 I-a II-a R 4
F
3 CF3 N b. BF 3 "OEt 2 0 H o III-a IV-a Step 1. Synthesis of II-a from I-a.
To a solution of compound I-a (4.55 g, 20.2 mmol) in anhydrous THF (40 mL) was added dimethylaminopyridine (0.25 g, 2.02 mmol) and trimethylsilyl isocyanate (6.05 g, 7.11 mL, 52.5 mmol). The mixture was stirred at room temperature for WO 98/45276 PCT/US98/06733 approximately 16 hours, then tetrabutylamonium fluoride (21 mL of 1 M solution in THF) was added. The thick slurry was diluted with additional THF (20 mL) and stirred at room temperature for 0.5 hours. The THF was removed under reduced pressure, the residue was taken up in EtOAc (100 mL) and washed sequentially with 1 N HC1 (70 mL), saturated aqueous NaHCO 3 (70 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over MgS0 4 filtered and concentrated under reduced pressure to afford a light yellow solid. The yellow color was removed upon trituration with hexanes to afford IIa (5.09 g, 94%) as a white solid: 1 H NMR (300 MHz, acetone-d 6 6 9.06 (br s, 1 7.48 1 7.40 (br s, 1 7.34 (dd, J 8.8, 2.6 Hz, 1 6.97 J 8.8 Hz, 1 19 F NMR (282 MHz, acetone-d6) 5 -86.33, -86.35; IR (KBr Pellet) 1724, 1678, 1398, 1198, 1174 cm- 1 MS (CI) m/e 266 (MH 100).
Step 2. Synthesis of III-a from II-a.
A suspension of II-a (5.09 g, 19.1 mmol) in toluene (150 mL) containing 4 A molecular sieves (approximately 100 mg) was heated at reflux for 16 hours. The resulting clear yellow solution was cooled to room temperature, the precipitated solids were dissolved in acetone and the molecular sieves were removed by vacuum filtration. The filtrate was concentrated under reduced pressure, and triturated with hexanes to afford III-a (4.25 g, 89%) as a yellow solid: IH NMR (300 MHz, acetone-d6) 8 7.86-7.82 2 7.61 J 8.8 Hz, 1 19F NMR (282 MHz, acetone-d6) 6 -67.88.
Step 3. Synthesis of IV-a from IIIa.
A solution of cyclopropylacetylene (13.0 mL of 30 wt% solution in toluene/THF/hexanes, 59.0 mmol) in anhydrous THF (118 mL) was cooled to -78 oC, treated with n-BuLi (32.8 mL of 1.6 M solution in hexanes, 52.4 mmol), warmed to 0 °C in an ice bath, and aged for 0.5 h. To a solution of III-a WO 98/45276 PCT/US98/06733 (3.12 g, 12.6 mmol) in anhydrous THF (66 mL) at -78 °C was added the lithium acetylide over approximately 10 minutes.
To this was added boron trifluoride etherate (0.89 g, 0.80 mL, 6.28 mmol), followed by removal of the cooling bath. The reaction was allowed to reach room temperature and stirred at room temperature for 4 hours before quenching with 1 M citric acid (100 mL). The mixture was concentrated under reduced pressure to 1/2 original volume, diluted with EtOAc (200 mL), the aqueous phase was removed and the organic phase was sequentially washed with saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl (100 mL). The organic phase was dried over MgS0 4 filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography MeOH/CH 2 Cl2) to afford a thick yellow oil from which was obtained crystalline IV-a (R 4 cyclopropyl) (3.85 g, 97%) as a white solid: mp 86.6-88 1H NMR (300 MHz, acetone-d 6 8 8.95 (br s, 1 7.51 (br s, 1 7.43 (br s, 1 7.40 (dd, J 8.8, 2.4 Hz, 1 7.02 J 8.8 Hz, 1 1.49-1.41 1 0.93-0.82 1 0.77- 0.74 1 19 F NMR (282 MHz, acetone-d6) 8 -82.96; IR (KBr Pellet) 1696, 1172 cm- 1 MS (CI) m/e calc'd for
C
1 4
H
1 oClF 3
N
2 0: 315.051201, found 315.051626; 315 51), 332 (M+NH 4 100); Analysis calc'd for C 14
H
1 0
N
2 ClF 3 0-0.25 H 2 0: C, 52.68; H, 3.32; N, 8.78; found: C, 52.61; H, 3.35; N, 8.28.
Example 2 Preparation of (+/-)-6-Chloro-4-isopropylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Isopropyl) A solution of III-a (50 mg, 0.201 mmol) was treated with the lithium acetylide derived from 3-methyl-l-butyne (62 mg, 93 mL, 0.905 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (35% EtOAc/hexanes) to afford 26mg (41%) of the desired product: 1 H NMR (300 MHz, 5 9.08 (br s, 1 7.59 (br s, 1 7.53 (br s, 1 7.40 (dd, J 8.4, WO 98/45276 PCT/US98/06733 2.2 Hz, 1 7.02 J 8.8 Hz, 1 2.81-2.68 1 H), 1.20 (dd, J 6.6 Hz, 6H); 19 F NMR (282 MHz, acetone-d 6 6 -83.05; MS (CI) m/e calc'd for C 1 4
H
1 2 C1F 3
N
2 0: 317.066851, found 317.069433; 317 43), 334 (M+NH4 100).
Example 3 Preparation of (+/-)-6-Chloro-4-(2-pyridyl)ethynyl-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 2-Pyridyl) A solution of III-a (100 mg, 0.402 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.81 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 C1 2 to afford 85 mg of the desired product: mp 105 OC dec.; 1 H NMR (300 MHz, acetone-d 6 8 9.14 (br s, 1 8.64-8.61 1 7.89-7.84 2 7.70- 7.66 2 7.48-7.43 2 7.09 J 8.8 Hz, 1 H); 19 F NMR (282 MHz, acetone-d6) 6 -82.48; IR (KBr Pellet) 1704, 1430, 1186 cm- 1 MS (CI) m/e calc'd for Ci 6
H
1 0 C1F 3
N
3 0: 352.046450, found 352.046956; 352 (MH 100); Analysis calc'd for Ci 6
H
9 C1F 3
N
3 0-0.125 H 2 0: C, 54.3; H, 2.56; N, 11.9; found: C, 54.71; H, 3.03; N, 11.3.
Example 4 Preparation of -6-Chloro-4-ethylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Ethyl) A solution of III-a (100 mg, 0.402 mmol) was treated with the the lithium acetylide derived from 1-butyne (109 mg, 2.01 mmol) according to the procedure of Step 3 of Example 1.
The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 79 mg of the desired product: 1
H
NMR (300 MHz, acetone-d 6 6 9.05 (br s, 1 7.54 (br s, 2 7.41-7.39 1 7.02 J= 8.4 Hz, 1 2.36-2.32 2 2.18-1.13 3 1 9 F NMR (282 MHz, acetone-d 6 6 WO 98/45276 PCTIUS98/06733 -82.99; MS (CI) m/e calc'd for C1 3 HjOC1F 3 N2O: 303.051201, found 303.051882; 303 55), 320 (M+NH 4 100).
Example Preparation of (+/-)-6-Chloro-4-phenylethynyl-4trifluoromethyl-3,4-dihydro-2() -quinazolinone (R 4 Phenyl) A solution of III-a (100 mg, 0.402 mnol) was treated with the the lithium acetylide derived from phenylacetylene (185 mg, 1.81 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 54 mg of the desired product: 1 H NMR (300 MHz, acetone-d6) 8 9.07 (br s, 1 H), 7.74 (br s, 1 7.67 (br s, 1 7.62-7.58 2 7.48- 7.40 4H), 7.08 J 8.4 Hz, 1 1 9 F NNR (282 MHz, acetone-d 6 5 -82.67; IR (KBr Pellet) 1696, 1186 cm- 1
MS
(CI) mle calc'd for C1 7 HllClF 3 N2O: 351.051201, found 351.051704; 351 51), 368 (M+NH 4 Analysis calc'd for C 17
H
1 0 C1F 3
N
2 0-0.25 H 2 0: C, 57.48; H, 2.98; N, 7.89; found: C, 57.00; H, 3.03; N, 7.48.
Examnle 6 Preparation of (+1-)-4-Cyclopropyiethynyl-6-methoxy-4trifluoromethyl-3,4-dihydro-2 (iN) -quinazolinone (R 4 Cyclopropyl) Me 0 a) TMSNC me PhCH3 TI CF3 DMAP/TH. i -H4 A mol. sieves b) TBAF/THF VI NH2N 0 H R4 V-a VI-a
CF
3
F
3 Me a. THF/n-BuLi/HCCR 4 Me N b. BF 3 -OEt 2
N
H
H
VII-a VIII-a Step 1. Synthesis of VI-a from V-a.
WO 98/45276 PCT/US98/06733 A solution of V-a (0.50 g, 2.28 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 0.58 g of the desired product: 1 H NMR (300 MHz, acetone-d6) 8 8.81 (br s, 1 7.17 (br s, 1 7.11 (br s, 1 7.00-6.92 2 6.83 1 3.76 3 19 F NMR (282 MHz, acetoned 6 8 -85.99.
Step 2. Synthesis of VII-a from VI-a.
A solution of VI-a (0.58 g, 2.21 mmol) was heated in toluene at reflux as described in Step 2 of Example 1 to afford 0.50 g of the desired product: 1 H NMR (300 MHz, acetone-d 6 6 7.52 (br s, 2 7.27 1 3.90 3 H); 19 F NMR (282 MHz, acetone-d6) 8 -68.08.
Step 3. Synthesis of VIII-a from VII-a.
A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (0.41 mL of 30 wt% solution in toluene/THF/hexanes, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 103 mg of the desired product: 1 H NMR (300 MHz, acetone-d 6 6 8.77 (br s, 1 7.29 (br s, 1 7.06 (br s, 1 6.99-6.90 2 3.77 3 1.46-1.38 1 0.91-0.85 2 H), 0.79-0.72 2 19 F NMR (282 MHz, acetone-d 6 8 -82.61; MS (CI) m/e calc'd for C 1 5
H
1 4
F
3
N
2 0 2 311.100738, found 311.099970; 311 100).
WO 98/45276 PCT/US98/06733 Example 7 Preparation of -4-Isopropylethynyl-6-methoxy-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
(R
4 Isopropyl) A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from 3-methyl-l-butyne (126 mg, 0.19 mL, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography MeOH/CH 2 C1 2 to afford mg of the desired product: mp 228-229 OC; 1 H NMR (300 MHz, acetone-d 6 6 8.72 (br s, 1 7.27 (br s, 1 H), 7.10 (br s, 1 7.00-6.91 2 3.77 3 2.73- 2.67 1 1.20 (dd, J 7.0, 1.5 Hz, 6 19 F NMR (282 MHz, acetone-d 6 8 -82.71; IR (KBr Pellet) 1696, 1428, 1190, 1176 cm- 1 MS (CI) m/e calc'd for C 1 5
H
16
F
3
N
2 0 2 313.116388, found 313.115871; 313 (MH+ 100), 330 (M+NH 4 15); Analysis calc'd for C 1 5
H
1 5
F
3
N
2 0 2 C, 57.69; H, 4.84; N, 8.97; found: C, 57.74; H, 5.01; N, 8.57.
Example 8 Preparation of (+/-)-6-Methoxy-4-(2-pyridyl)ethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
(R
4 2-Pyridyl) A solution of VII-a (100 mg, 0.410 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography MeOH/CH 2 Cl 2 to afford 56 mg (39%) of the desired product: 1 H NMR (300 MHz, acetone-d 6 6 8.81 (br s, 1 8.6.1 J 4.8 Hz, 1 7.88-7.82 1 H), 7.66 J 7.7 Hz, 1 7.61 (br s, 1 7.46-7.42 1 7.23 (br s, 1 7.06-6.97 2 3.79 3 19
F
NMR (282 MHz, acetone-ds) 6 -82.13; IR (KBr Pellet) 1698, 1518, 1464, 1430, 1244, 1208, 1184 cm-l; MS (CI) m/e calc'd for C17H 1 3
F
3
N
3 0 2 348.095987, found 348.095629; 348 (MH WO 98/45276 PCTIUS98/06733 100) Analysis calc Id f or C 1 7
H
1 2
F
3
N
3 0 2 25 C 3
H
6 0: C, 58.92; H, 3.76; N, 11.61; found: C, 59.38; H, 4.04; N, 11.35.
Examiple 9 Preparation of -6-Methoxy-4-phenylethynyl-4trifluoromethyl-3 ,4-dihydro-2 (1H) -quinazolinone (R$ Phenyl) A solution of VII-a (100 mng, 0.410 nmmo1) was treated with the the lithium acetylide derived from phenylacetylene (0.19 g, 1.85 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography MeOH/CH 2 Cl 2 to afford 34 mg (24%) of the desired product: mp 206.2-207.7 1 H NI4R (300 MHz, acetone-d6) 6 8.85 Cbr s, 1 H) 7.60-7.57 (mn, 3 H) 7.49-7.39 (in, 3 7.21 (br s, 1 7.05-6.96 (in, 2H), 3.79 3 H); 19 F NMR (282 MHz, acetone-d 6 -82.32; IR (KBr Pellet) 1696, 1516, 1430, 1236, 1204, 1184, 1128 crrr 1 MS (CI) mie calc~d f or ClBH 1 4
F
3
N
2 0 2 347.100738, found 347.10148 2; 347 (IM~HV, 100), 364 (M+NH 4 48); Analysis calc'd for ClBH 1 3
F
3
N
2 0 2
C,
62.143; H, 3.78; N, 8.10; found: C, 62.35; H, 3.58; N, 7 .83.
t WO 98/45276 PCT/US98/06733 Example Preparation of (+/-)-4-Cyclopropylethynyl-5,6difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)quinazolinone (R 4 Cyclopropyl) F 0 F OH F CF 3 F CF 3 a) TMSNCO F NHXylenes T F CF3 DMAP/THF
N
2 b) TBAF/THF N O NH2 H O X-a IX-a XI-a
R
4 a. THF/n-BuLi/HCCR 4 F H atm) F b. BF3-OEt2 F EtOH/EtOAc N T IO H XIII-a XII-a Step 1. Synthesis of X-a from IX-a.
A solution of IX-a (6.46 g, 28.7 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 6.74 g of the desired product: 1 H NMR (300 MHz, acetone-d 6 6 9.13 (br s, 1 7.45-7.32 2 7.18 (br s, 1 6.85-6.80 (m, 1 19 F NMR (282 MHz, acetone-d6) 8 -86.6 17.2, 3), -137.52-137.68 -148.47-148.59 1).
Step 2. Synthesis of XI-a from X-a.
A solution of X-a (6.74 g, 25.1 mmol) was heated in xylenes at reflux as described in Step 2 of Example 1, substituting xylenes for toluene, to afford 6.3 g (100%) of the desired product: 1 H NMR (300 MHz, acetone-d 6 8 7.92-7.83 1 7.46-7.44 1 19 F NMR (282 MHz, acetone-d 6 6 -70.7 38.7, -136.72 -146.47-146.57 1).
Step 3. Synthesis of XII-a from XI-a.
WO 98/45276 PCT/US98/06733 A solution of XI-a (6.28 g, 25.1 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (24.9 mL of 30 wt% solution in toluene/THF/hexanes, 0.113 mol) according to the procedure of Step 3 of Example 1. The resulting crude yellow oil was dissolved in acetone and concentrated under reduced pressure to deliver a yellow solid. Crystallization from acetone afforded 5.98 g of the desired material: mp 86.5-88.5 OC; 1H NMR (300 MHz, acetone-d 6 6 9.01 (br s, 1 7.46 (br s, 1 7.44-7.35 1 6.86-6.81 1 1.41-1.37 1 0.90-0.83 1 0.74-0.69 1 19F NMR (282 MHz, acetone-d6) 8 -83.3 J 12.9, -136.04-136.23 -148.14-148.26 IR (KBr Pellet) 1706, 1516, 1442, 1246, 1214, 1196 cm- 1 MS (CI) m/e calc'd for C 1 4
H
1 0
F
5
N
2 0: 317.071329, found 317.070836; 317 (MH 100), 334 (M+NH4 62); Analysis calc'd for C 14
H
9
F
5
N
2 0: C, 53.17; H, 2.88; N, 8.87; found: C, 53.30; H, 3.16; N, 8.53.
Example 11 Preparation of (+/-)-5,6-Difluoro-4-isopropylethynyl- 4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Isopropyl) A solution of XI-a (7.24 g, 28.9 mmol) was treated with the the lithium acetylide derived from 3-methyl-l-butyne (8.87 g, 13.3 mL, 0.130 mol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography MeOH/CH 2 C1 2 to afford a yellow oil. Crystallization from acetone afforded 6.77 g of the desired product: mp 79-80 1 H NMR (300 MHz, acetone-d 6 8 9.02 (br s, 1 7.50 (br s, 1 7.44-7.35 1 6.87-6.82 1 2.69-2.65 1 1.17 J 7.0 Hz, 6H); 19 F NMR (282 MHz, acetone-d6) 8 -83.4 J 12.9, -135.79-135.94 -148.14-148.26 MS (CI) m/e calc'd for C 14
H
12
F
5
N
2 0: 319.086979, found 319.087376; 319 100), 336 (M+NH4 76).
WO 98/45276 PCT/US98/06733 Example 12 Preparation of (+/-)-5,6-Difluoro-4-(2pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)quinazolinone (R 4 2-Pyridyl) A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography MeOH/CH 2 Cl 2 to afford 83 mg of the desired product: mp 219-220 1 H NMR (300 MHz, acetone-d 6 6 9.15 (br s, 1 8.61 J 4.4 Hz, 1 7.88-7.82 (m, 2H), 7.63 (dd, J 7.0, 1.1 Hz, 1 7.47-7.42 2H), 6.94-6.88 1 19 F NMR (282 MHz, acetone-d 6 8 -82.8 (d, J 12.9, -135.78-135.93 -147.86-147.98 1); IR (KBr Pellet) 1712, 1470, 1450, 1430, 1416, 1264, 1238, 1226, 1198, 1186 cm- 1 MS (CI) m/e calc'd for Ci 6
H
9
F
5
N
3 0: 354.066578, found 354.067821; 354 (MH 100).
Example 13 Preparation of (+/-)-5,6-Difluoro-4-ethylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 2-Ethyl) A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from 1-butyne (97 mg, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 69 mg of the desired product: mp 191-194 1 H NMR (300 MHz, acetone-d 6 8 9.03 (br s, 1 H), 7.50 (br s, 1 7.45-7.35 1 6.87-6.82 1 H), 2.34-2.27 2H), 1.20-1.15 3 1 9 F NMR (282 MHz, acetone-d 6 8 -83.3 J 12.9, -135.79-135.98 1), -148.16-148.29 IR (KBr Pellet) 1704, 1686, 1518, 1444, 1244, 1210, 1192, 1172 cm-l; MS (CI) m/e calc'd for
C
1 3
H
10
F
5
N
2 0: 305.071329, found 305.071146; 305 100); Analysis calc'd for C1 3
H
9 F5N20: C, 51.33; H, 2.98; N, 9.22; found: C, 51.00; H, 2.79; N, 8.99.
WO 98/45276 PCT/US98/06733 Example 14 Preparation of (+/-)-5,6-Difluoro-4-phenylethynyl-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 Phenyl) A solution of XI-a (100 mg, 0.400 mmol) was treated with the the lithium acetylide derived from phenylacetylene (0.18 g, 0.20 mL, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 92 mg of the desired product: 1H NMR (300 MHz, acetone-d6) 8 9.14 (br s, 1 H), 7.80 (br s, 1 7.57-7.54 2H), 7.49-7.40 4H), 6.92- 6.87 1 19F NMR (282 MHz, acetone-d 6 5 -83.0 J 12.9, -136.08-136.27 -147.87-148.00 MS (CI) m/e calc'd for C 1 7
H
10
F
5
N
2 0: 353.071329, found 353.071716; 353 (MH 42), 370 (M+NH 4 100).
Example Preparation of (+/-)-5,6-Difluoro-4-isopentyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Isopropyl) Synthesis of XIII-a from XII-a.
A solution of XIII-a (R 4 isopropyl) (26 mg, 82 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon (35 mg) under H 2 (1 atm) for 16 hours. The catalyst was removed by vacuum filtration through Celite and the filter cake was washed with EtOAc. The combined filtrates were concentrated under reduced pressure to afford 26 mg (100%) of the desired material. No further purification was necessary: 1 H NMR (300 MHz, acetone-d6) 6 8.88 (br s, 1 H), 7.41-7.31 1 6.89-6.81 2H), 2.55-2.50 1 H), 1.64-1.45 2H), 1.06-1.02 1 0.89 (dd, J 6.6, 2.2 Hz, 6H); 19F NMR (282 MHz, acetone-d6) 8 -83.22 J 12.1, -138.97-139.13 -148.46-148.58 IR (KBr Pellet) 1700, 1678, 1518, 1438, 1252, 1188, 1172 cm-1; MS WO 98/45276 PCT/US98/06733 (CI) mie calc'd f or C 1 4
H
1 6
F
5
N
2 0: 323.118280, found 323.116703; 323 (MHfl, 100), 340 (M+NH 4 57).
Example 16 Preparation of (+/-)-4-Butyl-5,6-difluoro-4trifluoromethyl-3,4-dihydro-2 (lH) -quinazolinone (R 4 Ethyl) A solution of XIII-a (R 4 ethyl) (20 mg, 66 rnmol) in ethanol (1 inL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H 2 according to the procedure of Example Purification by HPLC MeOH/CH 2 C12) afforded 12 mg (56%) of the desired product: IH NNR (300 MHz, acetone-d 6 8 8.89 (br s, I 7.41-7.32 (in, 1 6.86-6.81 (in, 2H), 2.57-2.47 (mn, 1 1. 56-1. 15 (mn, 5H) 0. 88 j 7.3 HZ, 3 H) 1 9
F
NMR (282 MHz, acetone-d6) 8 -83.19-83.24 (mn, -139.14 (s, -148.49-148.62 (mn, MS (CI) m/e calc'd for
C
13
H
14
F
5
N
2 0: 309.102629, found 309.103555; 309 100), 326 (M+NH 4 62).
WO 98/45276 PCTIUS98/06733 ExamPle 17 Preparation of (+1-)-4-Cyclopropylethynyl-6-fluoro-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Cyclopropyl) o F 3
OH
a) TMSNCO F F, CF, DMAP/THF NH Toluene TI
NH
2 b) TBAF/THF
H
XVI-a XIV-a XV-a a. THF/n-BuLi/HCCR 4 b. BF 3 -OEt 2
F
R 4 10% Pd/c F 3
H
2 (1 atm)F EtOH/EtOAcI XVIII -a XVII-a
THF/CH
3
CCR
4
F~
n-BuLi/O 'C XVI-a XIX-a Step 1. Synthesis of XV-a from XIV-a.
A solution of XIII-a (3.07 g, 14.8 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 2.81 g of the desired product.
Step 2. Synthesis of XVI-a from XV-a.
A solution of XV-a (6.74 g, 25.1 mmol) was heated in toluene at ref lux as described in Step 2 of Example 1 to afford 0.73 g of the desired product.
Step 3. Synthesis of XVII-a from XVI-a.
WO 98/45276 PCT/US98/06733 A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (1.43 mL of 30 wt% solution in toluene/THF/hexanes, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH2C1 2 to afford 44 mg of the desired product: mp 155 oC; 1 H NMR (300 MHz, acetone-d 6 8 8.86 (br s, 1 7.36 (br s, 1 7.30-7.27 1 H), 7.22-7.15 1 7.04-6.99 1 1.47-1.42 1 H), 0.90-0.87 2 0.76-0.75 2 1 9 F NMR (282 MHz, acetone-d 6 8 -82.86, -123.36-123.44; MS (CI) m/e calc'd for
C
1 4
H
1 1
F
4
N
2 0: 299.080751, found 299.079976; 299 (MH 100).
Example 18 Preparation of (+/-)-6-Fluoro-4-isopropylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Isopropyl) A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 3-methyl-l-butyne (0.13 g, 0.20 mL, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 C12) to afford 24 mg of the desired product: mp 158 OC; 1 H NMR (300 MHz, acetone-d 6 8 9.07 (br s, 1 7.60 (br s, 1 7.32-7.30 1 H), 7.24-7.16 1 7.05-6.99 1 2.77-2.67 1 H), 1.20 (dd, J 7.0, 2.6 Hz, 6H); 1 9 F NMR (282 MHz, acetone-d 6 8 -82.95, -123.41-123.49; MS (301) m/e calc'd for
C
1 4
H
1 3
F
4
N
2 0: 301.096401, found 301.096235; 301 (MH 100).
Example 19 Preparation of (+/-)-6-Fluoro-4-(2-pyridyl)ethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
(R
4 2-Pyridyl) A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 2-ethynylpyridine (0.20 g, 1.94 mmol) according to the procedure of Step 3 of WO 98/45276 PCT/US98/06733 Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 65 mg of the desired product: mp 155 OC; 1 H NMR (300 MHz, acetone-d 6 6 9.02 (br s, 1 8.60 J 4.0 Hz, 1 7.87-7.78 2 7.66 J 7.7 Hz, 1 7.45-7.41 2 7.26-7.20 1 H), 7.09-7.05 1 1 9 F NMR (282 MHz, acetone-d6) 8 -82.36, -122.94-123.02; MS (CI) m/e calc'd for Ci 6
H
10
F
4
N
3 0: 336.076000, found 336.074156; 336 (MH Example Preparation of (+/-)-6-Fluoro-4-ethylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Ethyl) A solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from 1-butyne (0.10 g, 1.94 mmol) according to the procedure of Step 3 of Example 1.
The resulting crude material was purified by HPLC MeOH/CH 2 Cl 2 to afford 40 mg of the desired product: mp 190 oC; 1 H NMR (300 MHz, acetone-d 6 8 8.86 (br s, 1 7.38 (br s, 1 7.34-7.31 1 7.22-7.16 1 7.05- 7.00 1 2.04-2.01 2 i.19-1.14 3 1 9
F
NMR (282 MHz, acetone-d 6 8 -75.392, -123.42-123.50; MS (CI) m/e calc'd for C 13
H
11
F
4
N
2 0: 287.080751, found 287.080740; 287 (MH 100).
Example 21 Preparation of (+/-)-6-Fluoro-4-phenylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Phenyl) A solution .of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from phenylacetylene (0.20 g, 0.21 mL, 1.94 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC MeOH/CH 2 C1 2 to afford 41 mg of the desired product: mp 107 OC; 1 H NMR (300 MHz, acetone-d 6 8 9.00 (br s, 1 7.69 (br s, 1 7.63-7.59 2 H), WO 98/45276 PCT/US98/06733 7.50-7.40 4H), 7.27-7.20 1 7.10-7.05 1 H); 1 9 F NMR (282 MHz, acetone-d6) 6 -82.56, -122.99-123.07; MS (CI) m/e calc'd for C 1 7
H
1 1
F
4
N
2 0: 335.080751, found 335.082057; 335 (MH 74), 352 (M+NH4 100).
Example 22 Preparation of (+/-)-6-Fluoro-4-isopentyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Isopropyl) Synthesis of XVIII-a from XVII-a.
A solution of XVII-a (R 4 isopropyl) (26 mg, 87 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H 2 according to the procedure of Example 15 to afford 15 mg of the desired product. No further purification was necessary: mp 179 OC; 1 H NMR (300 MHz, acetone-d 6 8 7.02-6.97 2 6.80-6.76 1 2.18- 2.09 2 1.92-1.82 2 1.52-1.45 1 0.88- 0.79 6 19 F NMR (282 MHz, acetone-d 6 8 -82.60, -123.72-123.84; MS (CI) m/e calc'd for C 14
H
1 7
F
4
N
2 0: 305.127707, found 305.126790; 305 (MH 100).
Example 23 Preparation of (+/-)-6-Fluoro-4-(2'-2-pyridyl)ethyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 2-Pyridyl) A solution of XVII-a (R 4 2-pyridyl) (33 mg, 99 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H 2 according to the procedure of Example 15 to afford 10 mg of the desired product. No further purification was necessary: mp 88 oC; 1 H NMR (300 MHz, acetone-d 6 6 8.35 J 4.4 Hz, 1 7.63 (dt, J 7.7, 1.5 Hz, 1 7.20-7.13 3 7.04-6.98 1 6.83- 6.79 1 2.84-2.78 1 2.68-2.48 2 2.27- 2.06 1 1 9 F NMR (282 MHz, acetone-d6) 8 -82.58, WO 98/45276 PCT/US98/06733 -123.26-123.34; MS (CI) m/e calc'd for Ci6Hi 4
F
4
N
3 0: 340.107300, found 340.107719; 340 (MH 100).
Example 24 Preparation of (+/-)-4-Butyl-6-fluoro-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
(R
4 Ethyl) A solution of XVII-a (R 4 ethyl) (24 mg, 84 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H 2 according to the procedure of Example 15 to afford 24 mg (100%) of the desired product. No further purification was necessary: mp 198 OC; 1 H NMR (300 MHz, acetone-d 6 8 7.03-6.97 2 6.80-6.76 1 2.18- 2.11 1 1.90-1.81 1 1.30-1.19 3 0.97- 0.80 4 1 9 F NMR (282 MHz, acetone-d 6 8 -82.692, -123.78-123.86; MS (CI) m/e calc'd for C1 3
H
1 5
F
4
N
2 0: 291.112051, found 291.112227; 291 100).
Example Preparation of -6-Fluoro-4-phenylethyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
(R
4 Phenyl) A solution of XVII-a (R 4 phenyl) (30 mg, 90 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H 2 according to the procedure of Example 15 to afford 20 mg of the desired product. No further purification was necessary: mp 98 OC; 1 H NMR (300 MHz, acetone-d 6 8 7.18-6.99 7H), 6.84-6.79 1 2.68-2.60 1 2.48-2.12 3 19 F NMR (282 MHz, acetone-d 6 8 -82.67, -123.24-123.32; MS (CI) m/e calc'd for C 17
H
15
F
4
N
2 0: 339.112051, found 339.110781; 339 (MH 100).
WO 98/45276 PCT/US98/06733 Example 26 Preparation of (+/-)-6-Fluoro-4-methylpropargyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (R 4 Methyl) Synthesis of XIX-a from XVI-a.
A solution of 2-butyne (94 mg, 1.75 mmol) in anhydrous THF (3.5 mL) was cooled to 0 OC, treated with n-BuLi (0.97 mL of 1.6 M solution in hexanes, 1.55 mmol), and aged for 0.5 h.
To a solution of XVI-a (90 mg, 0.388 mmol) in anhydrous THF (1.9 mL) at -78 OC was added the lithium anion over minutes, followed by boron trifluoride etherate (25 mL, 0.194 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 16 h at room temperature, quench by addition of 1 M citric acid (10 mL), dilute with EtOAc (50 mL), separate phases and wash the organic phase sequentially with saturated aqueous NaHC03 mL) and saturated aqueous NaCI (20 mL). The resulting material was purified by HPLC MeOH/CH 2 C2) to afford mg of the desired product: mp 181 oC; 1 H NMR (300 MHz, acetone-d 6 8 8.91 (br s, 1 7.27 8.4H), 7.18-7.08 (m, 1 7.02-6.97 2 3.29 (dd, J= 16.8, 2.6 Hz, 1 H), 3.00 (dd, J 16.8, 2.2 Hz, 1 1.61-1.59 3 19 F NMR (282 MHz, acetone-d6) 8 -81.86, -123.69-123.70; MS (CI) m/e calc'd for C 1 3H 11
F
4
N
2 0: 287.080751, found 287.080340; 287 (MH 75), 304 (M+NH 4 100).
WO 98/45276 WO 9845276PCTIUS98/06733 SCHEME 4: Chiral Resolution R4 R4R 4 C3 //C3 F Chiral HPLC N. H Separation NE.
N
H H H R3- Comoun R 3_ Co~.Qund R Comnound 6-Cl IV-a 6-Cl 1V-b 6-Cl IV-C 6-MeO VIII-a 6-MeO VIII-b 6-MeO VIII-C 5,6-diF XII-a 5,6-diF XII-b 5,6-diF XII-c 6-F XVII-a 6-F XVII-b 6-F XVII-C Examnles 27 and 28 Preparation of (-)-6-Chloro-4-cyclopropylethynyl-4trifluoromethyl-3, 4-dihydro-2 (lH) -quinazolinone (Example 27) and (.)-6-Chloro-4-cYclopropylethynyl-4trifluoromethyl'-3,4-dihydro-2(lH)-qUinazoljnone (Example 28) Resolution of IV-b,c from TV-a (R 4 Cyclopropyl).
Chiral HPLC utilizing a Chiralcel OD column, 3% isopropanol, 5% CH2Cl2 and 92% hexanes at ambient temperature with a 1.0 mL/min flow rate and detection at 250 nin afforded seperation of Tv-b from IV-c with enantiomeric excesses of 99% and 99.4%, respectively. IV-b: mp 106-109 [aID 2 -60.34' (c=0.274, MeOH) V-c: mplO5-107 [aID 2 5 +58.330 (C=0.288, MeQH).
Examnles 29 and Preparation of -4-Cyclopropylethynyl-5, 6-difluoro- 4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone 25 (Example 29) and (-)-4-Cyclopropylethynyl-5,6difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (Example Resolution of XTT-b, c from XTI-a (R 4 Cyclopropyl) WO 98/45276 PCT/US98/06733 Chiral HPLC utilizing a Chiralpak AD column, 5% water and 95% methanol at ambient temperature with a 0.8 mL/min flow rate and detection at 250 nn afforded seperation of XIIb from XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 187 ia]D 2 5 +1.460 (c=0.274, MeOH). XII-c: mp 187.5-188.8 0 C; [c(L]D 25 -1.450 (c=0.278, MeOH).
Examiples 31 and 32 Preparation of (-)-5,6-Difluoro-4-isopropylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 31) and (+)-5,6-Diffluoro-4-isopropylethynyl- 4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone (Example 32) Resolution of XII-b,c from XII-a (R 4 Isopropyl).
Chiral HPLC utilizing a Chiralpak AD column, 5% water and 95% methanol at ambient temperature with a 0.5 mL/min flow rate and detection at 250 nm afforded seperation of XIIb from XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 155 0 C; [aID 2 5 -2.140 (c=0.280, MeOH). XII-c: 98 0 C; [a]D 2 5 +4.450 (c=0.292, MeOH) Examples 33 and 34 Preparation of 6-Difluoro-4-ethyiethynyl-4trifluoromethyl-3,4-dihydro-2(iH)-quinazolinone (Example 33) and (+)-5,6-Difluoro-4-ethylethynyl-4trifluoromethyl-3,4-dihydro-2(1H)quinazolinone (Example 34) Resolution of XII-b,c from XII-a (R 4 Ethyl).
Chiral EPLC utilizing a AS column, 20% ethanol and hexanes at ambient temperature with a 1.0 mL/min flow rate and detection at 250 nm afforded seperation of XII-b from WO 98/45276 WO 9845276PCTIUS98/06733 XII-c with enantiomeric excesses of 100% and 99%, respectively. XII-b: mp 165-167 XII-c: mp 157-159 OC.
Examiles 35 and 36 Preparation of 5, 6-Difluoro-4- (2-hydroxyethyl) ethynyl- 4-trifluoromethyl-3, 4-dihydro-2 (lE)-guinazolinone (Example 35) and 5,6-DifJluoro-4-(1hydroxyethyl)ethynyl-4-trifluoromethyl-3,4-dihydro- 2(lH)-quinazolinone (Example 36) LiCaCCH9CH 2 0OTBS R F3 or F
F
3 LiCSCCH (OTBS) CH 3
F)N
F NTHF/BF 3 -OEt 2 N NH
HH
Comnound R Ex. 35 CH 2
CH
2
OTBS
Ex. 36 CH(OTBS)CH 3
R
F31 T AFf F N O
H
Comround R Ex. 35 CH 2
CH
2
OH
Ex. 36 CH(OH)CH 3 To a slurry of ketimine (300 mg, 1.20 mmol) in anhyd.
THF (11 mL) at -78 'C was sequentially added a precooled (0 solution of the silyl protected lithium acetylide (5.40 nmmol) and BF3.OEt2 (0.60 inmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by the addition of 1 M citric acid and diluted with EtOAc. The phases were separated, the organic phase was washed with water, sat. aq. NaHCO3 and sat. aq. NaCl. The organic extracts were dried over MgSO4, filtered and concentrated.
WO 98/45276 PCT/US98/06733 The material was purified by regular phase HPLC chromatography (41.4 mm Rainin Dynamax® column using 60 A silica 25 mL/min): 2.5% MeOH/CH 2 Cl 2 for 24 min, increase to MeOH/CH 2 Cl 2 over 4 min, 30% MeOH/CH2Cl2 for 10 min, and ramp back to 2.5% MeOH/CH2Cl2 over 2 min. The yield of the protected intermediates was 47% and 32%, respectively.
Example 35-intermediate. Mp 62.9-64 1H NMR (300 MHz, acetone-d 6 8 8.98 (br s, 1H), 7.41-7.32 2H), 6.83- 6.78 1H), 3.74 J 6.6 Hz, 2H), 2.47 J 6.6 Hz, 2H), 0.81 9H), 0.00 6H); 1 9 F NMR (282 MHz, acetoned 6 6 -83.17, -135.16--135.31, -148.09--148.22; MS (CI) calc'd for C19H24F5N202Si: m/z 435.152723, found 435.151149; 435 94), 452 (M+NH4+, 100); Analysis calc'd for
C
1 9
H
2 3
F
5
N
2 0 2 Si: C, 52.52; H, 5.35; N, 6.46; found: C, 52.65; H, 5.29; N, 6.31.
,Example 36-intermediate. 1 H NMR (300 MHz, acetone-d 6 8 8.96 (br s, 1H), 7.50 (br s, 1H), 7.37-7.28 1H), 6.79- 6.74 1H), 4.61 J 13.2, 6.6 Hz, 1H), 1.30 J 6.6 Hz, 3H), 0.78 9H), 0.01 6H); 1 9 F NMR (282 MHz, acetone-d 6 d -82.88--82.95, -135.20--135.42, -148.06--148.23; MS (CI) calc'd for C19H24F5N202Si: m/z 435.152723, found 435.152927; 435 51), 452 (M+NH4+, 100); Analysis calc'd for C 1 9
H
2 3
F
5
N
2 0 2 Si: C, 52.52; H, 5.35; N, 6.46; found: C, 52.54; H, 5.34; N, 6.69.
To a solution of the protected intermediate for Example (0.56 mmol) in THF (1.1 mL) was added TBAF (0.62 mL of M solution in THF). The resulting mixture was stirred at rt for 1 h, diluted with EtOAc, washed with 1 N HC1, sat. aq.
NaHC0 3 and sat. aq. NaCl. The organic extract was dried over MgSO 4 filtered and concentrated. The material was purified by regular phase HPLC chromatography (41.4 mm Rainin Dynamax® column using 60 A silica 25 mL/min): 2.5% MeOH/CH 2 Cl 2 for 24 min, increase to 30% MeOH/CH 2 Cl 2 over 4 min, MeOH/CH 2 Cl 2 for 10 min, and ramp back to 2.5% MeOH/CH 2 Cl 2 over 2 min. Example 35 was isolated in 82% yield.
Example 35. Mp 190-192 oC; 1 H NMR (300 MHz, acetone-d 6 8 9.05 (br s, 1H), 7.53 (br s, 1H), 7.45-7.36 1H), 6.88- 6.83 IH), 4.01-3.98 1H), 3.68-3.64 2H), 2.50 (t, WO 98/45276 PCT/US98/06733 J 6.6 Hz, 2H); 19 F NMR (282 MHz, acetone-d 6 5 -83.3, -135.68--135.88, -148.10--148.22; MS (CI) calc'd for
C
13
H
10
F
5
N
2 0 2 m/z 321.066244, found 321.066479; 321 (MH+, 100); Analysis calc'd for C 13
H
9
F
5
N
2 0 2 C, 48.76; H, 2.83; N, 8.76; found: C, 49.05; H, 3.23; N, 8.38.
Example 36 was synthesized in an analogous manner to deliver the title compound in 88% yield. Mp 190-191 1
H
NMR (300 MHz, acetone-d 6 5 9.06 (br s, 1H), 7.56 (br s, 1H), 7.46-7.37 1H), 6.88-6.83 1H), 4.58-4.57 2H), 1.39 J 5.5 Hz, 3H); 1 9 F NMR (282 MHz, acetone-d 6 5 -83.15, -135.40, -135.60, -148.08--148.20; MS (CI) calc'd for
C
1 3
H
10
F
5
N
2 0 2 m/z 321.066244, found 321.065983; 321 (MH+, 58), 338 (M+NH4+, 100); Analysis calc'd for C 13
H
9
F
5
N
2 0 2
C,
48.76; H, 2.83; N, 8.76; found: C, 48.84; H, 2.76; N, 8.63.
Example 37 Preparation of (+)-4-E-Cyclopropylethenyl-5,6difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)quinazolinone To a solution of XII-b (200 mg, 0.632 mmol) in anhyd.
THF (1.3 mL) at rt was added a solution of lithium aluminium hydride (1.3 mL of 1.0 M solution in THF). The resulting mixture was stirred at rt overnight. The reaction was quenched by addition of 10% NaOH (3 mL) and water (3 mL).
The mixture was diluted with EtOAc (30 mL) and the phases were separated. The organic phase was washed with sat. aq.
NaC1, dried over MgS0 4 filtered and concentrated. The title compound was purified by regular phase HPLC (41.4 mm Rainin Dynamax@ column using 60 A silica): 2.5% MeOH/CH 2 Cl 2 for 24 min, increase to 30% MeOH/CH 2 Cl 2 over 4 min, 30% MeOH/CH 2 Cl 2 for 10 min, and ramp back to 2.5% MeOH/CH 2 Cl 2 over 2 min. Mp 80-83 OC; 1 H NMR (300 MHz, acetone-d 6 d 9.07 (br s, 1H), 7.33 J=8.8 Hz, 1H), 6.94 (br s, 1H), 6.84-6.79 1H), 6.27 (dd, J 15.6, 7.5 Hz, 1H), 5.67 (dd, J 15.2, 9.4 Hz, 1H), 1.65-1.56 1H), 0.80-0.71 2H), 0.50-0.42 2H); 19 F NMR (282 MHz, acetone-d 6 d -82.68, -135.05, -148.49; MS (CI) calc'd for C 14
H
1 2
F
5
N
2 0: m/z 319.086979, found WO 98/45276 PCT/US98/06733 319.087755; 319 100); [a]D 2 0 +72.770 (c=0.382, MeOH); Analysis calc'd for C 14
HIF
5
N
2 0: C, 52.84; H, 3.48; N, 8.80; found: C, 53.02; H, 3.48; N, 8.61.
Example 38 Preparation of (-)-6-Chloro-4-E-cyclopropylethenyl-4trifluoromethyl-3,4-dihydro-2 (1H)-quinazolinone The title compound was prepared as described for Example 37 (starting from IV-b), except that it was purified using a Chiralcel OD column at 1.5 mL/min in 0.5%
CH
2 C1 2 /79.5% hexanes. Mp 87-89 OC; 1 H NMR (300 MHz, acetonedg) d 9.08 (br s, 1H), 7.40-7.25 2H), 7.04-6.90 2H), 6.28-6.18 1H), 5.64-5.52 1H), 1.68-1.55 1H), 0.83-0.71 2H), 0.53-0.41 2H); 19 F NMR (282 MHz, acetone-d 6 d -81.67; MS (CI) calc'd for C 1 4
H
1 3 C1F 3
N
2 0: m/z 317.066851, found 317.065857; 317 100); [C]D 2 0 -6.810 (c=0.382, MeOH); Analysis calc'd for C 14
H
1 2 C1F 3
N
2 0 0.27
C
3
H
6 0: C, 53.52; H, 4.13; N, 8.43; found: C, 53.90; H, 4.07; N, 8.80.
WO 98/45276 WO 9845276PCTIUS98/06733 Table 1* R ~12
H
Ex. R 3
R
1 R2R 8 M. P. Mass Spec 1 6-Cl CF 3 C=EC-CycPr H 86.6- 332 88 (M+NH 4 2 6-Cl CF 3 C C-iPr H 180 334 4 3 6-Cl CF 3 C-=C-2-Pyridyl H 105 352 (MH+) 4 6-Cl CF 3 C-=C-Et H 217- 303 (MH+) 6-Cl CF 3 C=-C-Ph H 104- 368 107 (M+NH 4 6 6-MeO CF 3 C-=C-cycPr H 208 311 (MH+) 7 6-MeO CF 3 C=-C-iPr H 228- 313.(MHl{) ____229 8 6-MeO CF 3 C-=C-2-Pyridyl H 97-98 348 (MH+) 9 6-MeO CF 3 C-=C-Ph H 206.2- 347 (MH+) ___207.7 5,6-diF CF 3 CE-C-cycPr H 101 317 (M'lli) 11 5,6-diF CF 3 C-=C-iPr H 79-80 319 (IvH{+) 12 5,6-diF CF 3 CE=C-2-Pyridyl H 219- 354 (MH+) 13 5,6-diF CF 3 C-=C-Et H 191- 305 (MH+) 14 5,6-diF CF 3 C=-C-Ph H 215- 370 1217 (M+NI 4 5,6-diF CF 3 CH2CH 2 CH (CH 3 2 H 192- 323 ___193' 16 5,6-diF CF 3
CH
2
CH
2
CH
2 CH3 H 309 (MH+) 17 6-F CF 3 C=-C-cycPr H 155 299 (IMfli) 18 6-F CF 3 C C-iPr H 158 301 (MH+) 19 6-F CF 3 C-=C-2-Pyridyl H 155 336 (IMfl{) 6-F CF 3 C-=C-Et H 190 287 (MH+) 21 6-F CF 3 CE=C-Ph H 107 352 M N H 4 22 6-F C 3
CH
2
CH
2 CH (CH3) H 179 f305 (MH+) WO 98/45276 WO 9845276PCTIUS98/06733 23 6-F CF 3
CH
2
CH
2 -2-Pyridyl H 88 340 (MH+) 24 6-F CF 3
CH
2
CH
2
CH
2
CH
3 H 198 291 (myH+) 6-F CF 3
CH
2
CH
2 Ph H 98 339 (mH+) 26 6-F CF 3
CH
2
C=-C-CH
3 H 181 304 (M-iNH 4 6-Cl CF 3 CE=C-cycPr H 106- 313 6-Cl CF 3 C=-C-cycPr H 105- 313 5,6-diF CF 3 C-=C-cycPr H 187 315 5,6-diF CF 3 C-=C-cycPr H 188- 315 1_ 189 5,6-diF CF 3 C=-C-iPr H 155 317 5,6-diF CF 3 C=-C-iPr H 98 317 5,6-di' CF 3 C=-C-Et H 165- 303 ___167 5,6-di' CF 3 C=-C-Et H 157- 303 ___159 5,6-diE' CF 3 C CCH 2
CH
2 OH H 190- 321 (MH+) 192 36 5,6-diF CF 3 C-=C-CH (OH) Me H 190- 338 __191
(M+NH
4 5,6-diF CF 3 C=C-cycPr H 80-83 319 (IM'fl) 6-Cl CF 3 C=C-cycPr H 187-89 317 (vl+ *Unless otherwise indicated, stereochemisty is WO 98/45276 WO 9845276PCT/US98/06733 Table 2* Ex. #R3RR28 1 6-Cl CF 3
C-=CCH
2
CH
2 OH H 2 6-Cl CF3 C=-C-CH(OH)Me H 3 6-Cl CF3 (2-Cl) Ph H 4 6-Cl CF3 C-C- (3 -C1) Ph H 6-Cl CF 3 CmC- (4-Cl) Ph H 6 6-Cl CF3 C=-C-(2-F)Ph H 7 6-Cl CF 3 C-=C-(3-F)Ph H 8 6-Cl CF 3 C=-C-(4-F)Ph H 9 6-Cl CF3 CC (2 -OH) Ph H 6-Cl CF 3 C=C- (3 -OH)Ph H 11 6-Cl CF 3 (4-OH) Ph H 12 6-Cl CF 3 (2-OMe) Ph H 13 6-Cl CF 3 C-C- (3 -OMe) Ph H 14 6-Cl CF 3 C-=C-(4-OMe)Ph H 6-Cl CF 3 (2-CN) Ph H 16 6-Cl CF 3 C-C- (3 -CN)Ph H 17 6-Cl CF 3 CC (4 -CN) Ph H 18 6-Cl CF 3 C-C- (2 -N02)Ph H 19 6-Cl CF 3 C=C (3 -NO 2 )Ph H 6-Cl CF 3 (4-NO 2 Ph H 21 6-Cl CF 3 C2-C- (2-NH2) Ph H 22 6-Cl CF 3 C-C- (3 -NH 2 Ph H 23 6-Cl1 CF 3 (4-NH 2 Ph H 24 6-Cl CF3 (2-NMe 2 Ph H 6-Cl CF 3 C=C- (3 -NMe 2 Ph H 26 6-Cl CF 3 C=C (4 -NMe 2 Ph H 27 6-Cl CF3 C=-C-3-Pyridyl H 28 6-Cl CF 3 C=-C-4-Pyridyl H WO 98/45276 WO 9845276PCTIUS98/06733 29 6-Cl CF 3 C=-C-2-furanyl H 6-Cl CF 3 C-=C-3-furanyl H 31 6-Cl CF 3 C-=C-2-thieriyl H 32 6-Cl CF 3 C-=C-3-thienyl H 33 6-Cl CF 3 C-=C-2-oxazolyl H 34 6-Cl CF 3 C=-C-2-thiazolyl H 6-Cl CF 3 CE=C-4-isoxazolyl H 36 6-Cl CF 3 CE=C-2-imidazolyl H 37 6-Cl CF 3
C=-CCH
2
CH
2 OH H 38 6-Cl CF 3 C=C-CH (OH) Me H 39 6-Cl CF 3 C=C-(2-Cl)Ph H 6-Cl CF 3 C-C-(3-Cl)Ph H 41 6-Cl CF3 C=-C-(4-Cl)Ph H 42 6-Cl CF 3 C=-C-(2-F)Ph H 43 6-Cl CF 3 C=-C-(3-F)Ph H 44 6-Cl CF 3 C=-C-(4-F)Ph H 6-Cl CF 3 C=C-(2-OH)Ph H 46 6-Cl CF 3 C=C- (3 -OH) Ph H 47 6-Cl CF 3 C=C-(4-OH)Ph H 48 6-Cl CF 3 C=C-(2-OMe)Ph H 49 6-Cl CF 3 C=C-(3-OMe)Ph H 6-Cl CF 3 C=C- (4 -OMe) Ph H 51 6-Cl CF 3 C=C- (2 -CN) Ph H 52 6-Cl CF 3 C=C-(3-CN)Ph H 53 6-Cl CF 3 C=C- (4 -CN) Ph H 54 6-Cl CF 3 C=C- (2 -N0 2 Ph H 6-Cl CF 3 C=C- (3 -N0 2 Ph H 56 6-Cl CF 3 C=C- (4-N02) Ph H 57 6-cl CF 3 C=C -NH 2 Ph H 58 6-Cl CF 3 C=C- (3 -NH 2 Ph H 59 6-Cl CF 3 C=C- (4-NH 2 Ph H 6-Cl CF 3 C=C- (2 -NMe 2 Ph H 61 6-Cl CF 3 C=C- (3-NMe 2 Ph- H 62 6-Cl CF 3 C=C- (4-NMe 2 Ph H WO 98/45276 WO 9845276PCTIUS98/06733 63 6-Cl CF 3 C=C-3-Pyridyl H 64 6-Cl CF 3 C=C-4-Pyridyl H 6-cl CF 3 C=C-2-furanyl H 66 6-Cl CF 3 C=C-3-furanyl H 67 6-Cl CF 3 C=C-2-thienyl H 68' 6-Cl CF 3 C=C-3-thienyl H 69 6-Cl CF3 C=C-2-oxazolyl H 6-Cl CF 3 C=C-2-thiazolyl H 71 6-Cl CF 3 C=C-4-isoxazolyl H 72 6-Cl CF3 C=C-2-irnidazolyl H 73 6-Cl CF 3
CH
2
CH
2 -cycPr H 74 6-Cl CF 3
CH
2
CH
2
CH
2
CH
2 OH H 6-Cl CF 3
CH
2
CH
2 -CH(OH)Me H 76 6-Cl CF 3
CH
2
CH
2 -Ph H 77 6-Cl CF 3
CH
2
CH
2 -C1) Ph H 78 6-Cl CF 3
CH
2
CH
2 -Cl) Ph H 79 6-Cl CF 3
CH
2
CH
2 (4-Cl) Ph H 6-Cl CF 3
CH
2
CH
2 -(2-F)Ph H 81 6-Cl CF 3
CH
2
CH
2 -(3-F)Ph H 82 6-Cl CF 3
CH
2
CH
2 -(4-F)Ph H 83 6-Cl CF 3
CH
2
CH
2 (2 -OH) Ph H 84 6-Cl CF 3
CH
2
CH
2 -OH) Ph H 6-Cl CF 3
CH
2
CH
2 -(4-OH)Ph H 86 6-Cl CF 3
CH
2 CH 2 (2-OMe) Ph H 87 6-Cl CF 3
CH
2
CH
2 -OMe) Ph H 88 6-Cl CF 3
CH
2
CH
2 (4-OMe) Ph H 89 6-Cl CF 3
CH
2
CH
2 -CN)Ph H 6-Cl CF 3
CH
2
CH
2 -CN) Ph H 91. 6-Cl CF 3
CH
2
CH
2 -CN) Ph H 92 6-Cl CF 3
CH
2
CH
2 (2-N0 2 Ph H 93 6-Cl CF 3
CH
2
CH
2 (3 -N0 2 Ph H 94 6-Cl CF 3
CH
2
CH
2 (4-N0 2 Ph H 6-Cl CF 3
CH
2
CH
2 -(2-NH- 2 )Ph H 96 6-Cl CF 3
CH
2 CH (3-NH 2 )Ph H WO 98/45276 WO 9845276PCTIUS98/06733 97 6-C1 CF 3
CH
2
CH
2 (4 -NH 2 Ph H 98 6-Cl CF 3
CH
2
CH
2 -N~e 2 )Ph H 99 6 -Cl CF 3
CH
2
CH
2 -NMe 2 Ph H 100 6-Cl CF3 CH 2
CH
2 -NMe 2 )Ph H 101 6-Cl CF3 CH 2
CH
2 -2-Pyridyl H 102 6-Cl CF 3
CH
2
CH
2 -3-Pyridyl H 103 6-Cl CF3 CH 2
CH
2 -4-Pyridyl H 104 6-Cl CF 3
CH
2
CH
2 -2-furanyl H 105 6-C1 CF 3
CH
2
CH
2 -3 furanyl H 106 6-Cl CF3 CH 2
CH
2 -4-f uranyl H 107 6 -Cl CF 3
CH
2
CH
2 -3-thienyl H 108 6-Cl CF 3
CH
2
CH
2 -2-oxazolyl H 109 6-Cl CF 3 CH2CH 2 -2-thiazolyl H 110 6-Cl CF 3
CH
2
CH
2 -4-isoxazolyl H il1 6-Cl CF 3 CH2CH 2 -2-imidazoly1 H 112 6-Cl CF 3 C-=C-cycPr CH 3 113 6-Cl CF 3 C-=C-Ph CH 3 114 6-Cl CF 3 CE=C-2-Pyridyl CH 3 115 6-C1 CF 3 C-=C-3-Pyridyl CH 3 116 6-Cl CF 3 C-=C-4-Pyridyl CH 3 117 6-Cl CF 3 C-=C-2-furany1 CH 3 118 6-Cl CF 3 C-=C-3-furany1 CH 3 119 6-Cl CF 3 C=-C-2-thienyl CH 3 120 6-Cl CF 3 C-=C-3-thieny1 CH 3 121 6-Cl CF 3 C=C-cycPr CH 3 122 6-Cl CF 3 C=C-Ph CH 3 123 6-Cl CF 3 C=C-2-Pyridyl CH 3 124 6-C1 CF 3 C=C-3-Pyridyl CH 3 125 6-Cl CF 3 C=C-4-Pyridyl CH 3 126 6-Cl CF 3 C=C-2-furanyl CH 3 127 6-Cl CF 3 C=C-3-furanyl CH3 128 6-Cl CF 3 C=C-2-thienyl CH 3 129 6-Cl CF 3 C=C-3-thienyl CH 3 130 6-Cl CF 3
CH
2
CH
2 -cycPr CH3 WO 98/45276 PCT[US98/06733 131 6-Cl CF 3
CH
2
CH
2 -Ph CH 3 132 6-Cl CF 3
CH
2
CH
2 -2-Pyridyl CH 3 133 6-Cl CF 3
CH
2
C
2 -3-Pyridyl CE 3 134 6-Cl CF 3
CH
2
CH
2 -4-Pyridyl CH 3 135 6-Cl CF 3
CH
2
CH
2 -2-furanyl CH 3 136 6-Cl CF 3
CH
2
C
2 -3-furanyl CE 3 137 6-Cl CF 3
CH
2
CH
2 -2-thienyl CH 3 138 6-Cl CF 3
CH
2
CH
2 -3-thienyl CH 3 139 6-Cl CF 3 C=-C-cycPr CH 2
CH
3 140 6-Cl CF 3 C=-C-Ph CH2CH 3 141 6-Cl CF 3 C-=C-2-Pyridyl CH 2
CH
3 142 6-Cl CF 3 C-=C-3-Pyridyl CH 2
CH
3 143 6-Cl CF 3 C=-C-4-Pyridyl CH 2
CH
3 144 6-Cl CF 3 C-=C-2-furanyl CH 2
CH
3 145 6-Cl CF 3 C-=C-3-furanyl CH 2
CH
3 146 6-Cl CF 3 C-=C-2-thienyl CH 2
CH
3 147 6-Cl CF 3 C=-C-3-thieriyl CH 2
CH
3 148 6-Cl CF 3 C=C-cycPr CH 2
CH
3 149 6-Cl CF 3 C=C-Ph CH 2
CH
3 150 CF 3 C=C-2-Pyridyl CH 2
CH
3 151 6-Cl CF 3 C=C-3-Pyridyl CH 2 CHi 3 152 6-Cl CF 3 C=C-4-Pyridyl CH 2
CH
3 153 6-Cl CF 3 C=C-2-furanyl CH 2
CH
3 154 6-Cl CF 3 C=C-3-furanyl CH 2
CH
3 155 6-Cl CF 3 C=C-2-thienyl CH 2
CH
3 156 6-Cl CF 3 C=C-3-thienyl CH 2
CH
3 157 6-Cl CF 3
CH
2
CH
2 -cycPr CH 2
CH
3 158 -Cl C 3
CH
2
CH
2 -Ph CH 2
CH
3 159 6-Cl CF 3
CH
2
CH
2 -2-Pyridyl CH 2
CH
3 160 6-Cl CF 3
CHCH
2 -3-Pyridy1 CH 2
CH
3 161 6-Cl CF 3 CH2CH 2 -4-Pyridyl CH 2
CH
3 162 6-Cl CF 3
CH
2
CH
2 -2-furanyl CH 2
CH
3 163 6-Cl CF 3 CH2CH 2 -3-furanyl CH 2
CH
3 164 6-Cl CF 3 CH2C 2 -2-thienyl CH 2
CH
3 WO 98/45276 WO 9845276PCT/US98/06733 165 6-cl CF 3 CH2CH 2 -3-thienyl CH2CH 3 166 6 -MeO CF 3 C -CCH 2
CH
2 0H H 167 6-MeO CF 3 C-C -CH (OH) Me H 168 6-MeO CF 3 C-C-(2-C1)Ph H 169 6-MeO CF 3 C-=C-(3-Cl)Ph H 170 6-MeO CF 3 C-=C-(4-C1)Ph H 171 6-Meo CF 3 C-=C-(2-F)Ph H 172 6-MeO CF 3 C-=C-(3-F)Ph H 173 6-MeO CF 3 C=-C-(4-F)Ph H 174 6-Meo CF 3 C=-C-(2-OH)Ph H 175 6-MeO CF 3 C-=C-(3-OH)Ph H 176 6-MeO CF 3 C-=C-(4-OH)Ph H 177 6-Meo CF 3 C-=C-(2-OMe)Ph H 178 6-Meo CF 3 C-=C-(3-OMe)Ph H 179 6-Meo CF 3 (4-OMe) Ph H 180 6-MeO CF 3 C-=C-(2-CN)Ph H 181 6-MeO CF 3 CaC-(3-CN)Ph H 182 6-MeO CF 3 C-=C-(4-CN)Ph H 183 6-Meo CF 3 caC -N0 2 Ph H 184 6-Meo CF 3 C=C (3 -NO 2 )Ph H 185 6-MeO CF 3 (4-NO 2 Ph H 186 6-MeO CF 3 C=C- (2 -NH 2 Ph H 187 6-Meo CF 3 C=C (3 -NH 2 Ph H 188 6-MeO CF 3 C-C (4 -NH 2 Ph H 189 6-MeO CF 3 (2-NMe 2 Ph H 190 6-Meo CF 3 C-C (3 -NMe 2 )Ph H 191 6-Meo CF 3 CC- (4 -Ne 2 Ph H 192 6-MeO CF 3 C=-C-3-Pyridyl H 193 6-Meo CF 3 C=-C-4-Pyridyl H 194 6-Meo CF 3 C=-C-2-furanyl H 195 6-MeO CF 3 C=-C-3 furany1 H 196 6-Meo CF 3 C=-C-2-thieny1 H 197 6-MeO CF 3 C-=C-3-thienyl H 198 6-MeO CF3 C-2C-2-oxazolyl H WO 98/45276 PCTIUS98/06733 199 6-MeO CF 3 C=-C-2-thiazolyl H 200 6-Meo CF 3 C-=C-4-isoxazolyl H 201 6-MeO CF 3 C=-C-2-imidazolyl H 202 6-MeO CF 3 C=CCH2CH2OH H 203 6-Meo CF 3 C=C-CH(OH)Me H 204 6-MeO CF 3 C=C-(2-C1)Ph H 205 6-Meo CF 3 C=C-(3-Cl)Ph H 206 6-MeO CF 3 C=C- (4 -C)Ph H 207 6-MeO CF 3 C=C-(2-F)Ph H 208 6-MeO CF3 C=C-(3-F)Ph H 209 6-MeO CF 3 C=C-(4-F)Ph H 210 6-MeO CF 3 C (2 -OH) Ph H 211 6-MeO CF 3 C (3 -OH) Ph H 212 6-MeO CF 3 C=C- (4-OH) Ph H 213 6-MeO CF 3 C=C-(2-OMe)Ph H 214 6-Meo CF3 C=C- (3 -OMe) Ph H 215 6-Meo CF 3 C=C-(4-OMe)Ph H 216 6-MeO CF 3 C (2 -CN) Ph H 217 6-Meo CF 3 C=C- (3-CN) Ph H 218 6-MeO CF 3 C=C- (4-CN) Ph H 219 6-Meo CF 3 C=C-(2 -N0 2 Ph H 220 6-MeO CF 3 C=C- (3-N0 2 Ph H 221 6-Meo CF 3 C=C- (4-N0 2 Ph H 222 6-Meo CF 3 C=C- (2-NH 2 Ph H 223 6-Meo CF 3 C=C-(3 -NH 2 Ph H 224 6-Meo CF 3 C=C- (4-NH 2 Ph H 225 6-MeO CF 3 C=C- (2 -NMe 2 Ph H 226 6-MeO CF 3 C=C- (3 -NMe 2 Ph H 227 6-Meo CF 3 C=C- (4-NMe2) Ph H 228 6-Meo CF 3 C=C-3-Pyridyl H 229 6-MeO CF 3 C=C-4-Pyridyl H 230 6-MeO CF 3 C=C-2-furanyl H 231 6-MeG CF 3 C=C-3-furanyl H 232 6-Meo CF 3 C=C-2-thienyl H WO 98/45276 WO 9845276PCT[US98/06733 233 6 -MeO CF 3 C=C-3-thienyl H 234 6-MeO CF 3 C=C-2-oxazolyl H 235 6-MeO CF 3 C=C-2-thiazolyl H 236 6-Meo CF 3 C=C-4-isoxazolyl H 237 6-Meo CF 3 C=C-2-imidazolyl H 238 6-MeO CF 3
CH
2
CH
2 -cycPr H 239 6-MeO CF 3
CH
2
CH
2 CH2CH 2 OH H 240 6-Meo CF 3
CH
2
CH
2 -CH (OH) Me H 241 6-MeO CF 3
CH
2
CH
2 -Ph H 242 6-Meo CF 3
CH
2
CH
2 -(2-Cl)Ph H 243 6-MeO CF 3
CH
2
CH
2 -C 1)Ph H 244 6-MeO CF 3
CH
2
CH
2 (4--Cl)Ph H 245 E-MeO CF 3
CH
2
CH
2 Ph H 246 6-MeO CF 3
CH
2
CH
2 Ph H 247 6-MeO CF 3
CH
2
CH
2 -(4-F)Ph H 248 6-MeO CF 3
CH
2
CH
2 -OH)Ph H 249 6-MeO CF 3
CH
2
CH
2 -OH) Ph H 250 6-MeO CF 3
CH
2
CH
2 -OH) Ph H 251 6-Meo CF 3
CH
2
CH
2 -OMe)Ph H 252 6-Meo CF 3
CH
2
CH
2 -OMe) Ph H 253 6-MeO CF 3
CH
2
CH
2 (4-OMe) Ph H 2 54 6-MeO CF 3
CH
2
CH
2 -CN) Ph H 255 6-Meo CF 3
CH
2
CH
2 -CN) Ph H 256 6-MeO CF 3
CH
2
CH
2 -CN)Ph H 257 6-Meo CF 3
CH
2
CH
2 (2-N0 2 Ph H 258 6-Meo CF 3
CH
2
CH
2 -N0 2 Ph H 259 6-MeO CF 3
CH
2
CH
2 -(4-N0 2 )Ph H 260 6-Meo CF 3
CH
2
CH
2
-NH
2 )Ph H 261 6-MeO CF 3
CH
2
CH
2 -(3-NH 2 )Ph H 262 6-MeO CF 3
CH
2
CH
2 (4-NH 2 Ph H 263 6-MeO CF 3
CH
2
CH
2 (2-NMe 2 Ph H 264 6-MeO CF 3
CH
2
CH
2 (3-NMe 2 Ph H 265 6-MeO CF 3
CH
2
CH
2 (4-NMe 2 Ph H 266 6-MeO CF 3
CI-
2
CH
2 -2-Pyridyl H WO 98/45276 WO 9845276PCT[US98/06733 267 6 -MeO CF 3
CH
2
CH
2 -3-Pyridyl H 268 6-MeO CF 3
CH
2
CH
2 -4-Pyridyl H 269 6 -MeO CF 3 CH2CH 2 -2-furanyl H 270 6-MeO CF 3 CH2CH 2 -3-furanyl H 271 6-MeO CF 3
CH
2
CH
2 -4-furanyl H 272 6-MeO CF 3
CH
2
CH
2 -3-thienyl H 273 6-MeO CF 3 CH2CH 2 -2-oxazolyl H 274 6-MeO CF 3
CH
2
CH
2 -2-thiazolyl H 275 6-MeO CF 3
CH
2
CH
2 -4-isoxazolyl H 276 6-Meo CF 3
CH
2
CH
2 -2-imidazolyl H 277 6-MeO CF 3 C-=C-cycPr CH 3 278 6-MeO CF 3 C=-C-Ph CM 3 279 6-MeO CF 3 C-=C-2-Pyridyl
CH
3 280 6-Meo CF 3 C=-C-3-Pyridyl
CM
3 281 6-Meo CF 3 C-=C-4-Pyridyl
CH
3 282 6-MeC CF 3 C-=C-2-furanyl
CH
3 283 6-Meo CF 3 CaC-3 furanyl CH 3 284 6-MeO CF 3 CE=C-2-thieny.
CH
3 285 6-MeO CF 3 C-=C-3-thienyl
CM
3 286 6-Meo CF 3 C=C-cycPr
CH
3 287 6-Meo CF 3 C=C-Ph
CH
3 288 6-MeO CF 3 C=C-2-Pyridyl
CH
3 289 6-Meo CF 3 C=C-3 -Pyridyl CH 3 290 6-MeO CF 3 C=C-4-Pyriciyl
CH
3 291 6-MeG CF 3 C=C-2-furanyl
CH
3 292 6-MeG CF 3 C=C-3-furanyl
CM
3 293 6-Meo CF 3 C=C-2-thienyl
CM
3 294 6-MeG CF 3 C=C-3-thienyl
CM
3 295 6-MeG CF 3 CH2CH 2 -cycPr CM 3 296 6-MeG CF 3
CH
2
CH
2 -Ph CH 3 297 6-MeG CF 3 CH2CH 2 -2-Pyridyl CM 3 298 6-MeG CF 3 CH2CH 2 -3-Pyridy.
CM
3 299 6-MeG CF 3 CH2CH 2 -4-Pyridyl CM 3 300 6-MeG CF 3 CH2CH 2 -2-furanyl CH 3 WO 98/45276 PCTIUS98/06733 301. 6-MeO CF3 CH2CH2-3-furaflyl
CH
3 302 6-MeO CF3 CH 2
CH
2 -2-thienyl -CH 3 303 6-MeO CF3 CH2CH 2 -3-thieny. CH 3 304 6-Meo CF 3 C-=C-cycPr CH2CH 3 305 6-MeO CF 3 c-ph CH 2
CH
3 306 6-Meo CF 3 C=-C-2-Pyridyl
CH
2
CH
3 307 6-MeO CF 3 C=-C-3-Pyridyl
CH
2
CH
3 308 6-MeO CF 3 C=-C-4-Pyridyl
CH
2
CH
3 309 6-MeO CF 3 C-=C-2-furanyl
CH
2
CH
3 310 6-Meo CF 3 C=-C-3-furanyl CH2CH 3 311 6-Meo CF 3 C-=C-2-thienyl
CH
2
CH
3 312 6-Meo CF 3 C-=C-3-thienyl
CH
2
CH
3 313 6-MeO CF 3 C=C-cycpr CH 2
CH
3 314 6-MeO CF 3 C=C-Ph CH 2
CH
3 315 6-MeO CF 3 C=C-2-Pyridy.
CH
2
CH
3 316 6-Meo CF 3 C=C-3-Pyridyl
CH
2
CH-
3 317 6-Meo CF 3 C=C-4-Pyridyl
CH
2
CH
3 318 6-MeO CF 3 C=C-2-furanyl
CH
2
CH
3 319 6-Meo CF 3 C=C-73-furanyl CH2CH 3 320 6-MeO CF 3 C=C-2-thienyl
CH
2
CH
3 321 6-Meo CF 3 C=C-3-thienyl
CH
2
CH
3 322 6-Meo CF 3
CH
2
CH
2 -cycPr CH 2
CH
3 323 6-DKeo CF 3
CH
2
CH
2 -Ph CH 2
CH
3 324 6-Meo CF 3 CH2CH 2 -2-Pyridyl CH 2
CH
3 325 6-Meo CF 3 CH2CH 2 -3-Pyridyl CH2CH 3 326 6-MeO CF 3 CH2CH 2 -4-Pyridyl CH 2
CH
3 327 6-Meo CF 3 CH2CH 2 -2-furanyl CH 2
CH
3 328 6-MeO CF 3
CH
2
CH
2 -3-furanyl CH 2
CH
3 329 6-MeO CF 3
CH
2
CH
2 -2-thienyl CH 2
CH
3 330 6-Meo CF 3
CH
2
CH
2 -3-thienyl CH 2
CH
3 331 5,6-diF CF 3 C-=C-(2-C1)Ph H 332 5,6-diF CF 3 cC--(3-Cl) Ph H 333 5,6-diF CF 3 (4-Cl) Ph H 334 5,6-diF CF 3 C=-C-(2-F)Ph H WO 98/45276 PCT/US98/06733 335 5, 6-diF CF 3 C=-C-(3-F)Ph H 336 5,6-diF CF 3 C=-C-(4-F)Ph H 337 5,6-diF CF 3 C-=C-(2-OH)Ph H 338 5,.6-diF CF 3 C-=C-(3-OH)Ph H 339 5,6-diF CF 3 CE=C- (4-OH) Ph H 340 5,6-diF CF 3 C-=C-(2-OMe)Ph H 341 5,6-diF CF 3 C=C (3 -OMe) Ph H 342 5,6-diF CF 3 (4-OMe) Ph H 343 5,6-diF CF 3 C-=C-(2-CN)Ph H 344 5,6-diF CF 3 C=-3-CrNPh H 345 5,6-diF CF 3 (4-CN) Ph H 346 5,6-diF CF 3 C-=C-(2-NO 2 )Ph H 347 5,6-diF CF 3 C-=C-(3-NO 2 )Ph H 348 5,6-diF CF 3 C-=C-(4-NO 2 )Ph H 349 5,6-diF CF 3 C=C (2 -NH 2 Ph H 350 5,6-aiF CF 3 C2=C-(3--NH2)Ph H 351 5,6-diF CF 3 C-EC- (4-NH 2 Ph H 352 5,6-diF CF 3 C=C- (2 -NMe 2 Ph H 353 5,6-diF CF 3 CE=C-(3-NMe2)Ph H 354 5,6-diF CF 3 C=-C-(4-NMe 2 )Ph H 355 5,6-diF CF 3 CE=C-3-Pyridyl H 356 5,6-diF CF 3 C-=C-4-Pyridyl H 357 5,6-diF CF 3 C-=C-2-furanyl H 358 5,6-diF CF 3 C=-C-3-furanyl H 359 5,6-diF CF 3 C-=C-2-thienyl H 360 5,6-diF CF 3 -thienyl H 361 5,6-diF CF 3 CE=C-2-oxazolyl H 362 5,6-diF CF 3 C2=C-2-thiazolyl H 363 5,6-diF CF 3 C=-C-4-isoxazolyl H 364 5,6-diF CF 3 C=-C-2-imidazolyl H 365 5,6-diF CF 3 C=C- (2-Cl) Ph H 366 5,6-diF CF 3 C=C-(3-Cl)Ph H 367 5,6-diF CF 3 C=C-(4-C1)Ph H 368 5,6-diF CF 3 C=C-(2-F)Ph H WO 98/45276 WO 9845276PCTIUS98/06733 369 5, 6-diF CF3 C=C-(3-F)Ph
H
370 5, 6-diF CF 3 C=C-(4-F)Ph
H
371 5, 6-diF CF 3 C=C- (2 -OH) Ph H 372 5,6-diF CF 3 C=C-(3-OH)Ph
H
373 5,6-diF CF 3 C=C- (4 -OH) Ph H 374- 5.6-diF CF 3 C=C- (2 -OMe) Ph H 375 5,6-diF CF 3 C=C- (3 -OMe) Ph H 376 5,6-diF CF 3 C=C- (4-OMe) Ph H 377 5,6-diF CF 3 C=C- (2 -CN) Ph H 378 5,6-diF CF 3 C=C-(3-CN)Ph
H
379 5,6-diF CF 3 C=C- (4-CN) Ph H 380 5,6-diF CF 3 C=C- (2 -N0 2 Ph H 381 5,6-diF CF 3 C=C- (3 -N0 2 Ph H 382 5,6-diF CF 3 C=C- (4-N0 2 Ph H 383 5,6-diF CF 3 C=C- (2 -NH 2 Ph H 384 5,6-diF CF 3 C=C- (3 -NH 2 Ph H 385 5,6-diF CF 3 C=C- (4-NH 2 Ph H 386 5,6-diF CF 3 C=C- (2 -NMe 2 Ph H 387 5,6-diF CF 3 C=C- (3 -NMe 2 Ph H 388 5,6-di' CF 3 C=C- (4 -NMe 2 Ph H 389 5,6-diF CF 3 C=C-3-Pyridyl
H
390 5,6-di' CF 3 C=C-4-Pyridyl
H
391 5,6-diF CF 3 C=C-2-furanyl
H
392 5,6-diE' CF 3 C=C-3-furanyl
H
393 5,6-diF CF 3 C=C-2-thienyl
H
394 5,6-diF CF 3 C=C-3-thienyl
H
395 5,6-diE' CF 3 C=C-2-oxazolyl
H
396 5,6-di' CF 3 C=C-2-thiazolyl
H
397 5,6-diE' CF 3 C=C-4--isoxazolyl
H
398 5,6-di' CF 3 C=C-2-imidazolyl
H
399 5,6-di' CF 3 CH2CH 2 -cycPr H 400 5,6-diF CF 3
CH
2
CH
2
CH
2
CH
2 OH H 401 5,6-di' CF 3 CH2CH2-CH(OH)Me
H
402 5,6-di' CF 3
CH
2
CH
2 -Ph .H WO 98/45276 PCTJUS98/06733 403 5, 6-diF CF 3
CH
2
CH
2 -CJ1)Ph H 404 5',6-diF CF 3
CH
2
CH
2 (3 -Cl)Ph H 405 5, 6-diF CF 3
CH
2
CH
2 -(4-Cl)Ph H 406 5,6-diF CF 3
CH
2
CH
2 Ph H 407 5,6-diF CF 3
CH
2
CH
2 Ph H 408 5,6-diF CF 3
CH
2
CH
2 Ph H 409 5,6-diF CF 3
CH
2
CH
2 -(2-OH)Ph H 410 5,6-diF CF 3
CH
2
CH
2 -OH) Ph H 411 5,6-diF CF 3
CH
2
CH
2 -(4-OH)Ph H 412 5,6-diF CF 3 CH2CH 2 (2-OMe) Ph H 413 5,6-diF CF 3
CH
2 CH2- (3 -OMe) Ph H 414 5,6-diF CF 3
CH
2
CH
2 -(4-OMe)Ph H 415 5,6-diF CF 3
CH
2
CH
2 -CN)Ph H 416 5,6-diF CF 3
CH
2
CH
2 -(3-CN)Ph H 417 5,6-diF CF 3
CH
2
CH
2 (4-CN) Ph H 418 5,6-diF CF 3
CH
2
CH
2 (2-N0 2 Ph H 419 5,6-diF CF 3
CH
2
CH
2 (3 -N0 2 Ph H 420 5,6-diF CF 3
CH
2
CH
2 (4-N0 2 Ph H 421 5,6-diF CF 3
CH
2
CH
2
-N{
2 Ph H 422 5,6-diF CF 3
CH
2
CH
2
-NH
2 Ph H 423 5,6-diF CF 3
CH
2
CH
2 (4-NH 2 Ph H 424 5,6-diF CF 3 CH2CH2- (2-NMe 2 Ph H 425 5,6-diF CF 3
CH
2
CH
2 -(3-NMe 2 )Ph H 426 5,6-diF CF 3
CH
2
CH
2 (4-NMe 2 Ph H 427 5,6-diF CF 3
CH
2
CH
2 -2-Pyridyl H 428 5,6-diF CF 3
CH
2
CH
2 -3-Fyridyl H 429 5,6-diF CF 3
CH
2
CH
2 -4-Pyridyl H 430 5,6-diF CF 3
CH
2
CH
2 -2-furanyl H 431 5,6-diF CF 3
CH
2
CH
2 -3-furanyl H 432 5,6-diF CF 3
CH
2
CH
2 -2-thienyl H 433 5,6-diF CF 3
CH
2
CH
2 -3-thienyl H 434 5,6-diF CF 3
CH
2
CH
2 -2-oxazolyl H 435 5,6-diF CF 3
CH
2
CH
2 -2-thiazolyl H 436 5,6-diF CF 3
CH
2
CH
2 -4-isoxazolyl H WO 98/45276 WO 9845276PCTIUS98/06733 437 5,6-diF CF 3
CH
2
CH
2 -2-iinidazolyl H 438 5,6-diF CF 3 C-=C-cycPr CE 3 439 5,6-diF CF 3 C-=C-2-Pyridyl CH 3 440 5,6-diF CF 3 C-=C-3-Pyridyl CE 3 441 5,6-diF CF 3 C-=C-4-.Pyridyl
CH
3 442 5,6-diF CF 3 C-=C-2-furanyl
CH
3 443 5,6-diF CF 3 C-=C-3-furanyl CE 3 444 5,6-diF CF 3 CE=C-2-thienyl
CH
3 445 5,6-diF CF 3 CE-C-3-thienyl
CH
3 446 5,6-diF CF 3 C=C-cycPr
CE
3 447 5,6-diF CF 3 C=C-2-Pyridyl
CE
3 448 5,6-diF CF 3 C=C-3-Pyridyl
CH
3 449 5,6-diF CF 3 C=C-4-Pyridyl
CE
3 450 5,6-diF CF 3 C=C-2-furanyl
CE
3 451 5,6-diF CF 3 C=C-3-furanyl
CE
3 452 5,6-diF CF 3 C=C-2-thienyl
CE
3 453 5,6-diF CF 3 C=C-3-thienyl
CE
3 454 5,6-diF CF 3
CH
2
CH
2 -cycPr CE 3 455 5,6-diF CF 3
CH
2
CH
2 -Ph CE 3 456 5,6-diF CF 3
CH
2
CH
2 -2-Pyridyl CE 3 457 5,6-diF CF 3 CH2CH2-3-Pyridy1
CE
3 458 5,6-diF CF 3
CH
2
CE
2 -4-Pyridyl CE 3 459 5, 6-diF CF 3
CH
2
CE
2 -2--furanyl CH 3 460 5,6-diF CF 3
CH
2
C
2 -3-furanyl CE 3 461 5,6-diF CF 3
CH
2 C2-2-thienyl
CE
3 462 5,6-diF CF 3
CH
2
C
2 -3-thienyl CE 3 463 5,6-diF CF 3 CE=C-cycPr CE 2
CH
3 464 5,6-diF CF 3 C-=C-Ph CE 2
CH
3 465 5,6-diF CF 3 C-=C-2-Pyridyl
CH
2
CH
3 466 5,6-diF CF 3 C-=C-3-Pyridy1
CH
2
CH
3 467 5,6-diF CF 3 C-=C-4-Pyridyl
CH
2
CH
3 468 5,6-diF CF 3 C=-C-2-furanyl
CH
2
CH
3 469 5,6-diF CF 3 C-=C-3-furanyl
CE
2
CH
3 470 5,6-djF CF 3 C-=C-2-thienyl
CE
2
CH
3 WO 98/45276 WO 9845276PCT/US98/06733 471 472 4.73 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 5, 6-diF 5, 6 -diF 5, 6-diF 5, 6 -diF 5, 6 -diF 5, 6-diF 5,6-diF 5,6-diF 5,6-diF 5, 6-diF 5,6-diF 5, 6-diF 5, 6-diF 5, 6-diF 5, 6 -diF 5, 6 -diF 5,6-diF 5, 6-diF 5, 6 -diF 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6 -diC 1 5,6-diCl 5, 6-diG).
5, 6-diCi 5, 6-diCl 5,6-diCi 5, 6-diCi 5, 6-diG).
5, 6-diG).
5,6-diG).
5, 6-diG).
5,6-diCl
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=-C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2
CH
2 -2 -Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
GH
2 -4 -Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 -3 -furanyl
CH
2
CH
2 -2 -thienyl
CH
2
CH
2 -3 -thieny).
(2-Cl) Ph CaC-(3-Cl) Ph Ph (2-F)Ph C=-C-(3-F)Ph C=-C-(4-F)Ph (2-OH) Ph Ph (4-OH) Ph C=-C-(2-OMe) Ph -OMe) Ph (4 -OMe) Ph (2-CN) Ph (3-CN) Ph CE=C- (4-CN) Ph
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
WO 98/45276 WO 9845276PCT/US98/06733 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCl 5, 6-diCl 5, 6-diCl 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-did].
5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCl 5, 6-diCi 5, 6-diCi 5, 6-did].
5, 6-diCi 5, 6-diCi 5, 6-diC).
5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 (2 -NO 2 Ph C C- (3 -N0 2 Ph C=-C-(4-NO 2 )Ph (2 -NTH 2 Ph (3 -NH 2 Ph (4-NH 2 Ph (2 -NMe 2 Ph (3 -NMe 2 Ph (4 -NMe 2 Ph C-=C-3 -Pyridyl C-=C-4 -Pyridyl C-=C-2 -furanyl C=-C-3 -furanyl C-=C-2-thieny1 C=-C-3 -thienyl CE-C-2 -oxazoly2.
C-=C-2 -thiazolyl CE=C-4 -isoxazolyl C-=C-2 -imidazolyl C=C- (2-Cl) Ph C=C- (3 -Cl) Ph C=C- (4-Cl) Ph C=C- Ph C=C- Ph C=C- Ph C=C- (2-OH) Ph C=C- (3 -OH) Ph C=C- (4 -OH) Ph C=C- (2-OMe) Ph C=C- (3-OMe) Ph C=C- (4-OMe) Ph C=C- (2 -CN) Ph C=C- (3 -CN) Ph C=C- (4-CN) Ph WO 98/45276 WO 9845276PCTIUS98/06733 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCl 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-did].
5, 6-didl 5, 6-did].
5, 6-diCi
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=C- (2-NO 2 Ph C=C- (3 -NO 2 Ph C=C- (4-NO 2 Ph C=C- (2-NH 2 Ph C=C-(3-NH 2 Ph C=C- (4-NH 2 Ph C=C- (2-NMe2) Ph C=C- (3 -NMe 2 Ph C=C- (4-NMe2) Ph C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl C=C-2 -oxazolyl C=C-2 -thiazolyl C=C-4 -isoxazolyl C=C-2 -imidazolyl
CH
2
CH
2 -cycPr
CH
2
CH
2
CH
2
CH
2
OH
CH
2
CH
2 -CH (OH)Me
CH
2
CH
2 -Ph
CH
2
CH
2 (2-Cl) Ph
CH
2 CH2 (3 -Cl1) Ph
CH
2
CH
2 (4-Cl) Ph
CH
2
CH
2 (2 Ph
CH
2
CH
2 (3 Ph CH2CH 2 Ph
CH
2
CH
2 (2-OH) Ph
CH
2
CH
2 (3-OH) Ph
CH
2
CH
2 (4 -OH) Ph
CH
2
CH
2 (2 -OMe) Ph CH2CH 2 (3 -OMe) Ph WO 98/45276 WO 9845276PCTIUS98/06733 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 5, 6-diCl 5, 6-diCJ.
5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCJ.
5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-didl
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2
CH
2 (4-OMe) Ph
CH
2
CH
2 (2 -CN) Ph
CH
2
CH
2 (3 -CN) Ph CH2CH 2 (4-CN) Ph
CH
2
CH
2 (2 -NO 2 Ph
CH
2
CH
2 (3-NO 2 Ph
CH
2
CH
2 (4 -NO 2 Ph
CH
2
CH
2 (2 -NH 2 Ph
CH
2
CH
2 (3 -NH 2 Ph
CH
2
CH
2 (4-NH 2 Ph
CH
2
CH
2 (2-NMe 2 Ph
CH
2
CH
2 (3-NMe 2 Ph
CH
2
CH
2 (4-NMe 2 )Ph
CH
2
CH
2 Pyridyl
CH
2
CH
2 -3 -Pyridyl CH2CH-4-Pyridyl
CE
2
CH
2 furanyl
CH
2
CH
2 furanyl CH2CH2-2-thienyJ.
CH
2
CH
2 thienyl
CH
2
CH
2 -2 -oxazolyl
CH
2
CH
2 -2 -thiaizoly.
CH
2
CH
2 -4 -isoxazoly].
CE-
2
CH
2 -2 -imidazolyl C=-C-cycPr C=-C-2 -Pyridyl C=-C-3 -Pyridyl C=-C-4 -Pyridyl CaC-2 -furanyl CE-C-3 -furanyl C-=C-2 -thienyl C-=C-3 -thienyl C=C-cycPr C=C-2 -Pyridyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CE
3
CE
3
CE
3
CE
3
CE
3
CE
3
CE
3
CE
3
CE
3
CH
3 WO 98/45276 WO 9845276PCTIUS98/06733 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 5,6-diCl 5, 6-diCl 5, 6-diCi 5, 6-diCl 5, 6-diCl 5, 6-diCi 5, 6-diCi 5, 6-diCl 5, 6-diCi 5, 6-diC).
5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diC2.
5, 6-diCi 5, 6-diCi 5, 6 -diC 1 5, 6-diCi 5, 6-diCl 5, 6-diCi 5,6-diCi 5, 6-diCJ.
5, 6-diCi 5, 6-diCi 5, 6 -diC 1 5, 6-diC).
5, 6-diCi 5, 6-diCi 5, 6-didl 5, 6-diCi 5, 6-diC).
5, 6-diCi 5, 6-diCi 5, 6-diCl CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=C-3 -Pyridyl C=C-4-Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C thienyl C=C-3 -thienyl
CH
2 CH2-cycPr
CH
2
CH
2 -Ph
CH
2
CH
2 -2 -Pyridyl
CH
2 CH2-3 -Pyridyl
CH
2
CH
2 Pyridyl
CH
2
CH
2 furanyl
CH
2 CH2 furanyl
CH
2
CH
2 thienyJ.
CH
2
CH
2 -3 -thienyl C=-C-cycPr C2-C-Ph C-=C-2 -Pyridyl CE=C-3 -Pyridyj.
C-=C-4 -Pyridyl C-=C-2 -furanyl C-=C-3 -furanyl C-=C-2-thienyl CE=C-3 -thienyl C=C-cycPr C=C- Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CU
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CU
3
CH
3
CH
3
CH
3
CU
3
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 WO 98/45276 WO 9845276PCTIUS98/06733 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 5, 6-didl 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCi 5, 6-diCl 5, 6-diCi 5, 6-diCl 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F 6-F
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3 CF3 CF3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2
CH
2 -Ph
CH
2
CH
2 Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 -3 -furanyl
CH
2
CH
2 thienyl
CH
2
CH
2 -3 -thienyl
C-=CCH
2
CH
2
OH
C-=C-CH (OH) Me (2-Cl) Ph Ph Ph Ph C=-C-(3-F)Ph Ph (2 -OH) Ph C2=C- (3-OH) Ph C2=C-(4-OH)Ph C2=C- Ph C-=C-(3-OMe) Ph Ph (2-CN) Ph (3-CN) Ph (4-CN) Ph C-=C-(2-NO 2 Ph (3-NO 2 Ph (4-NO 2 Ph (2-NH 2 Ph (3 -NH 2 Ph (4-NH 2 Ph CaC- (2 -NMe 2 Ph (3 -NMe 2 Ph CmC- (4 -NMe 2 Ph CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
WO 98/45276 WO 9845276PCTIUS98/06733 675 6-F CF 3 C-=C-3-Pyridyl H 676 6-F CF 3 CE=C-4-Pyridyl H 677 6-F CF 3 C-=C-2-furany. H 678 6-F CF 3 C=-C-3-furaiyl H 679 6-F CF 3 C-=C-2-thienyl H 680 6-F CF 3 C=-C-3-thienyl H 681 6-F CF 3 C-=C-2-oxazolyl H 682 6-F CF 3 C=-C-2-thiazoly1 H 683 6-F CF 3 C-=C-4-isoxazolyl H 684 6-F CF 3 C=-C-2-imidazolyl H 685 6-F CF 3
C=CCH
2
CH
2 OH H 686 6-F CF 3 C=C-CH(OH)Me H 687 6-F CF 3 C=C- (2-Cl) Ph H 688 6-F CF 3 C=C-(3-Cl)Ph H 689 6-F CF 3 C=C- (4-Cl) Ph H 690 6-F CF 3 C=C-(2-F)Ph H 691 6-F CF 3 C=C-(3-F)Ph H 692 6-F CF 3 C=C-(4-F)Ph H 693 6-F CF 3 C=C- (2-OH) Ph H 694 6-F CF 3 C=C-(3-OH)Ph H 695 6-F CF 3 C=C-(4-OH)Ph H 696 6-F CF 3 C=C-(2-OMe)Ph H 697 6-F CF 3 C=C- (3-OMe) Ph H 698 6-F CF 3 C=C-(4-OMe)Ph H 699 6-F CF 3 C=C-(2-CN)Ph H 700 6-F CF 3 C=C- (3 -CN) Ph H 701 6-F CF 3 C=C-(4-CN)Ph H 702 6-F CF 3 C=C-(2-N0 2 )Ph H 703 6-F CF 3 C=C- (3-NO 2 Ph H 704 6-F CF 3 C=C-(4-N0 2 )Ph H 705 6-F CF 3 C=C- (2-NH 2 Ph H 706 6-F CF 3 C=C- (3 -NH 2 Ph H 707 6-F CF 3 C=C-(4-NH 2 )Ph H 708 6-F CF 3 C=C-(2-NMe 2 )Ph H WO 98/45276 WO 9845276PCTIUS98/06733 709 6-F CF3 C=C-(3-NMe 2 )Ph H 710 6-F CF 3 C=C-(4-NMe 2 )Ph H 711 6-F CF 3 C=C-3-Pyridyl H 712 6-F CF3 C=C-4-Pyridyl H 713 6-F CF 3 C=C-2-furanyl H 714 6-F CF 3 C=C-3-furanyl H 715 6-F CF 3 C=C-2-thienyl H 716 6-F CF 3 C=C-3-thienyl H 717 6-F CF 3 C=C-2-oxazolyl H 718 6-F CF3 C=C-2-thiazolyl H 719 6-F CF 3 C=C-4-isoxazolyl H 720 6-F CF 3 C=C-2-imidazolyl H 721 6-F CF 3 CH2CH 2 -cycPr H 722 6-F CF 3
CH
2
CH
2
CH
2
CH
2 OH H 723 6-F CF 3
CH
2
CH
2 -CH (OH) Me H 724 6-F CF 3
CH
2
CH
2 -C1)Ph H 725 6-F CF 3
CH
2
CH
2 (3 -Cl)Ph H 726 6-F CF 3
CH
2
CH
2 -C1) Ph H 727 6-F CF3 CH 2
CH
2 2 Ph H 728 6-F CF 3
CH
2
CH
2 Ph H 729 6-F CF 3
CH
2
CH
2 Ph H 730 6-F CF 3
CH
2
CH
2 (2 -OH) Ph H 731 6-F CF 3
CH
2
CH
2 (3 -OH) Ph H 732 6-F CF 3
CH
2
CH
2 (4-OH) Ph H 733 6-F CF3 CH 2
CH
2 (2 -OMe) Ph H 734 6-F CF 3
CH
2
CH
2 (3 -OMe) Ph H 735 6-F CF 3
CH
2
CH
2 (4-OMe) Ph H 736 6-F CF3 CH 2
CH
2 -CN) Ph H 737 6-F CF 3
CH
2
CH
2 -CN) Ph H 738 6-F CF 3
CH
2
CH
2 -CN) Ph H 739 6-F CF 3
CH
2
CH
2 -N0 2 Ph H 740 6-F CF 3
CH
2
CH
2 (3 -N0 2 Ph H 741 6-F CF 3
CH
2
CH
2 (4-N0 2 Ph H 742 6-F CF 3
CH
2
CH
2 (2 -NH 2 Ph H WO 98/45276 WO 9845276PCTIUS98/06733 743 6-F CF 3
CH
2
CH
2
-NH
2 Ph H 744 6-F CF 3
CH
2
CH
2 -(4-NH 2 )Ph H 745 6-F CF 3
CH
2
CH
2 (2 -NMe 2 Ph H 746 6-F CF 3
CH
2
CH
2 -(3-NMe 2 )Ph H 747 6-F CF 3
CH
2
CH
2 -(4-NMe 2 )Ph H 748 6-F CF 3
CH
2
CH
2 -3-Pyridyl H 749 6-F CF 3
CH
2
CH
2 -4-Pyridyl H 750 6-F CF 3
CH
2
CH
2 -2-furanyl H 751 6-F CF 3
CH
2
CH
2 -3-furanyl H 752 6-F CF 3
CH
2
CH
2 -2-thienyl H 753 6-F CF 3
CH
2
CH
2 -3-thienyl H 754 6-F CF 3
CH
2
CH
2 -2-oxazolyl H 755 6-F CF 3
CH
2
CH
2 -2-thiazoly. H 756 6-F CF 3
CH
2
CH
2 -4-isoxazoly. H 757 6-F CF 3
CH
2
CH
2 -2-imidazolyl H 758 6-F CF 3 C=-C-cycPr CH 3 759 6-F CF 3 C-C-iPr CH 3 760 6-F CF 3 CE=C-Pr CH 3 761 6-F CF 3 C-=C-Bu CH 3 762 6-F CF 3 C=-C-iBu CH 3 763 6-F CF 3 C-CtBu CH 3 764 6-F CF 3 C-=C-Et CH 3 765 6-F CF 3 C-=C-Me CH 3 766 6-F CF 3 C=-C-Ph CH 3 767 6-F CF 3 cac-2-Pyridyl CH 3 768 6-F CF 3 CE=C-3-Pyridyl CH 3 769 6-F CF 3 CE-C-4-Pyridyl CH 3 770 6-F CF 3 C-=C-2-furanyl CH 3 771 6-F CF 3 CaC-3-furanyl CH 3 772 6-F CF 3 C-=C-2-thienyl CH 3 773 6-F CF 3 CE=C-3-thienyl CH 3 774 6-F CF 3 C=C-cycPr CH 3 775 6-F CF 3 C=C-iPr CH 3 776 6-F CF 3 C=C-Pr CH 3 WO 98/45276 WO 9845276PCTIUS98/06733 777 6-F CF 3 C=C-Bu CH 3 778 6-F CF 3 C=C-iBu CH 3 779 6-F CF 3 C=C-tBu CH 3 780 6-F CF3 C=C-Et CH 3 781 6-F CF 3 C=C-Me CH 3 782 6-F CF 3 C=C-Ph CH 3 783 6-F CF 3 C=C-2-Pyridyl CH 3 784 6-F CF 3 C=C-3-Pyridyl CE 3 785 6-F CF 3 C=C-4-Pyridyl CH 3 786 6-F CF3 C=C-2-furanyl CH 3 787 6-F CF 3 C=C-3-furanyl CH 3 788 6-F CF 3 C=C-2-thienyl CH 3 789 6-F CF 3 C=C-3-thienyl CE 3 790 6-F CF 3
CH
2
CH
2 -cycPr CH 3 791 6-F CF 3
CH
2
CH
2 -Ph CE 3 792 6-F CF 3
CH
2
C
2 -2-Pyridyl CE 3 793 6-F CF 3
CH
2
C
2 -3-Pyridyl CH 3 794 6-F CF 3
CH
2
C
2 -4-Pyridyl CE 3 795 6-F CF 3 CHC2-2-furanyl CH3 796 6-F CF 3
CH
2
C
2 -3-furanyl CE 3 797 6-F CF 3
CH
2
C
2 -2-thienyl CE 3 798 6-F CF 3
CH
2
C
2 -3-thienyl CE 3 799 6-F CF 3 C-=C-cycPr CH 2
CH
3 800 6-F CF 3 C-=C-Ph CH 2
CH
3 801 6-F CF 3 C-=C-2-Pyridyl CH 2
CH
3 802 6-F CF 3 C-=C-3-Pyridyl CH 2
CH
3 803 6-F CF 3 C-=C-4-Pyridyl CH 2
CH
3 804 6-F CF 3 C=-C-2-furanyl CH 2
CH
3 805 6-F CF 3 C=-C-3-furanyl CH 2
CH
3 806 6-F CF 3 C-=C-2-thienyl CH 2
CH
3 807 6-F CF 3 C-=C-3-thienyl CH 2
CH
3 808 6-F CF 3 C=C-cycPr CH 2
CH
3 809 6-F CF 3 C=C-Ph CE 2
CH
3 810 6-F CF 3 C=C-2-Pyridyl CH 2
CH
3 WO 98/45276 WO 9845276PCT/US98/06733 811 6-F CF 3 C=C-3-Pyridyl CH2CH 3 812 6-F CF3 C=C-4-Pyridyl CH2CH 3 813 6-F CF 3 C=C-2-furanyl
CH
2
CH
3 814 6-F CF 3 C=C-3-furanyl
CH
2
CH
3 815 6-F CF 3 C=C-2-thienyl
CH
2
CH
3 816 6-F CF 3 C=C-3-thienyl
CH
2
CH
3 817 6-F CF 3
CH
2
CH
2 -cycPr CH2CH 3 818 6-F CF 3
CH
2
CH
2 -Ph CH 2
CH
3 819 6-F CF 3
CH
2
CH
2 -2-Pyridyl CH 2
CH
3 820 6-F CF 3
CH
2
CH
2 -3-Pyridyl
CH
2
CH
3 821 6-F CF 3
CH
2
CH
2 -4-Pyridyl CH 2
CH
3 822 6-F CF 3
CH
2
CH
2 -2-furanyl CH 2
CH
3 823 6-F CF 3
CH
2
CH
2 -3-furanyl CH 2
CH
3 824 6-F CF 3
CH
2
CH
2 -2-thienyl CH 2
CH
3 825 6-F CF 3
CH
2
CH
2 -3-thienyl
CH
2
CH
3 826 5-Cl CF 3 C-=C-cycPr H 827 5-Cl, CF 3
CE=CCH
2
CH
2 0H H 828 S-Cl CF 3 C2=C-CH(OH)Me H 829 5-Cl CF 3 C-Ph H 830 5-Cl CF 3 C=C- (2 -Cl)Ph H 831 5-Cl CF 3 CEC-(3-Cl)Ph
H
832 5-Cl CF 3 (4-Cl) Ph H 833 5-cl CF 3 C-=C-(2-F)Ph H 834 5-Cl CF 3 C-=C-(3-F)Ph H 835 5-Cl CF 3 CaC-(4-F)Ph
H
836 5-Cl CF 3 C=C- (2 -OH)Ph H 837 5-Cl CF 3 C-C- (3 -OH)Ph H 838 5-Cl CF3 C-=C-(4-OH)Ph H 839 5-Cl CF 3 C-C- (2 -OMe) Ph H 840 5-Cl CF 3 C=C- (3 -OMe) Ph H 841 5-Cl CF 3 C-=C-(4-OMe)Ph
H
842 5-Cl CF 3 C-=C-(2-CN)Ph H 843 5-Cl CF 3 C=C- (3 -CN)Ph H 844 5-Cl CF 3 C=-C-(4-CN)Ph H WO 98/45276 WO 9845276PCTIUS98/06733 845 5-Cl CF3 C=-C-(2-NO 2 )Ph H 846 5-Cl CF 3 C-C- (3 -N0 2 )Ph H 847 5-Cl CF 3 C-=C-(4-NO 2 )Ph H 848 5-Cl CF 3 C-C- (2 -NH 2 Ph H 849 5-Cl CF 3 C=C- (3 -NH 2 Ph H 850 -5-Cl CF 3 CE=C-(4-NH 2 )Ph H 851 5-Cl CF 3 C-C- (2 -NMe 2 Ph H 852 5-C1 CF 3 C=C- (3 -NMe 2 Ph H 853 5-Cl CF 3 (4-NMe 2 Ph H 854 5-Cl CF 3 C-=C-2-Pyridyl H 855 5-Cl CF 3 C-=C-2-Pyridyl H 856 5-Cl CF 3 C-=C-3-Pyridyl H 857 5-Cl CF 3 C=-C-4-Pyridy1 H 858 5-Cl CF 3 C-=C-2 furanyl H 859 5-Cl CF 3 C=-C-3 furany1 H 860 5-C1 CF 3 C-=C-2-thienyl H 861 5-Cl CF 3 C-=C-3 thieriyl H 862 5-Cl CF 3 C-=C-2-oxazolyl H 863 5-Cl CF 3 C2=C-2-thiazolyl H 864 5-Cl CF 3 C-=C-4-isoxazolyl H 865 5-Cl CF 3 C=-C-2-imidazolyl H 866 5-Cl CF 3 C=C-cycPr H 867 5-Cl CF 3
C=CCH
2
CH
2 OH H 868 5-Cl CF 3 C=C-CH (OH) Me H 869 5-Cl CF 3 C=C-Ph H 870 5-Cl CF 3 C=C- (2 -Cl)Ph H 871 5-Cl CF 3 C=C-(3-Cl)Ph H 872 5-Cl CF 3 C=C-(4-Cl)Ph H 873 5 -Cl CF 3 C=C-(2-F)Ph H 874 5-Cl CF 3 C=C-(3-F)Ph H 875 5-Cl CF 3 C=C-(4-F)Ph H 876 5-Cl CF 3 C=C- (2 -OH) Ph H 877 5-Cl CF 3 C=C- (3 -OH) Ph H 878 5-Cl CF 3 C=C- (4 -OH) Ph H WO 98/45276 WO 9845276PCTIUS98/06733 879 5 -Cl CF 3 C=C-(2-OMe)Ph H 880 5-Cl CF 3 C=C-(3-OMe)Ph H 881 5-Cl CF 3 C=C- (4-OMe) Ph H 882 5-Cl CF 3 C=C- (2 -CN) Ph H 883 5-Cl CF 3 C=C-(3-CN)Ph H 884 5-Cl CF 3 C=C- (4-CN) Ph H 885 5-Cl CF3 C=C-(2-N0 2 )Ph H 886 5-Cl CF 3 C=C- (3-N0 2 Ph H 887 5-Cl CF 3 C=C- (4-N0 2 Ph H 888 5-Cl CF 3 C=C-(2-NH2)Ph H 889 5-Cl CF 3 c=C-(3-NH 2 )Ph H 890 5-Cl CF 3 C=C- (4-NH2) Ph H 891 5-Cl CF 3 C=C-(2-NMe2)Ph H 892 5-Cl CF 3 C=C- (3 -NMe 2 Ph H 893 5-Cl CF 3 C=C- (4-NMe 2 Ph H 894 5-Cl CF 3 C=C-2-Pyridyl H 895 5-Cl CF 3 C=C-2-Pyridyl H 896 5-Cl CF 3 C=C-3-Pyridyl H 897 5-Cl CF 3 C=C-4-Pyridyl H 898 5-Cl CF 3 C=C-2-furanyl H 899 5-Cl CF 3 C=C-3-furaiyl H 900 5-Cl CF 3 C=C-2-thienyl H 901 5-Cl CF 3 C=C-3-thienyl H 902 5-Cl CF 3 C=C-2-oxazolyl H 903 5-Cl CF 3 C=C-2-thiazolyl H 904 5-Cl CF 3 C=C-4-isoxazolyl H 905 5-Cl CF 3 C=C-2-imidazolyl H 906 5-Cl CF 3 CI-2CH 2 -cycPr H 907 5-Cl CF 3
CH
2
CH
2
CH
2
CH
2 0H H 908 5-Cl CF 3
CH
2
CH
2 -CH(QH)Me H 909 CF 3 CH2CH 2 Ph H 910 5-Cl CF 3
CH
2
CH
2 (2-C1) Ph H 911 5-Cl CF 3
CH
2
CH
2 (3 -C1)Ph H 912 5-Cl CF 3
CII
2
CH
2 (4-Cl) Ph H WO 98/45276 WO 9845276PCTIUS98/06733 913 5-Cl CF 3
CH
2
CH
2 F)Ph H 914 5 CF 3
CH
2
CH
2 -F)Ph H 915 5-Cl CF 3
CH
2
CH
2 -(4-F)Ph H 916 5-Cl CF 3
CH
2
CH
2 -(2-OH)Ph H 917 5-Cl CF 3
CH
2
CH
2 -OH) Ph H 918 5-Cl CF 3
CH
2
CH
2 -OH) Ph H 919 5-Cl CF 3
CH
2
CH
2 -(2-OMe)Ph H 920 5-Cl CF 3
CH
2
CH
2 (3 -OMe) Ph H 921 5-Cl CF 3
CH
2
CH
2 -(4-OMe)Ph H 922 5-Cl CF 3
CH
2
CH
2 -(2-CN)Ph H 923 5-Cl CF 3
CH
2
CH
2 -(3-CN)Ph H 924 5-Cl CF 3
CH
2
CH
2 -(4-CN)Ph H 925 5-Cl CF 3
CH
2
CH
2 -N0 2 Ph H 926 5-Cl CF 3
CH
2
CH
2 -N0 2 Ph H 927 5-Cl CF 3
CH
2
CH
2 -(4-N0 2 )Ph H 928 5-Cl CF 3 CH2CH 2 -NH2) Ph H 929 5-Cl CF 3
CH
2
CH
2 (3 -NH 2 Ph H 930 5-Cl CF 3
CH
2
CH
2
-NH
2 Ph H 931 5-Cl CF 3
CH
2
CH
2 -NMe 2 Ph H 932 5-Cl CF 3
CH
2
CH
2 -(3-NMe 2 )Ph H 933 5-Cl CF 3
CH
2
CH
2 -(4-NMe 2 )Ph H 934 5-Cl CF 3
CH
2
CH
2 -2-Pyridyl H 935 5-Cl CF 3
CH
2
CH
2 -3-Pyridyl H 936 5-Cl CF 3
CH
2
CH
2 -4-Pyridyl H 937 5-Cl CF 3
CH
2
CH
2 -2-furanyl H 938 5-Cl CF 3
CH
2
CH
2 -3-furanyl H 939 5-Cl CF 3
CH
2
CH
2 -2-thienyl H 940 5-Cl CF 3
CH
2
CH
2 -3-thienyl H 941 5 -Cl CF 3
CH
2
CH
2 -2-oxazolyl H 942 5-Cl CF 3
CH
2
CH
2 -2-thiazolyl H 943 5-Cl CF 3
CH
2
CH
2 -4-isoxazolyl H 944 5-Cl CF 3
CH
2
CH
2 -2-imidazolyl H 945 5-Cl CF 3 C-=C-cycPr CH 3 946 5-Cl CF 3 C-=C-Ph CH 3 WO 98/45276 PCTUS98/06733 947 5 -Cl CF 3 C=-C-2-Pyridyl
CH
3 948 5-Cl
CF
3 C-=C-3-Pyridyl
CH
3 949 5-Cl CF 3 C=-C-4-Pyridyl
CE
3 950 5-cl CF 3 C-=C-2-furanyl
CE
3 951 5-Cl
CF
3 C=-C-3-furanyl
CE
3 952 5-Cl
CF
3 C-=C-2-thienyl
CE
3 953 5-Cl
CF
3 C-=C-3-thienyl
CE
3 954 5-Cl
CF
3 C=C-cycPr
CH
3 955 5-Cl
CF
3 C=C-Ph
CH
3 .956 5-Cl CF 3 C=C-2-Pyridyl
CH
3 957 5-Cl
CF
3 C=C-3-Pyridyl
CH
3 958 5-Cl
CF
3 C=C-4-Pyridyl
CH
3 959 5-Cl
CF
3 C=C-2-furanyl
CH
3 960 5-Cl
CF
3 C=C-3-furanyl
CH
3 96.1 5-Cl
CF
3 C=C-2-thienyl
CH
3 962 5-Cl
CF
3 C=C-3-thienyl.
CH
3 963 5-Cl
CF
3
CH
2
CH
2 -cycPr
CH
3 964 5-Cl
CF
3
CH
2
CH
2 -Ph
CE
3 965 5-Cl
CF
3
CH
2
CH
2 -2-Pyridyl
CH
3 966 5-Cl
CF
3 CH2CH 2 -3-Pyridyl
CH
3 967 5-Cl
CF
3 CH2CH 2 -4-Pyridyl
CH
3 968 5-Cl
CF
3 CE2CH2-2-furanyl
CH
3 969 5-Cl
CF
3 CH2CH 2 -3-furanyl
CH
3 970 5-Cl
CF
3 CE2CH2-2-thienyl
CE
3 971 5-Cl
CF
3 CH2CH 2 -3-thienyl
CE
3 972 5-Cl
CF
3 C=-C-cycPr
CH
2
CH
3 973 5-Cl
CF
3 CR=C-Ph
CH
2
CH
3 974 5-Cl
CF
3 CE=C-2-Pyridyl
CH
2
CH
3 975 5-Cl
CF
3 C=-C-3-Pyridyl
CH
2
CH
3 976 5-Cl
CF
3 C-=C-4-Pyridyl
CH
2
CH
3 977 5-Cl
CF
3 C=-C-2-furanyl
CH
2
CH
3 978 5-Cl
CF
3 C=-C-3-furanyl
CH
2
CH
3 979 5-Cl
CF
3 C-=C-2-thienyl
CE
2
CH
3 980 5-Cl
CF
3 C=-C-3-thienyl
CH
2
CH
3 WO 98/45276 WO 9845276PCTIUS98/06733 981 5-Cl CF3 C=C-cycPr CH 2
CH
3 982 5-Cl CF 3 C=C-Ph CH 2
CH
3 983 5-cl CF 3 C=C-2-Pyridyl CH2CH 3 984 5-Cl CF 3 C=C-3-Pyridyl CH2CH 3 985 5-cl CF 3 C=C-4-Pyridyl CH 2
CH
3 986 5-Cl CF 3 C=C-2-furanyl CH 2
CH
3 987 5-Cl CF 3 C=C-3-furanyl CH 2
CH
3 988 5-Cl CF 3 C=C-2-thienyl CH 2
CH
3 989 5-Cl CF 3 C=C-3-thienyl CH 2
CH
3 990 5-Cl CF 3
CH
2
CH
2 -cycPr CH 2
CH
3 991 5-Cl CF 3
CH
2
CH
2 -Ph CH 2
CH
3 992 5-Cl CF 3
CH
2
CH
2 -2-Pyridyl CH 2
CH
3 993 5-Cl CF 3
CH
2
CH
2 -3-Pyridyl CH2CH 3 994 5-Cl CF 3
CH
2
CH
2 -4-Pyridyl CH 2
CH
3 995 5-Cl CF 3
CH
2
CH
2 -2-furanyl CH 2
CH
3 996 5-Cl CF 3
CH
2 CH2-3-furanyl CH 2
CH
3 997 5-Cl CF 3
CH
2
CH
2 -2-thienyl CH 2
CH
3 998 5-Cl CF 3
CH
2
CH
2 -3-thienyl CH 2
CH
3 999 5-F CF 3 C-=C-cycPr H 1000 5-F CF 3
C=-CCH
2
CH
2 OH H 1001 5-F CF 3 C-=C-CH (OH) Me H 1002 5-F CF 3 CR=C-Ph H 1003 5-F CF 3 C-=C-(2-Cl)Ph H 1004 5-F CF 3 C-C (3 -C1)Ph H 1005 5-F CF 3 CE=C- 4-Cl)Ph H 1006 5-F CF 3 CE=C-(2-F)Ph H 1007 5-F CF 3 C-=C-(3-F)Ph H 1008 5-F CF 3 C-=C-(4-F)Ph H 1009 5-F CF 3 C=-C-(2-OH)Ph H 1010 5-F CF 3 C-=C-(3-OH)Ph H 1011 5-F CF 3 C=-C-(4-OH)Ph H 1012 5-F CF 3 C=-C-(2-OMe)Ph H 1013 5-F CF 3 C-=C-(3-OMe)Ph H 1014 5-F CF 3 C-=C-(4-OMe)Ph H WO 98/45276 WO 9845276PCTIUS98/06733 1015 5-F CF3 C=-C-(2-CN)Ph H 1016 5-F CF 3 C-=C-(3-CN)Ph H 1017 5-F CF3 C=-C-(4-CN)Ph H 1018 5-F CF 3 C-C- (2 -N02) Ph H 1019 5-F CF 3 CE-C-(3-N0 2 )Ph H 1020 5-F CF 3 CE-C-(4-N0 2 )Ph H 1021 5-F CF 3 C=-C-(2-NH 2 )Ph H 1022 5-F CF 3 CE=C-(3-NH 2 )Ph H 1023 5-F CF 3 (4-NH 2 Ph H 1024 5-F CF3 C-C- (2 -NMe 2 Ph H 1025 5-F CF 3 C=C- (3 -NMe 2 Ph H 1026 5-F CF 3 (4-NMe 2 Ph H 1027 5-F CF 3 C-=C-2-Pyridy1 H 1028 5-F CF 3 CE-C-2-Pyridyl H 1029 5-F CF 3 C-=C-3-Pyridy1 H 1030 5-F CF 3 CE-C-4-Pyridyl H 1031 5-F CF 3 C=-C-2-furany1 H 1032 5-F CF 3 CE=C-3-furanyl H 1033 5-F CF 3 CaC-2-thienyl H 1034 5-F CF 3 C=-C-3-thieny1 H 1035 5-F CF 3 CE-C-2-oxazolyl H 1036 5-F CF 3 C-=C-2-thiazoly1 H 1037 5-F CF 3 C-=C-4-isoxazolyl H 1038 5-F CF 3 CE=C-2-imidazolyl
H
1039 5-F CF 3 C=C-cycPr H 1040 5-F CF 3
C=CCH
2
CH
2 OH H 1041 5-F CF 3 C=C-CH(OH)Me H 1042 5-F CF 3 C=C-Ph H 1043 5-F CF 3 C=C-(2-Cl)Ph
H
1044 5-F CF 3 C=C-(3-C1)Ph
H
1045 5-F CF 3 C=C-(4-Cl)Ph
H
1046 5-F CF 3 C=C-(2-F)Ph H 1047 5-F CF 3 C=C-(3-F)Ph
H
1048 5-F CF 3 C=C-(4-F)Ph
H
WO 98/45276 PCT/US98/06733 1049 5-F CF 3 C=C-(2-OH)Ph H 1050 5-F CF 3 C=C-(3-OH)Ph H 1051 5-F CF 3 C=C- (4-OH) Ph H 1052 5-F CF 3 C=C-(2-OMe)Ph H 1053 5-F CF 3 C=C- (3 -OMe) Ph H 1054 5-F CF 3 C=C-(4-OMe)Ph H 1055 5-F CF 3 C (2 -CN) Ph H 1056 5-F CF 3 C=C- (3 -CN) Ph H 1057 5-F CF 3 C=C- (4-CN) Ph H 1058 5-F CF 3 C=C-(2-N0 2 )Ph H 1059 5-F CF 3 C=C- (3 -N0 2 Ph H 1060 5-F CF 3 C=C-(4-N0 2 )Ph H 1061 5-F CF 3 C=C-(2-NH- 2 )Ph H 1062 5-F CF 3 C=C-(3-NH 2 )Ph H 1063 5-F CF 3 C=C-(4-NH 2 )Ph H 1064 5-F CF 3 C=C- (2 -NMe 2 Ph H 1065 5-F CF 3 C=C-(3-NMe 2 )Ph H 1066 5-F CF 3 C=C-(4-N~e 2 )Ph H 1067 5-F CF 3 C=C-2-Pyridyl H 1068 5-F CF 3 C=C-2-Pyridyl H 1069 5-F CF 3 C=C-3-Pyridy. H 1070 5-F CF 3 C=C-4-Pyridyl H 1071 5-F CF 3 C=C-2-furanyl H 1072 5-F CF 3 C=C-3-furanyl H 1073 5-F CF 3 C=C-2-thienyl H 1074 5-F CF 3 C=C-3-'thienyl H 1075 5-F CF 3 C=C-2-oxazolyl H 1076 5-F CF 3 C=C-2-thiazoly. H 1077 5-F CF 3 C=C-4-isoxazolyl H 1078 5-F CF 3 C=C-2--imidazolyl H 1079 5-F CF 3 CH2CH 2 -CYCPr H 1080 5-F CF 3
CH
2
CH
2
CH
2
CH
2 OH H 1081. 5-F CF 3
CH
2
CH
2 -CH (OH) Me H 1082 5-F CF 3
CH
2
CH
2 Ph H WO 98/45276 WO 9845276PCTIUS98/06733 1083 5-F CF 3 CH2CH 2 -(2-Cl)Ph H 1084 5-F CF 3
CH
2
CH
2 -C 1)Ph H 1085 5-F CF 3
CH
2
CH
2 (4 -C1)Ph H 1086 5-F CF 3
CH
2
CH
2 Ph H 1087 5-F CF 3
CH
2
CH
2 (3 Ph H .1088 5-F CF 3
CH
2
CH
2 Ph H 1089 5-F CF 3
CH
2
CH
2 -(2-OH)Ph H 1090 5-F CF 3
CH
2
CH
2 -(3-OH)Ph H 1091 5-F CF 3
CH
2
CH
2 -(4-OH)Ph H 1092 5-F CF 3
CH
2
CH
2 -OMe) Ph H 1093 5-F CF 3
CH
2
CH
2 Ome) Ph H 1094 5-F CF 3
CH
2
CH
2 -(4-Ome)Ph H 1095 5-F CF 3
CH
2
CH
2 -(2-CN)Ph H 1096 5-F CF 3
CH
2
CH
2 (3 -CN) Ph H 1097 5-F CF 3
CH
2
CH
2 -CN) Ph H 1098 5-F CF 3
CH
2
CH
2 -N02) Ph H 1099 5-F CF 3
CH
2
CH
2 -(3-N0 2 )Ph H 1100 5-F CF 3
CH
2
CH
2 (4-N 2 Ph H 1101 5-F CF 3
CH
2
CH
2 -(2-NH2)Ph H 1102 5-F CF 3
CH
2
CH
2
-NH
2 )Ph H 1103 5-F CF 3
CH
2
CH
2 (4-NH 2 Ph H 1104 5-F CF 3
CH
2
CH
2 (2-NMe 2 Ph H 1105 5-F CF 3
CH
2
CH
2 -Nme 2 )Ph H 1106 5-F CF 3 CH2CH 2 -(4-NMe 2 )Ph H 1107 5-F CF 3
CH
2
CH
2 -2-Pyridyl H 1108 5-F CF 3
CH
2
CH
2 -3-Pyridyl H 1109 5-F CF 3
CH
2
CH
2 -4-Pyridyl H 1110 5-F CF 3
CH
2
CH
2 -2-furanyl H 1111 5-F CF 3
CH
2
CH
2 -3-furanyl H 1112 5-F CF 3
CH
2
CH
2 -2-thienyl H 1113 5-F CF 3
CH
2
CH
2 -3-thienyl H 1114 5-F CF 3
CH
2
CH
2 -2-oxazolyl H 1115 5-F CF 3
CH
2
CH
2 -2-thiazolyl H 1116 5-F CF 3 CH2CH 2 -4-isoxazolyl H WO 98/45276 WO 9845276PCT/US98/06733 1117 5-F CF 3
CH
2
CH
2 -2-imidazolyl H 1118 5-F CF 3 C=-C-cycPr CH 3 1119 5-F CF 3 CR-C-Ph CH 3 1120 5-F CF3 C-=C-2-Pyridyl CH 3 1121 5-F CF 3 C-=C-3-Pyridyl CH 3 1122 5-F CF 3 C-=C-4-Pyridyl CH 3 1123 5-F CF3 C-=C-2-furany1 CH 3 1124 5-F CF 3 C-=C-3-furanyl CH 3 1125 5-F CF 3 C=-C-2-thienyl CH 3 1126 5-F CF 3 C-=C-3-thienyl CH 3 1127 5-F CF 3 C=C-cycPr CH 3 1128 5-F CF 3 C=C-Ph CH 3 1129 5-F CF 3 C=C-2-Pyridyl CH 3 1130 5-F CF 3 C=C-3-Pyridyl CH 3 1131 5-F CF 3 C=C-4-Pyridyl CH 3 1132 5-F CF 3 C=C-2-furanyl CH 3 1133 5-F CF 3 C=C-3-furanyl CH 3 1134 5-F CF 3 C=C-2-thienyl CH 3 1135 5-F CF 3 C=C-3-tbhienyl CH 3 1136 5-F CF 3
CH
2
CH
2 -cycPr CH 3 1137 5-F CF 3
CH
2
CH
2 -Ph CE 3 1138 5-F CF 3
CH
2
CH
2 -2-Pyridyl CH 3 1139 5-F CF 3
CH
2
CH
2 -3-Pyridyl CH 3 1140 5-F CF 3
CH
2
CH
2 -4-Pyridyl CH 3 1141 5-F CF 3 CH2CH 2 -2 furanyl CH 3 1142 5-F CF 3
CH
2
CH
2 -3-furanyl CH 3 1143 5-F CF 3
CH
2
CH
2 -2-thienyl CH 3 1144 5-F CF 3 CH2CH2-3-thienyl CH 3 1145 5-F CF 3 C=-C-cycPr CH 2
CE
3 1146 5-F CF 3 C=RC-Ph CH 2
CH
3 1147 5-F CF3 C-=C-2-Pyridy1 CH 2
CH
3 1148 5-F CF 3 CE-C-3-Pyridyl CH 2
CH
3 1149 5-F CF 3 C=-C-4-Pyridyl CH 2
CH
3 1150 5-F CF 3 CE=C-2-furanyl CH 2
CH
3
I.
WO 98/45276 PCT/US98/06733 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C-=C-3 -furanyl C=-C-2-thieny1 C=-C-3-thieny1 C=C-cycPr C=C-Ph C=C-2-Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furariyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2
CH
2 -2 -Pyridyl
CH
2 CH2-3 -Pyridyl
CH
2
CH
2 -4 -Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2 CH2-3 -furanyl
CH
2
CH
2 -2 -thienyl
CH
2
CH
2 -3 -thienyl CE-C-cycPr CaC-Ph C=-C-2 -Pyridyl C-=C-3 -Pyridyl C=-C-4 -Pyridyl C=-C-2 -furanyl C-=C-3 -furanyl CE=C-2 -thienyl C=-C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3-Pyridyl
CH
2
CH
3
CH
2
CH
3
CH
2 CHi 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
C-
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
H
H
H
H
H
H
H
H
H
H
H
H
H
WO 98/45276 WO 9845276PCTIUS98/06733 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3 C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2
CH
2 -2-Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 -4-Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 furarxyl
CH-
2
CH
2 -2-thienyl
CH
2
CH
2 -3 -thienyl C=-C-cycPr CE=C-Ph CE=C-2 -Pyridyl C-=C-3 -Pyridyl C-=C-4-Pyridyl C-=C-2 -furanyl CE=C-3 -furanyl C=-C-2-thienyl C-=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4-Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH
3
CH
3
CE
3
CH
3
CH
3
CH
3
CE
3
CH
3
CH
3
CH
3
CH
3
CH
3
CE
3
CE
3
CH
3
CE
3 CH3
CH
3
CE
3
CH
3
I.
WO 98/45276 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 PCTIUS98/06733 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-C1, 6-F 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl- 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl
CF
3
CF
3 CF3 CF3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2 CH2-2 -Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 -4-Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 -3-furanyl
CH
2
CH
2 -2 -thienyl
CH
2
CH
2 -3 -thieriyl C=C cycPr C=-C-Ph C=-C-2 -Pyridyl C2=C-3 -Pyridyl C=-C-4-Pyridy1 C-=C-2 -furanyl C-=C-3 -furanyl C-=C-2 -thienyl CE=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4-Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2 CH2 Pyridyl
CH
2 CH2-3 -Pyridyl
CH
2 CH2 Pyridyl
CH
2 CH2 furanyl
CH
2 CH2-3 -furanyl
CH
2
CH
2 -2-thienyl
CH
2 CH2-3 -thienyl
CE
3
CE
3
CH
3
CH
3
CH
3
CE
3
CE
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
WO 98/45276 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 PCTIUS98/06733 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 5-F, 6-Cl 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F CF3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3 C-=C-cycPr C=-C-Ph C=-C-2 -Pyridyl C-=C-3 -Pyridyl C-=C-4-Pyridyl CE-C-2 -furanyl CE=C-3 -furanyl CE=C-2-thienyl CE=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3-furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2
CH
2 -2 -Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 -4-Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 -3 -furanyl
CH
2
CH
2 -2 -thienyl
CH
2
CH
2 -3 -thienyl C-=C-cycPr C=-C-Ph C-=C-2-pyridyl C-=C-3-Pyridyl C-=C-4 -Pyridyl C-=C-2 -furanyl C=2C-3 -furanyl
CE
3
CE
3
CH
3
CH
3
CH
3
CE
3
CH
3
CH
3
CH
3
CE
3
CE
3
CE
3
CE
3
CE
3
CH
3
CE
3
CE
3
CE
3
CH
3
CE
3
CE
3
CE
3
CE
3
CH
3
CE
3
CE
3
CE
3
H
H
H
H
H
H
H
WO 98/45276 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 PCTIUS98/06733 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-C1, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-01, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-01, 8-F 6-Cl, 8-F 6-01, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-01,'8-F 6-Cl, 8-F 6-01, 8-F 6-01, 8-F 6-01, 8-F 6-Cl, 8-F
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C-=C-2-thienyl C=-C-3-thienyl C=C-cycPr C=C-Ph 0=0-2 -Pyridyl 0=0-3 -Pyridyl 0=0-4 -Pyridyl 0=0-2 -furanyl 0=0-3 -furanyl 0=0-2 -thienyl 0=0-3 -thienyl
CH
2
CH
2 -cycPr 0H20H 2 -Ph 0H 2 0H 2 -2 -Pyridyl
CH
2
CH
2 -3 -Pyridyl 0H 2 CH2-4 -Pyridyl
CH
2 CH2-2 -furanyl
CH
2
CH
2 -3 -furanyl
CH
2
CH
2 -2-thienyl
CH
2
CH
2 thienyl C=-C-cycPr C=-C-Ph C-=C-2-Pyridy1 C=-C-3 -Pyridyl C020-4-Pyridyl CE=C-2 -furanyl C=-0-3 -furanyl CE=C-2 -thienyl -thienyl C=C-cycPr 0=0-Ph 0=0-2 -Pyridyl 0=0-3 -Pyridyl C=C-4-pyridyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3 WO 98/45276 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 PCT/US98/06733 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6 -OH 3 6 -OH 3 6 -CH3 6 -CH 3 6-CH 3 6 -CH 3 6-OH 3 6 -OH 3 6 -CH 3 6 -CH 3 6-OH 3 6 -OH 3 6 -CH 3 6 -OH 3 6-CH 3 6 -OH 3 6 -CH 3 6 -CH 3 6 -OH 3 6 -OH 3 6 -CH 3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3 CF3
CF
3
OF
3
CF
3
CF
3
OF
3 CF3
CF
3
CF
3
CF
3
OF
3
OF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
OF
3 CF3
OF
3
CF
3 CF3
CF
3
CF
3
CF
3 C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
OH
2 -cycPr
CH
2
OH
2 -Ph
CH
2
CH
2 -2 -Pyridyl
OH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 -4-Pyridyl CH2CH 2 furanyl
CH
2
CH
2 -3 -furanyl
CH
2
CH
2 -2-thienyl 0H 2
CH
2 -3 -thienyl C-=C-cycPr CO-C-Ph C=-O-2 -Pyridyl O-=O-3 -Pyridyl CEOC-4 -Pyridyl C=-O-2 -furanyl O-=O-3 -furanyl C-O-2 -thienyl C-=O-3 -thienyl O=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2-furanyl 0=0-3 -furanyl 0=0-2 -thienyl 0=0-3 -thienyl
OH
2
CH
2 -cyc Pr
CH
2
CH
2 -Ph
CH
2
OH
2 -2 -Pyridyl
CH
3
CH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
OH
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
WO 98/45276 PCTIUS98/06733 1355 6-CE 3 CF3 CH2CH 2 -3-Pyridyl H 1356 6-CH 3
CF
3
CE
2
CH
2 -4-Pyridyl H 1357 6-CH 3
CF
3
CE
2
CH
2 -2-furanyl H 1358 6-CH 3
CF
3
CH
2
CH
2 -3-furanyl H 1359 6-CH 3
CF
3
CH
2
CH
2 -2--thienyl H 1360 6-CE 3
CF
3
CH
2
CH
2 -3-th-ienyl H 1361 6-CH 3
CF
3 CmC-cycPr
CE
3 1362 6-CE 3
CF
3 C=-C-Ph
CH
3 1363 6-CH 3
CF
3 C-=C-2-Pyridyl
CE
3 1364 6-CH 3
CF
3 C-=C-3-Pyridyl
CH
3 1365 6-CH 3
CF
3 CE=C-4-Pyridyl
CH
3 1366 6-CH 3
CF
3 C-=C-2-furanyl
CH
3 1367 6-CH 3
CF
3 C-=C-3-furanyl
CH
3 1368 6-CE 3
CF
3 C-=C-2-.thienyl
CH
3 1369 6-CH 3
CF
3 C=-C-3-thieny1
CH
3 1370 6-CH 3
CF
3 C=C-cycPr
CH
3 1371 6-CH 3
CF
3 C=C-Ph
CE
3 1372 6-CH 3
CF
3 C=C--2-Pyridyl
CE
3 1373 6-CE 3
CF
3 C=C-3-Pyridyl
CH
3 1374 6-CH 3
CF
3 C=C-4-Pyridyl
CH
3 1375 6-CH 3
CF
3 C=C-2-furanyl
CH
3 1376 6-CH 3
CF
3 C=C-3-furanyl
CE
3 1377 6-CH 3
CF
3 C=C-2-thienyl
CH
3 1378 6-CH 3
CF
3 C=C-3-thienyl
CH
3 1379 6-CE 3
CF
3
CH
2 CH2-cycPr CH3 1380 6-CE 3
CF
3
CE
2
CH
2 -Ph CE 3 1381 6-CE 3
CF
3
CH
2
CE
2 -2-Pyridyl
CE
3 1382 6-CE 3
CF
3
CH
2
CH
2 -3-Pyridyl
CE
3 1383 6-CE 3
CF
3
CE
2 CH2-4-Pyridyl
CE
3 1384 6-CE 3
CF
3
CH
2
C
2 -2-furanyl
CE
3 1385 '6-CE 3
CF
3
CH
2
C
2 -3-furanyl
CE
3 1386 6-CE 3
CF
3
CE
2
CH
2 -2-thienyl
CE
3 1387 6-CE 3
CF
3
CH
2
CH
2 -3-thienyl
CE
3 1388 6-C0CE 3
CF
3 C-=C-cycPr
H
WO 98/45276 WO 9845276PCTIUS98/06733 1389 6-COCK 3 CF3 C=-C-Ph H 1390 6-COCK 3
CF
3 C-=C-2-Pyridyl H 1391 6-COCK 3
CF
3 CE=C-3-Pyridyl H 1392 6-COCH 3
CF
3 C-=C-4-Pyridyl H 1393 6-COCH 3
CF
3 C-=C-2-furanyl H 1394 6-COCH 3
CF
3 C=-C-3-furany. H 1395 6-C0CH 3
CF
3 C=-C-2-thienyl H 1396 6-COCH 3
CF
3 C-=C-3-thieiy1 H 1397 6-NH 2
CF
3 C-=C-cycPr H 1398 6-N'H 2
CF
3 C=-C-Ph H 1399 6-NH 2
CF
3 CE=C-2-Pyridyl H 1400 6-NH 2
CF
3 C=-C-3-Pyridyl 1401 6-NH 2
CF
3 C-=C-4-Pyridyl H 1402 6-NH 2
CF
3 C=-C-2-furanyl H 1403 6-NHl 2
CF
3 C-=-3-furanyl H 1404 6-NH 2
CF
3 C=-C-2-thienyl H 1405 6-NH 2
CF
3 C-=C-3-thienyl H 1406 6-NMe 2
CF
3 C5-C-cycPr H 1407 6-NMe 2
CF
3 C-=C-Ph H 1408 6-NMe 2
CF
3 CE=C-2-Pyridyl H 1409 6-NMe 2
CF
3 C=-C-3-Pyridy1 H 1410 6-NMe 2
CF
3 CE=C-4-Pyridyl H 1411 6-NMe 2
CF
3 C-=C-2-furany1 H 1412 6-NMe 2
CF
3 C=-C-3-furany1 H 1413 6-NMe2 CF 3 CE-C-2-thienyl H 1414 6-NMe2 CF 3 C-=C-3-thieny1 H 1415 7-Cl CF 3 CE-C-cycPr H 1416 7-Cl CF 3 CR-C-Ph H 1417 7-Cl CF 3 C-=C-2-Pyridyl H 1418 7-Cl CF 3 C -3Prd1H 1419 7-Cl CF 3 C=--4-Pyridy1 H 1420 7-Cl CF 3 C-=C-2-furany1 H 1421 7-Cl CF 3 C=-C-3-furany1 H 1422 7-Cl CF 3 C-=C-2-thieny1 H WO 98/45276 WO 9845276PCT/US98/06733 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 7-Cl 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2 O0- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6 -OCH 2
O-
6-OCH 2
O-
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3 CF3 CF3
CF
3 CF3 C=-C-3 -thienyl C=-C-cyc Pr
C-=CCH
2
CH
2 0H C=-C-CH (OH) Me CE=C-Ph CE-C- (2-Cl) Ph (3-C1) Ph CmC- (4-Cl) Ph CE=C- Ph C2=C-(3-F)Ph C-=C-(4-F)Ph (2-OH) Ph (3 -OH) Ph (4-OH) Ph C-C (2 Ph (3 -OMe) Ph Ph CR=C- (2-CN) Ph C2=C- (3-CN) Ph CE=C- (4-CN) Ph (2 -NO 2 Ph C-=C-(3-NO 2 Ph (4-N0 2 Ph (2 -NH 2 Ph (3 -NH 2 Ph (4-NH 2 Ph CE=C- (2-NMe 2 Ph (3 -NMe2) Ph (4-NMe 2 Ph C-=C-2 -Pyridyl C=-C-2 -Pyridyl C=-C-3 -Pyridyl C-=C-4 -Pyridyl C-=C-2 -furanyl WO 98/45276 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 PCT/US98/06733 5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2 o- 5, 6-OCH 2
O-
5, 6-OCH20- 5, 6-OCH 2
O-
6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -COCH 3 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6 -NH 2 6-NMe 2 6 -NMe 2 6-NMe 2 6-NMi 2 6-NMe 2 6-NMe 2 6 -NMe 2 6-NMe 2 6 -NMe 2
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=-C-3 -furanyl C-=C-2 -thienyl C-=C-3 -thienyl C-=C-2 -oxazoly.
C=-C-2-thiazoly1 C--C-4-isoxazolyl C-=C-2 -imidazolyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 furanyl C=C-2 -thienyl C=C-3 -thienyl WO 98/45276 WO 9845276PCTIUS98/06733 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 7 -Cl 7-Cl 7-Cl 7-Cl 7 -Cl 7 -Cl 7-Cl 7 -Cl 7 -Cl 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5,1 6 -OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2 0-
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3 C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2-thienyl C=C-3 -thienyl C=C-cycPr
C=CCH
2
CH
2
OH
C=C-CH (OH)Me C=C-Ph C=C- (2 -Cl) Ph C=C- (3 -Cl) Ph C=C- (4-Cl) Ph C=C- Ph C=C-(3-F)Ph C=C- Ph C=C- (2 -OH) Ph C=C- (3 -OH) Ph C=C- (4 -OH) Ph C=C- (2-OMe) Ph C=C- Ph C=C- Ph C=C- (2-CN) Ph C=C- (3 -CN) Ph C=C- (4 -CN) Ph C=C- (2 -N0 2 Ph C=C- (3 -N0 2 Ph C=C- (4-N02) Ph C=C- (2-NH2) Ph C=C- (3 -NH2) Ph C=C- (4-NH2) Ph WO 98/45276 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 PCTIUS98/06733 5, 6-OCHi 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5,1 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2 O0- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-QCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6 -OCH 2
O-
5, 6 -OCH 2
O-
5, 6 -OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=C- (2 -NMe 2 Ph C=C- (3-NMe 2 Ph C=C- (4-NMe 2 Ph C=C-2 -Pyridyl C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thieny.
C=C-3 -thienyl C=C-2 -oxazolyl C=C-2-thiazoly.
C=C-4 -isoxazolyl C=C-2 -imidazolyl CH2CH2-cycPr
CH
2
CH
2
CH
2
CH
2
OH
CH
2
CH
2 -CH (OH) Me
CH
2
CH
2 Ph
CH
2
CH
2 (2 -Cl1) Ph
CH
2
CH
2 Ph
CH
2
CH
2 (4-Cl) Ph
CH
2
CH
2 (2 Ph
CH
2
CH
2 (3 Ph
CH
2
CH
2 (4 Ph
CH
2
CH
2 -OH) Ph
CH
2
CH
2 (3 -OH) Ph
CH
2
CH
2 (4 -OH) Ph
CH
2
CH
2 (2 -OMe) Ph CH2CH 2 -(3-OMe) Ph
CH
2
CH
2 (4 -OMe) Ph
CH
2
CH
2 (2-CN) Ph
CH
2
CH
2 (3-CN) Ph
CH
2
CH
2 (4 -CN) Ph WO 98/45276 1559 1560 1561 1562 1563 1564* 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 PCTIUS98/06733 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2 o-
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2
CH
2 (2-NO 2 Ph
CH
2
CH
2 (3 -NO 2 Ph
CH
2
CH
2 (4-NO 2 Ph
CH
2
CH
2 (2-NH 2 Ph
CH
2
CH
2 (3 -NH 2 Ph
CH
2
CH
2 (4-NH 2 Ph
CH
2
CH
2 (2 -NMe 2 Ph
CH
2
CH
2 (3 -NMe 2 Ph
CH
2
CH
2 (4 -NMe 2 Ph
CH
2
CH
2 Pyridyl
CH
2
CH
2 -3-Pyridyl
CH
2
CH
2 -4-Pyridyl
CH
2
CH
2 furanyl
CH
2
CH
2 -3 -furariyl
CH
2
CH
2 thienyl
CH
2
CH
2 -3 -thienyl
CH
2
CH
2 -2 -oxazolyl
CH
2
CH
2 -2 -thiazolyl
CH
2
CH
2 -4 -isoxazolyl
CH
2
CH
2 -2 -imidazolyl C=-C-cycPr C=RC-Ph C=-C-2 -Pyridyl C-=C-3 -Pyridyl C-=C-4 -Pyridyl CE=C-2 -furanyl C-=C-3 -furanyl C-=C-2 -thienyl C-=C-3 -thienyl C=C-cycPr C=C-Ph C=C-2 -Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CE
3
CH
3
CH
3
CE
3
CH
3
CE
3
CH
3
CH
3
CH
3
CH
3
CH
3
CE
3
CE
3 CH3 WO 98/45276 WO 9845276PCTIUS98/06733 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 1625 1626 5, 6-OCH2O- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5,1 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
Q-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
Q-
5, 6-OCH 2
O-
5, 6-0CH 2 0- 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-0CH 2 0- 5, 6-OCH 2
Q.-
5, 6-OCH 2
O-
5, 6-OCH 2
Q-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
Q-
5, 6-OCH 2
O-
5, 6-OCH20-
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C=C-2 -furanyl C=C-3 -furanyl C=C-2 -thienyl C=C-3 -thienyl
CH
2
CH
2 -CYCPr
CH
2
CH
2 -Ph
CH
2 CH2-2 -Pyridyl
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 Pyridyl
CH
2
CH
2 fur anyl
CH
2
CH
2 -3-furanyl
CH
2
CH
2 -2-thienyl
CH
2
CH
2 -3 -thienyl CE-C-cycPr C=-C-Ph C=-C-2 -Pyridyl C2=C-3 -Pyridyl Pyridyl C=-C-2 -furanyl C=-C-3 -furanyl C=-C-2 -thienyl C-=C-3 -thienyl C=C-cycPr C=C-Ph C=C Pyridyl C=C-3 -Pyridyl C=C-4 -Pyridyl C=C-2 -furanyl C=C-3 -furanyl C=C-2-thienyl C=C-3 -thienyl
CH
2
CH
2 -cycPr
CH
2
CH
2 -Ph
CH
2 CH2-2-Pyridyl C8 3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2 CH3
CH
2 CH3
CH
2
CH
3
CH
2 CH3
CH
2 CH3 WO 98/45276 WO 9845276PCTIUS98/06733 1627 1628 1629 1630 1631 1632 5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH 2
O-
5, 6-OCH- 2 0-
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2
CH
2 -3 -Pyridyl
CH
2
CH
2 -4-Pyridyl
CH
2
CH
2 -2 -furanyl
CH
2
CH
2 -3 -furanyl CHi 2
CH
2 -2 -thienyl
CH
2 CH2-3 -thienyl
CH
2 CHi 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 CHi 2
CH
3
CH
2
CH
3 *Unless otherwise indicated, stereochemisty is 101 WO 98/45276 WO 9845276PCT[US98/06733 Table 3*
H
EX.
1 2 3 4 6 7 8 9.
11 12 13 14 is 16 17 18 19 21 22 23 24 26 27 28 6-Cl 6-Cl 6 -Cl 6-Cl 6-Cl 6-Cl 6-Cl 6-Cl 6-Cl 6-Cl 6-Cl 6-Cl 6 -Cl 6-Cl 6-Cl 6-C1 6-Cl 6-Cl 6-Cl 6-C1 6-Cl 6-Cl 6 -Cl 6-C1 6-Cl 6-Cl 6-Cl
CRI
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 C-=C-Pr C=-C-Bu CE=C- iBu tBu CE=C-Me
CH
2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH(CH
3 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 Bu
CH
2
CE=C-CH
3
CH
2 CmC-CH 2
CH
3 C-=C-iPr CR=C-Pr CE=C-Bu CE=C- iBu CE-C- tBu CH=C-Et C=-C-Me
CH
2 C2-C-CH 3
CH
2
C-=C-CH
2
CH
3
CH
2
CH
2 CH (H)2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 -tBu C-=C-iPr CE=C-Pr C-=C-Bu
R
8
H
H
H
H
H
H
H
H
H
H
H
H
CR
3
CR
3
CH
3
CR
3
CR
3
CH
3
CR
3
CH
3
CR
3
CR
3
CR
3
CR
3
CR
3
CR
2
CH
3
CH
2
CH
3
CH
2
CH
3 102 WO 98/45276 PTU9/63 PCTIUS98/06733 29 6-Cl CF 3 C=-C-iBu
CH
2
CH
3 6-Cl CF 3 C=-C-tBu
CH
2
CH
3 31 6-Cl CF 3 C-=C-Et
CH
2
CH
3 32 6-Cl CF 3 C C-Me
CH
2
CH
3 33 6-Cl CF 3 CH2C=-C-CH 3
CH
2
CH
3 34 6-Cl CF 3
CH
2
C=-C-CH
2
CH
3
CH
2
CH
3 6-Cl CF 3 CH2CH 2 CH (CH 3 2
CH
2
CH
3 36 6-Cl CF 3
CH
2
CH
2
CH
2
CH
3
CH
2
CH
3 37 6-Cl CF 3
CH
2
CH
2
CH
3
CH
2
CH
3 38 6-Cl CF 3 CH2CH 2 -tBu CH 2
CH
3 39 6-MeO CF 3 CR=C-Pr
H
6-Meo CF 3 C-=C-Bu
H
41 6-Meo CF3 C=-C-iBu
H
42 6-MeO CF 3 C-=C-tBu
H
43 6-MeO CF 3 C-=C-Et
H
44 6-MeO CF 3 CE=C-Me
H
6-MeO CF 3
CH
2
CE=C-CH
3
H
46 6-Meo CF 3 CH2C-=C-CH 2
CH
3
H
47 6-MeG CF 3 CH2CH 2
CH
2
CH
2
CH
3
H
48 6-Meo CF 3
CH
2
CH
2 CH (CH 3 2
H
49 6-MeG CF 3
CH
2
CH
2
CH
2
CH
3
H
6-MeG CF 3
CH
2
CH
2
CH
3
H
51 6-MeG CF 3
CH
2
CH
2 -tBu H 52 6-MeG CF 3
CH
2
C-=C-CH
3
H
53 6-MeG CF 3 CH2C-=C-CH 2
CH
3
H
54 6-MeG
CF
3 C=-C-iPr
CH
3 6-MeG CF 3 C-=C-Pr
CH
3 56 6-MeG
CF
3 C-=C-Bu
CH
3 57 6-MeG CF 3 C-=C-iBu
CH
3 58 6-MeG
CF
3 C-=C-tBu
CH
3 59 6-MeG CF 3 C-=C-Et
CH
3 6-MeG
CF
3 CR=C-Me
CH
3 61 6-MeG
CF
3
CH
2
CE=C-CH
3 CH 3 62 6-MeG
CF
3
CH
2 C=-C-CHqCH 3
CH
3 103
I.
WO 98/45276 PCT/US98/06733 63 6-MeO CF 3 CH2CH 2 CH (CH 3 2 CH3 64 6 -MeO CF 3
CH
2
CH
2
CH
2
CH
3
CH
3 6-MeO CF 3
CH
2
CH
2 CHi 3
CH
3 66 6-MeO CF 3
CH
2
CH
2 -tBu CH 3 67 6-Meo CF 3 C-=C-iPr CH 2
CH
3 68 6-MeO CF 3 C-=C-Pr CH 2
CH
3 69 6-MeO CF 3 C=-C-Bu CH 2
CH
3 6-MeO CF 3 C=-C-iBu CH 2
CH
3 71 6-MeO CF 3 C-=C-tBU CH 2
CH
3 72 6Meo CF3 -=CEt C2CH 72 6-Meo CF 3 C-=C-Me CH2CH 3 73 6-MeO CF 3 C2=C-e3 CH 2
CH
3 74 6-MeO CF 3
CH
2
CC-HCH
3
CH
2
CH
3 6-MeO CF 3
CH
2 CHCCH CH 3
CH
2
CH
3 76 6-MeO CF 3
CH
2
CH
2 CH (CH 3
CH
2
CH
3 77 6-meo CF 3
CHCH
2
CH
2
CH
3
CH
2
CH
3 78 6-MeO CF 3
CH
2
CH
2
CH
3 u CH 2
CH
3 5,G-diF CF 3 C=-C-Pr H 81 5,6-diF CF 3 C-=C-Bu H 82 5,6-diF CF 3 CE=C-iBu H 83 5,6-diF CF 3 C=-C-tBu H 84 5,6-diF CF 3 C-=C-Me H 5, 6-diF CF 3
CH
2
C=-C-CH
3
H
86 5, 6-diF CF 3
CH
2
C-=C-CH
2
CH
3
H
87 5,6-diF CF 3
CH
2
CH
2
CH
2
CH
2
CH
3
H
88 5,6-diF CF 3
CH
2
CH
2
CH
3
H
89 5,6-diF CF 3 CH2CH 2 -tBu H 5,6-diF CF3 C-=C-iPr CH 3 91 5,6-diF CF 3 C-=C-Pr CH 3 92 5,6-diF CF 3 CE=C-Bu
CH
3 93 5,6-diF CF3 CE=C-iBu CH 3 94 5,6-diF CF 3 C-=C-tBu
CH
3 5, 6-diF CF 3 C-=C-Et CH 3 96 5,6-diF CF 3 C=-C-Me CH3 104 WO 98/45276 WO 9845276PCTIUS98/06733 97 5, 6-diF CF 3 C=-C-Ph CH 3 98 5, 6-diF CF 3
CH
2
C=-C-CH
3
CH
3 99 5, 6-diF CF 3
CH
2
C=-C-CH
2
CH
3
CH
3 100 5,6-diF CF 3
CH
2
CH
2 CH (CH 3 2
CH
3 101 5, 6-diF CF 3
CH
2
CH
2
CH
2
CH
3
CH
3 102 5,6-diF CF 3
CH
2
CH
2
CH
3
CH
3 103 5,6-diF CF 3
CH
2
CH
2 -tBu CH 3 104 5,6-diF CF 3 C-=C-iPr CH 2
CH
3 105 5,6-diF CF 3 C-=C-Pr CH 2
CH
3 106 5,6-diF CF 3 CE-C-Bu CH 2
CH
3 107 5, 6-diF CF 3 CE=C-iBu CH 2
CH
3 108 5,6-diF CF 3 C=-C-tBu CH 2
CH
3 109 5,6-diF CF 3 CE=C-E t CH2CH 3 110 5,6-diF CF 3 cac-me CH 2
CH
3 il1 5, 6-diF CF 3
CH
2
C=-C-CH
3
CH
2
CH
3 112 5,6-diF CF 3
CH
2 CaC-CH 2
CH
3
CH
2
CH
3 113 5,6-diF CF 3
CH
2
CH
2
CH(CH
3 2
CH
2
CH
3 114 5, 6-diF CF 3
CH
2
CH
2
CH
2
CH
3
CH
2
CH
3 115 5,6-diF CF 3
CH
2
CH
2
CH
3
CH
2
CH
3 116 5, 6-diF CF 3
CH
2
CH
2 -tBu CH 2
CH
3 117 6-F CF 3 C=RC-Pr H 118 6-F CF 3 C-=C-Bu H 119 6-F CF 3 C=-C-iBu H 120 6-F CF 3 C=-C-tBu H 121 6-F CF 3 C=-C-Me H 122 6-F CF 3
CH
2
C-=C-CH
2
CH
3
H
123 6-F CF 3
CH
2
CH
2
CH
2
CH
2
CH
3
H
124 6-F CF 3 CH2CH2CH 3
H
125 6-F CF 3 CH2CH 2 -tBu H 126 6-F CF 3 C-=C-iPr CH 3 127 6-F CF3 C-=C-Pr
CH
3 128 6-F CF 3 CE=C-Bu
CH
3 129 6-F CF 3 C-=C-iBu
CH
3 130 6-F CF 3 C=-C-tBu
CH
3 105 WO 98/45276 PTU9/63 PCT/US98/06733 131 6-F CF 3 C=-C-Et
CH
3 132 6-F CF 3 CR=C-Me
CH
3 133 6-F CF 3 -CC3CH 3 134 6-F CF 3 CH 2C=EC-CH 2
CH
3
CH
3 135 6-F CF 3
CH
2
CH
2 CH (CH 3 2
CH
3 136 6-F CF 3
CH
2
CH
2
CH
2
CH
3
CH
3 137 6-F CF 3
CH
2
CH-
2 C11 3
CH
3 138 6-F CF 3 CH2CH 2 -tBu CH 3 139 6-F CF 3 C-=C-iPr
CH
2
CH
3 140 6-F CF 3 C-=C-Pr
CH
2
CH
3 141 6-F CF 3 C-=C-Bu
CH
2
CH
3 142 6-F CF 3 iBu CH 2
CH
3 143 6-F CF 3 CE=C-tBu
CH
2
CH
3 144 6-F CF 3 C=-C-Et
CH
2
CH
3 145 6-F CF 3 CR=C-Me
CH
2
CH
3 146 6-F CF 3
CH
2
C-=C-CH
3
CH
2
CH
3 147 6-F CF 3 CH2C-=C-CHgCH 3 i CH 2
CH
3 148 6-F CF 3
CH
2
CH
2 CH (CH 3 2
CH
2
CH
3 149 6-F CF 3
CH
2
CH
2
CH
2
CH
3
CH
2
CH
3 150 6-F CF 3
CH
2
CH
2
CH
3
CH
2
CH
3 151 6-F CF 3
CH
2
CH
2 -tBu CH 2
CH
3 152 5-Cl CF 3 CE=C-iPr
H
153 5-Cl CF 3 CE=C-Pr
H
154 5-Cl CF 3 CE=C-Bu
H
155 5-Cl CF 3 C-=C-iBu
H
156 5-Cl CF 3 CE-C-tBu
H
157 5-Cl CF 3 C=EC-Et
H
158 5-C1 CF 3 C-=C-Me
H
159 5-Cl CF 3
CH
2
C-=C-CH
3
H
160 5-Cl CF 3
CH
2
C=EC-CH
2
CH
3
H
161 5-Cl CF 3 CH2CH 2
CH
2
CH
2
CH
3
H
162 5-Cl CF 3
CH
2
CH
2 CH (CH 3 2
H
1 6 blC 3C 2 H C 2 H 163 5-Cl CF 3
CHCH
2
CH
2
CH
3
H
106 WO 98/45276 PCTIUS98/06733 165 5-Cl CF 3
CH
2
CH
2 -tBu H 166 5-Cl CF 3 CE-C-iPr CH 3 167 5-Cl CF 3 C=EC-Pr CH 3 168 5-Cl CF 3 CE=C-Bu CH 3 169 5-Cl CF 3 CE=C-iBu CH 3 170 5-Cl CF 3 CE=C-tBu CH 3 171 5-Cl CF 3 CEOC-Et
CH
3 172 5-Cl CF 3 CEOC-Me
CH
3 173 5-Cl CF 3
CH
2 COEC-CH3 CH 3 174 5-Cl CF 3
CH
2
CEC-CH
2
CH
3
OH
3 175 5-Cl CF 3
CH
2
CH
2 CH (CH 3 2
CH
3 176 5-Cl CF 3
CH
2
CH
2
CH
2
CH
3
CH
3 177 5-Cl CF 3
CH
2
CH
2
CH
3
CH
3 178 5-Cl CF 3
CH
2
CH
2 -tBu CH 3 179 5-Cl CF 3 CE-C-iPr CH 2
CH
3 180 5-Cl CF 3 CEOC-Pr CH 2
CH
3 181 5-Cl CF 3 CE=C-Bu CH 2
CH
3 182 5-Cl CF 3 CEOC-iBu CH 2
CH
3 183 5-Cl CF 3 CEOC-tBu CH2CH 3 184 5-Cl CF 3 CEOC-Et CH 2
CH
3 185 5-Cl CF 3 CEOC-Me CH 2
CH
3 186 5-Cl CF 3
CH
2
COEC-CH
3
CH
2
CH
3 187 5-Cl CF 3
CH
2
CE=C-CH
2
CH
3
CH
2
CH
3 188 5-Cl CF 3
CH
2
CH
2 CH (C1 3 2
CH
2
CH
3 189 5-Cl CF 3
CH
2
CH
2
CH
2
CH
3 CH2CH 3 190 5-Cl CF 3
CH
2
CH
2
CH
3
CH
2
CH
3 191 5-Cl CF 3
CH
2
CH
2 -tBu CH 2
CH
3 192 5-F CF 3 CEOC-iPr H 193 5-F CF 3 CEOC-Pr H 194 5-F CF 3 CEOC-Bu H 195 5-F CF 3 CEOC-iBu H 196 5-F CF 3 CEOC-tBu H 197 5-F CF 3 CEOC-Et H 198 5-F CF 3 CEOC-Me H 107
I,
WO 98/45276 PCT/US98/06733 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-F 5-Cl, 6-F CF3- CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2 C-=C-CH3
CH
2
C=-C-CH
2
CH
3
CH
2
CH
2
CH
2
CH
2 CH3 CH2CH 2 CH (CH3) 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH-
3
CH
2
CH
2 -t.BU C-=C-iPr CR-C-Pr C=-C-Bu C-=C-iBu tBu C-C -E t C=-C-Me
CH
2
C-=C-CH
3
CH
2 C=-C-CHqCH-A
CH
2
CH
2 CH (CH 3
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 -tBu CE=C-iPr C=-C-Pr C=-C-Bu C-=C-iBu t~u C2-C-Et C-=C-Me CH2C-=C-CH 3
CH
2 C=C -CH 2
CH
3
CH
2
CH
2 CH (CH 3 2 CH2CHi 2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 -tBu C-=C-iPr
H
H
H
H
H
H
H
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3 CH2CH 3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
H
108 WO 98/45276 WO 9845276PCTIUS98/06733 233 234 2.35 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 5-Cl, 6-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3 CF3
CF
3
CF
3 CF3 C=-C-Pr C-=C-Bu CR=C-iBti C=-C-tBu C-=C-Et CE=C-Me
CH
2 C=-C-CH3
CH
2
C=-C-CH
2
CH
3
CH
2
CH
2 CH (CH 3 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 -tBu C=-C-iPr C=RC-Pr C-=C-Bu C-=C-iBu CE-C- tBu C-=C-Et C-=C-Me
CH
2
C-=C-CH
3
CH
2
C=-C-CH
2 )CH3A
CH
2
CH
2 CH (CH 3 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3 CH2CH 2 -tBU CE=C-iPr C=RC-Pr C-=C-Bu C=-C-iBU C=-C-tBu C=-C-Et caC-me
CH
2
C=-C-CH
3
CH
2 C=C -CR 2
>CHM
109
H
H
H
H
H
H
H
H
H
H
H
H
CM
3
CH
3
CM
3
CH
3
CM
3
CH
3
CH
3
CH
3
CH
3 CH3
CH
3
CH
3
CH
3
H
H
H
H
H
H
H
H
H
WO 98/45276 WO 9845276PCT/US98/06733 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6-Cl, 8-F 6 -CH 3 6 -CH 3 6 -CH 3 6 -CH 3 6 -CH 3 6 -CH 3 6 -CH 3 6 -CH 3 6 -CE 3 6 -CH 3 6 -CH 3 6 -CE 3 6 -CE 3 6 -CE 3 6-CH 3 6 -CE 3 6 -CE 3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3 CF3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CF
3
CH
2 CH2CH (CE3) 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CE
3
CH
2 CE2 -tBu CE-C-iPr C-=C-Pr C-=C-Bu CR=C- iBu C-=C-tBu C-=C-Et C-=C-Me
CH
2
C=-C-CH
3
CH
2
C-=C-CH
2
CH
3
CH
2
CH
2 CH (CE 3 2
CH
2
CH
2
CH
2
CH
3
CH
2
CH
2
CH
3
CH
2
CH
2 -tBU C-=C-iPr C=RC-Pr C-=C-Bu C-=C-iBu C-=C-tBu C=-C-Et CRC-me
CH
2 C-=C-CH3
CE
2
C=C-CHE
2
CE
3
CH
2
CH
2 CE (CE 3 2
CH
2
CH-
2
CH
2 CHi 3
CH
2
CH
2
CH
3
CH
2
CE
2 -tBU C=EC-iPr C-=C-Pr C-=C-Bu CE=C-iBu
H
H
H
H
CH
3
CE
3
CE
3
CE
3
CE
3
CE
3
CE
3
CH
3
CE
3
CE
3
CE
3
CE
3
CE
3
H
H
H
H
H
H
H
H
H
H
H
H
H
CE
3
CE
3
CE
3
CH
3 110 WO 98/45276 WO 9845276PCT/US98/06733 301 6 -CE 3
CF
3 C-=C-tBu CH 3 302 6 -CE 3
CF
3 C-=C-Et CE 3 303 6 CH 3
CF
3 C=-C-Me CE 3 304 6 -CH 3
CF
3
CH
2
C-=C-CH
3
CH
3 305 6-CE 3
CF
3 CHCC-CHqCH-A CH 3 306 6 -CH 3
CF
3
CH
2
CH
2 CH (CH 3 2
CH
3 307 6-CE 3
CF
3
CH
2
CH
2
CH
2
CH
3
CH
3 308 6-CE 3
CF
3
CE
2
CH
2
CH
3
CE
3 309 6-CE 3
CF
3
CE
2
CH
2 -tBu CE 3 310 6-C0CE 3
CF
3 C-=C-iPr E 311 6-C0CE 3
CF
3 C2-C-Pr H 312 6-COCE 3
CF
3 C2=C-Bu H 313 6-COCH 3
CF
3 C-=C-iBu E 314 6-COCE 3
CF
3 C=-C-tBu H 315 6-COCE 3
CF
3 C-=C-Et E 316 6-C0CE 3
CF
3 C-=C-Me E 317 6-NH 2
CF
3 C=-C-ipr H 318 6-NH 2
CF
3 C-=C-Pr E 319 6-NH 2
CF
3 C-=C-Bu E 320 6-NH 2
CF
3 C-=C-iBu E 321 6-NH 2
CF
3 C-=C-tBu H 322 6-NH 2
CF
3 CE=C-Et H 323 6-NH 2
CF
3 CE=C-Me E 324 6-NMe 2
CF
3 C-=C-iPr H 325 6-NMe 2
CF
3 C-=C-Pr H 326 6-NMe 2
CF
3 C=-C-Bu E 327 6-NMe 2
CF
3 C-=C-iBu E 328 6-NMe 2
CF
3 C-=C-tBu H 329 6-NMe 2
CF
3 C-=C-Et H 330 6-NMe 2 CH CM 331 -Cl CF 3 C-=C-iMr 332 7-Cl CF 3 C=-C-Pr E 333 7-Cl CF 3 C=-C-Bu H 334 7-Cl CF 3 C-=C-iBu E 334 7Cl CF C-=C111 WO 98/45276 WO 9845276PCTIUS98/06733 335 336 337 7-Cl 7-Cl 7-Cl CF3- CF3 CF3 C=-C-tBu CSC-Et CE-C-Me *Unless otherwise indicated, stereocheinisty is 112 WO 98/45276 PCTJUS98/06733 Utility The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula possess HIV reverse transcriptase inhibitory activity and are Stherefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.
The compounds of formula of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV.
Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.
The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.
Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention 113 WO 98/45276 PCT/US98/06733 would be indicative of the presence of HIV reverse transcriptase and HIV virus.
As used herein "Ig" denotes microgram, "mg" denotes milligram, denotes gram, "lL" denotes microliter, "mL" denotes milliliter, denotes liter, "nM" denotes nanomolar, "IM" denotes micromolar, "mM" denotes millimolar, denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, MO.
HIV RNA Assay DNA Plasmids and in vitro RNA transcripts: Plasmid pDAB 72 containing both gag and pol sequences of (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Barn HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at -70 0 C. The concentration of RNA was determined from the A260.
Probes: Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, CA) DNA synthesizer by addition of biotin to the 5' terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5'-biotin -CCCTATCATTTTTGGTTTCCAT 3' was complementary to nucleotides 2374-2395 of HXB2.
Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, CA.).
The pol reporter probe CTGTCTTACTTTGATAAAACCTC was complementary to nucleotides 2403-2425 of HXB2. The gag 114 WO 98/45276 PCT/US98/06733 reporter probe CCCAGTATTTGTCTACAGCCTTCT was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research S1984, 12, 387). The reporter probes were prepared as 0.5 pM stocks in 2 x SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 pM stocks in water.
Streptavidin coated plates: Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, MA).
Cells and virus stocks: MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or FCS for MT-4 cells, 2 mM L-glutamine and 50 pg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70 0 C. Infectious titers of HIV-1(RF) stocks were 1-3 x 107 PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.
For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5 x 105 cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2 x 10 6 /mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37 0
C.
HIV RNA assay: Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin WO 98/45276 PCT/US98/06733 oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37 0 C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 LL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 .1 of a hybridization cocktail containing 4 X SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37 0 C, the plate was again washed 6 times.
Immobilized alkaline phosphatase activity was detected by addition of 100 LL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in bufferB (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgC12, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid).
The plates were incubated at 37 0 C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.
Microplate based compound evaluation in HIV-1 infected MT-2 cells: Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc).
After compound dilution, MT-2 cells (50 gL) were added to a final concentration of 5 x 105 per mL (1 x 105 per well).
Cells were incubated with compounds for 30 minutes at 37 0 C in a C02 incubator. For evaluation of antiviral potency, an 116 WO 98/45276 PCT/US98/06733 appropriate dilution of HIV-l (RF) virus stock (50 gL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 RL.
Eight wells per plate were left uninfected with 50 gL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.
After 3 days of culture at 37'C in a humidified chamber inside a C02 incubator, all but 25 jL of medium/well was removed from the HIV infected plates. Thirty seven gL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe.
Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37*C incubator.
Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 gL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.
In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC90 value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 gg/mL. values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-l (RF) when this procedure was followed. This concentration of virus corresponded to -3 x 105 PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, WO 98/45276 PCT/US98/06733 IC9 0 values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC90 for ddC, determined in each assay run, should be between 0.1 and 0.3 gg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC 90 was found to be less than For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2X concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.
Protein Binding and Mutant Resistance In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold: 1. Many drugs are extensively bound to plasma proteins.
Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-l-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood.
Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site HIV-l reverse transcriptase, HIV-l RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound 118 WO 98/45276 PCTIUS98/06733 in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.
2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate.
Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-I, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-l which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.
Dosage and Formulation The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with 119 WO 98/45276 PCTIUS98/06733 pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.
Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
Similar diluents can be used to make compressed tablets.
Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over .a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
120 WO 98/45276 PCT/US98/06733 In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, mg of cellulose, and 6 mg magnesium stearic.
Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.
Tablets A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, milligrams of magnesium stearate, 275 mg of microcrystalline 121 WO 98/45276 PCT/US98/06733 cellulose, 11 mg of starch and 98.8 mg of lactose.
Appropriate coatings may be applied to increase palatability or delay absorption.
Susiension An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, and 0.025 mg of vanillin.
Iniectable A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.
Combination of comDonents and (b) Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components and are to be treated the same or independently, each agent of component may also be treated the same or independently.
Components and of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component and (b) are not formulated together in a single dosage unit, the component may be administered at the same time as component or in any order; for example component of this invention may be administered first, followed by administration of component or they may be administered in the revserse order. If component contains more that one agent, one RT inhibitor and one protease inhibitor, 122 WO 98/45276 PCT/US98/06733 these agents may be administered together or in any order.
When not administered at the same time, preferably the administration of component and occurs less than about one hour apart. Preferably, the route of administration of component and is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.
As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
The proper dosage of components and of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component By way of general guidance, when the compounds of component and component are administered in combination, the dosage amount of each component may be reduced by about relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.
123 WO 98/45276 PCT/US98/06733 The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to S minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated.
By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric releasepolymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components and via a coating or some other material, contact may also be prevented between the individual agents of component Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the 124 WO 98/45276 PCT/US98/06733 enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.
Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component and one or more compounds of component in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component and component may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component and component may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, 125 f 126 either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude S the presence or addition of one or more other feature, integer, step, component or group thereof.
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Claims (26)

1. A compound of formula R 1 R 2 R3N R8 H I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 1 is C1- 3 alkyl substituted with 1-7 halogen; R 2 is selected from C 1 -5 alkyl substituted with 1-2 R 4 alkenyl substituted with 1-2 R 4 and C2- 5 alkynyl substituted with 1 R 4 R 3 at each occurrence, is independently selected from C1- 4 alkyl, OH, C1- 4 alkoxy, F, Cl, Br, I, NR 5 R 5a NO 2 CN, C(O)R 6 NHC(O)R 7 and alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form R 4 is selected from C3- 5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-5 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R 3 R 5 and R 5a are independently selected from H and C1- 3 alkyl; R 6 is selected from H, OH, C 1 -4 alkyl, C1- 4 alkoxy, and R 7 is selected from C1- 3 alkyl and C-_ 3 alkoxy; R 8 is selected from H, C3-5 cycloalkyl, and C1-3 alkyl; and, 127 WO 98/45276 PCT/US98/06733 n is selected from 0, 1, 2, 3, and 4.
2. A compound according to Claim 1, wherein: R 1 is C1- 3 alkyl substituted with 1-7 halogen; R 2 is selected from C 1 -5 alkyl substituted with 1 R 4 C 2 alkenyl substituted with 1 R 4 and C 2 5 alkynyl substituted with 1 R 4 R 3 at each occurrence, is independently selected from CI-4 alkyl, OH, C1- 4 alkoxy, F, Cl, Br, I, NR 5 R 5a NO 2 CN, C(O)R 6 NHC(O)R 7 and alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form -OCH 2 0-; R 4 is selected from C 3 -5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 R 5 and R 5 a are independently selected from H, CH 3 and C 2 H 5 R 6 is selected from H, OH, CH 3 C 2 H 5 OCH 3 OC 2 H 5 and R 7 is selected from CH 3 C 2 H 5 OCH 3 and OC 2 H 5 R 8 is selected from H, cyclopropyl, CH 3 and C 2 H 5 and, n is selected from 0, 1, 2, and 3.
3. A compound according to Claim 2, wherein: R 1 is selected from CF 3 and C 2 F 5 128 WO 98/45276 PCT/US98/06733 R 2 is selected from C1- 3 alkyl substituted with 1 R 4 C 2 -3 alkenyl substituted with 1 R 4 and C2-3 alkynyl substituted with 1 R 4 R 3 at each occurrence, is independently selected from C1-3 alkyl, OH, C1- 3 alkoxy, F, Cl, Br, I, NR5R 5a NO 2 CN, C(O)R 6 NHC(O)R 7 and NHC(O)NR 5 R 5 a; alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form R 4 is selected from C3- 5 cycloalkyl substituted with 0-2 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 R 6 is selected from H, OH, CH 3 C 2 H 5 OCH 3 OC 2 H 5 and R 7 is selected from CH 3 C 2 H 5 OCH 3 and OC 2 H 5 R 8 is selected from H, CH 3 and C 2 H5; and, n is selected from 0, 1, and 2.
4. A compound according to Claim 3, wherein: R 1 is CF 3 R 2 is selected from C1- 3 alkyl substituted with 1 R 4 C2-3 alkenyl substituted with 1 R 4 and C 2 -3 alkynyl substituted with 1 R 4 129 WO 98/45276 PCT/US98/06733 R 3 at each occurrence, is independently selected from C1- 3 alkyl, OH, C 1 -3 alkoxy, F, Cl, NR 5 R 5 a, NO2, CN, C(O)R 6 NHC(O)R 7 and NHC(O)NR5 R alternatively, if two R 3 's are present and are attached to adjacent carbons, then they may combine to form R 4 is selected from cyclopropyl substituted with 0-1 R 3 phenyl substituted with 0-2 R 3 and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R 3 wherein the heterocyclic system is selected from 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2- imidazolyl; R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 R 6 is selected from H, OH, CH 3 C 2 H 5 OCH 3 OC 2 H 5 and NR 5 R 7 is selected from CH 3 C 2 H 5 OCH 3 and OC 2 H 5 R 8 is selected from H, CH 3 and C 2 H 5 and, n is selected from 1 and 2. A compound according to Claim 4, wherein the compound is of formula Ia: 1 R2 R8 RNO H Ia.
6. A compound according to Claim 4, wherein the compound is of formula Ia: 130 WO 98/45276 WO 9845276PCT/US98/06733 H lb.
7. A compound according to Claim 1, wherein the compound is selected from: -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4- dihydro-2 (lH) -quinazolinone; -6-Chloro-4- (2-pyridy l) ethynyl-4-trifluoromethyl-3 ,4- dihydro-2 (lH) -quinazolinone; -6-Chloro-4--phenylethynyl-4-trifluoromethyl-3, 4-dihydro- 2 (1H) -quinazolinone; -4-Cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4- dihydro-2 (li) -quinazolinone; -6-Methoxy-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; -6-Methoxy--4-phenylethynyl-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; -4-Cyclopropylethynyl-5, 6-difluoro-4--trifluoromethyl- 3, 4-dihydro-2 (1H) -quinazolinone; 6-Difluo-ro-4- (2-pyridyl) ethynyl-4-trifluoromethyl- 3, 4-dihydro-2 (lH) -quinazolinone; 6-Difluoro-4-phenylethynyl-4-trifluoromethyl-3, 4- dihydro-2 (11) -quinazolinone; 131 (-)-4-Cyclopropylethynyl-6-f luoro-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; (-)-6-Fluoro-4- (2-pyridyl) ethyriyl-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; 6-Pluoro-4-phenylethynyl-4-trif luoromethyl-3 ,4-dihydro- 2 (li) -quinazolinone; (1)-6-Fluoro-4- (2 '-2-pyridyl) ethyl-4-trif luoromethyl-3,4- dihydro-2 (1H) -quinazolinone; -E-Fluoro-4-phenylethyl-4-trifluoronethyl-3 ,4-dihydro- 2 (lI) -quinazolinone; -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; dihydro-2(1H)-quinazolinone; -4-Cyclopropylethynyl-5, 6-difluoro-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; (--4-Cyclopropylethnyl-5, 6-difluoro-4-trifluoromethyl-,4 dihdiho-2o(2H) -quinazolinone; ad -6-Chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3, 4- dihydro-2 (1H) -quinazolinone; or a pharmaceutically acceptable salt thereof. 132 -133
8. A compound selected from: (+/-)-6-Chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2( 1 H)- quinazolinone; (+/-)-6-Chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2( I H)-qui nazol inone; (+/-)-4-Isopropylethynyl-6-methoxy-4-trifl uoromethyl-3, 4-dihydro-2( 1 H)- quinazolinone; (+/-)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)- quinazolinone; (+/-)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2( I H )-quinazol inone; (+/-)-5,6-Difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2( I H )-qui nazol inone; (+/-)-6-Fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2( 1 H)- quinazolinone; ::(+/-)-6-Fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2( I H)-quinazol inone; (-)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2( 1 H)- quinazolinone; (+)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2( H)- quinazolinone; (-)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2( 1 H)-quinazolinone; 6-Difluoro-4-ethylethynyl-4-trifluoromethy-3, 4-dihydro-2( I H )-quinazolinone; or a pharmaceutically acceptable salt thereof. -134
9. A compound according to claim 7, wherein the compound is: chloro-4-cyclopropylethynyl-4-trifluoromethyl34-dihydro-2(1 H)-quinazol inone, or a pharmaceutically acceptable salt form thereof.
10. A compound according to claim 7, wherein the compound is: chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4..dihydro-2(1 H)-quinazol inone, or a pharmaceutically acceptable salt form thereof.
11. A compound according to claim 7, wherein the compound, is: chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro.2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
12. A compound according to claim 7, wherein the compound is: cyclopropylethynyl-6-methoxy-4-trifluoromethyl.3,4dihydro-2( 1 H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof.
13. A compound according to claim 7, wherein the compound is: *methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-qui nazol inone, or a pharmaceutically acceptable salt form thereof. *14. A compound according to claim 7, wherein the compound is: methoxy-4-phenylethynyl-4-trifluoromethyl-3, 4-dihydro-2(1 H)-qu inazol inone, or a 0 A pharmaceutically acceptable salt form thereof. *25 15. A compound according to claim 7, wherein the compound is: cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2( I H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
16. A compound according to claim 7, wherein the compound is: (I) 5, 6-difl uoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3 ,4-di hydro-2( 1 H)-quinazol i none, or a pharmaceutically acceptable salt form thereof. -135-
17. A compound according to claim 7, wherein the compound is: 5,6-difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
18. A compound according to claim 7, wherein the compound is: cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
19. A compound according to claim 7, wherein the compound is: fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof. A compound according to claim 7, wherein the compound is: fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
21. A compound according to claim 7, wherein the compound is: fluoro-4-(2'-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
22. A compound according to claim 7, wherein the compound is: fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof. 25 23. A compound according to claim 7, wherein the compound is: chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
24. A compound according to claim 7, wherein the compound is: chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof. -136- A compound according to claim 7, wherein the compound is: cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
26. A compound according to claim 7, wherein the compound is: cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
27. A compound according to claim 7, wherein the compound is: cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1 H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
28. A compound according to claim 7, wherein the compound is: chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone, or a pharmaceutically acceptable salt form thereof.
29. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt form thereof.
30. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt form thereof. o: 25 31. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: a compound of any one of claims 1-28 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
32. A method according to claim 31, wherein the reverse transcriptase S 4' inhibitor is selected from AZT, 3TC, ddl, ddC, d4T, delavirdine, TIBO derivatives, -137- BI-RG-587, nevirapine, L-697, 661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HYB 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-
378. 33. A method according to claim 32, wherein the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir, and indinavir. 34. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: a compound of any one of claims 1-28 or steroisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers. 35. The use of a compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt form thereof, in the preparation of a medicament 20 for the treatment of HIV infection. 36. A compound according to any one of claims 1 to 28; a pharmaceutical composition of claim 29; a method of any one of claims 30 to 33; a pharmaceutical kit of claim 34; or the use of claim 35, wherein the 25 pharmaceutically acceptable salt is selected from: hydrochloric acid salt, hydrobromic acid salt, sulfuric acid salt, phosphoric acid salt, acetic acid salt, Ssuccinic acid salt, glycolic acid salt, stearic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, ascorbic acid salt, maleic acid salt, fumaric acid salt, toluenesulfonic acid salt, methanesulfonic acid salt, and oxalic acid salt. 37. A compound of any one of claims 1 to 28, substantially as herein A described with reference to any one of the Examples. -138- 38. A pharmaceutical composition of claim 29, substantially as herein described with reference to any one of the Examples. 39. A method of any one of claims 30 to 33, substantially as herein described with reference to any one of the Examples. A pharmaceutically acceptable kit of claim 34, substantially as herein described with reference to any one of the Examples. 41. The use of claim 35, substantially as herein described with reference to any one of the Examples. DATED this 20 th day of March, 2001. DU PONT PHARMACEUTICALS COMPANY By their Patent Attorneys: CALLINAN LAWRIE S S
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