CA2334332A1 - Substituted quinoxalin-2(1h)-ones useful as hiv reverse transcriptase inhibitors - Google Patents

Abstract

The present invention relates to quinoxalin-2(1H)-ones of formula (I) or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same and methods of using the same for treating viral infection or as an assay standard or reagent.

Description

SUBSTITUTED QUINOXALIN-2(1H)-ONES USEFUL AS HIV REVERSE
TRANSCRIPTASE INHIBITORS
FTELD OF THE INVENTTnu This invention relates generally to substituted quinoxalin-2(1H)-ones which are useful as in'.iibitors of HIV
reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.
BACKGROUND OF THE INVENT~Q~T
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.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag pot fusion polyprotein. The polyprotein is WO 00/00478 PCT/US99/1_4395 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: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) 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 treating 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 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, WO 00/00478 PCTlUS99/14395 nucleoside analogs, such as 3'-azido-3'-deoxythymidine (A?T), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxythymidinene (d4T), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-3'-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV
reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U. S. Patent Number 5,519,021, the contents of which are hereby incorporated herein by reference, describes reverse transcriptase inhibitors which are benzoxazinones of the formula:

Z
wherein X is a halogen, Z may be O. However, benzoxazinones are not part of the present invention.
U.S. Patent No. 5,693,641 depicts bicyclic pyrimidine derivatives useful as anticoagulants of the formula:

R1- \ Z' 'N N R~
N~~
RZ N O
~Z2 R5 R3 '~ \ Ra wherein Z1 and Z2, independently, can be -0-, -NR5-, or -OCH2-; RS is H, alkyl, aryl, or aralkyl; R6 and R7 can be a variety of groups. Compounds of this sort are not within the scope of the presently claimed invention.
EP 0,657,166 A1 illustrates quinoxalines of the formula:

N
R1 ~ R3 N X
~2 R
which in combination with at least one nucleoside exhibit an antiviral effect. The application describes quinoxalines generally, wherein X is O or S; R2 or RS can be a variety of groups including H, alkyl, alkenyl, alkynyl, cycloalkyl, substituted carbonyl, substituted oxycarbonyl, substituted aminocarbonyl; and R3 or R4, can be a variety of groups including H, alkyl, alkenyl, cycloalkyl, and aryl, but not IO alkynyl. However, EP 0,657,166 A1 does not disclose by exemplification compounds wherein R3 or R4 are -CF3, -CF2CF3, -CF2CF2CF3 or cyclopropyl, compounds wherein R3 or R4 are alkynyls or substituted alkynyls.
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.
It has unexpectedly been found that compounds of the present invention, most preferably, 3-(perfluoroalkyl)-3,4-dihydro-1,H-quinoxalin-2-ones, are useful as HIV reverse transcriptase inhibitors.
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 or prodrug form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises WO 00/00478 PCT/US99/~4395 administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) 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 or prod rug 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 (I):

X ~W N R2 f Y.w ~ ~ C
Z N A
H
(I) wherein A, W, X, Y, Z, R1, R2, and Cf 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):

X ~W ( N C f Y.
Z N A
H
(I) or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CRS;
Z is N or CR6;
Cf is cyclopropyl or C1_3 alkyl substituted with 3-7 halogen;
provided that the number of W, X, Y, and Z which are N, is zero, one or two;
R1 is selected from:
-C02R12 , -COR12 . -S02R12 . -SOR12 , -CONHR12 , -(CHR7)pCHR?RB, -(CHR7)pCH=CR7R8, -(CHR7)pC=C-Re, -C1_6 alkyl substituted with 0-3 R11, -(CH2)pphenyl substituted with 0-3 R1~, and -(CH2)p(C3-S cycloalkyl);
R2 is selected from:
-CH=CR7R8, WO 00/00478 PCT/US99/1_4395 -C=C-RS, -CH=CHCHR7R8, -(CHR~)pCHR~R8, -(CHR~)pCH=CR~RB, -(CHR~)pC=-C-R8, -C1_q alkyl substituted with 0-3 R11, -(CHz)pphenyl substituted with 0-3 Rlo, and -(CH2)p(C3_5 cycloalkyl);
R3 is selected from:
H, F, C1, Br, I, -OH, OCF3, -CN. N02, CHO, C(=O)CH3, C (=O) CF3, C (=O)NH2, C (=0)NHCH3, NR~R7a, NR~C (=O) OR7b, C (=O) OR7, SRS, S (=O) R~, S02R~, S02NHR~, NR~S02R~b, C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyl, CZ_3 alkynyl, C1_3 alkoxy, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted With 0-2 Rlo;
R4 is selected from:
H, F, C1, Br, I, -OH, OCF3, -CN, N02, CHO, C(=O)CH3, C(=O)CF3, C(=0)NH2, C(=O)NHCH3, NR7R78, NR~C(=O)OR~b, C(=O)OR~, SRS, S(=O)R~, S02R~, S02NHR~, NR7S02R~b, C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyl, C2_3 alkynyl, Cl_3 alkoxy, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo;
-?-WO 00/00478 PCTlUS99/1_4395 alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring, said carbocyclic ring being aromatic or nonaromatic, said carbocyclic ring being substituted with 0-2 Rlo;
alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms atoms selected from the group consisting of N, O, and S, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 Rlo;
R5 is selected from H, F, C1, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring, said carbocyclic ring being aromatic or nonaromatic, said carbocyclic ring being substituted with 0-2 Rlo;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms atoms selected from the group consisting of N, O, and S, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 Rlo;
R6 is selected from:
H. OH, F, C1, Br, I, OCF3, -CN, N02, CHO, C(=0)CH3, C(=O)CF3, C(=0)NH2, C(=O)NHCFi3, NR~R7a~
NR~C(=O)OR~b, C(=O)OR~, SRS, S(=O)R~, S02R~, S02NHR~, NR~S02R~b, _g_ C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyl, C2_3 alkynyl, Cl_3 alkoxy, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo;
R~, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
Rya, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;;
Rib. at each occurrence, is methyl, ethyl, propyl, or butyl;
R8, at each occurrence, is selected from:
H, F, C1, Br, I, CH(-OCH2CH20-), C1_4 haloalkyl, c:,; 6 alkyl substituted with 0-3 R11, C2_6 alkenyl, C3-~ cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, buto xy, and F;
Rlo, at each occurrence, is selected :from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, C1, Br, I, CN, NR~R?a, arid C (=O) CH3;
R1I, at each occurrence, is selected from ORS, CN, F, C1, Br, I. NOZ. NR~R~a, CHO, C(=O)CH3, C(=O)NH2;

WO 00!00478 PCT/US99/14395 R12, at each occurrence, is selected from C1_6 alkyl, C2_g alkenyl, C2_4 alkynyl, C3-7 cycloalkyl, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo, -(CH2)pphenyl substituted with 0-2 Rlo, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, 2, and 3;
provided, if, simultaneously, each of W, X, Y, and Z are carbon, then R2 is not unsubstituted C1_4 alkyl.
In a preferred embodiment, the present invention provides a novel compound of Formula (II), wherein:
wherein:
A is 0 or S;
R3 R1 , Cf R5 ~ N A
s H
R
(II) Cf is -CF3, -CF2CF3, or -CFZCF2CF3;
R1 is selected from:
-C02R12, -COR12, -S02R12, -SOR12, -CONHR12, -(CHR~)pCHR~Re, -(CHR~)pCH=CR7Rg, -(CHR~)pC~C-R8, -C1-6 alkyl substituted with 0-3 R11, WO 00/00478 PCT/US9911 _4395 -(CH2)pphenyl substituted with 0-3 Rlo, and -(CH2)p(C3_g cycloalkyl);
R2 is selected from:
-CH=CR~R8, -C=-C-Ra , -CH=CHCHR~R8, -(CHR~)pCHR~R8, -(CHR~)pCH=CR7R8, -(CHR7)pC~C-Rg, -(CH2)pphenyl substituted with 0-3 R1~, and -(CH2)p(C3_5 cycloalkyl);
R3 is selected from:
H, F, C1, Br, I, -OH, OCF3, -CN, N02, CHO, C(=0)CH3, C (=0) CF3, C (=O) NH2. C (=O) NHCH3, NR~R~a, NR7C (=O) OR~b, C (=O) OR7, SR7, S (=O) R7, S02R?, S02NHR7, NR~SOZR7b, C1_3 alkyl substituted with 0-3 Rli, C2_3 alkenyl, C2_3 alkynyl, Cl_3 alkoxy, phenyl substituted with 0-2 RlO, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 RZ~;
R4 is selected from:
H, F, C1, Br, I, -OH, OCF3, -CN, N02, CHO, C(=0)CH3, C(=0)CF3, C(=O)NH2, C(=O)NHCH3, NR7R7n~
NR7C(=O)OR7b, C(=O)OR~, SR7, S(=O)R~, S02R~, S02NHR7, NR~S02R~b, C1_3 alkyl substituted with 0-3 RZl, C2_3 alkenyl, C2_3 alkynyl, C1_3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo;
alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-. -0-CH2-CH2-O-, or -CH=CH-CH=CH-;
20 R5 is selected from H. F, C1, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-, -O-CH2-CH2-O-, or -CH=CH-CH=CH-;
R6 is selected from:
H, OH, F, C1, Br, I, OCF3, -CN, N02. CHO, C(=O)CH3, C(=O)CF3, C(=O)NH2, C(=O)NHCH3, NR?R7a~
NR7C ( =O ) OR7b, C ( =O ) OR7 , SR' S ( =O ) R7 , S02R7 , S02NHR7 , NR~S02R~b.
C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyT, C2-3 alkynyl, Cl_3 alkoxy, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo;
R~, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;;
Rib, at each occurrence, is methyl, ethyl, propyl, or butyl;

R8, at each occurrence, is selected from:
H, F, C1, Br, I, CH(-OCHZCHZO-), C1_4 haloalkyl, C1_6 alkyl substituted with 0-3 R11, C2_6 alkenyl, C3_~ cycloalkyl substituted v,ith 0-2 R9, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-2 Rlo;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R1~, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, C1, Br, I, CN, NR7R~a, and C(=0)CH3;
R11, at each occurrence, is selected from ORS, CN, F, C1, Br, I, N02, NR?R~8, CHO, C(=O)CH3, Cu':7)NH2;
R12, at each occurrence, is selected from C1_6 alkyl, C2_4 alkenyl, C2_4 alkynyl, C3_~ cycloalkyl, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-2 Rlo -(CH2)pphenyl substituted with 0-2 Rlo, and -(CH2)p(C3_5 cycloalkyl); and p, at each occurrence, is selected from 0, l, 2, and 3.
In a further preferred embodiment, the present invention provides a novel compound of Formula (II), wherein:

WO 00!00478 PCT/US99l14395 A is 0 or S;
Cf is -CF3, -CF2CF3, or -CF2CF2CF3;
R1 is selected from:
-COZR12, -COR12. -S02R12~ -SOR12, -CONHR12, -(CHR~)pCHR~R8, -(CHR~)pCH=CR~RB, -(CHR~)pC=C-Ra, -C1-5 alkyl substituted with 0-3 R11, -(CH2)pphenyl substituted with 0-3 Rla, and _(CH2)p(C3_5 cycloalkyl);
R2 is selected from:
-CH=CR~R8, -C=C-R8, -CH=CHCHR~R8, -(CHR~)pCHR~Rg, -(CHR~)pCH=CR~RB, -(CHR~)pC=C-R8, -(CH2)pphenyl substituted with 0-3 R1~, and -(CHZ)p(C3_5 cycloalkyl);
R3 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -N02, -CHO, -C (=O) CH3, -C(=O)CF3, -C(=O)NH2, -C(=0)NHCH3, -NH2, -NHCH3.
-N(CH3)2, -NHC(=O)OCH3, -C(=0)OCH3, -SCH3, -S(=0)CH3, -S02CH3, -S02NHCH3, -NHSOZCH3, C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyl, C2_3 alkynyl, C1_3 alkoxy, R4 is selected from:
H, F, C1, Br, I, -OH, OH, -OCF3, -CN, -N02, -CHO, -C(=O)CH3, -C(=O)CF3. -C(=0)NH2. -C(=0)NHCH3, -NH2.
-NHCH3, -NHCH2CH3, -N(CH3)2. -N(CH2~3)2.

WO 00100478 PCTIUS99/1.4395 -NHC(=O)OCH3, -NHC(=0)OCH2CH3, -C(=O)OCH3, -C(=0)OCH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3, -S(=0)CHZCH3, -S02H, -SOzCHg, -SOZCH2CH3, -S02NHCH3, -S02NHCH2CH3, -NHS02CH3, -NHS02CH2CH3, C1_3 alkyl substituted with 0-3 R11, C2_3 alkenyl, C2_3 alkynyl, C1_3 alkoxy, alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -0-CH2-O-, -0-CH2-CH2-O-, or -CH=CH-CH=CH-;
R5 is selected from H, F, C1, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -0-CH2-O-, -O-CH2-CH2-O-, or R6 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -N02, -CHO, -C(=O)CH3, 2 5 -C ( =O ) CF 3 , -C ( =O ) NH2 , -C ( =0 ) NHCH3 , -NHZ , -NHCH3 , -N(CH3)2, -NHC(=O)OCH3, -C(=0)OCH3, -SCH3, -S(=0)CH3, -S02CH3, -S02NHCH3, -NHS02CH3, C1_3 alkyl substituted with 0-3 R11 C2_3 alkenyl, C2-3 alkynyl, C1_3 alkoxy, R~, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
Rya, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;;

WO 00/00478 PCTIUS9911_4395 R8, at each occurrence, is selected from:
H, F, C1, Br, I, CH(-OCHZCH20-), C1_q haloalkyl, C1_6 alkyl substituted with 0-3 R11, C2_6 alkenyl, C3_~ cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R1~, at each-occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, C1, Br, I, CN, NR~R~a, and C(=O)CH3 R11, at each occurrence, is selected from ORS, CN, F, C1, Br, I, N02, NR~R7a, CHO, C(=O)CH3, C(=O)NH2;
R12, at each occurrence, is selected from C1_6 alkyl, C2_4 alkenyl, C2_q alkynyl, C3_~ cycloaikyl, phenyl substituted with 0-2 Rlo, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rlo, -(CH2)pphenyl substituted with 0-2 Rlo, and -(CHZ)ptC3_5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, 2, and 3.
In a more further preferred ennbodiment, the present invention provides a novel compound of Formula (II), wherein:

A is O;
Cf is -CF3 or -CF2CF3%
R1 is selected from:
-C02R12, -COR12, _g02R12~
-(CHR~)pCHR~Ra, -(CHR~)pCH=CR~RB, -(CHR~)pC=-C-R8, -C1-5 alkyl substituted with 0-3 R~l, -(CH2)pphenyl substituted with 0-3 Rl~, and -(CH2)p(C3_5 cycloalkyl);
R2 is selected from:
-CH=CR~RB, -C---C-R8 , -CH=CHCHR~R8, -(CHR~)pCHR~RS.
-(CHR~)pCH=CR~RB, -(CHR~)pC=C-R8, -(CH2)pphenyl substituted with 0-3 Rl~, and -(CH2)p(C3_5 cycloalkyl)%
R3 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -N02, -CHO, -C(=O)CH3, -C(=0)CF3, -NH2, -NHCH3, -N(CH3)2. -CF3, -CH3, -CH2CH3, -OCH3. and -OCH2CH3, R4 is selected from:
H, F, CI, Br, I, -OH, OH, -OCF3, -CN, -NOa, -CHO, -C(=0)CH3. -C(=O)CF3, -C(=O)NH2, -C(=0)NHCH3, -NH2, -NHCH3, -N(CH3)2. -NHC(=0)OCH3, -C(=0)OCH3, -CF3, -CH3. -CH2CH3, -OCH3, and -OCH2CH3%
RS is selected from H, F, C1, Br, I, -OH, -CH3, -CH2GH3, -OCH3, and -OCH2CH3;
R6 is selected from:

WO 00100478 PCT/US991~4395 H, F, C1, Br, I, -OH, -OCF3, -CN, -N02, -CHO, -C(=0)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)z, -CF3, -CH3, -CH2CH3. -OCH3, and -OCH2CH3;
R~, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R8, at each occurrence, is selected from:
H, F, C1, Br, I, CH(-OCH2CH20-), C1_4 haloalkyl, C1_4 alkyl substituted with 0-3 R11, C2_q alkenyl, C3_6 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R1~, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R1~, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, C1, Br, I, CN, -NH2. -rlHCH3. -NHCH2CHg, -N(CH3)2, -N(CH2CH3)2, and C(=0)CH3;
R11, at each occurrence, is selected from ORS, CN, F, C1, Br, I, N02, -NH2, -NHCH3, -NHCHZCH3, -N(CH3)2, -N(CH2CH3)2.
CHO, C(=O)CH3, C(=O)NH2;
R12, at each occurrence, is selected from C1_6 alkyl, C2_4 alkenyl, C2_4 alkynyl, C3_6 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl, -(CH2)pphenyl substituted with 0-2 R1~, and -(CH2)p(C3_S cycloalkyl); and p, at each occurrence, is selected from 0, 1, and 2.
In an even more further preferred embodiment, the present invention provides a novel compound of Formula (III);

R4 N Rz / ~ CF3 RS ~ H O

(III) wherein:
R1 is selected from:
-CF3, -CF2H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)Z, -CH2CH2C(CH3)3, -CH2CH2CH(CH3)CH3, -CH(=CH2)CH3, -CH2CH=CH2, -CH2-CH=C(CH3)2, -CHZ-C=CH, -CHZ-C--_CCH3, -CH2Ph, -cycPr, -CH2cycPr, -CHZCH2cycPr, -COZCH3, -C02CH2CH3, -C02CH2CH2CH3, -COZCH2CH2CH2CH3.
-COZCH(CH3)2, -C02CH2CH(CH3)2, -C02CH2Ph, -C02cycPr, -C02CH2cycPr, -C02CHZCH=CHz, -S02CH2CH3, -SOZCH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2, and -COCH2cycPr;
R2 is selected from:
benzyl, phenethyl, -CH2CH2cycPr, -CSC-CH3, -CSC-CFg, -CSC-Et, -C~-iPr, -C~-cycPr, WO 00!004?8 PCT/US99/i_4395 -C=C-1-(CH3)cycPr, -C-~-CH=CH2, -C=C-C(=CH2)CH3, -CH=CH-CH3, -CH=CH-CF3, -CH=CH-Et, -CH=CH-iPr, -CH=CH-cycPr, -CH~H-CH=CH2, -CH2-C~-CH3, -CH2-C=C-CF3, -CH2-C=C-Et, -CH2-C---C-iPr, -CH2-C---C-cycPr, -CH2-C---C-CH=CH2, -CH2-CH=CH2, -CH2-CH=CH-CH3, -CH2-CH=CH-CF3, -CHZ-CH=CH-Et, -CH2-CH=CH-iPr, -CH2-CH=CH-cycPr, -CH2-CH=CH-CH=CH2, -CH2-CH=C(CH3)2, and -CH=CH-CH2-cycPr;
R3 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -NOz, -C(=O)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3, R4 is selected from:
H, F, C1, Br, I, -OH, OH, -OCF3, -CN, -N02, -C(=0)CH3, -C(=O)CF3, -C(=O)NH2, -C(=0)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)OCH3, -C(=O)OCH3, -CF3, -CH3, W2~3 ~ -OCH3 , and -OCH2CH3 ;

R5 is selected from H, F, and C1; and R6 is selected from:
H, F, Cl -OH, -OCF3, -CF3, -CH3, and -OCH3.
In a further preferred embodiment, a compound of the present invention is selected from:
4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(methyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(methyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(allyl)-3-(trifluoromethyl)-3,4-dihydro-guinoxalin-2(1H)-one;
4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(benzyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylmethyl)-3-(allyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(propargyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(allyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(cyclopropylmethyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

WO 00!00478 PCTNS99/14395 6-(chloro)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(isobutyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(ally!)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(cyclopropylmethyl)-3-(phenethyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(ally!)-3-(phenethyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(methoxy)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(methoxy)-4-(ally!)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylmethyl)-3-(1-propynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ally!)-3-(1-propynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3 (trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(propen-2-yl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isobutoxycarbanyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(n-butoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(allyloxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(benzyloxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(n-propylsulfonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(phenylcarbonyl)-3-(2-cyclopropylethynyl)-3 (trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(neopentyl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(2-propynyl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(iH)-one;
4-(ethylsulfonyl)-3-(2-cyclopropylethynyl)-3 (trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropylsulfonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(methoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(propen-2-yI-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3 (trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-guinoxalin-2(1H)-one; and 6-(fluoro)-4-(propen-2-yl-oxycarbonyl)-3-(2-cyclopropylethynyl;-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one.
In a most preferred embodiment, the present invention provides a novel compound of Formula (I), Formula (II) or Formula (III), or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R1, Cf, A, W, X, Y, and Z are as defined above; and R2 is -C=C-R8 or -(CHR~)pC=C-R8.
In another preferred embodiment, the present invention provides a compound of Formula (IIb):

~W N
Cf Z N A
H
(IIb) wherein:

A is O or S;
W is N or CR3 ;
X is N or CR4;
Y is N or CRS;
Z is N or CR6;
Cf is -CF3, -CF2CF3, or -CF2CF2CF3;
provided that one or two of W, X, Y, and Z are N;
R1 is selected from:
-C02R12, -COR12, -S02R12, -(CHR~)pCHR~R8, -(CHR~)pCH=CR~R8, -(CHR~)pC~C-R8, -C1_5 a~ yl substituted with 0-3 R11, -(GH2)pphenyl substituted with 0-3 R1~, and -(CH2)p(C3_5 cycloalkyl);
R2 is selected from:
-CH=CR~R8, -C=-C-RS , -CH=CHCHR7R8 , -(CHR~)pCHR~R8, -(CHR7)pCH=CR~RB, -(CHR~)pC~C-R8, -(CHZ)pphenyl substituted with 0-3 R10, and -(CH2)p(C3_5 cycloalkyl);
R3 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -N02, -CHO, -C(=0)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3, R4 is selected from:
H, F, C1, Br, I, -OH, OH, -OCF3, -CN, -N02, -CHO, -C(=0)CH3, -C(=O)CF3, -C(=0)NH2, -C(=0)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -CF3, -CH3, -CHzCH3, -OCH3, and -OCH2CH3;
RS is selected from H, F, C1, Br, I, -OH, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;

R6 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=0)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R~, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
Re, at each occurrence, is selected from:
H, F, C1, Br, I, CH(-OCH2CH20-), C1_4 haloalkyl, C1_q alkyl substituted with 0-3 R11, C2_4 alkenyl, C3_6 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R1~, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R1~, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, C1, Br, I, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and C(=O)CH3;

Rii, at each occurrence, is selected from ORS, CN, F, C1, Br, I , N02 , -NH2 , -NHCH3 , -NHCH2CH3 , -N (CH3 } 2 . -N ( CH2CH3 ) 2 .
CHO, C ( =O ) CH3 , C ( =O ) NH2 ;
Riz, at each occurrence, is selected from C1_6 alkyl, C2_~ alkenyl, C2_4 alkynyl, C3_6 cycloalkyl, phenyl substituted with 0-2 R1~, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl, -(CH2)pphenyl substituted with 0-2 R1~, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, and 2.
In more preferred embodiment, the present invention provides a compound of Fort., ~_a (IIIa}

Rz X ~W N
I ~ ~CF3 Y~Z N O
H
(IIIb) wherein:
R1 is selected from:
-CF3, -CF2H. -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CHZCH3, -CH(CH3)2. -CH2CH(CH3)2. -CH2CH2C(CH3)3, -CH2CHZCH(CH3}CH3, -CH(=CH2)CH3, -CH2CH=CH2, -CH2-CH~(CH3)2. -CH2-C=CH, -CHZ-C=CCH3, -CH2Ph. -cycPr, -CHZCycPr. -CH2CH2cycPr, -C02CH3, -C02CH2CH3, -COZCH2CH2CH3; -C02CH2CH2CH2CH3, -C02CH(CH3)2, -C02CH2CH(CH3)2, -COZCHZPh, -C02cycPr, -C02CH2cycPr, -C02CH2CH=CH2, -S02CHZCH3, -S02CH(CH3)2, -COCH3, -COCH2CH3. -COCHZCH2CH3, -COCH(CH3)2, and -COCH2cycPr;
R2 is selected from:
benzyl, phenethyl, -CH2CHZCycPr, -C=C-CH3, -C=C-CF3, -C=C-Et, -C~-iPr, -C~-cycPr, -CSC-1-{CH3)cycPr, -CSC-CH=CHZ, -C=_C-C(=CH2)CH3, -CH=CH-CH3, -CH~Fi-CF3, -CH=CH-Et, -CH=CH-iPr, -CH=CH-cycPr, -CH~H-CH=CH2, -CHZ-C~-CH3.
-CH2-C=C-CF3, -CH2-C=C-Et, -CH2-C---C-iPr, -CH2-C=C-cycPr, -CH2-C=C-CH=CH2, -CH2-CH--CH2, -CHZ-CH=CH-CH3, -CH2-CH=CH-CF3, -CH2-CH=CH-Et, -CH2-CH=CH-iPr, -CHZ-CH=CH-cycPr, -CHZ-CH=CH-CH=CH2, -CH2-CH=C(CH3)2, and -CH=CH-CH2-cycPr;
R3 is selected from:
H, F, C1, Br, I, -OH, -OCF3. -CN, -N02, -C(=O)CH3, -C ( =O ) CF3 , -NHZ . -NH~~Ei3 . -N ( CH3 ) 2 , -CF3 . -CH3 , -CH2CH3, -OCH3, and -OCHZCH3, R4 is selected from:
H, F, C1, Br, I, -OH, OH, -OCF3, -CN, -NOZ, -C(=0)CH3, -C(=O)CF3, -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=0)OCH3, -C(=O)OCH3, -CF3, -CH3, -CH2CH3. -OCH3, arid -OCHZCH3~
R5 is selected from H, F, and C1; and R6 is selected from:
H, F, CI -OH, -OCF3, -CF3, -CH3, and -OCH3~
In another preferred embodiment, the present invention provides a compound of Formula (Ia) or (Ib):

WO 00/00478 PC'T/US99/14395 ,W N R2 ,W N , RZ
X~ ~ ..~Cf X~ ~ ~Cf Y~~ Yes.
Z H A Z H A
Ia Ib or a stereoisomer or pharmaceutically acceptable salt form thereof.
In a second 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 IO pharmaceutically acceptable salt form thereof.
In a third 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 pharmaceutically acceptable salt form thereof.
In a fourth embodiment, the present inw~ntion 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) a compound of Formula (I); and, (b) 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 a nucleoside reverse transcriptase inhibitor.
In another more preferred embodiment, the HIV reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, efavirenz, and d4T and the protease WO 00/00478 PCTlUS99/14395 inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.
In an even more preferred embodiment, the HIV reverse transcriptase inhibitor is selected from AZT, rescriptor, efavirenz, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.
In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the HIV
reverse transcriptase inhibitor is efavirenz.
In another still further preferred embodiment, the protease inhibitor is indinavir.
In a fifth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(s) a comp~eund of Formula (I); and, (b) 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 sixth 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).
In a seventh embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) 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.

WO 00/00478 PC'TJUS99/14395 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 iri 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.
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 uses.
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.
The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis.
Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide.
sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylamanonium carbonate, and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexyl~mine, N,N,N'-triethylenediamine, N,N-dimethyloctylamine;
1,5-diazabicyclo[4.3.0]non-5-ene (DBN);
1,4-diazabicyclo(2.2.2]octane (DABCO);
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);
tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.
Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.
Suitable ether solvents include, but are not intended to .~e limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.
Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DNg'), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.
As used herein, the term "amine protecting group" (or "N-protected") refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term "amine protecting group reagent" refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group.
Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference.
Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocaxbonyl and dithiasuccinoyl.

Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl))methyloxycarbonyl; 2-trimethylsilyl-ethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)-ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyl-oxycarbonyl; 2-(p-toluenesulfonyl)ethyloxy-carbonyl;
m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolyl-methyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl;
m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl;
3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyl-oxycarbonyl; N'-p-toluenesulfonylaminocarbonyl; t-amyloxy-carbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxy-carbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl;
phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl;
5-dibenzylsuberyl; triphenylmethyl; benzylidene;
diphenylmethylene; or methanesulfonamide.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C1-6 alkyl" denotes alkyl having 1 to 6 carbon atoms, ie. methyl, ethyl, propyl, butyl, pentyl, hexyl, and branched isomers therin.. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, i-pentyl, n-pentyl, and s-pentyl. "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 (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. "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 s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. "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, butenyl 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 point along the chain, such as ethynyl, propynyl, butynyl 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 7- membered monacyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon 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 unsatuxated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N. O 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 one, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than one.
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 number of S and 0 atoms in the aromatic heterocycle is not more than one.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 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 oxazolidinyi. 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 (RT).
Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, efavirenz (DuPont Merck), rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U901525), PNU142721 (Pharmacia and Upjohn), TIHO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).
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), I~tI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), DMP450 (DuPont Merck), and U-103017 (Pharmacia and Upjohn).
Additional examples include the cyclic protease inhibitors disclosed in W093/07128, W094/19329, W094/22840, and PCT
Application Number US96/03426 and the protease inhibitors disclosed in W094/04993, W095/33464, W096/28,418, and W096/28,464.
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 amanonium 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, malefic, 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 Remi.ngton's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
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 (I) 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 (I), 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 the compounds 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 (i.e., =O) group, then 2 hydrogens on the atom are replaced.
"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 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 c~znbination is greater than the additive effect of the co~:,pounds 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.
$:C7~TBF~.~
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.

The following abbreviations are used herein:
cycPr cyclopropyl ACN acetonitrile AcOH acetic acid CAN ceric ammonium nitrate DCE dichloroethane DIBAL-H diisobutylaluminum hydride 10DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide EtOAc ethyl acetate EtOH ethyl alcohol 15MCPBA m-chloroperoxybenzoic acid PMBC1 p-methoxybenzyl chloride pyr pyridine SEMC1 2,-(trimethylsilyl>ethoxymethyl chloride TEA triethyl amine 20TFA trifluoroacetic acid THF tetrahydrofuran -In the Schemes which follow: Cf is shown as a CF3 group, but could be any one of the presently described R1 groups; G
25 represents R3, R3a, R3b, or R3~ or any combination of these groups.
Schemed illustrates a method for making 3,3-disubstituted-3,4-dihydroquinoxalin-2-ones starting from an 30 appropriately substituted ortho-phenylenediamine. The phenylenediamine is stirred with condensed hexafluoro-propylene oxide to form compounds of formula ~, after which the cyclic amide moiety of ~ is protected, for example with SEM, to form compounds of formula 2_. Addition of 35 appropriately substituted organometallics, RZM, provide the 3,3-disubstituted compounds ,~. Treatment with base is followed by the addition of an appropriately substituted alkyl halide, RlBr, to form compounds of formula 4_. The product ~ are deprotected to give compounds of the present invention.
BCH~ 1 G \ ~z Hexafluoropropylene oxide G \ N~CF3 / NaHC03, ether SEMC1, DIPEA, DMF G I \ N~ CF3 RZM, THF
N O
SEM

G ~ \ N~CF3 RlBr, tBuOK, THF G \ N R
/ ~CF3 SEM O ~~ O

Rl 2 BFg.EtZO, CHZC12 G \ R
/ ~CF3 ~N
O
H
SCE la Y'W~ ~2 Hexafluoropropylene oxide X~W~~ CF3 ..
Z ~ NaHC03 , ether Y' Z ~ 0 Scheme la illustrates a method, analogous to Scheme 1, of making derivatives to tetrahydroquinoxalinone compounds of formula ;Z wherein W, X, Y, and/or Z are nitrogen.

sc~ a 0~ OR12 G ~ N R2 Ri2C02C1, nBuLi, THF G ~ N CF3 ~ / ~CF3 I /
~N O N
S~ SEM
_3 O~ OR12 LiBF4, CH2Clz G ~ N~[ R
[ _CF3 / NCO
H

Scheme 2 illustrates the acylation of 3,4-dihydro-quinoxalin-2-ones. Treatment of compounds of formula 3_, as can be prepared by Scheme 1, with base is followed by the addition of an appropriately substituted chloroformate, R12C02C1 to form compounds of formula ~. The product 6_ is deprotected to give compounds of formula ~.

S' H Rz ' z G ' ~ N~CF3 RlzgOzCl, nBuLi, THF G ~ ~ N~CF3 ~N O
SEM O SEM
_3 0=S' BF3 . Et20, CHZClz _ G ~ N~ Rz / NCO
H

In analogous fashion to Scheme 2, treatment of a compound of formula 3_ with base followed by an appropriately substituted sulfonyl chloride, R12S02C1, provide protected compounds ,$, as shown in Scheme 3. The product is deprotected to give compounds of formula ~.
Analogous to Schemes 2 acid 3, Scheme 4 describes the preparation of amides, ,Z,Q, from acid chlorides R12COC1.
In an alternative route to the synthesis of 3,4-IO dihydroquinoxalin-2-ones, as shown in Scheme 5, a substituted quinoxalin-2-one, ~, can be O-protected to form a compound of formula ~. The addition of an organometallic reagent R2M
followed by the quenching of the resulting anion with a chloroformate can produce compounds of formula ~. The deprotection of a compound ~ will result in compounds of formula 7.

O'' R12 H 2 G ~N z G ~ ~ N~C 3 RIZCOC1, nF , T~i, TH ~ ( ~ CF3 _N
SEM O S~ O
O Rlz BF3.Et20, CH2C12 G I ~ N~CF3 N O
H

~ N~CF3 PMBC1, Ag2C03, DMF G ' ~ N~CF3 N O N OPMB
H

(1) nBuLi, THF, RZM G~N R
f ~ CF3 (2) NaI, EtCOOCl, THF ~ N OPMB
COOR
CAN, AcCN:HzO G ~ N~ R2 \~~ I'CF3 N O
H

Scheme 6 illustrates yet another route for the preparation of compounds of the present invention. N-oxide compound ~. can provide a substrate for the addition of organometallic species R2::~~, followed by the reductive cleavage of the resulting N-hydroxy compound to form compounds of formula ~. Subsequent substitution at the 4-position by R1 radicals is performed as previously described.
Compounds the present invention that are thioamides can be prepared as illustrated in Sceme 7 by treating the corresponding amides with either Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] or phosphorous pentasulfide.

SC's 6 H
G ~ N~CF3 NaCNBH3, AcOH, MeOH G I ~ N~CF3 ~

O
SEM SEM
O

a ~4 mCPBA, CH2C12 G ( ~ N~ CF3 R2M, THF

SEM

G I ~ N~CF3 Zn, AcOH ~ G ~ ~ N~CF3 ,,,,~~ O ~ O
N N
SEM SEM

RlBr, tBuOK, THF G ( ~ N~ CF3 BF3.Et20, CH2Cl2~
N O
SEM
Ri G N~ R2 NCO
H

X'W ~ N Cf Lawesson's Reagent X%W ~ N
Z H O Z H S
One isomer of a compound of Formula (I) may display superior activity compared with the other. Thus; both of the following stereochemistries, (Ia) and (Ib), are considered to be a part of the present invention.

t 2 I 2 X ~W N R f X~W N R
C I ~ ~ '~~~Cf Y~~ ~ ~' Y~.
Z H A Z H A
(Ia) (Ib) When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Ant.imicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula (I) may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet.
lett. 1995, 36, 8937-8940. In addition, separation may be achieved by selective cystallization, optionally in the presence of a chiral acid or base thereby forming a chiral salt.
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 nc,:. intended to be limiting thereof .
Abbreviations used in the Examples are defined as follows: anal. for combustion analysis, "g" for gram or grams, HRMS for high resolution mass spectrometry, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "mmol" for millimole or millimoles, "h" for hour or hours, "HPLC" for high performance liquid chromatography, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS"
for mass spectroscopy, "TLC" for thin layer chromatography.
For further clarification of the stereochemistry, in compounds with stereochemistry designated as "ref-(3S,5S)"
the 3-substituent is cis to the 5-trifluoromethyl group while in compounds with stereochemistry designated as "ref-(3R,5S)"
the 3-substituent is traps to the 5-trifluoromethyl group.

Preparation of 4-(cyclopropylmstbyl)-3-(a-cyclopro~ylmthyayl) -3- ( trifluorcsnethyl ) -3, 4-dihydro-quiacacalia-a ( 1H) -oae .
N "' N O
Fi5 Sten AA: Preparation of compound of formula ~ wherein G = H
To a slurry of 1,2-phenylenediamine (10.8 g, 100 mmol) in ether (200 mL) at room temperature was added sodium bicarbonate (25.4 g, 300 mmol) followed by the condensation of hexafluoropropylene oxide (21 g, 120 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture is diluted with water (500 mL) and extracted with EtOAc (3x200 mL). The combined EtOAc extracts were dried over anhydrous Na2S04 and concentrated in vacuo to provide 19.3 g of compound of formula ~ (21.4 g theoretical, 90%). 1H NMR (300 MHz, CD3COCD3) S 11.67(br s, 1H), 7.93(m, 1H), 7.75(m, 1H), 7.46(m, 2H). 19F NMR (282 MHz, CD3COCD3) 8 -70.93(s, 3F). High resolution mass spec: calculated for C9H6NZOF3 (M+H)+:
215.0423; found: 215.0432.
Step B: Preparation of compound of formula ~ wherein G = H
To a solution of quinoxalin-2-one of formula ~ (5.64 g, 26.3 mmol) in DMf (120 mL) at room temperature was added diisopropylethylamine (18.32 mL, 105.2 mmol) followed by SEMC1 (9.28 mL, 52.6 m~nol) and the resulting reaction mixture was allowed to stir at room temperature for 14 hours. The reaction mixture is poured onto 1N HC1 and extracted with ether (3x100 mL). The combined ether extracts were dried over anhydrous Na2S04 and concentrated in vacuo.
Chromatography (Si02, 10% EtOAc-hexanes eluant) provided 8.15 g of compound of formula ~ (9.05 g theoretical, 90%). 1H NMR
(300 MHz, CDC13) 8 8.02(m, 1H), 7.74(m, 2H), 7.48(m, 1H), 5.77(s, 2H), 3.74(t, J = 8Hz, 2H), 0.98(t, J = BHz, 2H), 0.01(s, 9H). 19F I~ (282 MHz, CDC13) b -61.53 s, 3F). Mass spec. (NH3-CI): 345(M+H)* (54.6%), 317 (100%).
Sten CC: Preparation of compound of formula ~ wherein G = H, R2 = cyclopropylacetylene To a solution of cyclopropylacetylene (23.4 mL, 106.2 mmol) in THF (150 mL) at 0°C was added nBuLi (59 mL, 94.4 mmol) and the resulting reaction mixture was allowed to stir at 0°C for 30 minutes. Thereafter the reaction mixture was cannulated to stirred solution of quinoxalinone of formula 2_ (8.15 g, 23.6 mmol) in THF (300 mL) at -78°C. The dry ice bath is removed and the reaction mixture is stirred for an additional minutes. The reaction mixture is poured onto saturated NH4C1 and extracted with ether (3x100 mL) and the combined ether extracts were dried over anhydrous Na2S04 and 20 concentrated in vacuo. Chromatography (Si02, 10% EtOAc-hexanes eluant) provided 8.95 g of compound of formula ~, (9.68 g theoretical, 92%). 1H NMR (300 MHz, CDC13) S 7.36m, 1H), 7.26(m, 1H), 7.08(m, 2H), 6.91(m, 1H), 5.52(d, J = llHz, 1H), 5.30(d, J = llHz, 1H), 3.61(t, J = 8Hz, 2H), 1.38(m, 1H), 0.93(t, J = 8Hz, 2H), 0.85(m, 2H), 0.54(m, 2H). 1gF NMR
(282 MHz, CDC13) 8 -75.22(s, 3F). Mass spec. (NH3-CI):
411(M+H)*, 5.2%, 383 (100%).
Sten DD: Preparation of compound of formula ø wherein G = H, R2 = cyclopropylacetylene and R1 = cyclopropylmethyl To a solution of protected quinoxalinone of formula 3_ (123 mg, 0.3 mmol) in DMF' (4 mL) at room temperature was added tBuOK in THF (1.5 mL, 1.5 mmol) was added cyclopropylmethyl bromide (290 E1.1, 3.0 mmol) and the resulting reaction mixture was allowed to stir at 80°C for 14 hours. The reaction mixture is poured onto water and extracted with ether (3x50 mL) and the combined ether extracts were dried over anhydrous WO 00100478 PCTlUS99/14395 Na2S04 and concentrated in vacuo. Chromatography (Si02, 10~
EtOAc-hexanes eluant) provided 69 mg of compound of formula ø, (139 mg theoretical, 50$). 1H NMR (300 MHz, CDC13) 8 7.42(m, IH), 7.12(m, 1H), 7.02(m, 1H), 6.94(m, 1H), 5.94(d, J
- llHz, 1H), 5.05(d, J = llHz, 1H), 3.9(m, 1H), 3.68(t, J =
8Hz, 2H), 3.45(m, 1H), 1.42(m, 1H), 1.2(m, 1H), 0.9(m, 6H), 0.6(m, 1H), 0.45(m, 1H), 0.35(m, 2H), 0.01(s, 9H). Mass spec. (NH3-CI): 465(M+H)+, 50~, 437 (90~), 335(M-SEM+H+, 1000 .
S t~j, E
To a solution of the alkylated quinoxalinone of formula 4_ (69 mg, 0.15 mmol) in CH2C12 (1 mL) at room temperature was added BF3.Et20 (95 ).~L, 0.75 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 20 minutes. The reaction mixture was poured onto saturated NaHC03 and extracted with CHZC12 (3x25 mL) and the combined CH2C12 extracts were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was taken up in MeOH (1 mL) and 15~ NaOH
(lmL) was added to the reaction and the resulting reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was poured onto water and extracted with CH2C12 (3x25 mL) and the combined CH2C12 extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography (Si02, 10~ EtOAc-hexanes eluant) provided 41 mg of the title compound, (50 mg theoretical, 82~). IH NMR (300 MHz, CDC13) 8 9.46(br s, 1H), 7.1(m, 1H), 6.95(m, 1H), 6.85(m, 2H), 3.87(dd, J = 4, lSHz, 1H), 3.35(dd, J = 8, lSHz), 1.4(m, 1H), 1.2(m, 1H), 0.9(m, 4H), 0.6(m, 1H), 0.4(m, 3H). 19F NMR (282 MHz, CDC13) S -73.38(s, 3F). High resolution mass spec: calculated for ClgH1gN20F3 (M+H)+:
335.1371; found: 335.1371.
$~
Preparation of 4-(aoath~yl)-3-(2-cyclopropylsthyayl)-3-(trif lnoroemethyl ) -3, 4-di~dro-quinoocs7.ia-a ( 1H) -one .

~H3 i N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D methyl iodide was used instead of cyclopropylmethyl bromide: 1H iVMR (300 MHz, CDC13) S 8.75(br s, 1H), 7.1(m, 1H), 6.85(m, 3H), 3.25(s, 3H), 1.4(m, 1H), 0.85(m, 4H). High resolution mass spec:
calculated for C15H14N20F3 (M+H)+: 295.1058; found: 295.1073.
~CAMpLE ~
Preparation of 3-(a-butyl)-3-(trifluora~etl~yl)-3,4-dihydro-quinoxalin-2(iH)-one.
H
~~nBu II I'CF3 ~~ NCO
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C n-butyl magnesium chloride was used instead of lithium cyclopropyl acetylide: 1H NMR (300 l~iz, CDC13) S 8.8(br s, 1H), 6.9(m, 1H), 6.75(m, 3H), 4.05(s, 1H), 2.2(m, 1H), 1.85(m, 2H), 1.35(m, 2H), 0.9(m, 3H). High resolution mass spec:
calculated for C13H16N20F3 (M+H)+: 273.1214; found: 273.1210.
Preparation of 4-(methyl)-3-(n-butyl)-3-(trifluoro~ethyl)-3,4-dihydm-quinoxalin-2(18)-one.
~H3 ~nBu ['CF3 NCO
H

The title compound was prepared in a manner similar to the product of Example 1, except that in Step C n-butyl magnesium chloride was used instead of lithium cyclopropyl acetylide and in Step D methyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) S 8.85(br s, 1H), 7.05(m, 1H), 6.8(m, 3H), 2.95(s, 3H), 2.65(m, 2H), 2.1(m, 1H), 1.4(m, 4H), 0.95(m, 3H). High resolution mass spec: calculated for C14H1gN20F5 (M+H)*: 287.1371; found:
287.1362.
'"
Preparation of 3-(2-cyclopropylsthyayl)-3-(trifluorcm~sthyl)-3,4-dibydro-quinoxalia-Z(1S)-ous.
H

N O
H
The title compound was prepared in a manner similar to the product of Example 1, Step C: 1H NMR (300 MHz, CDC13) 8 9.0(br s, 1H), 7.0(m, 1H), 6.85(m, 2H), 6.8(m, 1H), 4.45(br s, 1H), 1.4(m, 1H), 0.8-0.6(m, 4H). 19F NMR (282 MHz, CDC13) S -77.13(s, 3F). High resolution mass spec: calculated for C14H11N20F5 (M)*: 280.0823; found: 280.0828.
E7CA~Lg 6 Prsparation of 3-(allyl)-3-(trifluoranethyl)-3,4-dihydro-qusnoxali.a-2(18)-oas.
H

N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C allyl magnesium bromide was used instead of lithium cyclopropyl acetylide: 1H NMR (300 MHz, CDC13) 8 8.25(br s, lH), 6.95(m, 1H), 6.75(m, 3H), 5.85(m, 1H), 5.25(m, 2H), 4.2(br s, 1H), 3.1(m, 1H), 2.65(m, 1H). 19F NMR (282 MHz, CDC13) 8 -71.16(s, 3F). High resolution mass spec: calculated for C12H12N20F3 (M+H)+: 257.0901; found: 257.0898.

Preparation of 4-(allyl)-3-(2-cyclopropylethyayl)-3-(trifluoroanat~rl ) -3, 4-831~y~dro-quiaoxalia-Z ( iH) -oas.
i ~ CF3 'N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) 8 9.4(br s, 1H), 7.0(m, 1H), 6.8(m, 3H), 5.8(m, 1H), 5.2(m, 2H), 4.6(m, 1H), 4.2(m, 1H), 1.4(m, 1H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) S -74.49(s, 3F). High resolution mass spec: calculated for C1~H16N20F3 (M+H)*:
321.1214; found: 321.1198.
2 0 87C111~L13 8 Preparation of 4-(beazyl)-3-(2-cyclopropyletl~nyl)-3-(trifluoramaethyl)-3,4-dihydro-quiaoxalin-2(1H)-one.
~Hz Ph i N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D benzyl bromide was used instead of cyclopropylmethyl bromide: 1H NMR
(300 MHz, CDC13) 8 8.85(br s, 1H), ?.3(m, SH), 7.25(m, 1H), 6.8(m, 3H), 5.3(d, J = llHz, 1H), 4.6(d, J = llHz, 1H), 1.35(m, 1H), 0.8(m, 2H), 0.6(m, 2H). 1gF NMR (282 MHz, CDC13) 8 -78.08(s, 3F). High resolution mass spec: calculated for C21H1sN20F5 (M+H)+: 371.1371; found: 371.1365.
Preparation of 4-(cyclopropylmathyl)-3-(allyl)-3-(trifluoromstl~yl)-3,4-dihydro-quinoualia-2(1H)-one.
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C allyl magnesium bromide was used instead of lithium cyclopropyl acetylide: 1H NMR (300 MHz, CDC13) S 8.35(br s, 1H), 7.1(M, 2H), 6.85(m, 1H), 6.75(m, 1H), 5.9(m, 1H), 5.25(m, 2H), 3.45(M, 2H), 3.2(m, 1H), 2.8(M, 1H), 1.0(m, 1H), 0.7(m, 1H), 0.55(m, 1H), 0.3(m, 2H). 19F NMR (282 MHz, CDC13) b -70.22(s, 3F). High resolution mass spec: calculated for C16H1gN20F3 (M+H)+: 311.1371; found: 311.1325.
2 0 E7C~L8~ 10 Preparation of 4-(proparQyl)-3-(2-cyclopropyletbyayl)-3-(trifluorometbyl)-3,4-dihydro-qufaoxalin-2(iH)-one.
N

The title compound was prepared in a manner similar to the product of Example 1, except that in Step D propargyl bromide was used instead of cyclopropylmethyl bromide: 1H NMR
(300 MHz, CDC13) S 9.35(br s, 1H), 7.15(m, 2H), 6.95(m, 2H), 4.6(dd, J = 2,28Hz, 1H), 4.4(dd, J = 2,18Hz, 1H), 2.25(t, J =
2Hz, 1H), 1.4(m, 1H), 0.9(m, 4H). Anal. (C1~H13N20F3) Calcd:

WO 00/00478 PCTlUS99/14395 C, 64.15; H, 4.126; N, 8.80; Found: C, 64.23; H, 4.00; N, 8.61.
$~CAIIFLE I1 Preparation of 4-(cycloprapyl~thyl)-3-(a-cyclopropylett~ynyl)-3-(trifluorcanethyl)-3,4-dihydro-quinoxalin-a(1H)-oaw.
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D
cyclopropylethyl bromide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) S 9.2(br s, 1H), 7.0(m, 1H), 6.8(M, 3H), 4.0(m, 1H), 3.65(m, 1H), 1.6-1.35(m, 3H), 0.9(m, 3H), 0.7(m, 1H), 0.45(m, 1H), 0.1(m, 1H).
Anal. (C1gH19N20F3) Calcd: C, 65.51; H, 5.507; N, 8.04; F,,r 16.36; Found: C, 65.23; H, 5.51; N, 8.05; F, 15.97.
2 0 EXiI~LE 12 Preparation of 4-(isopropyl)-3-(a-cyclopropylet~ynyl)-3-(trifluoraanethyl)-3,4-dihydro-quinoxalin-a(18)-one.
N i N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D isopropyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR
(300 MHz, CDC13) 8 8.4(br s, 1H), 7.05(m, 1H), 7.0(m, 1H), 6.9(m, 1H), 6.8(m, 1H), 4.6(p, J = 7Hz, 1H), 1.45(d, J 7Hz, 3H), 1.4(m, 1H), 1.2(d, J = 7Hz, 3H), 0.9(m, 4H). High resolution mass spec: calculated for C17H18N20F3 (M+H)+:
323.1371; found: 323.1364.
BXAMyl~B 13 preparation of 6-(fluoro)-4-(allyl)-3-(n-butyl)-3-(trifluoramethyl)-3,4-dihydro-quinoxalin-2(iFt)-tee.
~nBu F~N~CF3 ~~,,,,~~~ NCO
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step A 4-fluoro-1,2-phenylenediamine was used instead of 1,2-phenylenediamine, in Step C nbutyl magnesium bromide was used instead of lithium cyclopropylmethyl acetylide and in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) S 9.2(br s, 1H), 6.65(m, 1H), 6.5(m, 2H), 5.8(m, 1H), 5.35(m, 'H), 4.0(m, 2H), 2.65(m, 1H), 2.0(m, 1H), 1.4(m, 4H), 0.95(m, .iH). 19F NMR (282 MHz, CDC13) b -73.60(s, 3F), -147.85(s, 1F). High resolution mass spec: calculated for C16H18NOF4 (M)+: 330.1335; found: 330.1332.
R7~'1~ 14 Preparatioa of 6-(fluoro)-4-(allyl)-3-(a-cyclopropyletl~y~yl)-3- (trif luoroaaetl~yl ) -3, 4-dibydro-qniaoacalin-Z ( 18) -one .
F ~ N ii The title compound was prepared in a manner similar to the product of Example 1, except that in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) 8 9.65(br s, 1H), 6.6(m, 1H), 6.5(m, 2H), 5.8(m, 1H), 5.2(m, 2H), 4.6(m, 1H), 4.1(m, 1H), 1.4(m, 1H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) 8 -74.62(s, 3F), -117.46(s, 1F). High resolution mass spec: calculated for C1~H15N20F4 (M+H)+: 339.1120; found: 339.1143.

L~ 15 Preparation of 6-(fluoro)-4-(cyclopro~rylmatbyl)-3-(2-cyclopropylathyayl)-3-(trifluorcm~sthyl)-3,4-dihydro-quiaoxalia-2(1H)-oae.
F ~ N i N O
H
The title compound was prepared in a manner similar to the product of Example 1: 1H I~t (300 I~Iz, CDC13) 8 9. 0 (br s, 1H), 6.75(m, 2H), 6.55(m, 1H), 3.8(m, 1H), 3.35(m, 1H), 1.4(m, 1H), 1.15(m, 1H), 0.9(m, 4H), 0.6(m, 1H), 0.5(m, 1H), 0.35 (m, 2H) . 19F lit (282 l~iz, CDC13) S -74.34 (s, '~) , -117.47(s, 1F). Anal. (C18H16NZOF4 1/2H20) Calcd: C, 59.83; H, 4.74; N, 7.75; Found: C, 59.56; H, 4.61; N, 7.37.

Preparation of 6-(fluoro)-4-(cyclopropylamethyl)-3-(a-butyl)-3-(trifluorcm~athyl)-3,4-dihydro-quiaoxalin-2(1H)-one.
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C nbutyl magnesium bromide was used instead of lithium cylcopropylmethyl acetylide: 1H Nl~t (300 l~iz, CDC13) 8 96.6(br s, 1H), 6.7(m, 2H), 6.5(m, 1H), 3.45(m, 1H), 3.15(m, 1H), 2.75(m, 1H), 1.9(m, 1H), 1.75(m, 1H), 1.4(m, 3H), 1.05(m, 1H), 0.95(m, 3H), 0.65(m, 2H), 0.35(m, 2H). 19F Nl~t (282 N~Iz, CDC13) b -73.36(s, 3F), -117.79(s, 1F). Anal.
(C17H2pN20F4) Calcd: C, 59.30; H, 5.85; N, 8.145; Found: C, 58.98; H, 5.73; N, 7.90.
$ul~l~r.E i7 Preparation of 6-(ahloro)-4-(cycloprapylmetl~yl)-3-(Z-cyclopropyletvynyl)-3-(trifluora~thyl)-3,4-dil~ydro-quinoxalin-a(18)-o~n..
C1 ,~ N
1~ CF3 v 'N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step A 4-chloro-1,2-phenylenediamine was used instead of 1,2-phenylenediamine:
1H Nit (300 l~Iz, CDC13) 8 9 .5 (br s, 1H) , 6.9 (m, 1H) , 6.8 (m, 2H), 1.4(m, 1H), 1.2(m, iH), 0.95(m, 4H), 0.6(m, 1H), 0.5(m, 1H), 0.35(m, 2H). 19F Nt~t (282 I~iz, CDC13) 8 -71.80is, 3F).
Anal. (C1aH16N2OC1F3) Calcd: C, 58.62; H, 4.37; N, 7.606; F, 15.45; C1, 9.61; Found: C, 58.27; H, 4.39; N, 7.46; F, 15.83;
C1, 9.62.
Preparation of 6-(chloro)-4-(isobutyl)-3-(a-cyclopropyletl~yqyl ) -3- ( trif luoraausthyl ) -3, 4-diby~dro-quiaoxalia-a(iH)-o~.
c The title compound was prepared in a manner similar to the product of Example 1, except that in Step D isoamyl bromide was used instead of cyclopropylmethyl bromide: 1H NMR
(300 MHz, CDC13) 8 9.5(br s, 1H), 6.8(m, 2H), 6.7(rn, 1H), 3.9(m, 1H), 3.6(m, 1H), 1.7(m, 1H), 1.6(M, 1H), 1.4(m, 2H), 0.95(d, J = 7Hz, 3H), 0.9(d, J = 7Hz, 3H), 0.9-0.8(m, 4H).
19F ~ (282 MHz, CDC13) S -71.67(s, 3F). Anal.
(ClgH2pN20C1F3) Calcd: C, 59.30; H, 5.248; N, 7.289; F, 14.81;
C1, 9.21; Found: C, 59.12; H, 5.19; N, 7.04; F, 15.09; f1, 9.22.

Preparation of 6-(chloro)-4-(allyl)-3-(a-ayclopropylethynyl)-3-(trifluoraanethyl)-3,4-di~ydro-qufaoxalia-2(1H)-one.
C1 ~ N i N O
H
The title compound was prepared in a manner similar to the product of Example l, except that in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) S 9.65(br s, 1H), 6.8(m, 2H), 6.75(m, 1H), 5.8(m, 1H), 5.3(m, 2H), 4.6(m, 1H), 4.1(m, 1H), 1.4(m, 1H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) S -71.88(s, 3F). Anal.
(C17H14N20C1F3) Calcd: C, 57.56; H, 3.987; N, 7.906; F, 16.07;
C1, 9.99; Found: C, 57.87; H, 4.25; N, 7.61; F, 15.93; C1, 9.82.
ALE ZO
Prsparatioa of 6-(chloro)-4-(cyclopropylan~atb~yl)-3-(phenet~yl)-3-(trifluoro~etl~,yl)-3,4-dihydro-quiaoxalia-2(1H)-one.

WO 00/OOd78 PCT/US99/14395 C1 ~ N~ CH2CH2Ph ['CF3 NCO
H
The title compound was prepar;~d in a manner similar to the product of Example 1, except that in Step C phenethyl magnesium bromide was used instead of lithium cyclopropylmethyl acetylide: 1H NMR (300 MHz, CDC13) b 8.9(br s, 1H), 7.25(m, 5H), 7.)(m, 1H), 6.8(m, 1H), 6.65(m, 1H), 3.5(m, 1H), 3.3(m, 1H), 3.0(m,2H), 2.75(m, 1H), 2.3(m, 1H), 1.1(m, 1H), 0.8(m, 2H), 0.4(m, 2H). High resolution mass spec: calculated for C21H2oN20F3C1 (M)+: 408.1216; found:
408.1197.
praparatian of 6-(chloro)-4-(allyl)-3-(pl~sasthyl)-3-(trifluora~stbyl)-3,4-dihydro-quiaoxalia-2(1H)-one.
C 1 N~CHZCH2 Ph \~ CF3 v 'N 0 H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C phenethyl magnesium bromide was used instead of lithium cyclopropylmethyl acetylide and in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) 8 9.5(br s, 1H), 7.25(m, 2H), 6.8(m, 1H), 5.9(m, 1H), 5.3(m, 1H), 5.)(m, 1H), 4.3(m, 1H), 4.1(m, 1H), 3.1(m, 1H), 2.9-2.8(m, 2H), 2.3(m, 1H). Anal. (C2oH1aN20C1F3) Calcd: C, 60.84; H, 4.605; N, 7.105; F, 14.44; C1, 8.989; Found: C, 61.39; H, 4.83; N, 6.68; F, 14.25; C1, 8.89.

PraDaration of 6-(methoxy)-4-(cyclopropylmathyl)-3-(2-cyclopropylethynyl)-3-(trifluorc~ethyl)-3,4-dihydro-quinoxalin-2(1H)-one.
The title compound was prepared in a manner similar to the product of Example 1, except that in Step A 4-methoxy-1,2-phenylenediamine was used instead of 1,2-phenylenediamine: 1H NMR (300 MHz, CDC13) 8 8.95(br s, 1H), 6.8(m, lH), 6.6(m, 1H), 6.4(M, 1H), 3.9(m, 1H), 3.8(m, 3H), 3.4(m, 1H), 1.4(m, 1H), 1.2(m, 1H), 0.9(m, 4H), 0.6(m, 1H), 0.45(m, 1H), 0.35(m, 2H). 19F NMR (282 MHz, CDC13) b -73.19(s, 3F). Anal. (C19Hi9N202F3) Calcd: C, 62.63; H, 5.266; N, 7.698; F, 15.64; Found: C, 62.17; H, 5.36; N, 7.20;
F, 14.79. .
$~h8 a3 Preparation of 6-(methoxy)-4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluorom~etl~yl)-3,4-dihydro-quiaoxalin-2(1H)-one.
Me ~ N i.

N O
H
The title compound was prepared in a manner similar to the product of Example 1, except that in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) 8 9.0(br s, 1H), 6.7(m, 1H), 6.35(m, 2H), 5.8(m, 1H), 5.2(m, 2H), 4.6(m, 1H), 4.1(M, 1H),3.8(s, 3H), 1.4(m, 1H), 0.95(m, 4H). 19F NMR (282 MHz, CDC13) b -73.44(s, 3F).

Anal. (C18H17N202F3) Calcd: C, 61.71; H, 4.89; N, 8.006; F, 16.27; Found: C, 62.34; H, 4.94; N, 7.81; F, 15.00.
$~~LE 24 Preparation of 4-(cyclopropylmethyl)-3-(1-propyayl)-3 ( trif luosomathyl ) -3, 4-8il~dxo-qtiiacxalia-a ( 1H) -o~ae .
The title compound was prepared in a manner similar to the product of Example 1, except that in Step C lithium propyne was used instead of lithium cylocpropylmethyl acetylide: 1H NMR (300 MHz, CDC13) S 8.1(br s, 1H), 7.1(m, 1H), 6.9(m, 1H), 6.8(m, 1H), 6.75(m, 1H), 3.85(m, 1H), 3.4(m, 1H), 2.)(s, 3H), 1.4(m, 1H), 0.6(m, 1H), 0.45(m, 1H), 0.35(m, 2H). 19F NMR (282 MHz, CDC13) S -71.16(s, 3F). High resolution mass spec: calculated for C16H16NZOF3 (M+H)+:309.1214; found:309.1224.
Preparation of 4-(allyl)-3-(1-propy~yl)-3-(trifluorc~athyl)-3,4-dibydro-qufaoxalin-Z(1H)-oae.
The title compound was prepared in a manner similar to the product of Example l, except that in Step C lithium propyne was used instead of lithium cyclopropylmethyl acetylide and in Step D allyl iodide was used instead of cyclopropylmethyl bromide: 1H NMR (300 MHz, CDC13) 8 8.4(br s, 1H), 7.0(m, 1H), 6.8(m, 3H), 5.8(m, 1H), 5.2(m, 2H), 4.6(m, 1H), 4.2(m, 1H0, 2.0(s, 3H). 19F NMR (282 MHz, CDC13) 8 -71.79(s, 3F). High resolution mass spec: calculated for C15H14N20F3 (M+H)+: 295.1058; found: 295.1056.
Preparation of 4-(ethoaqrcarbor~yl)-3-(a-cyclopropyletb~yl) -3-(trifluoromethyl)-3,4-dihydro-Quinoxalia-a(iH)-one.
O~ OEt N
~ CF3 _N O
H
Step A: Preparation of compound of formula ø wherein G = H, R2 = cyClopropylacetylene and R1 = COOEt To a solution of protected quinoxalinone of formula 3_ as prepared in step C in Example 1 (147 mg, 0.42 mmol) in THF
(1.5 mL) at -78°C was added nBuLi (0.31 mL, 0.5 mmol) and stir~:ad for 5 minutes. Thereafter ethyl chloroformate (80 N.L, 0.84 mmol) was added to the reaction mixture which was allowed to warm to room temperature and stir for an hour.
The reaction mixture was poured onto saturated ammonium chloride and extracted with ether (3x25 mL) and the combined ether extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography (Si02, 10$ EtOAc-hexanes eluant) provided 122 mg of compound of formula ø, (202 mg theoretical, 60~). 1H NMR (300 MHz, CDC13) $ 7.46(m, 1H), 7.30(m, 1H), 7.15(m, 2H), 5.82(d, J = llHz, 1H), 5.15(d, J = llHz, 1H), 4.4(m, 2H), 3.7(m, 2H), 1.4(m, 4H), 0.9(m, 6H), 0.01(s, 9H). 19F NMR (282 MHz, CDC13) 8 -73.06(s, 3F).
Mass spec. (NH3-CI): 483(M+H+, 1000 .
Sten B:
To a solution of the acylated quinoxalinone of formula ø (84 mg, 0.17 mmol) in CH2C12 (1 mL) at room temperature was added LiBF4 (1M in ACN, 0.85 mL, 0.85 mmol) and the resulting WO 00/00478 PCT/US99li 4395 reaction mixture was heated to reflex for 14 hours. The reaction mixture was poured onto saturated water and extracted with ether (3x25 mL) and the combined ether extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography (Si02, 20% EtOAc-hexanes eluant) followed by a PTLC (Si02, 5% EtOAc-CH2C12 eluant) provided 15 mg of the title compound, (60 mg theoretical, 25%). 1H NMR
(300 MHz, CDC13) 8 8.06(br s, 1H), 7.35(m, 1H), 7.05(m, 2H), 6.8(m, 1H), 4.37(m, 2H), 1.4(m, 4H), 0.9(m, 4H). 19F NMR
(282 MHz, CDC13) 8 -73.55(s, 3F). High resolution mass spec:
calculated for C1~H15N203F3 (M+H)+: 353.1113; found: 353.1093.
ale Z6A
Preparation of 4-(ethaaqrcarbonyl)-3-(2-cyclopropyletI~yayl) -3-(trifluoromethyl)-3,4-dibydro-quinoxalin-Z(18)-oue.
ii CF3 _ H
Sten AA: Preparation of compound of formula ~ wherein G = H.
To a solution of the quinoxalinone of formula ~ as prepared in step A in Example 1 (3.55 g, 16.59 mmol) in DMf (35 mL) at room temperature was added silver carbonate (13.74 g, 49.7 mmol) follwed by PNJBC1 (2.48 mL, 18.25 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 14 hours protected from light by aluminum foil. The reaction mixture was filtered through Celite and the filterate washed with water. The organic layers were dried over anhydrous Na2SOQ and concentrated in vacuo.
Chromatography (Si02, 5% EtOAc-hexanes) provided 1.28 g of compound of formula ~, (5.54 g theoretical, 23%). 1H NMR
(300 MHz, CDC13) 8 8.2(m, 1H), 7.9(m, 1H), 7.8(m, 1H), 7.46(d, J = 9Hz, 2H), 6.93(d, J = 9Hz, 2H), 5.59(s, 2H), 3.81(s, 3H).
19F ~ (282 MHz, CDC13) b -68.38(s, 3F). High resolution mass spec: calculated for C1~H14N202F3 (M+H)+: 335.1007; found:
335.1012.
Step B: Preparation of compound of formula ~ wherein G = H, R2 = cyclopropylacetylene and R1 = COOEt To a solution of cyclopropylacetylene (297 ~t.L, 2.25 mmol) in THF (5 mL) at 0°C was added nBuLi (1.25 mL, 2 mmol) and the resulting reaction mixture was allowed to stir at 0°C for 30 minutes. Thereafter the reaction mixture was cannulated to stirred solution of quinoxalinone of formula ~ (167 mg, 0.5 mmol) in THF (2.5 mL) at -78°C. The dry ice bath is removed and the reaction mixture is allowed to warm up as it stirred for an hour. NaI (300 mg, 2 mmol) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at room temperature for 10 minutes. Thereafter ethyl chloroformate (478 ~,L, 5 mmol) was added to the reaction mixture was stirred for an additional 10 minutes. The reaction mixture is poured onto saturated NH4C1 and extracted with ether (3x50 mL) and the combined ether extracts were dried over anhydrous Na2S04 and concentrated in vacuo.
Chromatography (Si02, 10% EtOAc-hexanes eluant) provided 78 mg of compound of formula 1~, (236 mg theoretical, 33%) 1H NMR
(300 MHz, CDC13) 8 7.37(d, J = 9Hz, 2H), 7.35(m, 1H), 7.2(m, 1H), 7.15(m, 2H), 6.9(d, J = 9Hz, 2H), 6.90(d, J = l2Hz, 1H), 5.26(d, J = l2Hz, 1H), 4.35(m, 2H), 3.81(s, 1H), 1.37(t, J =
7Hz, 3H), 1.25(m, 1H), 0.8(m, 2H), 0.6(m, 2H). Mass spec.
(NH3-CI): 473(M+H)+ (20%), 353 (M-PMB+H+~100%).
Stey~ C:
To a stirred solution of the PMB protected quinoxalinone of formula 1_~, (28 mg, 0.06 nanol) in CH3CN:H20 (9:1) at room temperature was added CAN (162 mg, 0.30 manol) and the resulting reaction mixture was allowed to stir at room temperature for one hour. The reaction mixture was poured onto water and extracted with EtOAc (3x25 mL) and the combined EtOAc extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography (Si02, 20% EtOAc-hexanes eluant) provided 16 mg of the title compound, (21 mg theoretical, 76~). 1H NMR (300 MHz, CDC13) 8 8.06(br s, 1H), 7.35(m, 1H), 7.05(m, 2H), 6.8(m, 1H), 4.37(m, 2H), 1.4(m, 4H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) 8 -73.55(s, 3F).
High resolution mass spec: calculated for C1~H15N203F3 (M+H)+;
353.1113; found: 353.1093.
S~,IZ
Preparation of 4-(iaopropo~ycarbonyl)-3-(2-cycloyropylethyayl)-3-(trifluoraarethyl)-3,4-dil~ydro-duinoxalin-a(1H)-one.

The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) b 8.4(br s, 1H), 7.35(m,lH), 7.15(m, 1H), 6.8(m, 1H), 5.15(p, J = 7Hz, 1H), 1.45(m, 1H), 1.4(d, J =
7Hz, 3Hz, 3H), 1.35(d, J = 7Hz, 3H), 0.85(m, 4H). 19F NMR
(282 MHz, CDC13) S -73.46(s, 3F). High resolution mass spec:
calculated for ClgH1gN203F3 (M+H)+: 367.1269; found: 367.1286.
susaa~s a s Preparation of 4-(propea-2-yl-oo~ycarboayl)-3-(Z-cyclonroDylethys~l) -3-(triflnorcm~stbyl)-3,4-dihy~dro-quino~alia-Z(18)-ooe.
i N O
H

The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropenyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) S 8.6(br s, 1H), 7.4(m, 1H), 7.15(m, 2H), 6.85(m, 1H), 4.85(4.87(d, J = 2Hz, 2H), 4.78(d, J = 2Hz, 1H), 2.05(s, 3H), 1.4(m, 1H), 0.85(m, 4H). 19F NMR (282 MHz, CDC13) b -73.60(s, 3F). High resolution mass spec: calculated for C1gH16N203F3 (M+H)+: 365.1113; found: 365.1100.
8~1~'L~ 29 Preparation of 4-(isobutoxycarboayl)-3-(2-cyclopropylet~ynyl) -3-(trifluoroanethyl)-3,4-dihydro-quinoxalin-2(y.S)-one.
O
!.
'CF3 W
O
H
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isobutyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) b 8.6(br s, 1H), 7.3(m, 1H), 7.15(m, 1H), 6.85(m, 1H), 4.2(dd, J = 7,3Hz, 1H), 3.95(dd, J = 7,3Hz, 1H), 2.1(p, J = 7Hz, 1H), 1.4(m, 1H), 0.95(d, J = 3Hz, 3H), 0.9(d, J = 3Hz, 3H), 0.85(m, 4H). 19F NMR (282 MHz, CDC13) S
-73.49(s, 3F). High resolution mass spec: calculated for ClgHZpN203F3 (M+H)+: 381.1426; found: 381.1445.

Preparation of 4-(n-buto~r~carbonyl)-3-(2-cycloprapylethyayl) -3 - ( trif luoraaneti~yl ) -3, 4-dihydro-quinaoralia-a ( 1H) -one .
i N O
H

WO 00/00478 PCT/US99/t4395 The title compound was prepared in a manner similar to the product of Example 26, except that in Step A nbutyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) S 8.65(br s, 1H), 7.3(m, 1H), 7.1(m, 2H), 6.85(m, 1H), 4.4(m, 1H), 4.2(m, 1H), 1.65(m, 2H), 1.45(m, 2H), 1.4(m, 1H), 0.95(t, J = SHz, 3H), 0.85(m, 4H). 19F NMR
(282 MHz, CDC13) 8 -73.53(s, 3F). High resolution mass spec:
calculated for C19H2oN2O3F3 (M+H)*: 381.1426; found: 381.1421.
LlIP ~ 31 Preparation of 4-(allylo~carbooyl)-3-(a-cyclopropylet~rr~l) -3- (trif luoraerathyl ) -3, 4-dil~ydro-quinoacalia-a ( iH) -one .
i H O
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A allyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) 8 8.95(br s, 1H), 7.3(m, 1H), 7.15(m, 2H), 6.85(m, 1H), 6.0(m, 1H), 5.45-5.3(m, 2H), 4.9-4.7(m, 1H), 1.4(m, 1H), 0.85(M, 4H). 19F NMR (282 MHz, CDC13) & -73.57(s, 3F). High resolution mass spec: calculated for C1gH16NZ03F3 (M+H)+: 365.1113; found: 365.1119.
~1 preparatioa of 4- (ben~yrlo~carbooo~yl) -3- (Z-ayclopropylethyayl) -3-(trifluoromethyl)-3,4-dil~yaro-quiaoacalia-a(iS)-one.
p, _pr~Ph \ i CFg / N O
H

The title compound was prepared in a manner similar to the product of Example 26, except that in Step A benzyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) 8 8.6(br s, 1H), 7.4(m, 5H), 7.3(m, 1H), 7.15(m, 2H), 6.85(, 1H), 5.45-5.2(m, 3H), 1.35(m, 1H), 0.75(m, 4H). 19F NMR (282 MHz, CDC13) 8 -73.54(s, 3F). High resolution mass spec: calculated for C22H1gNz03F3 (M+H)+:
415.1284; found: 415.1269.
~f.711~L8 33 Preparation of 4-(a-propylsulfonyl)-3-(2-cyclopropylethyayl) -3-(trifluorcm~et~yl)-3,4-dihydro-quinoxalia-2(18)-oae.
~S02nPr ~ N
~ CF3 'N O
H
The title compound was prepared in a manner similar to the product of Example 40, except that in Step A
n-propylsulfonyl chloride was used instead of isopropylsulfonyl chloride: 1H NMR (300 MHz, CDC13) 8 8.1(br s, 1H), 7.4(m, 1H), 7.2(m, 1H), 7.15(m, 1H), 6.85(M, 1H), 3 .65 (m, 1H) , 3.3 (m, 1H) , 2.0 (m, 2H) , 1.45 (m, 1H) , 1.1 (t, J =
7Hz, 3H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) b -73.17(s, 3F). High resolution mass spec: calculated for C17H1gN203F3S
(M+H)+: 387.0990; found: 387.0996.
BXA1~LE 34 Preparation of 4-(pheaylcarbo~l)-3-(2-cyclopropylethynyl)-3-( trif luorom~ethyl ) -3, 4-dibydro-quinoacalia-2 ( 18) -oae .
O~ Ph N i N O
H

WO 00/00478 PCTlUS99/14395 The title compound was prepared in a manner similar to the product of Example 37, except that in Step A benzoyl chloride was used instead of isobutyzyl chloride: 1H NMR (300 MHz, CDC13) b 8.2(br s, 1H), 7.55(m, 2H), 7.45(m, 1H), 7.3(m, 2H), 7.)(m, 1H), 6.85(M, 1H), 6.75(m, 1H), 6.9(m, 1H), 1.35(m, 1H), 0.8(m, 4H). 1gF NMR (282 MHz, CDC13) 8 -72.16(s, 3F). High resolution mass spec: calculated for C21H16N202F3 (M+H)+: 385.1163; found: 385.1184.
Preparation of 4-(neopentyl-oxycarboayl)-3-(Z-cyclopropylethynyl) -3-(trifluoro~sth~l)-3,4-dihydro-quinoxalia-2 (lii) -one.
N

N O
H
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A neopentyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) S 8.55(br s, 1H), 7.3(m, 1H), 7.15(m, 2H), 6.85(m, 1H), 4.3(d, J = llHz, 1H), 3.8(d, J = llHz, 1H), 1.4(m, 1H), 1.0(s, 9H), 0.85(m, 4H). 19F NMR (282 MHz, CDC13) S -73.42(s, 3F). High resolution mass spec: calculated for C20H22N203F3 (M+H)+: 395.1582; found: 395.1587.

prsparati~ of 4-(2-propy~l-oaqr~aarbo~yl)-3-(Z-cyclopropyle~thynyl) -3-(triiluorom~ethyl)-3,4-dil~ydro-quinoxalia-2(1x)-onm.

N

N O
H
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A propargyl chloroformate was used instead of ethyl chloroformate: 1H Nl~t (300 I~iz, CDC13) 8 9.0 (br s, 1H) , ?.35 (m, 1H) , 7.15 (m, 2H) , 6.9(m, 1H), 4.95(dd, J - 2,13Hz, 1H), 4.85(dd, J = 2,13Hz, 1H), 2.95(t, J = 2Hz, 1H), 1.4(m, 1H), O.BS(m, 4H). 19F lit (282 l~iz, CDC13) S -73.62(s, 3F). Anal. (C17H13N203F3) Calcd:
C, 59.637; H, 3.626; N, 7.73; F, 15.76; Found: C, 60.18; N, 3.84, N, 7.38; F, 15.66.

Preparation of 4-(isopropylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluosromethyl)-3,4-dibydm-quiao~calin-2 ( 7.a) -one.
O
N i N O
H
Step Preparation of compound of formula ~ wherein G = H, R2 = cyclopropylacetylene and R1 = COiPr To a solution of protected quinoxalinone of formula 3_ as prepared in step C in Example 1 (250 mg, 0.61 mmol) in THF
(2.5 mL) at -78°C was added nBuLi (0.53 mL, 0.85 mmol) followed by isobutyryl chloride (0.15 mL, 1.46 mmol) and the resulting reaction mixture was allowed to stir for an hour with warming to room temperature. The reaction mixture is poured onto saturated NHqcl and extracted with ether (3x50mL) and the combined ether extracts were dried over anhydrous Na2SOq and concentrated in vacuo. Chromatography (Si02, 5%
EtOAc-hexanes eluant} provided 189 mg of compound of formula ,~Q, (293 mg theoretical, 64%). 1H NMR (300 MHz, CDC13) 8 7.5(m, 1H), 7.2(m, 2H}, 6.9(m, 1H), 5.85(d, J = llHz, 1H), 5.29d, J = llHz, 1H), 3.7(m, 2H), 3.15(m, 1H), 1.4(m, 1H), 1.31(d, ..T = 7Hz, 3H), 1.13(d, J = 7Hz, 3H), 0.95(m, 2H), 0.85(M, 4H). Mass spec. (NH3-CI): 481(M+H+, 100%).
Step B:
To a solution of the acylated quinoxalinone of formula ~Q
(189 mg, 0.39 mmol) in CH2C12 (2 mL) at 0°C was added BF3.Et20 (110 ~,L, 0.87 nunol} and the resulting reaction mixture was allowed to stir at 0°C for 30 minutes and stirred for an additional hour with warniing to room temperature.. To the reaction mixture was added MeOH (1 mL) and 15% NaOH (1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was poured onto water and extracted with CH2C12 (3x25 mL) and the combined CH2C12 extracts were dried over anhydrous Na2S04 and concentrates ..n vacuo. Chromatography (Si02, 25% acetone-hexanes eluant) followed by PTLC (Si02, CH2C12 eluant) provided 10.5 mg of the title compound, (136.5 mg theoretical, 7.7%). 1H NMR (300 MHz, CDC13) $ 8.65(br s, 1H), 7.15(m, 2H), 6.95(m, 2H), 3.15(m, 1H), 1.4(m, 1H), 1.28(d, J
- 7Hz, 3H), 1.11(d, J = 7Hz, 3H), 0.8(m, 4H). 19F NMR (282 MHz, CDC13) $ -72.78(s, 3F). High resolution mass spec:
calculated for C18H18N202F3 (M+H}+: 351.1320; found: 351. 1299.
~L8 38 8rsparation of 4-(cy~clo~ro~ylcarboayl)-3-(Z-cy~clopropyl~thyayl ) -3 - ( trif luosbm~tl~rl ) -3, 4 -dibydro-quinoxalia-Z(18)-one.

N i ~ CF3 'N O
H
The title compound was prepared in a manner similar to the product of Example 37, except that in Step A cyclopropane carbonyl chloride was used instead of isobutyryl chloride: iH
NMR (300 MHz, CDC13) 8 8.6(br s, 1H), 7.35(m, iH), 7.2-7.0(m, 2H), 6.9(m, 1H), 1.95(m, 1H), 1.35(m, 2H), 1.2(m, 1H), 1.0(m, 1H), 0.9(m, 1H), 0.85(m, 4H). High resolution mass spec:
calculated for Ci8H16N202F3 (M+H)*: 349.1163; found: 349.1153.

Preparation of 4-(athylsulfo~yl)-3-(2-cyclopropylethyayl) -3-( tri f luoraanethyl ) -3 , 4 -dil~ydro-Quinoxalia-Z ( iH ) -one .
~02Et N i ~I CF3 v 'N O
H
The title compound was prepared in a manner similar to the product of Example 40, except that in Step A
ethylsulfonyl chloride was used instead of isopropylsulfonyl chloride: 1H NMR (300 MHz, CDC13) S 8.8(br s, 1H), 7.4(m, 1H), 7.25(m, 1H), 7.15(m, 1H), 6.9(m, 1H), 3.75(p, J = 7Hz, 1H), 3.45(p, J = 7Hz, 1H), 1.5(t, J = 7Hz, 3H), 1.4(m, 1H), 0.9(m, 4H). 1SF NMR (282 MHz, CDC13) 8 -73.13(s, 3F). High resolution mass spec: calculated for C16H16N203F3S (M+H)+:
373.0833; found: 373.0829.
~L8 40 preparation of 4-(isopropylsulfonyl)-3-(a-cyclopropylethyayl) -3-(trifluoram~ethyl)-3,4-dihyaio-quiaoxalin-2(1H)-one.

S02 i Pr N

N O
H
Sten A:A: Preparation of compound of formula ~ wherein G = H, R2 = cyclopropylacetyle::~e and R1 = SOOiPr To a solution of protected quinoxalinone of formula ~ as prepared in step C in Example 1 (250 mg, 0.61 mmol) in THF
(2.5 mL) at -78°C was added nBuLi (0.53 mL, 0.85 mmol) followed by isopropylsulfonyl chloride (164 N,L, 1.46 mmol) and the reaction mixture was allowed to warm to room temperature and stir for an hour. The reaction mixture was poured onto saturated NaHC03 and extracted with ether (3x25 mL) and the combined ether extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography (Si02, 10%
EtOAc-hexanes eluant) provided 51 mg of compound of formula (315 mg theoretical, 16%). 1H NMR (300 MHz, CDC13) 8 7.5(m, 1H), 7.35(m, 2H), 7.2(m, 1H), 5.8(d, J = llHz, 1H), 5.15(d, J = llHz, 1H), 4.25 1H), 3.7(m, 2H), 1.65(m, 3H), 1.45(m, 4H), 0.95(m, 5H), 0.01(s, 9H). Mass spec. (NH3-CI):
534(M+NH4+, 100%).
Step B:
To a solution of the sulfonamide-quinoxalinone of formula ,$
(51 mg, 0.099 mmol) in CH2C12 (1 mL) at 0°C was added BF3.Et20 (27 ~tL, 0.22 mmol) and the resulting reaction mixture was allowed to stir at 0°C for 30 minutes, and stirred for an additional 1 hour with warming to room temperature. To the reaction mixture was added MeOH (1 mL) and 15% NaOH (1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was poured onto water and extracted with CH2C12 (3x25 mL) and the combined CH2C12 extracts were dried over anhydrous Na2S04 and concentrated in vacuo. Chromatography/PTLC (Si02, 25%
acetone-hexanes eluant) provided 14 mg of the title compound, (38 mg theoretical, 37%). 1H NMR (300 MHz, CDC13) S 8.63(br WO 00/00478 PCT/US99l14395 s, 1H), 7.4(m, 1H), 7.25(m, 1H), 7.15(m, 1H), 6.85(m, 1H), 4.2(m, 1H), 1.6(d, J = 7Hz, 3H), 1.45(m, 1H), 1.39(d, J =
7Hz, 3H), 0.9(m, 4H). 19F NMR (282 MHz, CDC13) 8 -73.05(x, 3F). High resolution mass spec: calculated for Cl~H1gN203F3S
(M+H)+: 387.0990; found: .387.1002.
$3C~LPLE 41 Preparation of 4-(matho~qrcarbonyl)-3-(2-cyclapropylethyayl) -3- (trif luorcm~ethyl ) -3, 4-dihy~dro-quiaoxalia-2 ( 18) -one.
i ~ CF3 _N O
H
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A methyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) s 8.45(br s, 1H), 7.25(m, 1H), 7.05(m, 2H), 6.85(m, 1H), 8.85(x, #J), 1.4(m, 1H), 0.85(m, 4H). 19F NMR
(282 MHz, CDC13) 8 -73.65(x, 3v). High resolution mass spec:
calculated for C16H14N203F3 (M+H)*: 339.0956; found: 339.0932.

87CA~~LI: 42 Preparation of 6-(chloro)-4-(ethoxycarbonyl)-3-(2-cyclopropylethyayl)-3-(trifluora~etl~yl)-3,4-dib~8ro-quiaoxalin-2(18)-one.
of ( CF3 O
The title compound was prepared in a manner similar to the product of Example 26: 1H NMR (300 MHz, CDC13) S 8.65(br s, 1H), 7.35(m, 1H), 7.1(m, 1H), 6.8(m, 1H), 4.45-4.3(m, 2H), 1.4(t, J = 7Hz, 3H), 1.35(m, 1H), 0.85(m, 4H). 19F NMR (282 MHz, CDC13) b -73.54(s, 3F). High resolution mass spec:
calculated for C17H13N203F3C1 (M-H)+: 385.0566; found:
385.0570.
~AD~LE 43 8raparatioa of 6-(chloro)-4-(iaopropasycsrboayl)-3-(Z-cyclopropylat~yayl)-3-(trifluoramatbyl)-3~4-dibydro-quiaoxalin-2(iH)-oae.
C
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropyl chloroformate was used instead of ethyl chloroformate: iH NMR
(300 MHz, CDC13) 8 8.65(br s, 1H), 7.45(m, 1H), 7.35(m, 1H), 15(m, 1H), 6.8(m, 1H), 5.15(p, J = 7Hz, 1H), 1.4(d, J = 7Hz, 3H), 1.38(d, J = 7Hz, 3H), 1.35(m, 1H), 0.~.(m, 4H). 19F NMR
(282 MHz, CDC13) 8 -73.47(s, 3F). High resolution mass spec:
calculated for C1gH15N203F3C1 (M-H)+: 399.0723; found:
399.0719.
B'~L~~..44 Preparation of 6-(chloro)-4-(propsa-a-yl-o~eyaarbonyl)-3-(2-cycloprapyl.thyr~yl ) -3- (trifluosro~tl~yl ) -3, 4-d,i~y8ro-quincxalia-2(iH)-ons.
C
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropenyl chloroformate was used instead of ethyl chloroformate: 1H NMR
(300 MHz, CDC13) 8 8.8(br s, 1H), 7.4(m, 1H), 7.15(m, 1H), 6.8(m, 1H), 4.9(m, 1H), 4.8(m, 1H), 2.05(s, 3H), 1.4(m, 1H), 0.85(m, 4H). 19F NMR (282 MHz, CDC13) S -73.60(s, 3F). High resolution mass spec: calculated for C1gH13N203F3C1 (M-H)*:
397.0566; found: 397.0563.

Preparation of 6-(fluoro)-4-(othoxycarbo~yl)-3-(2-cyclopropylathyayl)-3-(trifluoramethyl)-3,4-dihydro-quinoxalia-a(18)-one.
The title compound was prepared in a manner similar to the product of Example 26: 1H NMR (300 MHz, CDC13) 8 8.7(br s, 1H), 7.1(m, 1H'" 6.8(m, 2H), 4.4(m, 2H), 1.42(t, J = 7Hz, 3H), 1.4(m, 1H), 0.85(m, 4H). 1gF NMR (282 MHz, CDC13) 8 -73.54(s, 3F), -117.47(s, 1F). High resolution mass spec:
calculated for C1~H13N203F4 (M-H)*: 369.0862; found: 369.0852.
~~LS 46 Preparation of 6- ( f luoro) -4- ( isopropo~qtcari~onyl ) -3- ( 2-cyclopropylethya~l)-3-(trifluoromethyl)-3,4-dihydro-quinoxalia-2(18)-one.
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropyl chloroformate was used instead of ethyl chloroformate: 1H NMFt (300 MHz, CDC13) S 8.85(br s, 1H), 7.15(m, 1H), 6.8(m, 2H), 5.15(p, J = 7Hz, 1H), 1.45(d, J = 7Hz, 3H), 1.42(d, J = 7Hz, 3H), 1.4(m, 1H), 0.85(m, 4H). 19F lit (282 MHz, CDC13) b -73.45(s, 3F), -117.63(s, 1F). High resolution mass spec:
calculated for C1gH15N203F4 (M-H)+: 385.1018; found: 383.1045.

Preparatioa of 6-(fluoro)-4-(Drapes-Z-~1-oo~carl~onyl)-3-(a-cyclopropylet~yayl)-3-(trifluoraorethyl)-3,4-dibydro-quiaoacalia-a ( la) -aaa.
The title compound was prepared in a manner similar to the product of Example 26, except that in Step A isopropenyl chloroformate was used instead of ethyl chloroformate: 1H 1w~'c,t (300 MHz, CDC13) S 9.0(br s, 1H), 7.2(m, 1H), 6.85(m, 2H), 4.9(m, 1H), 4.8(m, 1H), 2.05(s, 3H), 1.4(m, 1H), 0.85(m, 4H).
19F NMR (2B2 MHz, CDC13) S -73.61(s, 3F), -117.10(s, 1F).
High resolution mass spec: calculated for C1gH15N203F4 (M+H)+:
383.1018; found: 383.1018.
_77-Table 1 R
G \ N1 Rz H
Ex. G R 1 R2 mass spec #

1 H CH2cycPr ~C_cycpr 280.0828 2 H Me ~C~ycpl. 295.1073 3 H H nButyl 273.1211 4 H Me nButyl 287.1363 5 H H C-=C-cycPr 335.1371 6 H H allyl 257.0898 7 H allyl ~C_cycPr 321.1199 8 H benzyl ~C-cycPr 371.1365 9 H CHZcycPr allyl 311.1353 10 H propargyl ~C~ycpr 319.1057 11 H CH2CHZcycPr ~C_cycPr 349.1555 12 H isopropyl ~C_cycPr 323.1365 13 6-F allyl nButyl 330.1332 14 6-F allyl ~C_cycPi. 339.1143 15 6-F CH2cycPr ~C_cycPr 353.1265 16 6-F CH2cycPr nButyl 344.1520 17 6-CI CH2cycPr ~C_cycPr 369.0995 18 6-CI isobutyl ~C_cycPr 385.1298 19 6-Cl allyl ~C_cycPr 355.0839 20 6-CI CH2cycPr phenethyl 408.1198 21 6-Cl allyl phenethyl 395.1111 22 6-OMe CH2cycPr ~C~ycPr 365.1463 23 6-OMe allyl ~C-cycPr 351.1212 24 H CH2cycPr ~C_Me 309.1224 25 H allyl (~C_Me 295.1057 26 H COOEt ~C~ycpi, 353.1093 _78_ 27 H ~COOiPr C~C_cycPr 367.1286 28 H COOC(CH2)Me C~C_cycPr 365.1011 29 H COOiBu C=C_cycPr 381.1445 30 H COOnBu C~C_cycPr 381.1422 31 H COOCH2CHCH2 CSC-cycpr 365.1120 32 H COOBn C~C~ycPr 415.1285 33 H S02nPr C$C_cycPr 387.0997 34 H COPh (~C_cycPr 385.1184 35 H COOCH2iBu C~C_cycPr 395.1288 36 H COOCH2CCCH3 C~C~ycPI. 363.0950 37 H COiPr C~C~ycpt. 351.1299 38 H COcycPr C~C~ycPr 349.11 39 H S02Et C~C~ycpl. 373.0829 40 H S02iPr ~C_cycPr 387.1002 41 H COOCH3 C=C~ycPr 339.0932 42 6-Cl COOEt C~C~ycp=, 385.0570 43 6-CI COOiPr C=C_cycPr 399.0719 44 6-Cl COOC(CH2)CH3C~C_cycpr 397.0563 -.

45 6-F COOEt ~C_cycPr 369.0852 46 6-F COOiPr C=C_cycpi. 383.1045 47 6-F COOC(CH2)CH3CsC_cycpr 383.1019 *Unless othezvuise noted, stereochemistry is (+/-).
Tables 2 and 3 show representative compounds of the present invention. Each formula shown at the start of Table 2 and 3 is intended to be paired with each entry in the table which follows.
_79_ Table 2 C1 N1 Rz C1 N1 Rz C1 N1 Rz / ~ CF3 ~ / ~ CF3 ( / ~ CF3 a b c F R
F N1 Rz F N1 Rz F N1 Rz / ~ CF3 I / ~ CF3 ~ / ~ CF3 H O H O H O
d a f F Nl Rz C1 Nl Rz Me0 N R2 I / ~ CF3 I / ~ CF3 I / ~ CF3 g h i C1 R F R Me0 R1 Me0 Nl Rz Me0 Nl Rz Cl N R2 / ~ CF3 ~ / ~ CF3 ~ / ~ CF3 3 ~ Z
Rl ~ O R
Me0 R2 Me Nl Rz O Nl Rz F ( / N~ CF3 ( / ~ CF3 I / ~ CF3 m n g ~~,, CCRz N1~~,,CCRz HzN ~ / ~CF3 I / ~CF3 H O H O
r s Table 2 cont Ex. gl g2 Ex. gl g2 # #

201 -CH3 n-butyl 228 -CH -CH=CH-3-Fur 202 -CH3 benzyl 229 -CH3 -CH=CH-2-Imid 203 -CH3 phenethyl 230 -CH3 -CH=CH-5-Imid 204 -CH3 -CH2CH2-cycPr231 -CH3 -CH2C~C-CH3 205 -CH3 -CSC-CH3 232 -CH3 -CH2CfC-CF3 206 -CH3 -C~-CF3 233 -CH3 -CH2C~C-Et 207 -CH3 -C:C-Et 234 -CH3 -CH2C~C-iPr 208 -CH3 -CaC-iPr 235 -CH3 -CH2C~-cycPr 209 -CH3 -CSC-cycPr 236 -CH3 -CH2CsC-CH=CH2 210 -CH3 -CSC-1-(Me)cycPr237 -CH3 -CH2C~C-2-Fur 211 -CH3 -CSC-CH=CH2 238 -CH3 -CH2C~C-3-Fur 212 -CH3 -CSC-C(=CH2)CH3239 -CH3 -CH2C~C-2-Imid 213 -CH3 -CEC-2-pyridyl240 -CH3 -CH2C~C-5-Imid xl4 -CH3 -CSC-3-pyridyl241 -CH3 -CH2CH=CH2 215 -CH3 -CSC-2-Fur 242 -CH3 -CH2CH=CH-CH3 216 -CH3 -CSC-3-Fur 243 -CH3 -CH2CH=CH-CF3 217 -CH3 -C3C-2-Imid 244 -CH3 -CH2CH=CH-Et 218 -CH3 -C$C-5-Imid 245 -CH3 -CH2CH=CH-iPr 219 -CH3 -CH=CH-CH3 246 -CH3 -CH2CH=CH-cycPr 220 -CH3 -CH=CH-CF3 247 -CH3 -CH2CH=CHCH=CH2 221 -CH3 -CH=CH-Et 248 -CH3 -CH2CH=C(CH3)2 222 -CH3 -CH=CH-iPr 249 -CH3 -CH2CH=CH-2-Fur 223 -CH3 -CH=CH-cycPr 250 -CH3 -CH2CH=CH-3-Fur 224 -CH3 -CH=CH-CH=CH2251 -CH3 -CH2CH=CH-2-Imid 225 -CH3 -CH=CH-2-pyridyl252 -CH3 -CH2CH=CH-5-Imid 226 -CH3 -CH=CH-3-pyridyl253 -CH3 -CH=CHCH2-cycPr 227 -CH3 -CH=CH-2-Fur 254 -CH3 -CH=CHCH2-2-Fur a-rur szanas =or turan-Z-yl * 3-Fur stands for furan-3-yl * 2-Imid stands for imidazol-2-yl * 5-Imid stands for imidazol-5-yl Table 2 cont.
Ex. gl g2 Ex. gl g2 # #

301 -CH(CH3)2 n-butyl 328 -CH(CH3)2 -CH=CH-3-Fur 302 -CH(CH3)2 benzyl 329 -CH(CH3)2 -CH=CH-2-Imid 303 -CH(CH3)2 phenethyl 330 -CH(CH3)2 -CH=CH-5-Imid 304 -CH(CH3)2 -CH2CH2-cycPr331 -CH(CH3)2 -CH2C~-CH3 305 -CH(CH3)2 -C'd-CH3 332 -CH(CH3)2 -CH2C~-CF3 306 -CH(CH3)2 -C~-CF3 333 -CH(CH3)2 -CH2C~-Et 307 -CH(CH3)2 -CSC-Et 334 -CH(CH3)2 -CH2C~-iPr 308 -CH(CH3)2 -C---C-iPr 335 -CH(CH3)2 -CH2C~C-cycPr 309 -CH(CH3)2 -C=-C-cycPr 336 -CH(CH3)2 -CH2C=C-CH=CH2 310 -CH(CH3)2 -C=C-1-(Me)cycPr337 -CH(CH3)2 -CH2CsC-2-Fur 311 -CH(CH3)2 -C--_C-CH=CH2338 -CH(CH3)2 -CH2C~-3-Fur 312 -CH(CH3)2 -C~-C(=CH2)CH3339 -CH(CH3)2 -CH2C$C-2-Imid 313 -CH(CH3)2 -Cx-2-pyridyl340 -CH(CH3)2 -CH2C~-5-Imid 314 -CH(CH3)2 -C-C-3-pyridyl341 -CH(CH3)2 -CH2CH=CH2 315 -CH(CH3)2 -C~-2-Fur 342 -CH(CH3)2 -CH2CH=CH-CH3 316 -CH(CH3)2 -C$C-3-Fur 343 -CH(CH3)2 -CH2CH=CH-CF3 317 -CH(CH3)2 -C~-2-Imid 344 -CH(CH3)2 -CH2CH=CH-Et 318 -CH(CH3)2 -C~-5-Imid 345 -CH(CH3)2 -CH2CH=CH-iPr 319 -CH(CH3)2 -CH=CH-CH3 346 -CH(CH3)2 -CH2CH=CH-cycPr 320 -CH(CH3)2 -CH=CH-CF3 347 -CH(CH3)2 -CH2CH=CHCH=CH2 321 -CH(CH3)2 -CH=CH-Et 348 -CH(CH3)2 -CH2CH=C(CH3)2 322 -CH(CH3)2 -CH=CH-iPr 349 -CH(CH3)2 -CH2CH=CH-2-Fur 323 -CH(CH3)2 -CH=CH-cycPr350 -CH(CH3)2 -CH2CH=CH-3-Fur 324 -CH(CH3)2 -CH=CH-CH=CH2351 -CH(CH3)2 -CH2CH=CH-2-Imid 325 -CH(CH3)2 -CH=CH-2-pyridyl352 -CH(CH3)2 -CH2CH=CH-5-Imid 326 -CH(CH3)2 -CH=CH-3-pyridyl353 -CH(CH3)2 -CH=CHCH2-cycPr 327 -CH(CH3)2 -CH=CH-2-Fur354 -CH(CH3)2 -CH=CHCH2-2-Fur WO 00/004?8 PCT/US99/14395 Table 2 cont.
Ex.# gl g2 Ex.# gl g2 401 -CH2CH(CH3)2n-butyl 428 -CH2CH(CH3)2-CH=CH-3-Fur 402 -CH2CH(CH3)2benzyl 429 -CH2CH(CH3)2-CH=CH-2-Imid 403 -CH2CH(CH3)2henethyl 430 -CH2CH(CH3)2-CH=CH-5-Imid 404 -CH2CH(CH3)2-CH2CH2-cycPr431 -CH2CH(CH3)2-CH2C~C-CH3 405 -CH2CH(CH3)2-CSC-CH3 432 -CH2CH(CH3)2-CH2CeC-CF3 406 -CH2CH(CH3)2-CaC-CF3 433 -CH2CH(CH3)2-CH2C~-Et 407 -CH2CH(CH3)2-C~-Et 434 -CH2CH(CH3)2-CH2C~C-iPr 408 -CH2CH(CH3)2-CSC-iPr 435 -CH2CH(CH3)2-CH2CaC-cycPr 409 -CH2CH(CH3)2-CeC-cycPr 436 -CH2CH(CH3)2-CH2CaC-CH=CH2 410 -CH2CH(CH3)2-C$C-1-(Me)cycPr437 -CH2CH(CH3)2-CH2C~C-2-Fur 411 -CH2CH(CH3)2-CSC-CH=CH2 438 -CH2CH(CH3)2-CH2C~-3-Fur 412 -CH2CH(CH3)2-CsC-C(=CH2)CH3439 -CH2CH(CH3)2-CH2C~-2-Imid 413 -CH2CH(CH3)2-CSC-2-pyridyl440 -CH2CH(CH3)2-CH2CeC-5-Imid 414 -CH2CH(CH3)2-CeC-3-pyridyl441 -CH2CH(CH3)2-CH2CH=CH2 415 -CH2CH(CH3)2-CSC-2-Fur 442 -CH2CH(CH3)2-CH2CH=CH-CH3 416 -CH2CH(CH3)2-C~-3-Fur 443 -CH2CH(CH3)2-CH2CH=CH-CF3 417 -CH2CH(CH3)2-CSC-2-Imid 444 -CH2CH(CH3)2-CH2CH=CH-Et 418 -CH2CH(CH3)2-C~-5-Imid 445 -CH2CH(CH3)2-CH2CH=CH-iPr 419 -CH2CH(CH3)2-CH=CH-CH3 446 -CH2CH(CH3)2-CH2CH=CH-cycPr 420 -CH2CH(CH3)2-CH=CH-CF3 447 -CH2CH(CH3)2-CH2CH=CHCH=CH2 421 -CH2CH(CH3)2-CH=CH-Et 448 -CH2CH(CH3)2-CH2CH=C(CH3)2 422 -CH2CH(CH3)2-CH=CH-iPr 449 -CH2CH(CH3)2-CH2CH=CH-2-Fur 423 -CH2CH(CH3)2-CH=CH-cycPr450 -CH2CH(CH3)2-CH2CH=CH-3-Fur 424 -CH2CH(CH3)2-CH=CH-CH=CH2451 -CH2CH(CH3)2-CH2CH=CH-2-Imid 425 -CH2CH(CH3)2-CH=CH-2-pyridyl452 -CH2CH(CH3)2-CH2CH=CH-5-Imid 426 -CH2CH(CH3)2-CH=CH-3-pyridyl453 -CH2CH(CH3)2-CH=CHCH2-cycPr 427 -CH2CH(CH3)2-CH=CH-2-Fur454 -CH2CH(CH3)2-CH=CHCH2-2-Fur Table 2 cont.
Ex.#gl g2 Ex.# gl g2 SO1 -CH2CH2CH3>2n-butyl 52B -CH2CH2~t~312-CH=CH-3-Fur 502 -CH2CH2~~CH3>2benzyl 529 -~2CH2CH~CH3~2-CH=CH-2-Imid 503 -CH2CH2~3)2phenethyl 530 -CH2CH2CH(CH3)2-CH=CH-5-Imid 504 -CH2~2~~cH3)2-CH2CH2-cycPr531 -CH2~2~H3)2-CH2CgC-CH3 505 -~2CH2~H3)2-C~-CH3 532 -CH2CH2CH(~3)2-CH2C-~-CF3 -CH2~2~ -C~C-CF3 53 -CH2CH2CH -CH2 C~-Et 0 H3 ~ 2 3 W3 ) 2 507 -CH2CH2CH(CH3~2-C=C-Et 534 -CH2CH2Cti(CH3)2-CH2C~-iPr 5 -~2CH2~ -C=C- i Pr 5 -~2CH2CH -CH2 CSC-cyc 0 H3 ~ 2 3 3 > 2 Pr 509 -CH2CH2cH -C=-C-cYcPr 53 -CH2CH2~ -CH2C=C-CH=CH2 3 > 2 6 ~CH3 ~

510 -CH2~2~~cH3>2-CeC-1-(Me)cycPr537 -CH2CH2~~CH3>2-CH2CC-2-Fur 511 -CH2~2~ -C~-CH=CH2 53 -CH2CH2CH -CH2C~-3 -Fur 3 > 2 8 (CH3 ) 512 -~2~T2~~CH3)2-CeC-C(=CH2)CH3539 -CH2CH2CH~CH3)2-CH2C~-2-Imid 513 -~2~2~~CH312-CC-2-PYridyl540 -~2CH2~CH3~2-CH2C~-5-Imid 514 -CH2Cfi2CH~CH3)2-C-=C-3-PYridyl541 -CH2~2~3)2-CH2CH=CH2 515 -~2CH2CH~CH3O2-C-C-2-Fur 542 -CH2~2CH~CH3~2-CH2CH=CH-CH3 516 -~2CH2CH~CH3>2-C=C-3-Fur 543 -~2~2~~CH3~2-CH2CH=CH-CF3 517 -CH2~2~3~2 -C=C-2-Imid 544 -~2CH2CH~CH3)2-CH2CH=CH-Et 518 -CH2CH2~~CH3)2-CSC-5-Imid 545 -CH2CH2CH3>2-CH2CH=CH-iPr 519 -CH2CH2~3)2-CH=CH-CH3 546 -~2CH2~312-CH2CH=CH-cycPr 520 -CH2CH2CH~CH3~2-CH=CH-CF3 547 -CH2CH2CH(CH3>2-CH2CH=CHCH=CH2 521 -CH2CH2~~CH3)2-CH=CH-Et 548 -~2CH2~~CH3~2-CH2CH=C(CH3)2 522 -CH2CH2CH~CH3)2-CH=CH-iPr 549 -~2CH2~t~3)2-CH2CH=CH-2-Fur 523 -~2~2~~cH3)2-CH=CH-cycPr550 -CE;2CH2~3)2-CH2CH=CH-3-Fur 524 -cH2CH2CfilCH3)2-CH=CH-CH=CH2551 -~2~2CH3)2-CH2CH=CH-2-Imid 525 -CH2CH2CH~CH3)2-CH=CH-2-pyridyl552 -CH2~2CH~CH3)2-CH2CH=CH-5-Imid 526 -CH2CH2~3)2-CH=CH-3-pyridyl553 -CH2CH2CHt~3)2-CH=CHCH2-cycPr 527 -~2CH2CH~CH3)2-CH=CH-2-Fur554 -~2CH2~312-CH=CHCH2-2-Fur Table 2 cont.
Ex.~gl g2 Ex.~gl g2 601 -~2~2C(~3)3n-butyl 628 -~2~2C(~3)3-CH=CH-3-Fur 602 -~2~2C benzyl 629 -Cf32CFI2C -CH=CH-2-Imid (~3 ) (CH3 ) 603 -~2~2C(~3)3henethyl 630 -~2~2C(~3)3-CH=CH-5-Imid 604 -~2~2C -CH2CH2-cycPr631 -CHZCH2C -CH2C~-CH3 (~3 ) (CH3 ) 60 -~2~2C -C~C-CH3 632 -CHaCH2C -CH2C=C-CF3 5 (~3 ) (CH3 ) 606 -CH2CHZC(CH3)3-Cry-CF3 633 -CHZCH2C(CH3)3-CH2CeC-Et 607 -CH2CHZC(CH3>3-CSC-Et 634 -CH2CFI2C(CH3)3-CH2C~C-iPr 608 -~2~2C(~3)3-C'~-iPr 635 -~2~2C(~3)3-CH2C-=C-cycPr 609 -CH2~2C(~3)3-CSC-cycPr 636 -CHZCH2C(CH3)3-CH2C~C-CH=CH2 610 -CH2CH2C(c~i3)3-CaC-1-(Me)cycPr637 -~2~2C(~3)3-CH2C~-2-Fur 611 -CH2CHZC(CH3)3-C-sC-CH=CH2 638 -cH2CH2C(CH3)3-CH2CC-3-Fur 612 -CH2Cx2C -~C-C (=CH2 63 -~2~2C (~3 -CH2C$C-2-Imid (Cx3 ) ) CH3 9 ) 3 613 -~2~2C(~3)3-CSC-2-pyridyl640 -CH2CH2C(CH3)3-CH2CeC-5-Imid 614 -CH2Cx2c -~-3-pyridyl 641 -~2~2C (~3 -CH2CH=CH2 (c:~i3 ) 3 ) 3 615 -~2~2C(~3)3-CSC-2-Fur 642 -CH2CH2C(CH3)3-CH2CH=CH-CH3 616 -CHZCHZC -CSC-3-Fur 643 -~2~2C (~3 -CH2CH=CH-CF3 (CH3 > ) 3 617 -CHZCHZC(CH3)3-C;C-2-Imid 644 -CH2CH2C(CH3)3-CH2CH=CH-Et 618 -~2~2C(~3)3-C~C-5-Imid 645 -CH2CH2C(CA3)3-CH2CH=CH-iPr 619 -~2~2C -CH=CH-CH3 646 -CH2CH2C -CH2CH=CH-cycPr (~3 ) (CH3 ) 620 -~2~2C(~3)3-CH=CH-CF3 647 -CHZCH2C(CH3)3-CH2CH=CHCH=CH2 621 -~2~2C(~3)3-CH=CH-Et 648 -CH2CHZC(CH3)3-CH2CH=C(CH3)2 622 -CH2~2C(~3)3-CH=CH-iPr 649 -CH2CH2C(CH3)3-CH2CH=CH-2-Fur 623 -~2~2C(~3)3-CH=CH-cycPr 650 -~2~2C(~3)3-CH2CH=CH-3-Fur 624 -~2~2C -CH=CH-CH=CH2651 -CHyCtI2C -CH2CH=CH-2-Imid (~3 ) (CH3 ) 625 -~2~2C -CH=CH-2-pyridyl652 -CH2CH2C -CH2CH=CH-5-Imid (~3 ) (CS3 ) 626 -~2~2C(~3)3-CH=CH-3-pyridyl653 -CH2CH2C(CEi3)3-CH=CHCH2-cycPr 627 -CHZCH2C(CH3)3-CH=CH-2-Fur 654 -~2~2C(~3)3-CH=CHCH2-2-Fur Table 2 cont.
Ex.#gl g2 Ex.#gl g2 701 -CH2cycPr n-butyl 728 -CH2cycPr -CH=CH-3-Fur 702 -CH2cycPr benzyl 729 -CH2cycPr -CH=CH-Z-Imid 703 -CH2cycPr henethyl 730 -CH2cycPr -CH=CH-5-Imid 704 -CH2cycPr -CH2CH2-cycPr731 -CH2cycPr -CH2C~C-CH3 705 -CH2cycPr -CsC-CH3 732 -CH2cycPr -CH2C~C-CF3 706 -CH2cycPr -C~-CF3 733 -CH2cycPr -CH2CEC-Et 707 -CH2cycPr -C$C-Et 734 -CH2cycPr -CH2C~-iPr 708 -CH2cycPr -CeC-iPr 735 -CH2cycPr -CH2C~-cycPr 709 -CH2cycPr -CSC-cycPr 736 -CH2cycPr -CH2C~-CH=CH2 710 -CH2cycPr -CSC-1-(Me)cycPr737 -CH2cycPr -CH2C~-2-Fur 711 -CH2cycPr -CeC-CH=CH2 738 -CH2cycPr -CH2C~-3-Fur 712 -CH2cycPr -CSC-C(=CH2)CH3739 -CH2cycPr -CH2C~-2-Imid 713 -CH2cycPr -C~-2-pyridyl740 -CH2cycPr -CH2C~C-5-Imid 714 -CH2cycPr -CEC-3-pyridyl741 -CH2cycPr -CH2CH=CH2 715 -CH2cycPr -CgC-2-Fur 742 -CH2cycPr -CH2CH=CH-CH3 716 -CH2cycPr -CSC-3-Fur 743 -CH2cycPr -CH2CH=CH-CF3 717 -CH2cycPr -C=C-2-Imid 744 -CH2cycPr -CH2CH=CH-Et 718 -CH2cycPr -CSC-5-Imid 745 -CH2cycPr -CH2CH=CH-iPr 719 -CH2cycPr -CH=CH-CH3 746 -CH2cycPr -CH2CH=CH-cycPr 720 -CH2cycPr -CH=CH-CF3 747 -CH2cycPr -CH2CH=CHCH=CH2 721 -CH2cycPr -CH=CH-Et 74B -CH2cycPr -CH2CH=C(CH3)2 722 -CH2cycPr -CH=CH-iPr 749 -CH2cycPr -CH2CH=CH-2-Fur 723 -CH2cycPr -CH=CH-cycPr 750 -CH2cycPr -CH2CH=CH-3-Fur 724 -CH2cycPr -CH=CH-CH=CH2751 -CH2cycPr -CH2CH=CH-2-Imid 725 -CH2cycPr -CH=CH-2-pyridyl752 -CH2cycPr -CH2CH=CH-5-Imid 726 -CH2cycPr -CH=CH-3-pyridyl753 -CH2cycPr -CH=CHCH2-cycPr 727 -CH2cycPr -CH=CH-2-Fur 754 -CH2cycPr -CH=CHCH2-2-Fur ~ ~ r n n ~

WO 00/00478 PCTIUS99lI4395 Table 2 cont.
Ex.~gl g2 Ex.~gl g2 II
801 -CH2CH2cycPrn-butyl 828 -CH2CH2cycPr-CH=CH-3-Fur 802 -CH2CH2cycPrbenzyl 829 -CH2CH2cycPr-CH=CH-2-Imid 803 -CH2CH2cycPrphenethyl 830 -CH2CH2cycPr-CH=CH-5-Imid 804 -CH2CH2cycPr-CH2CH2-cycPr831 -CH2CH2cycPr-CH2CsC-CH3 805 -CH2CH2cycPr-C~-CH3 832 -CH2CH2cycPr-CH2CsC-CF3 806 -CH2CH2cycPr-CSC-CF3 833 -CH2CH2cycPr-CH2C~C-Et 807 -CH2CH2cycPr-CSC-Et 834 -CH CH
2 2cYcPr -CHZC$C-iPr 808 -CH2CH2cycPr-CSC-iPr 835 -CH2CH2cycPr-CH2C~eC-cycPr 809 -CH2CH2cycPr-C=C-cycPr 836 -CH2CH2cycPr-CH2C~C-CH=CH2 810 -CH2CH2cycPr-C~-1-(Me)cycPr837 -CH2CH2cycPr-CH2C$C-2-Fur 811 -CH2CH2cycPr-CSC-CH=CH2 838 -CH2CH2cycPr-CH2C~C-3-Fur 812 -CH2CH2cycPr-CSC-C(=CH2)CH3B39 -CH2CH2cycPr-CH2CsC-2-Imid 813 -CH2CH2cycPr-CSC-2-pyridyl840 -CH2CH2cycPr-CH2CsC-5-Imid 814 -CH2CH2cycPr-C~-3-pyridyl841 -CH CH
2 2cYcpr -CH2CH=CH2 815 -CH2CH2cycPr-C=C-2-Fur 842 -CH2CH2cycPr-CH2CH=CH-CH3 816 -CH2CH2cycPr-CSC-3-Fur 843 -CH2CH2cycPr-CH2CH=CH-CF3 817 -CH2CH2cycPr-C=C-2-Imid 844 -CH2CH2cycPr-CH2CH=CH-Et 818 -CH2CH2cycPr-CSC-5-Imid 845 -CH2CH2cycPr-CH2CH=CH-iPr B19 -CH2CH2cycPr-CH=CH-CH3 846 -CH2CH2cycPr-CH2CH=CH-cycPr 820 -CH2CH2cycPr-CH=CH-CF3 847 -CH2CH2cycPr-CH2CH=CHCH=CH2 821 -CH2CH2cycPr-CH=CH-Et B48 -CH2CH2cycPr-CH2CH=C(CH3)2 822 -CH2CH2cycPr-CH=CH-iPr 849 -CH2CH2cycPr-CH2CH=CH-2-Fur 823 -CH2CH2cycPr-CH=CH-cycPr 850 -CH2CHZcycPr-CH2CH=CH-3-Pur 824 -CH2CH2cycPr-CH=CH-CH=CH2851 -CH2CH2cycPr-CH2CH=CH-2-Imid 825 -CH2CH2cycPr-CH=CH-2-pyridyl852 -CH CH
2 2cYcpr -CH2CH=CH-5-Imid 826 -CH2CH2cycPr-CH=CH-3-pyridyl853 -CH2CH2cycPr-CH=CHCH2-cycPr 827 -CH2CH2cycPr-CH=CH-2-Fur 854 -CH2CH2cycPr-CH=CHCH2-2-Fur Table 2 cont.
Ex.# g1 g2 Ex.#gl g2 901 -CH2CH~H2 n-butyl 928 -CH2CH=CH2-CH=CH-3-Fur 902 -CH2CH~H2 benzyl 929 -CH2CH~H2 -CH=CH-2-/mid 903 -CH2CH=CH2henethyl 930 -CH2CH~H2 -CH=CH-5-/mid 904 -CH2CH~H2 -CH2CH2-cycPr931 -CH2CH~H2 -CH2C~-CH3 905 -CH2CH~H2 -CSC-CH3 932 -CH2CH~H2 -CH2C~C-CF3 906 -CH2CH~H2 -C~-CF3 933 -CH2CH~H2 -CH2C~-Et 907 -CH2CH~H2 -C~-Et 934 -CH2CH~H2 -CH2C$C-iPr 908 -CH2CH~H2 -C-~-iPr 935 -CH2CH~H2 -CH2C~C-cycPr 909 -CH2CH~H2 -CSC-cycPr 936 -CH2CH~H2 -CH2C~C-CH=CH2 910 -CH2CH~H2 -CSC-1-(Me)cycPr937 -CH2CHxH2 -CH2C~-2-Fur 911 -CH2CH~H2 -C=C-CH=CH2 938 -CH2CH=CH2-CH2CasC-3-Fur 912 -CH2CH~H2 -CSC-C(=CH2)CH3939 -CH2CH~H2 -CH2C-~C-2-Imid 913 -CH2CH=CH2-C=-C-2-pyridyl940 -CH2CH~H2 -CH2C=C-5-Zmid 914 -CH2CH=CH2-CC-3-pyridyl941 -CH2CH~H2 -CH2CH=CH2 915 -CH2CH=CH2-CC-2-Fur 942 -CH2CH~H2 -CH2CH=CH-CH3 916 -CH2CH~H2 -C=C-3-Fur 943 -CH2CH~H2 -CH2CH=CH-CF3 917 -CH2CH~H2 -C-~-2-Imid 944 -CH2CH~H2 -CH2CH=CH-Et 918 -CH2CH=CH2-C~-5-Imid 945 -CH2CH~H2 -CH2CH=CH-iPr 919 -CH2CHxH2 -CH=CH-CH3 946 -CH2CH=CH2-CH2CH=CH-cycPr 920 -CH2CH~H2 -CH=CH-CF3 947 -CH2CH~H2 -CH2CH=CHCH=CH2 921 -CH2CH~H2 -CH=CH-Et 948 -CH2CH~Fi2-CH2CH=C (CH3 ) 2 922 -CH2CH~H2 -CH=CH-iPr 949 -CH2CH~H2 -CH2CH=CH-2-Fur 923 -CH2CH~H2 -CH=CH-cycPr 950 -CH2CH~H2 -CH2CH=CH-3-Fur 924 -CH2CH~H2 -CH=CH-CH=CH2951 -CH2CH~H2 -CH2CH=CH-2-Imid 925 -CH2CH--CH2-CH=CH-2-pyridyl952 -CH2CH=CH2-CH2CH=CH-5-Imid 926 -CH2CH~H2 -CH=CH-3-pyridyl953 -CH2CH~H2 -CH=CHCH2-cycPr 927 -CH2CH~H2 -CH=CH-2-Fur 954 -CH2CH~H2 -CH=CHCH2-2-Fur Table 2 cont.
Ex.#R1 g2 Ex.~ Rl R2 1001-C(~H2)CH3n-butyl 1028 -C(xH2)CH3-CH=CH-3-Fur 1002-C(~H2)CH3benzyl 1029 -C(~H2)CH3-CH=CH-2-Imid 1003-C(-CH2)CHgphenethyl 1030 'C(~H2)CH3-CH=CH-5-Imid 1004-C(~H2)CH3-CH2CH2-cycPr1031 -C(~H2)CH3-CH2CaC-CH3 1005-C (~H2 -C?~C-CH3 1032 -C (~H2 -CH2C~C-CF3 ) CH3 ) CH3 1006-C (xH2 -C~-CF3 1033 -C (~H2 -CH2CcC-Et ) CH3 ) CH3 1007-C(~H2)CH3-C;C-Et 1034 -C(=CH2)CH3-CH2C~-iPr 1008-C(=CH2)CH3-C=C-iPr 1035 -C(~H2)CH3-CH2C~C-cycPr 1009-C(=CH2)CH3-C~-cycPr 1036 -C(~H2)CH3-CH2C~-CH=CH2 1010-C(=CH2)CH3-C~-1-(Me)cycPr1037 -C(~H2)CH3-CH2CgC-2-Fur 1011-C(xH2)CH3-C=C-CH=CH2 1038 -C(xH2)CH3-CHZC~C-3-Fur 1012-C(=CH2)CH3-CfC-C(=CH2)CH31039 -C(~H2)CH3-CH2C~C-2-Imid 1013-C(=CH2)CH3-CSC-2-pyridyl1040 -C(xH2)CH3-CH2C~C-5-Imid 1014-C(~H2)CH3-C~-3-pyridyl1041 -C(~H2)CH3-CH2CH=CH2 1015-C (= ~e~>-CSC-2-Fur 1042 -C (~H2 -CH2CH=CH-CH3 ) CH3 ) CH3 1016-C(=CH2)CHg-CiC-3-Fur 1043 -C(~H2)CH3-CH2CH=CH-CF3 1017-C(~H2)CH3-CSC-2-Imid 1044 -C(=CH2)CH3-CH2CH=CH-Et 1018-C(=CH2)CH3-CEC-5-Imid 1045 -C(~H2)CH3-CH2CH=CH-iPr 1019-C(=CH2)CH3-CH=CH-CH3 1046 -C(~H2)CH3-CH2CH=CH-cycPr 1020-C(=CH2)CH3-CH=CH-CF3 104? -C(=CH2)CHg-CH2CH=CHCH=CH2 1021-C(~H2)CH3-CH=CH-Et 1048 -C(xH2)CH3-CH2CH=C(CH3)2 1022-C(=CH2)CH3-CH=CH-iPr 1049 -C(~H2)CH3-CH2CH=CH-2-Fur 1023-C(~H2)CH3-CH=CH-cycPr 1050 -C(=CH2)CH3-CH2CH=CH-3-Fur 1024-C(~H2)CH3-CH=CH-CH=CH21051 -C(aCH2)CH3-CH2CH=CH-2-Imid 1025-C(=CH2)CH3-CH=CH-2-pyridyl1052 -C(~:H2)CH3-CH2CH=CH-5-Imid 1026-C(~H2)CHg-CH=CH-3-pyridyl1053 -C(~H2)CH3-CH=CHCH2-cycPr 1027-C(~H2)CH3-CH=CH-2-Fur 1054 -C(~H2)CH3-CH=CHCH2-2-Fur Table 2 cont.
Ex.#gl g2 Ex.#gl g2 1101CH2CH=C(Me)2n-butyl 1128CH2CH=C(Me)2-CH=CH-3-Fur 1102CH2CH=C(Me)2benzyl 1129CH2CH=C(Me)2-CH=CH-2-Imid 1103CH2CH=C(Me)2henethyl 1130CH2CH~(Me)2-CH=CH-5-Imid 1104CH2CH=C(Me)2-CH2CH2-cycPr1131CH2CH~(Me)2-CH2C~-CH3 1105CH2CH~ -C~-CH3 1132CH2CH~ (Me)-CH2C~-CF3 (Me) 2 2 1106CH2CH~(Me)2-CSC-CP3 1133CH2CH~(Me)2-CH2C~-Et 1107CH2CH~(Me)2-CSC-Et 1134CH2CH~(Me)2-CH2C~-iPr 1108CH2CH~(Me)2-CeC-iPr 1135CH2CH=C(Me)2-CH2C=C-cycPr 1109CH2CH~(Me)2-CeC-cycPr 1136CH2CHx (Me)2-CH2C~-CH=CH2 1110CH2CH~(Me)2-CaC-1-(Me)cycPr1137CH2CH=C(Me)2-CH2C~-2-Fur 1111CH2CH~(Me)2-CeC-CH=CH2 1138CH2CH=C(Me)2-CH2C=C-3-Fur 1112CH2CH~(Me)2-C$C-C(=CH2)CH31139CH2CH=C(Me)2-CH2C=C-2-Imid 1113CH2CHx -C~-2-pyridyl1140CH2CH=C(Me)2-CH2C-~-5-Imid (Me)2 1114CH2CH~(Me)2-C~-3-pyridyl1141CH2CH=C(Me)2-CH2CH=CH2 1115CH2CH~ -C~-2-Fur 1142CH'2CH=C -,:H2CH=CH-CH3 (Me) 2 (Me) 2 1116CH2CH~(Me)2-C~-3-Fur 1143CH2CH~(Me)2-CH2CH=CH-CF3 1117CH2CH~(Me)2-CSC-2-Imid 1144CH2CH~(Me)2-CH2CH=CH-Et 1118CH2CH~(Me)2-C~-5-Imid 1145CH2CH=C(Me)2-CH2CH=CH-iPr 1119CH2CH~(Me)2-CH=CH-CH3 1146CH2CH=C(Me)2-CH2CH=CH-cycPr 1120CH2CH=C(Me)2-CH=CH-CF3 1147CH2CH~(Me)2-CH2CH=CHCH=CH2 1121CH2CH~(Me)2-CH=CH-Et 1148CH2CHx (Me)2-CH2CH=C(CH3)2 1122CH2CH=CIMe)2-CH=CH-iPr 1149CH2CH~(Me)2-CH2CH=CH-2-Fur 1123CH2CH~(Me)2-CH=CH-cycPr 1150CH2CHx (Me)2-CH2CH=CH-3-Fur 1124CH2CH~(Me)2-CH=CH-CH=CH21151CH2CH~(Me)2-CH2CH=CH-2-Imid 1125CH2CH~(Me)2-CH=CH-2-pyridyl1152CH2CH~(Me)2-CH2CH=CH-S-Imid 1126CH2CH=C(Me)2-CH=CH-3-pyridyl1153CH2CH~(Me)2-CH=CHCH2-cycPr 1127CH2CH~(Me)2-CH=CH-2-Fur 1154CH2CH~(Me)2-CH=CHCH2-2-Fur _gp_ Table 2 cont.
Ex.4 gl g2 Ex.~ gl g2 1101 benzyl n-butyl 1128 benzyl -CH=CH-3-Fur 1102 benzyl benzyl 1129 benzyl -CH=CH-2-Imid 1103 benzyl phene~hyl 1130 benzyl -CH=CH-5-Imid 1104 benzyl -CH2CH2-cycPr1131 benzyl -CH2C-..C-CH3 1105 benzyl -CSC-CH3 1132 benzyl -CH2C~C-CF3 1106 benzyl -C~-CF3 1133 benzyl -CH2C~-Et 1107 benzyl -CSC-Et 1134 benzyl -CH2CeC-iPr 1108 benzyl -CeC-iPr 1135 benzyl -CH2C~C-cycPr 1109 benzyl -C'eC-cycPr 1136 benzyl -CH2CfC-CH=CH2 1110 benzyl -CSC-1-(Me)cycPr1137 benzyl -CH2CeC-2-Fur 1111 benzyl -CeC-CH=CH2 1138 benzyl -CH2C~-3-Fur 1112 benzyl -C$C-C(=CH2)CH31139 benzyl -CH2C~-2-Imid 1113 benzyl -C'C-2-pyridyl1140 benzyl -CH2C~C-5-Imid 1114 benzyl -CSC-3-pyridyl1141 benzyl -CH2CH=CH2 1115 benzyl -C~-2-Fu-r 1142 benzyl -CH2CH=CH-CH3 1116 benzyl -CeC-3-Fur 1143 benzyl -CH2CH=CH-CF3 1117 benzyl -CSC-2-Imid 1144 benzyl -CH2CH=CH-Et 1118 benzyl -CeC-5-Imid 1145 benzyl -CH2CH=CH-iPr 1119 benzyl -CH=CH-CH3 1146 benzyl -CH2CH=CH-cycPr 1120 benzyl -CH=CH-CF3 1147 benzyl -CH2CH=CHCH=CH2 1121 benzyl -CH=CH-Et 1148 benzyl -CH2CH=C(CH3)2 1122 benzyl -CH=CH-iPr 1149 benzyl -CH2CH=CH-2-Fur 1123 benzyl -CH=CH-cycPr1150 benzyl -CH2CH=CH-3-Fur 1124 benzyl -CH=CH-CH=CH21151 benzyl -CH2CH=CH-2-Imid 1125 benzyl -CH=CH-2-pyridyl1152 benzyl -CH2CH=CH-5-Imid 1126 benzyl -CH=CH-3-pyridyl1153 benzyl -CH=CHCH2-cycPr 1127 benzyl -CH=CH-2-Fur1154 benzyl -CH=CHCH2-2-Fur Table 2 cont.
Ex.#R1 R2 Ex.#R1 g2 1201-CH2-C=CH n-butyl 1228-CH2-C~CH -CH=CH-3-Fur 1202-CH2-C~H benzyl 1229-CH2-C~H -CH=CH-2-Imid 1203-CH2-C=CH phenethyl 1230-CH2-C~H -CH=CH-5-Imid 1204-CH2-C-CH -CH2CH2-cycPr1231-CH2-C~CH -CH2C-C-CH3 1205-CH2-C~CH -CSC-CH3 1232-CH2-CsCH -CHZC~-CF3 1206-CH2-C-CH -CSC-CF3 1233-CH2-C~H -CH2C~C-Et 1207-CH2-G~CH -CSC-Et 1234-CH2-C~H -CHZC~-iPr 1208-CH2-C=-CH-C~-iPr 1235-CH2-C~CH -CH2C~-cycPr 1209-CH2-C=-CH-C~-cycPr 1236-CH2-C~H -CH2C~C-CH=CH2 1210-CH2-C~CH -CffC-1-(Me)cycPr1237-CH2-C=CH -CH2C~-2-Fur 1211-CH2-C~H -C-=C-CH=CH2 1238-CH2-C~H -CH2C~-3-Fur 1212-CH2-C-CH -C=C-C(=CH2)CH31239-CH2-C~H -CH2C~-2-Imid 1213-CH2-C=CH -C=C-2-pyridyl1240-CH2-C=-CH -CH2C~-5-Imid 1214-CH2-C=CH -C=C-3-pyridyl1241-CH2-C=-CH -CH2CH=CH2 1215-CH2-C=CH -C~-2-Fur ..'.42-CH2-C=CH -CH2CH=CH-CH3 1216-CH2-C~H -CSC-3-Fur 1243-CH2-C-~H -CH2CH=CH-CF3 1217-CH2-C=CH -C~-2-Imid 1244-CH2-C~CH -CH2CH=CH-Et 1218-CH2-C~H -CSC-5-Imid 1245-CH2-C~CH -CH2CH=CH-iPr 1219-CH2-CeCH -CH=CH-CH3 1246-CH2-CfCH -CH2CH=CH-cycPr 1220-CH2-C~H -CH=CH-CF3 1247-CH2-C~H -CH2CH=CHCH=CH2 1221-CH2-C~H -CH=CH-Et 1248-CH2-C~H -CH2CH=C(CH3)2 1222-CH2-C~H -CH=CH-iPr 1249-CH2-C~H -CH2CH=CH-2-Fur 1223-CH2-CcCH -CH=CH-cycPr 1250-CH2-C~H -CH2CH=CH-3-Fur 1224-CH2-C~CH -CH=CH-CH=CH21251-CH2-C~CH -CH2CH=CH-2-Imid 1225-CH2-C~CH -CH=CH-2-pyridyl1252-CH2-C~H -CH2CH=CH-5-Imid 1226-CH2-~H -CH=CH-3-pyridyl1253-CH2-C~CH -CH=CHCH2-cycPr 1227-CH2-C~H -CH=CH-2-Fur 1254-CH2-C~H -CH=CHCH2-2-Fur Table 2 cont.
Ex gl g2 Ex gi g2 .1~ .
~k 1301-C02CH3 n-butyl 1328-C02CH3 -CH=CH-3-Fur 1302-C02CH3 benzyl 1329-C02CH3 -CH=CH-2-Imid 1303-C02CH3 phenethyl 1330-C02CH3 -CH=CH-5-Imid 1304-C02CH3 -CH2CH2-cycPr1331-C02CH3 -CH2CgC-CH3 1305-C02CH3 -CSC-CH3 1332-C02CH3 -CH2C~C-CF3 1306-C02CH3 -C~-CF3 1333-C02CH3 -CH2C~C-Et 1307-C02CH3 -C~-Et 1334-C02CH3 -CH2CsC-iPr 1308-C02CH3 -C:C-iPr 1335-C02CH3 -CH2CmC-cycPr 1309-C02CH3 -CSC-cycPr 1336-C02CH3 -CH2CC-CH=CH2 1310-C02CH3 -C$C-1-(Me)cycPr1337-C02CH3 -CH2C~C-2-Fur 1311-C02CH3 -C$C-CH=CH2 1338-C02CH3 -CH2C~C-3-Fur 1312-C02CH3 -CSC-C(=CH2)CH31339-C02CH3 -CH2C~-2-Imid 1313-C02CH3 -CSC-2-pyridyl1340-C02CH3 -CH2C~C-5-Imid 1314-C02CH3 -C~-3-pyridyl1341-C02CH3 -CH2CH=CH2 1315-C02CH3 -CSC-2-Fur 1342-C~.;~'H3 -CH2CH=CH-CH3 1316-C02CH3 -CSC-3-Fur 1343-C02CH3 -CH2CH=CH-CF3 1317-C02CH3 -C~-2-Imid 1344-C02CH3 -CH2CH=CH-Et 1318-C02CH3 -CSC-5-Imid 1345-C02CH3 -CH2CH=CH-iPr 1319-C02CH3 -CH=CH-CH3 1346-C02CH3 -CH2CH=CH-cycPr 1320-C02CH3 -CH=CH-CF3 1347-C02CH3 -CH2CH=CHCH=CH2 1321-C02CH3 -CH=CH-Et 1348-C02CH3 -CH2CH=C(CH3)2 , 1322-C02CH3 -CH=CH-iPr 1349-C02CH3 -CH2CH=CH-2-Fur 1323-C02CH3 -CH=CH-cycPr 1350-C02CH3 -CH2CH=CH-3-Fur 1324-C02CH3 -CH=CH-CH=CH21351-C02CH3 -CH2CH=CH-2-Imid 1325-C02CH3 -CH=CH-2-pyYidyl1352-C02CH3 -CH2CH=CH-5-Imid 1326-CO2CH3 -CH=CH-3-pyridyl1353-C02CH3 -CH=CHCH2-cycPr 1327-C02CH3 -CH=CH-2-Fur 1354-C02CH3 -CH=CHCH2-2-Fur i ~ a ~

Table 2 cont.
Ex.#R1 R2 Ex.# R1 R2 1401-C02CH2CH3n-butyl 1428 -C02CH2CH3-CH=CH-3-Fur 1402-C02CH2CH3benzyl 1429 -C02CH2CH3-CH=CH-2-Imid 140 -C02CH2CH3phenethyl 1430 -C02CH2CH3-CH=CH-5-Imid 1404-C02CH2CH3-CH2CH2-cycPr1431 -C02CH2CH3-CH2C~C-CH3 1405-C02CH2CH3-CEC-CH3 1432 -C02CH2CH3-CH2C~-CF3 1406-C02CH2CH3-C~-CF3 1433 -C02CH2CH3-CH2C~C-Et 1407-C02CH2CH3-C-=C-Et 1434 -C02CH2CH3-CH2C~C-iPr 1408-C02CH2CH3-C=-C-iPr 1435 -C02CHZCH3-CH2C~-cycPr 1409-C02CH2CH3-C~-cycPr 1436 -C02CH2CH3-CH2C~-CH=CH2 1410-C02CH2CH3-C~-1-(Me)cycPr1437 -C02CH2CH3-CH2C~C-2-Fur 1411-C02CH2CH3-C=C-CH=CH2 1438 -C02CH2CH3-CH2C=C-3-Fur 1412-CO2CH2CH3-C~-C(=CH2)CH31439 -C02CH2CH3-CH2C~-2-Imid 1413-C02CH2CH3-C~-2-pyridyl1440 -C02CH2CH3-CH2C~-5-Imid 1414-C02CH2CH3-C~-3-pyridyl1441 -C02CH2CH3-CH2CH=CH2 1415-C02CH2CH3-CSC-2-Fur 1442 -C02CH2CH3-CH2CH=CH-CH3 1416-C02CH2CH3-CsC-3-Fur 1443 -C02CH2CH3-CH2CH=CH-CF3 1417-C02CH2CH3-CSC-2-Imid 1444 -C02CH2CH3-CH2CH=CH-Et 1418-C02CH2CH3-C~C-5-Imid 1445 -C02CH2CH3-CH2CH=CH-iPr 1419-C02CH2CH3-CH=CH-CH3 1446 -C02CH2CH3-CH2CH=CH-cycPr 1420-C02CH2CH3-CH=CH-CF3 1447 -C02CH2CH3-CH2CH=CHCH=CH2 1421-C02CH2CH3-CH=CH-Et 1448 -C02CH2CH3-CH2CH=C(CH3)2 1422-C02CH2CH3-CH=CH-iPr 1449 -C02CH2CH3-CH2CH=CH-2-Fur 1423-C02CH2CH3-CH=CH-cycPr 1450 -C02CH2CH3-CH2CH=CH-3-Fur 1424-C02CH2CH3-CH=CH-CH=CH21451 -C02CH2CH3-CH2CH=CH-2-Imid 1425-C02CH2CH3-CH=CH-2-pyridyl1452 -C02CH2CH3-CH2CH=CH-5-Imid 1426-C02CH2CH3-CH=CH-3-pyridyl1453 -C02CH2CH3-CH=CHCH2-cycPr 1427-C02CH2CH3-CH=CH-2-Fur 1454 -C02CH2CH3-CH=CHCH2-2-Fur Table 2 cont.
Ex.# gl g2 Ex.# gl g2 1501 -C02CH(CH3)2n-butyl 1528 -C02CH(CH3)2-CH=CH-3-Fur 1502 -C02CH(CH3)2benzyl 1529 -C02CH(CH3)2-CH=CH-2-Imid 1503 -C02CH(CH3)2phenethyl 1530 -C02CH(CH3)2-CH=CH~ i-Imid 1504 -C02CH(CH3)2-CH2CH2-cycPr1531 -C02CH(CH3)2-CH2C~C-CH3 1505 -C02CH(CH3)2-C=C-CH3 1532 -C02CH(CH3)2-CH2C~C-CF3 1506 -C02CHtCH3)2-C~-CF3 1533 -C02CH(CH3)2-CH2C~C-Et 1507 -C02CH(CH3)2-CSC-Et 1534 -C02CH(CH3)2-CH2CsC-iPr 1508 -C02CH(CH3)2-CSC-iPr 1535 -C02CH(CH3)2-CH2C~C-cycPr 1509 -C02CH(CH3)2-CSC-cycPr 1536 -C02CH(CH3)2-CH2CsC-CH=CH2 1510 -C02CH(CH3)2-C~-1-(Me)cycPr1537 -C02CH(CH3)2-CH2CfC-2-Fur 1511 -C02CH(CH3)2-C=-C-CH=CH21538 -CD2CH(CH3)2-CH2C~C-3-Fur 1512 -C02CH(CH3)2-CSC-C(=CH2)CH31539 -C02CH(CH3)2-CH2CsC-2-Imid 1513 -C02CH(CH3)2-C$C-2-pyridyl1540 -C02CH(CH3)2-CH2CaC-5-Imid 1514 -C02CH(CH3)2-C-~-3-pyridyl1541 -C02CH(CH3)2-CH2CH=CH2 1515 -C02CH(CH3)2-C~-2-Fur 1542 -C02CH(CH3)2-CH2CH=CH-(.
,, 1516 -C02CH(CH3)2-CSC-3-Fur 1543 -C02CH(CH3)2-CH2CH=CH-CF3 1517 -C02CH(CH3)2-Cx-2-Imid 1544 -C02CH(CH3)2-~2CH=CH-Et 1518 -C02CH(CH3)2-C~-5-Imid 1545 -C02CH(CH3)2-CH2CH=CH-iPr 1519 -C02CH(CH3)2-CH=CH-CH3 1546 -C02CH(CH3)2-CH2CH=CH-cycPr 1520 -C02CH(CH3)2-CH=CH-CF3 1547 -co2cH(cH3)2-CH2CH=CHCH=CH2 1521 -C02CH(CH3)2-CH=CH-Et 1548 -C02CH(CH3)2-CH2CH=C(CH3)2 .

1522 -C02CH(CH3)2-CH=CH-iPr 1549 -C02CH(CH3)2-CH2CH=CH-2-Fur 1523 -C02CH(CH3)2-CH=CH-cycPr1550 -C02CH(CH3)2-CH2CH=CH-3-Fur 1524 -C02CH(CH3)2-CH=CH-CH=CH21551 -C02CH(CH3)2-CH2CH=CH-2-Imid 1525 -C02CH(CH3)2-CH=CH-2-pyridyl1552 -C02CH(CH3)2-CH2CH=CH-5-Imid 1526 -C02CH(CH3)2-CH=CH-3-pyridyl1553 -C02CH(CH3)2-CH=CHCH2-cycPr 1527 -C02CH(CH3)2-CH=CH-2-Fur1554 -C02CH(CH3)2-CH=CHCH2-2-Fur Table 2 cont.
Ex.# R1 R2 Ex.# Rl R2 1601 C02CH2CH2CH3n-butyl 1628 C02CH2CH2CH3-CH=CH-3-Fur 1602 C02CH2CH2CH3benzyl 1629 C02CH2CH2CH3-CH=CH-2-Imid 1603 C02CH2CH2CH3henethyl 1630 C02CH2CH2CH3-CH=CH-5-Imid 1604 C02CH2CH2CH3-CH2CH2-cycPr1631 C02CH2CH2CH3-CH2C~-CH3 1605 C02CH2CH2CH3-C~-CH3 1632 C02CH2CH2CH3-CH2C~-CF3 1606 C02CH2CH2CH3-C~-CF3 1633 C02CH2CH2CH3-CH2Cs~-Et 1607 C02CH2CH2CH3-C=-C-Et 1634 C02CH2CH2CH3-CH2CsC-iPr 1608 C02CH2CH2CH3-C-=C-iPr 1635 C02CH2CH2CH3-CH2C~C-cycPr 1609 C02CH2CH2CH3-C---C-cycPr1636 C02CH2CH2CH3-CH2C~-CH=CH2 1610 C02CH2CH2CH3-C~-1-(Me)cycPr1637 C02CH2CH2CH3-CH2C-C-2-Fur 1611 C02CH2CH2CH3-C=C-CH=CH2 1638 C02CH2CH2CH3-CH2C~C-3-Fur 1612 C02CH2CH2CH3-C=C-C(=CH2)CH31639 C02CH2CH2CH3-CH2C~C-2-Imid 1613 C02CH2CH2CH3-C~-2-pyridyl1640 C02CH2CH2CH3-CH2C~-5-Imid 1614 C02CH2CH2CH3-C=C-3-pyridyl1641 C02CH2CH2CH3-CH2CH=CH2 _~15 C02CH2CH2CH3-CEC-2-Fur 1642 C02CH2CH2CH3-CH2CH=CH-CH3 1616 C02CH2CH2CH3-C~-3-Fur 1643 C02CH2CH2CH3-CH2CH=CH-CF3 1617 C02CH2CH2CH3-CSC-2-Imid 1644 C02CH2CH2CH3-CH2CH=CH-Et 1618 C02CH2CH2CH3-CSC-5-Imid 1645 C02CH2CH2CH3-CH2CH=CH-iPr 1619 C02CH2CH2CH3-CH=CH-CH3 1646 C02CH2CH2CH3-CH2CH=CH-cycPr 1620 C02CH2CH2CH3-CH=CH-CF3 1647 C02CH2CH2CH3-CH2CH=CHCH=CH2 1621 C02CH2CH2CH3-CH=CH-Et 1648 C02CH2CH2CH3-CH2CH=C(CH3)2 1622 C02CH2CH2CH3-CH=CH-iPr 1649 C02CH2CH2CH3-CH2CH=CH-2-Fur 1623 C02CH2CH2CH3-CH=CH-cycPr1650 C02CH2CH2CH3-CH2CH=CH-3-Fur 1624 C02CH2CH2CH3-CH=CH-CH=CH21651 C02CH2CH2CH3-CH2CH=CH-2-Imid 1625 C02CH2CH2CH3-CH=CH-2-pyridyl1652 C02CH2CH2CH3-CH2CH=CH-5-Imid 1626 C02CH2CH2CH3-CH=CH-3-pyridyl1653 C02CH2CH2CH3-CH=CHCH2-cycPr 1627 C02CH2CH2CH3-CH=CH-2-Fur1654 C02CH2CH2CH3-CH=CHCH2-2-Fur Table 2 cont.
Ex.#R1 g2 Ex.#Ri 1I R2 --1701-C02~2~(~3)2n-butyl 1728-C02CH2CHtCH3)2-CH=CH-3-Fur 1702-~2~2~(~3)2benzyl 1729-~CH2CH(CEI3)2-CH=CH-2-Imid 1703-C02~2~(~3)2phenethyl 1730-C02CH2c~ItCH3)2-CH=CH-5-Imid 1704-o02CH2CH(CH3)2-CH2CH2-cycPr1731-C02Cii2CHtt~t3)2-CH2C~C-CH3 1705-C02CH2CFi(CEt3)2-CeC-CH3 1732-CO2CH2CH(CH3)2-CH2C~C-CF3 1706-coZCH2cH(cx3)2-c~c-cF3 1733-co2cHacHtcH3)a-cH2c~c-Et 1707-COZCH2CH(CH3)2-CSC-Et 1734-C02CH2CH(CH3)2-CH2C~C-iPr 1708-~2~2CH(~3)2-C;C-iPr 1735-C02CH2CH(CH3)2-CH2C~-cycPr 1709-C02Cx2CH(CH3)2-CSC-cycPr 1736-C02CH2CH(CH3)2-CH2C~-CH=CH2 1710-CO2CH2CH(CH3)2-CsC-1-(Me)cycPr1737-CO2CH2CH(CH3)2-CH2C=C-2-Fur 1711-CO2CH2CH(CH3)2-C-~-CH=CH2 1738-C02~2~(~3)2-CH2C~C-3-Fur 1712-C02CH2CH(CH3)2-~-C(=CH2)CH31739-C02CF12CH(CH3)2-CH2C;C-2-Imid 1713-C02CH2CH(CH3)2-CeC-2-pyridyl1740-C02CH2CH(CH3)2-CH2C$C-5-Imid 1714-C02CH2CH(CH3)2-CSC-3-pyridyl1741-C02CH2CtilCH3)2-cH2CH=cH2 1715-CO2cx2CFi(cH3)2-(~-2-Fur 1742-CO2CH2CH(CH3)2-CH2CH=CH-CH3 1716-C02CH2cH(CH3)2-CSC-3-Pur 1743-C02cH2CH(c~i3)2-CH2CH=CH-CF3 1717-~CH2CH(CH3)2-CSC-2-Imid 1744-C02CH2CH(CH3)2-CH2CH=CH-Et 1718-C02CH2CH(CH3)2-C~-5-Imid 1745-CO2CH2CH(CH3)2-CH2CH=CH-iPr 1719-C02~2~(~3)2-CH=CH-CH3 1746-C02~2~f~T3)2-CH2CH=CH-cycPr 1720-C02CH2CH(CH3)2-CH=CH-CF3 1747-C02CH2CH(CH3)2-CH2CH=CHCH=CH2 1721-C02CH2CH(CH3)2-CH=CH-Et 1749-C02CFI2CH(CH3)2-CH2CH=C(CH3)2 1722-C02CH2CH(CH3)2-CH=CH-iPr 1749-COaCH2CH(CH3)2-CH2CH=CH-2-Fur 1723-~CH2CHfCH3)2-CH=CH-cycPr 1750-~2CH(Cii3)2-CH2CH=CH-3-Fur 1724-CO2CH2C7i(CH3)2-CH=CH-CH=CH21751-~02CH2CH(Qi3)2-CH2CH=CH-2-Imid 1725-C02CH2~(~3)2-CH=CH-2-pyridyl1752-C02CH2CEt(CH3)2-cH2CH=cH-5-Imid 1726-C02CH2CH(CH3)2-CH=CH-3-pyridyl1753-CO2Cfi2CH(CH3>2-CH=CHCH2-cycPr 1727-CO2CH2CH(CH3)2-CH=CH-2-Fur 1754-COaCH2CH(CH3)2-CH=CHCH2-2-Fur Table 2 cont.
Ex.# gl R2 Ex.# R1 R2 1801 -C02(CH2)3CH3n-butyl 1828 -C02(CH2)3CH3-CH=CH-3-Fur 1802 -C02(CH2)3CH3benzyl 1829 -C02(CH2)3CH3-CH=CH-2-Imid 1803 -C02(CH2)3CH3phenethyl 1830 -C02(CH2)3CH3-CH=CH-5-Imid 1804 -C02(CH2)3CH3-CH2CH2-cycPr1831 -C02(CH2)3CH3-CH2C=C-CH3 1805 -C02(CH2)3CH3-CSC-CH3 1832 -C02(CH2)3CH3-CH2C~-CF3 1806 -C02(CH2)3CH3-C~-CF3 1833 -C02(CH2)3CH3-CH2C~C-Et 1807 -C02(CH2)3CH3-C~-Et 1834 -C02(CH2)3CH3-CH2C=C-iPr 1808 -C02(CH2)3CH3-CSC-iPr 1835 -C02(CH2)3CH3-CH2C~-cycPr 1809 -C02(CH2)3CH3-C=-C-cycPr 1836 -C02(CH2)3CH3-CH2C~-CH=CH2 1810 -C02(CH2)3CH3-C~-1-(Me)cycPr1837 -C02(CH2)3CH3-CH2C~-2-Fur 1811 -C02(CH2)3CH3-C-=C-CH=CH21838 -C02(CH2)3CHg-CH2C~C-3-Fur 1812 -C02(CH2)3CH3-C~-C(=CH2)CH31839 -C02(CH2)3CH3-CH2C=C-2-Imid 1813 -C02(CH2)3CH3-C~-2-pyridyl1840 -C02(CH2)3CH3-CH2C~-5-Imid 1814 -C02(CH2)3CH3-C$C-3-pyridyl1841 -C02(CH2)3CH3-CH2CH=CH2 1815 -C02(CH2)3CH3-CSC-2-Fur 1842 -C02(CH2)3CH3-CH2CH=CH-CH3 1816 -C02(CH2)3CH3-CSC-3-Fur 1843 -C02(CH2)3CH3-CH2CH=CH-CF3 1817 -C02(CH2)3CH3-C~-2-Imid 1844 -C02(CH2)3CH3-CH2CH=CH-Et 1818 -C02(CH2)3CH3-CW 5-Imid 1845 -C02(CH2)3CH3-CH2CH=CH-iPr 1819 -C02(CH2)3CH3-CH=CH-CH3 1846 -C02(CH2)3CH3-CH2CH=CH-cycPr 1820 -C02(CH2)3CH3-CH=CH-CF3 1847 -C02(CH2)3CH3-CH2CH=CHCH=CH2 1821 -C02(CH2)3CH3-CH=CH-Et 1848 -C02(CH2)3CH3-CH2CH=C(CH3)2 1822 -C02(CH2)3CH3-CH=CH-iPr 1849 -C02(CH2)3CH3-CH2CH=CH-2-Fur 1823 -C02(CH2)3CH3-CH=CH-cycPr1850 -C02(CH2)3CH3-CH2CH=CH-3-Fur 1824 -C02(CH2)3CH3-CH=CH-CH=CH21851 -C02(CH2)3CH3-CH2CH=CH-2-Imid 1825 -C02(CH2)3CH3-CH=CH-2-pyridyl1852 -C02(CH2)3CH3-CH2CH=CH-5-Imid 1826 -C02(CH2)3CH3-CH=CH-3-pyridyl1853 -C02(CH2)3CH3-CH=CHCH2-cycPr 1827 -COZ(CH2)3CH3-CH=CH-2-Fur1854 -C02(CH2)3CH3-CH=CHCH2-2-Fur Date: 12/1/00 29 : LEONZIEE Time: 10:32:17 Al~
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\\server~name PSCRIPT Page Separator Table 2 cont.
Ex.# R1 R2 Ex.#R1 R2 1901 -C02CH2CH=CHZn-butyl 1928-C02CH2CH=CH2-CH=CH-3-Fur 1902 -C02CH2CH=CH2benzyl 1929-C02CH2CH=CH2-CH=CH-2-Imid 1903 -C02CHZCH=CHZphenethyl 1930-C02CH2CH=CH2-CH=CH-5-Imid 1904 -C02CH2CH=CH2-CH2CH2-cycPr1931-C02CH2CH=CH2-CH2C=C-CH3 1905 -C02CH2CH=CHZ-C~-CH3 1932-C02CH2CH=CH2-CH2C~-CF3 1906 -C02CH2CH=CHZ-Cx-CF3 1933-COZCH2CH=CH2-CH2C~-Et 1907 -COZCH2CH=CHa-C=C-Et 1934-C02CH2CH=CHZ-CH2C~-iPr 1'908-C02CH2CH=CHZ-C---C-iPr 1935-C02CH2CH=CH2-CH2C~-cycPr 1909 -C02CH2CH=CH2-C=-C-cycPr 1936-C02CH2CH=CH2-CH2C~C-CH=CH2 1910 -C02CH2CH=CH2-C-=C-1-(Me)cycPr1937-COZCH2CH=CH2-CH2C~C-2-Fur 1911 -COZCH2CH=CHZ-C~-CH=CH2 1938-C02CH2CH=CH2-CH2C-~-3-Fur 1912 -COZCH2CH=CH2-C=-C-C(=CH2)CH31939-C02CH2CH=CH2-CH2C~-2-Imid 1913 -C02CH2CH=CHZ-C=-C-2-pyridyl1940-C02CH2CH=CH2-CH2C=C-5-Imid 1914 -COZCH2CH=CHZ-C---C-3-pyridyl1941-C02CH2CH=CH2-CH2CH=CH2 1915 -C02CHZCH=CHZ-C~-2-Fur 1942-C02CH2CH=CH2-CH2CH=CH-CH3 1916 -C02CHZCH=CH2-CSC-3-Fur 1943-C02CH2CH=CH2-CH2CH=CH-CF3 1917 -COZCH2CH=CH2-CSC-2-Imid 1944-C02CH2CH=CH2-CH2CH=CH-Et 1918 -C02CHZCH=CH2-C-=C-5-Imid 1945-COZCH2CH=CH2-CH2CH=CH-iPr 1919 -C02CH2CH=CHZ-CH=CH-CH3 1946-COZCHZCH=CHZ-CH2CH=CH-cycPr 1920 -COZCHZCH=CH2-CH=CH-CF3 1947-C02CH2CH=CH2-CH2CH=CHCH=CH2 1921 -C02CH2CH=CH2-CH=CH-Et 1948-C02CH2CH=CH2-CH2CH=C(CH3)2 1922 -C02CH2CH=CH2-CH=CH-iPr 1949-C02CH2CH=CH2-CH2CH=CH-2-Fur 1923 -C02CH2CH=CH2-CH=CH-cycPr 1950-C02CH2CH=CH2-CH2CH=CH-3-Fur 1924 -C02CH2CH=CH2-CH=CH-CH=CH21951-C02CH2CH=CH2-CH2CH=CH-2-Imid 1925 -C02CH2CH=CH2-CH=CH-2-pyridyl1952-C02CH2CH=CHZ-CH2CH=CH-5-Imid 1926 -C02CH2CH=CH2-CH=CH-3-pyridyl1953-C02CH2CH=CH2-CH=CHCH2-cycPr 1927 -C02CH2CH=CH2-CH=CH-2-Fur 1954-C02CH2CH=CH2-CH=CHCH2-2-Fur Table 2 cont.
Ex.~gl g2 Ex.# I gl g2 2001-C02CH2(C6H5)n-butyl 0 -C02CH2(C6H5)-CH=CH-3-Fur 2002-C02CH2(C6H5)benzyl 2029 -C02CHg(C6H5)-CH=CH-2 -Imid 2003-C02CH2(CgHS)phenethyl 2030 -COZCHZ(C6H5)-CH=CH-5-Imid 2004-C02CH2(C6H5)-CH2CH2-cycPr2031 -C02CH2(C6H5)-CH2C~-CH3 2005-C02CH2(C6H5)-C~-CH3 2032 -C02CH2(C6H5)-CH2C~C-CF3 2006-C02CH2(C6H5)-CSC-CF3 2033 -C02CH2(C6H5)-CH2C~C-Et 2007-C02CH2(C6H5)-CiC-Et 2034 -COZCHZ(C6H5)-CH2C~C-iPr 2008-COZCH2(CgHS)-C~-iPr 2035 -C02CHa(C6H5)-CH2CeC-cycPr 2009-C02CH2(C6H5)-CfC-cycPr 2036 -COZCH2(C6H5)-CH2C3C-CH=CH2 2010-COZCH2(C6H5)-C;C-1-(Me)cycPr2037 -C02CH2(C6H5)-CH2CeC-2-Fur 2011-C02CH2(C6H5)-CSC-CH=CH2 2038 -C02CHZ(C6H5)-CH2C~C-3-Fur 2012-C02CH2(C6H5)-CSC-C(=CH2)CH32039 -C02CHZ(C6H5)-CH2C~C-2-Imid 2013-C02CH2(C5H5)-C~-2-pyridyl2040 -C02CH2(C6H5)-CH2C=C-5-Imid 2014-COzCH2(C6H5)-CSC-3-pyridyl2041 -C02CH2(C6H5)-CH2CH=CH2 2015-C02CH2(CgHS)-CSC-2-Fur 2042 -C02CHZ(C6H5)-CH2CH=CH-CH3 2016-C02CH2(C6H5)-C$C-3-Fur 2043 -COZCH2(CgHg}-CH2CH=CH-CF3 2017-COyCH2(C6H5)-CeC-2-amid 2044 -G02CH2(C6H5)-CH2CH=CH-Et 2018-COZCHZ(C6H5)-CSC-5-Imid 2045 -COZCH2(C6H5)-CH2CH=CH-iPr 2019-C02CH2(C5H5)-CH=CH-CH3 2046 -C02CH2(C5H5)-CH2CH=CH-cycPr 2020-C02CH2(C6H5)-CH=CH-CF3 2047 -C02CH2(C6H5)-CH2CH=CHCH=CH2 2021-C02CH2(C6H5)-CH=CH-Et 2048 -C02CH2(C6H5)-CH2CH=C(CH3)2 2022-C02CH2(C6H5)-CH=CH-iPr 2049 -C02CH2(C6Hg)-CH2CH=CH-2-Fur 2023-COZCH2(C6H5)-CH=CH-cycPr 2050 -C02CH2(C6H5}-CH2CH=CH-3-Fur 2024-C02CH2(C6H5)-CH=CH-CH=CH22051 -C02CH2(CgHS)-CH2CH=CH-2-Imid 2025-COZCH2(C6H5)-CH=CH-2-pyridyl2052 -C02CH2(C6H5)-CH2CH=CH-5-Imid 2026-C02CH2(C6H5)-CH=CH-3-pyridyl2053 -COZCH2(C6H5)-CH=CHCH2-cycPr 2027-C02CH2(C6H5)-CH=CH-2-Fur 2054 -C02CH2(C6H5)-CH=CHCH2-2-Fur Table 2 cont.
Ex.# Rl R2 Ex.#Rl H2 2101 -COZcycPr n-butyl 2128-C02cycPr -CH=CH-3-Fur 2102 -COZcycPr benzyl 2129-C02cycPr -CH=CH-2-Imid 2103 -COZcycPr phenethyl 2130-C02cycPr -CH=CH-5-Imid 2104 -C02cycPr -CH2CH2-cycPr2131-C02cycPr -CH2CgC-CH3 2105 -C02cycPr -C~-CH3 2132-COZcycPr -CH2C;C-CF3 2106 -C02cycPr -CC-CF3 2133-COZcycPr -CH2C~-Et 2107 -COZcycPr -C~-Et 2134-COZcycPr -CH2C~C-iPr 2108 -COZcycPr -CSC-iPr 2135-C02cycPr -CH2C~-cycPr 2109 -C02cycPr -CSC-cycPr 2136-COZcycPr -CH2C~-CH=CH2 2110 -C02cycPr -C-~C-1-(Me)cycPr2137-CO~cycPr -CH2C=C-2-Fur 2111 -C02cycPr -CSC-CH=CH2 2138-C02cycPr -CH2C~C-3-Fur 2112 -C02cycPr -C=-C-C(=CH2)CH32139-C02cycPr -CH2C~C-2-Imid 2113 -COZcycPr -C=C-2-pyridyl2140-C02cycPr -CH2C~C-5-Imid 2114 -C02cycPr -C=C-3-pyridyl2141-C02cycPr -CH2CH=CH2 2115 -C02cycPr -CSC-2-Fur 2142-C02cycPr -CH2CH=CH-CH3 2116 -C02cycPr -C=C-3-Fur 2143-C02cycPr -CH2CH=CH-CF3 2117 -COZcycPr -CSC-2-Imid 2144-COZcycPr -CH2CH=CH-Et 2118 -C02cycPr -C=C-5-Imid 2145-C02cycPr -CH2CH=CH-iPr 2119 -C02cycPr -CH=CH-CH3 2146-C02cycPr -CH2CH=CH-cycPr 2120 -COZcycPr -CH=CH-CF3 2147-C02cycPr -CH2CH=CHCH=CH2 2121 -C02cycPr -CH=CH-Et 2148-C02cycPr -CH2CH=C(CH3)2 2122 -C02cycPr -CH=CH-iPr 2149-COgcycPr -CH2CH=CH-2-Fur 2123 -C02cycPr -CH=CH-cycPr 2150-C02cycPr -CH2CH=CH-3-Fur 2124 -C02cycPr -CH=CH-CH=CH22151-COycycPr -CH2CH=CH-2-Imid 2125 -C02cycPr -CH=CH-2-pyridyl2152-C02cycPr -CH2CH=CH-5-Imid 2126 -C02cycPr -CH=CH-3-pyridyl2153-C02cycPr -CH=CHCH2-cycPr 2127 -COZcycPr -CH=CH-2-Fur 2154-C02cycPr -CH=CHCH2-2-Fur s,.

Table 2 cont.
Ex.~ gl g2 Ex.~gl g2 2201 -C02CHZcycPrn-buty 2228-C02CH2cycPr-CH=CH-3-Fur 2202 -C02CH2cycPrbenzyl 2229-COZCHZcycPr-CH=CH-2-7snid 2203 -C02CH2cycPrphenethyl 2230-C02CH2cycPr-CH=CH-5-Imid 2204 -C02CH2cycPr-CH2CH2-cycPr2231-C02CH2cycPr-CH2C=C-CH3 2205 -C02CHZcycPr-CSC-CH3 2232-C02CHZcycPr-CH2CiC-CF3 2206 -C02CH2cycPr-C~-CF3 2233-C02CH2cycPr-CH2C~C-Et 2207 -C02CHZcycPr-CSC-Et 2234-COgCH2cycPr-CH2C~C-iPr 2208 -COZCH2cycPr-CSC-iPr 2235-COZCH2cycPr-CH2C3C-cycPr 2209 -C02CH2cycPr-CfC-cycPr 2236-COZCH2cycPr-CH2C~C-CH=CH2 2210 -C02CH2cycPr-CSC-1-(Me)cycPr2237-C02CH2cycPr-CH2C~-2-Fur 2211 -COZCH2cycPr-CSC-CH=CH2 2238-C02CH2cycPr-CH2~-3-Fur 2212 -COZCHZcycPr-CSC-C(=CH2)CH32239-COZCH2cycPr-CH2C~C-2-Imid 2213 -COZCH2cycPr-CSC-2-pyridyl2240-C02CHZcycPr-CH2C$C-S-Imid 2214 -COZCH2cycPr-CSC-3-pyridyl2241-COZCH2cycPr-CH2CH=CH2 '215 -COZCHgcycPr-CSC-2-Fur 2242-C02CHZcycPr-CH2CH=CH-CH3 2216 -COZCH2cycPr-CSC-3-Fur 2243-COgCH2cycPr-CH2CH=CH-CF3 2217 -C02CH2cycPr-CSC-2-Imid 2244-C02CHZcycPr-CH2CH=CH-Et 2218 -C02CHZcycPr-CSC-5-Imid 2245-C02CH2cycPr-CH2CH=CH-iPr 2219 -COZCH2cycPr-CH=CH-CH3 2246-C02CHZCycPr-CH2CH=CH-cycPr 2220 -COZCH2cycPr-CH=CH-CF3 2247-COZCH2cycPr-CH2CH=CHCH=CH2 2221 -C02CH2cycPr-CH=CH-Et 2248-COZCH2cycPr-CH2CH=C(CH3)2 2222 -C02CH2cycPr-CH=CH-iPr 2249-C02CH2cycPr-CH2CH=CH-2-Fur 2223 -COZCH2cycPr-CH=CH-cycPr 2250-C02CH2cycPr-CH2CH=CH-3-Fur 2224 -C02CHZcycPr-CH=CH-CH=CH22251-COZCH2cycPr-CH2CH=CH-2-Imid 2225 -C02CH2cycPr-CH=CH-2-pyridyl2252-C02CH2cycPr-CH2CH=CH-5-Imid 2226 -C02CH2cycPr-CH=CH-3-pyridyl2253-C02CH2cycPr-CH=CHCH2-cycPr 2227 -COZCH2cycPr-CH=CH-2-Fur 2254-C02CHZcycPr-CH=CHCH2-2-Fur WO 00/00478 PGT/iJS99/14395 Table 2 cont.
Ex.#R1 R2 Ex.# R1 R2 2301-S02CH2CH3n-butyl 2328 -S02CH2CH3-CH=CH-3-Fur 2302-S02CH2CH3benzyl 2329 -S02CH2CH3-CH=CH-2-Imid 2303-S02CH2CH3phenethyl 2330 -S02CH2CH3-CH=CH-5-Imid 2304-S02CH2CH3-CH2CH2-cycPr2331 -S02CH2CH3-CH2C~C-CH3 2305-S02CH2CH3-CSC-CH3 2332 -S02CH2CH3-CH2C~-CF3 2306-S02CH2CH3-CSC-CF3 2333 -S02CH2CH3-CH2C~-Et 2307-S02CH2CH3-C~-Et 2334 -S02CH2CH3-CH2C~-iPr 2308-S02CH2CH3-CSC-iPr 2335 -S02CH2CH3-CH2Cx-cycPr 2309-S02CH2CH3-CeC-cycPr 2336 -S02CH2CH3-CH2C=C-CH=CH2 2310-S02CH2CH3-CSC-1-(Me)cycPr2337 -S02CH2CH3-CH2CC-2-Fur 2311-S02CH2CH3-C=C-CH=CH2 2338 -S02CH2CH3-CH2C~C-3-Fur 2312-S02CH2CH3-C~-C(=CH2)CH32339 -S02CH2CH3-CH2CaC-2-Imid 2313-S02CH2CH3-C~-2-pyridyl2340 -S02CH2CH3-CH2C~-5-Imid 2314-S02CH2CH3-CC-3-pyridyl2341 -S02CH2CH3-CH2CH=CH2 2315-S02CH2CH3-CSC-2-Fur 2342 -S02CH2CH3-t"~32CH=CH-CE:

2316-S02CH2CH3-C~-3-Fur 2343 -S02CH2CH3-CH2CH=CH-CF3 2317-S02CH2CH3-CSC-2-/mid 2344 -S02CH2CH3-CH2CH=CH-Et 2318-S02CH2CH3-C=-C-5-Imid 2345 -S02CH2CH3-CH2CH=CH-iPr 2319-S02CH2CH3-CH=CH-CH3 2346 -S02CH2CH3-CH2CH=CH-cycPr 2320-S02CH2CH3-CH=CH-CF3 2347 -S02CH2CH3-CH2CH=CHCH=CH2 2321-S02CH2CH3-CH=CH-Et 2348 -S02CH2CH3-CH2CH=C(CH3)2 2322-S02CH2CH3-CH=CH-iPr 2349 -S02CH2CH3-CH2CH=CH-2-Fur 2323-S02CH2CH3-CH=CH-cycPr 2350 -S02CH2CH3-CH2CH=CH-3-Fur 2324-S02CH2CH3-CH=CH-CH=CH22351 -S02CH2CH3-CH2CH=CH-2-Imid 2325-S02CH2CH3-CH=CH-2-pyridyl2352 -S02CH2CH3-CH2CH=CH-5-Imid 2326-S02CH2CH3-CH=CH-3-pyridyl2353 -S02CH2CH3-CH=CHCH2-cycfr 2327-S02CH2CH3-CH=CH-2-Fur 2354 -S02CH2CH3-CH=CHCH2-2-Fur i ti ", f Table 2 cont.
Ex gl g2 Ex. gl I g2 . )k #

2401 -S02CH(CH3)2n-butyl 2428-S02CH(CH3)2-CH=CH-3-Fur 2402 -S02CH(CH3)2benzyl 2429-S02CH(CH3)2-CH=CH-2-Imid 2403 -S02CH(G~i3)2phenethyl 2430-S02CH(CH3)2-CH=CH-5-Imid 2404 -S02CH(CH3)2-CH2CH2-cycPr2431-S02CH(CH3)2-CH2C~-CH3 2405 -S02CH(CH3)2-CSC-CH3 2432-S02CH(CH3)2-CH2C~C-CF3 2406 -S02CH(CH3)2-C~-CF3 2433-S02CH(CH3)2-CH2C~C-Et 2407 -S02CH(CH3)2-C~-Et 2434-S02CH(CH3)2-CH2CeC-iPr 2408 -S02CH(CH3)2-C~-iPr 2435-S02CH(CH3)2-CHZC~C-cycPr 2409 -S02CH(CH3)2-CSC-cycPr 2436-S02CH(CH3)2-CH2C~C-CH=CH2 2410 -S02CH(CH3)2-C~-1-(Me)cycPr2437-S02CH(CH3)2-CH2C~-2-Fur 2411 -S02CH(CH3)2-C~-CH=CH2 2438-S02CH(CH3)2-CH2C~-3-Fur 2412 -S02CH(CH3)2-C~-C(=CH2)CH32439-S02CH(CH3)2-CH2C~-2-Imid 2413 -S02CH(CH3)2-CSC-2-pyridyl2440-S02CH(CH3)2-CH2C~C-5-Imid 2414 -S02CH(CH3)2-C$C-3-pyridyl2441-S02CH(CH3)2-CH2CH=CH2 2415 -S02CH(CH3)i'eC-2-Fur 2442-S02CH(CH3)2-CH2CH=CH-CH3 ;

2416 -S02CH(CH3)2-CgC-3-Fur 2443-S02CH(CH3)2-CH2CH=CH-CF3 2417 -S02CH(CH3)2-C~-2-Imid 2444-S02CH(CH3)2-CH2CH=CH-Et 2418 -S02CH(CH3)2-CaC-5-Imid 2445-S02CH(CH3)2-CH2CH=CH-iPr 2419 -S02CH(CH3)2-CH=CH-CH3 2446-S02CH(CH3)2-CH2CH=CH-cycPr 2420 -S02CH(CH3)2-CH=CH-CF3 2447-S02CH(CH3)2-CH2CH=CHCH=CH2 2421 -S02CH(CH3)2-CH=CH-Et 2448-S02CH(CH3)2-CH2CH=C(CH3)2 2422 -S02CH(CH3)2-CH=CH-iPr 2449-S02CH(CH3)2-CH2CH=CH-2-Fur 2423 -S02CH(CH3)2-CH=CH-cycPr 2450-S02CH(CH3)2-CH2CH=CH-3-Fur 2424 -S02CH(CH3)2-CH=CH-CH=CH22451-S02CH(CH3)2-CH2CH=CH-2-Imid 2425 -S02CH(CH3)2-CH=CH-2-pyridyl2452-S02CH(CH3)2-CH2CH=CH-5-Imid 2426 -S02CH(CH3)2-CH=CH-3-pyridyl2453-S02CH(CH3)2-CH=CHCH2-cycPr 24271-S02CH(CH3)2-CH=CH-2-Fur 2454-S02CH(CH3)2-CH=CHCH2-2-Fur I , Table 2 cont.
Ex.#gl g2 Ex.# gl g2 2501-C(=O)CH3 n-butyl 2528 -C(=O)CH3 -CH=CH-3-Fur 2502-C(=O)CH3 benzyl 2529 -C(=0)CH3 -CH=CH-2-Imid 2503-C(=0)CH3 phenethyl 2530 -C(=O)CH3 -CH=CH-5-Imid 2504-C(=0)CH3 -CH2CH2-cycPr2531 -C(=0)CH3 -CH2C~-CH3 2505-C(=O)CH3 -CSC-CH3 2532 -C(=0)CH3 -CH2C~-CF3 2506-C(=O)CH3 -CSC-CF3 2533 -C(=O)CH3 -CH2C~-Et 2507-C(=O)CH3 -C~-Et 2534 -C(=0)CH3 -CH2C~-iPr 2508-C(=O)CH3 -CSC-iPr 2535 -C(=O)CH3 -CH2C=-C-cycPr 2509-C(=O)CH3 -C~-cycPr 2536 -C(=O)CH3 -CH2C~-CH=CH2 2510-C(=O)CH3 -CSC-1-(Me)cycPr2537 -C(=O)CH3 -CH2C~C-2-Fur 2511-C(=O)CH3 -C$C-CH=CH2 2538 -C(=O)CH3 -CH2C~-3-Fur 2512-C(=O)CH3 -CSC-C(=CH2)CH32539 -C(=O)CH3 -CH2C~C-2-Imid 2513-C(=O)CH3 -~-2-pyridyl 2540 -C(=O)CH3 -CH2C=-C-5-Imid 2514-C(=O)CH3 -C$C-3-pyridyl2541 -C(=O)CH3 -CH2CH=CH2 2515-C(=O)CH3 -CSC-2-Fur 2542 -C(=O)~-~3-CH2CH=CH-CH3 2516-C(=O)CH3 -C~-3-Fur 2543 -C(=0)CH3 -CH2CH=CH-CF3 2517-C(=O)CH3 -CaC-2-Imid 2544 -C(=O)CH3 -CH2CH=CH-Et 2518-C(=O)CH3 -C~-5-Imid 2545 -C(=O)CH3 -CH2CH=CH-iPr 2519-C(=O)CH3 -CH=CH-CH3 2546 -C(=O)CH3 -CH2CH=CH-cycPr 2520-C(=0)CH3 -CH=CH-CF3 2547 -C(=O)CH3 -CH2CH=CHCH=CH2 2521-C(=0)CH3 -CH=CH-Et 2548 -C(=O)CH3 -CH2CH=C(CH3)2 2522-C(=0)CH3 -CH=CH-iPr 2549 -C(=O)CH3 -CH2CH=CH-2-Fur 2523-C(=O)CH3 -CH=CH-cycPr 2550 -C(=O)CH3 -CH2CH=CH-3-Fur 2524-C(=0)CH3 -CH=CH-CH=CH22551 -C(=O)CH3 -CH2CH=CH-2-Imid 2525-C(=O)CH3 -CH=CH-2-pyridyl2552 -C(=O)CH3 -CH2CH=CH-5-Imid 2526-Cf=O)CH3 -CH=CH-3-pyridyl2553 -C(=O)CH3 -CH=CHCH2-cycPr 2527!-C(=0)CH3 -CH=CH-2-Fur 2554 -C(=O)CH3 -CH=CHCH2-2-Fur ~ ~ ~ I

f Table 2 cont.
Ex.# R1 'R2 Ex.#R1 R2 2601 -C(=0)CH2CH3n-butyl 2628-C(=O)CH2CH3-CH=CH-3-Fur 2602 -C(=0)CH2CH3benzyl 2629-C(=O)CH2CH3-CH=CH-2-Imid 2603 -C(=O)CH2CH3phenethyl 2630-C(=O)CH2CH3-CH=CH-S-Imid 2604 -C(=0)CH2CH3-CH2CH2-cycPr2631-C(=O)CH2CH3-CH2C~C-CH3 2605 -C(=0)CH2CH3-C~-CH3 2632-C(=O)CH2CH3-CH2C~-CF3 2606 -C(=0)CH2CH3-CSC-CF3 2633-C(=O)CH2CH3-CH2C~-Et 2607 -C(=O)CH2CH3-CaC-Et 2634-C(=O)CH2CH3-CH2CteC-iPr 2608 -C(=O)CH2CH3-C~-iPr 2635-C(=O)CH2CH3-CH2C~-cycPr 2609 -C(=O)CH2CH3-CSC-cycPr 2636-C(=O)CH2CH3-CH2C~C-CH=CH2 2610 -C(=O)CH2CH3-Cf=C-1-(Me)cycPr2637-C(=O)CH2CH3-CH2C~C-2-Fur 2611 -C(=O)CH2CH3-CffgC-CH=CH22638-C(=O)CH2CH3-CH2C$C-3-Fur 2612 -C(=O)CH2CH3-C~-C(=CH2)CH32639-C(=OICH2CH3-CH2CaC-2-Imid 2613 -C(=0)CH2CH3-CSC-2-pyridyl2640-C(=O)CH2CH3-CH2C~C-5-Imid 2614 -c(=O)CH2cH3-Cf~C-3-pyridyi2641-C(=o)cH2cH3-CH2cH=cH2 2615 -C(=0)CH2CH3-C$C-2-Fur '?r42-C(=O)CH2CH3-CH2CH=CH-CH3 2616 -C(=0)CH2CH3-CSC-3-Fur 2643-C(=O)CH2CH3-CH2CH=CH-CF3 2617 -C(=O)CH2CHg-CSC-2-Imid 2644-C(=O)CH2CH3-CH2CH=CH-Et 2618 -C(=0)CH2CH3-CsC-5-Imid 2645-C(=O)CH2CH3-CH2CH=CH-iPr 2619 -C(=0)CH2CH3-CH=CH-CH3 2646-C(=O)CH2CH3-CH2CH=CH-cycPr 2620 -C(=O)CH2CH3-CH=CH-CF3 2647-C(=0)CH2CH3-CH2CH=CHCH=CH2 2621 -C(=0)CH2CH3-CH=CH-Et 2648-C(=O)CH2CH3-CH2CH=C(CH3)2 2622 -C(=O)CH2CH3-CH=CH-iPr 2649-C(=O)CH2CH3-CH2CH=CH-2-Fur 2623 -C(=O)CH2CH3-CH=CH-cycPr 2650-C(=0)CH2CH3-CH2CH=CH-3-Fur 2624 -C(=O)CH2CH3-CH=CH-CH=CH22651-C(=O)CH2CH3-CH2CH=CH-2-Imid 2625 -C(=0)CH2CH3-CH=CH-2-pyridyl2652-C(=O)CH2CH3-CH2CH=CH-5-Imid 2626 -C(=0)CH2CH3-CH=CH-3-pyridyl2653-C(=O)CH2CH3-CH=CHCH2-cycPr 2627 -C(=0)CH2CH3-CH=CH-2-Fur 2654-C(=O)CH2CH3-CH=CHCH2-2-Fur ~yC 00~7g PCTNS99/14395 Table 2 cont.
Ex.# gl g2 Ex.# gl g2 2701 -C(=O)CH2cH2CH3n-butyl 2728 -C(~)CH2CH2CH3-CH=CH-3-Fur 2702 -C(~)CH2CH2CH3benzyl 2729 -C(=O)CH2CH2CH3-CH=CH-2-Imid 2703 -C(~)Cxacx2ctt3henethyl 2730 -C(~>C7i2CH2CH3-CH=CH-5-Imid 2704 -C(=o>a~2CH2CH3-CH2CH2-cycPr2731 -C(=O)CH2CH2cx3=CH2CgC-CH3 2705 -C(~)CHZCH2CH3-CSC-CH3 2732 -c(~l~igCH2CH3-CH2CsC-CF3 2706 -C(=O)c~2cx2cx3-~C-CF3 2733 -C(~)CEIZCH2CH3-CH2C~-Et 2707 -C(=o)c~IZCHZCHg-~C-Et 2734 -c(~)CH2c~I2CH3-CH2CsC-iPr 2708 -C(~)CH2CH2CH3-C~-iPr 2735 -C(~)CH2CH2c~3_CH2~_cycPr 2709 -C(~)CEI2CFt2CH3-CSC-cycPr 2736 -C(=0)CH2csi2C~i3-CH2C=C-CH=CH2 2710 -C(~)CH2CH2CH3-CeC-1-(Me)cYcPr2737 -C(~)CHZCH2CH3-CH2C~C-2-Fur 2711 -C(=O)CH2CFi2Ctt3-CSC-CH=CH2 2738 -C(~)cx2CH2CH3-CH2C=C-3-Fur 2712 -C(=olcxZCx2cx3-C!~-C(=CH2)CH32739 -c(~)CHaCH2CH3-CH2CC-2-amid 2713 -C(=O)CHZCH2CH3-CSC-2-pyridyl2740 -C(~)CH2Cf32CH3-CH2C~C-5-Imid 2714 -c(=o)CH2CH2CH3-C=C-3-pyridyl2741 -C(~)CH2CH2CH3-CH2CH=CH2 2715 -C(=O)CH2CH2CH3-C~-2-Fur 2742 -C(~>CHZCH2C~I3-CH2CH=CH-CH3 2716 -C(~)CH2CH2CH3-C~-3-Fur 2743 -C(~)CH2CH2CH3-CH2CH=CH-CF3 2717 -c(=o)cH2cH2cx3-C~-2-Imid 2744 -C(=O)CHgCS2cci3-CH2CH=CH-Et 2718 -C(=O)CH2CH2c~3-C=C-5-Imid 2745 -C(=O)CHZCH2CH3-CH2CH=CH-iPr 2719 -C(=O)CHZCH2CH3-CH=CH-CH3 2746 -C(=O)CHaCH2CH3-CH2CH=CH-cycPr 2720 -C(=O)CHZCH2CH3-CH=CH-CF3 2747 -C(~)CH2CH2CH3-CH2CH=CHCH=CH2 2721 -C(=O)CH2CH2CH3-CH=CH-Et 2748 -C(~)CH2Cii2CH3-CH2CH=C(CH3)2 2722 -C(~)CHZCH2CH3-CH=CH-iPr 2749 -C(~)CHaCH2CH3-CH2CH=CH-2-Fur 2723 -C(~)CH2CH2Qi3-CH=CH-cycPr2750 -C(~)CHyCH2CEi3-CH2CH=CH-3-Fur 2724 -C(~)Cli2Cti2CH3-CH=CH-CH=CH22751 -C(~)CH2CH2CH3-CH2CH=CH-2-Imid 2725 -C(~)CHZC~i2CH3-CH=CH-2-pyridyl2752 -C(~)CH2CH2CH3-CH2CH=CH-5-Imid 2726 -C(~)CH2CH2Cti3-CH=CH-3-pyridyl2753 -C(~)CH2CH2CA3-CH=CHCH2-cycPr 2727 -C(~)CH2CH2CH3-CH=CH-2-Fur2754 -C(~)CH2CH2CH3-CH=CHCH2-2-Fur Table 2 cont.
Ex.# Rl R2 Ex.~ I Rl ~- R2 2801 -C(=o)CH(cH3)2n-butyl 2828 -C(=0)CH(Cti3)2-CH=CH-3-Fur 2802 -C(~)CHICH3>2benzyl 2829 -C(~)CH(Cx3)2-CH=CH-2-Imid 2803 -C(~)CH(C1~3)2phenethyl 2830 -C(=o)CH(c~3)2-CH=CH-5-Imid 2804 -C(~)CH(CH;)2-CH2CH2-cycPr2831 -C(~)CH(CS3>2-CH2C~-CH3 2805 -C(=o)cH(cx3)2-CSC-cH3 2832 -C(=o)CH(Cx3>2-CH2C~-CF3 2806 -C(~)CH(CH3)2-CSC-CF3 2833 -C(~)c3i1CH3)2-CH2C~-Et 2807 -C(~)CH(Cx3)2-CaC-Et 2834 -C(~)CH(CH3)2-CH2C;C-iPr 2808 -C(=o)CH(cx3)2-C~-iPr 2835 -c(~)CH(CH;)2-CH2C~C-cycPr 2809 -C(~)CH(Cti3)2-C~-cycPr 2836 -C(=O)Cx(CH3)2-CH2C~C-CH=CH2 2810 -c(~)CH(CH3)2-CSC-1-(Me)cycPr2837 -C(=O)CH(CH3)2-CH2CsC-2-Fur 2811 -CI=0)CH(CH3)2-C~-CH=CH2 2838 -C(~)CH(CH3)2-CH2C~-3-Fur 2812 -C(=O)CH(CH3)2-CeC-C(=CH2)CH32839 -C(=O)CIi(CH3)2-CH2CC-2-Imid 2813 -C(~)CH(CH3)2-CaC-2-pyridyl2840 -C(~)CH(CH3)g-CH2C=C-5-Imid 2814 -C1~)CH(CH3)2-C~-3-pyridyl2841 -C(~)CH(Cti3)2-CH2CH=CH2 2815 -C(~)C8(CH3)2-CSC-2-Fur 2842 -C(~)CH(CH3)2 --~H2CH=CH-CH3 2816 -C(~)cxlc~i3)2-C~-3-Fur 2843 -C(~)CH(Cx3)2-CH2CH=CH-CF3 2817 -c(=0)CH(CH3)2-CSC-2-Imid 2844 -C(~)CH(CH3)2-CH2CH=CH-Et 2818 -C(~)CH(CHg)2-CaC-5-Imid 2845 -C(~)CH(CH3)2-CH2CH=CH-iPr 2819 -C(~)CH(CH3)2-CH=CH-CH3 2846 -C(~)CfiiCH3)2-CH2CH=CH-cycPr 2820 -C(=0)CH(CH3)2-CH=CH-CF3 2847 -C(~)CH(CH3)2-CH2CH=CHCH=CH2 2821 -C(~)CH(CH3)2-CH=CH-Et 2848 -C1~)C~IlCH3)2-CH2CH=C(CH3)2 2822 -c(~)CHICx3)2-CH=CH-iPr 2849 -C(~)Cx(C83)2-CH2CH=CH-2-Fur 2823 -C(~)CFI(CHg)2-CH=CH-cycPr2850 -C(~)CH(CH3)2-CH2CH=CH-3-Fur 2824 -C(~)CH(CH3)2-CH=CH-CH=CH22851 -CLO)CEi(CEI3)2-CH2CH=CH-2-Imid 2825 -C(=O)CH(CH3)2-CH=CH-2-pyridyl2852 -C(~)CFi(C~t312-CH2CH=CH-5-Imid 2926 -C(s0)CH(CH3)2-CH=CH-3-pyridyl2853 -C(~)CH(CH3)2-CH=CHCH2-cycPr 2827 -C(=O)Cx(CH3)2-CH=CH-2-Fur2854 -C(~)CH(CH3)2-CH=CHCH2-2-Fur Table 2 cont.
Ex.#R1 R2 Ex.# R1 R2 2901-C(=0)cycPrn-butyl 2928 -C(=O)cycPr-CH=CH-3-Fur 2902-C(=O)cycPrbenzyl 2929 -C(=0)cycPr-CH=CH-2-Imid 2903-C(=O)cycPrphenethyl 2930 -C(=O)cycPr-CH=CH-5-Imid 2904-C(=0)cycPr-CH2CH2-cycPr2931 -C(=O)cycPr-CH2C=-C-CH3 2905-C(=0)cycPr-C=-C-CH3 2932 -C(=O)cycPr-CH2C~C-CF3 2906-C(=O)cycPr-CSC-CF3 2933 -C(=O)cycPr-CH2C~-Et 2907-C(=O)cycPr-C-~-Et 2934 -C(=O)cycPr-CH2C~-iPr 2908-C(=0)cycPr-C'=C-iPr 2935 -C(=O)cycPr-CH2C~-cycPr 2909-C(=O)cycPr-C~-cycPr 2936 -C(=O)cycPr-CH2C~-CH=CH2 2910-C(=O)cycPr-C=C-1-(Me)cycPr2937 -C(=O)cycPr-CH2C~-2-Fur 2911-C(=0)cycPr-C=-C-CH=CH22938 -C(=O)cycPr-CH2C~-3-Fur 2912-C(=O)cycPr-CSC-C(=CH2)CH32939 -C(=O)cycPr-CH2C$C-2-Imid 2913-C(=O)cycPr-C-=C-2-pyridyl2940 -C(=O)cycPr-CH2C~C-5-Imid 2914.-C(=O)cycPr-CSC-3-pyridyl2941 -C(=O)cycPr-CH2CH=CH2 2915-C(=O)c;-r.Pr-C=C-2-Fur 2942 -C(=0)cycPr-CH2CH=CH-CH3 2916-C(=0)cycPr-C-=C-3-Fur 2943 -C(=O)cycPr-CH2CH=CH-CF3 2917-C(=0)cycPr-C=C-2-Imid 2944 -C(=0)cycPr-CH2CH=CH-Et 2918-C(=0)cycPr-C=C-5-/mid 2945 -C(=O)cycPr-CH2CH=CH-iPr 2919-C(=0)cycPr-CH=CH-CH3 2946 -C(=0)cycPr-CH2CH=CH-cycPr 2920-C(=O)cycPr-CH=CH-CF3 2947 -C(=O)cycPr-CH2CH=CHCH=CH2 2921-C(=O)cycPr-CH=CH-Et 2948 -C(=O)cycPr-CH2CH=C(CH3)2 2922-C(=O)cycPr-CH=CH-iPr 2949 -C(=O)cycPr-CH2CH=CH-2-Fur 2923-C(=O)cycPr-CH=CH-cycPr2950 -C(=O)cycPr-CH2CH=CH-3-Fur 2924-C(=O)cycPr-CH=CH-CH=CH22951 -C(=0)cycPr-CH2CH=CH-2-Imid 2925-C(=OcycPr -CH=CH-2-pyridyl2952 -C(=O)cycPr-CH2CH=CH-5-Imid 2926-C(=O)cycPr-CH=CH-3-pyridyl2953 -C(=0)cycPr-CH=CHCH2-cycPr 2927-C(=0)cycPr-CH=CH-2-Fur2954 -C(=O)cycPr-CH=CHCH2-2-Fur *Unless otherwise noted, stereochemistry is (+/-) and in R2 all double bonds are traps.

Table 3 i ~2 1 R2 Me i R2 1 R
Cl N ~ F N ~ O N ~ N
/ ~ CF3 ~ / ~ CF3 ~ / ~ CF3 ~ / ~ CF3 O ~ O ~ O ~ 0 a b c d C1 '"1 RZ F "1 R2 Oe a'1 RZ "1 F2 \ ~ CF3 ( \ ~ CF3 ~~i ~ ~ CF3 I '~ ~O F3 N ~ O N ~T O N ~ O N
f Q h C1 R1 R2 F Ri R2 Me C1 Ri R2 Me F R1 R2 N N a 1J No ~CF3 ! \ ~CF3 i ~ ~CF3 I ~CF3 N H O N ~,,~0 N ~ O N # O
to ~ j k 1 C1 Ri RZ F i R2 C1 R1 RZ F R1 RZ
C1 N C1 ~ F FF
\ ~ CF3 I ~ CF3 I ~ ~ CF3 I \ ~ CF3 N ~ 0 N ~T O N ~ 0 N ~ O
m a p Q
C1 Ni RZ F "'1 R2 oe Ni R2 "1 R
N / ~ CF3 N / ~ CF3 lN.~~ ~0 F3 N / ~O F3 ~ ° ~ °
r s t a C1 Ri R2 F R1 R2 Me C1 Ri RZ Me F R1 R2 N / ~ N \ ~ N / ~ N / ~O
O # O ~ O
v w x y C1 ~i R2 F R1 RZ ~1 Ra N / ~ CP; N ~ ~ CF3 N~\~ ~ CFg 0 ~ O ~ ~ O
z as bb Table 3 cont.
Ex.# R1 R2 4001 -CHZ-CH=CH2 n-butyl 4002 -CH2-CH=CH2 benzyl 4003 -CHz-CH=CH2 phenethyl 4004 -CHZ-CH=CH2 -CH2CH2-cycPr 4005 -CH2-CH=CH2 -CaC-CH3 4006 -CHZ-CH=CH2 -C---C-CF3 4007 -CH2-CH=CHZ -C-=C-Et 4008 -CH2-CH=CH2 -C=C-iPr 4009 -CH2-CH=CH2 -C=C-cycPr 4010 -CH2-CH=CH2 -C-=C-1-(Me)cycPr 4011 -CHZ-CH=CH2 -C---C-CH=CH2 4012 -CH2-CH=CH2 -CH=CH-CH3 4013 -CH2-CH=CH2 -CH=CH-CF3 4014 -CH2-CH=CH2 -CH=CH-Et 4015 -CH2-CH=CHZ -CH=CH-iPr 4016 -CH2-CH=CH2 -CH=CH-cycPr 4017 -Cii2-CH=CH2 -CH=CH-CH=CH2 4018 -CH2-CH=CH2 -CH2-C-_-C-CHg 4019 -CHZ-CH=CH2 -CHZ-C=C-CF3 4020 -CH2-CH=CHZ -CH2-C-C-Et 4021 -CH2-CH=CH2 -CH2-CSC-iPr 4022 -CH2-CH=CHZ -CH2-C---C-cycPr 4023 -CH2-CH=CH2 -CH2-C=C-CH=CH2 4024 -CH2-CH=CH2 -CH2-CH=CH2 4025 -CHZ_CH=CHZ -CHZ-CH=CH-CH3 4026 -CH2-CH CH2 -CH2-CH~Fi-CF3 4027 -CH2-CH=CH2 -CH2-CH=CH-Et 4028 -CH2-CH=CH2 -CH2-CH~:H-iPr 4029 -CH2-CH--CHZ -CH2-CH=CH-cycPr 4030 -CH2-CH=CH2 -CH2-CH=CH-CH=CH2 403 1 -CHZ-CH=CH2 -CH2-CH=C(CH3)2 WO 00!00478 PC'TNS99/14395 4032 -CH2-CH=CH2 -CH=CH-CH2-cycPr 4033 -CH2-CH=CH2 n-butyl 4034 -CH2-cycPr benzyl 4035 -CH2-cycPr phenethyl 4036 -CH2-cycPr -CH2CH2-cycPr 4037 -CH2-cycPr -CSC-CH3 4038 -CH2-cycPr -C---C-CF3 4039 -CH2-cycPr -CSC-Et 4040 -CH2-cycPr -C-~-ipr 4041 -CH2-cycPr -CSC-cycPr 4042 -CH2-cycPr -C--C-1-(Me)cycPr 4043 -CH2-cycPr -C--=C-CH=CH2 4044 -CHZ-cycPr -CH=CH-CH3 4045 -CH2-cycPr -CH=CH-CF3 4046 -CH2-cycPr -CH=CH-Et 4047 -CHZ-cycPr -CH=CH-iPr 4048 -CH2-cycPr -CH=CH-cycPr 4049 -CH2-cycPr _ 4050 -CH2-cycPr -CH2_C~C-CH3 4051 -CH2-cycPr -CH2-C=C-CF3 4052 -CH2-cycPr -CH2-CSC-Et 4053 -CH2-cycPr -CH2-C=C-iPr 4054 -CH2-cycPr -CH2-C-~C-cycPr 4055 -CHZ-cycPr -CHZ-CSC-CH=CH2 4056 -CH2-cycPr -CH2-CH=CHZ

4057 -CH2-cycPr -CH2-CH=CH-CH3 4058 -CH2-cycPr -CH2-CH=CH-CF3 4059 -CH2-cycPr -CH2-CH=CH-Et 4060 -CH2-cycPr -CH2-CH--CH-iPr 4061 -CHZ-cycPr -CH2-CH=CH-cycPr 4062 -CH2-cycPr -CH2-CHI-CH=CH2 4063 -CH2-cycPr -CH2-CH=C(CH3)2 4064 -CH2-cycPr -CH=CH-CH2-cycPr 4065 -C02CH2CH3 n-butyl 4066 -C02CH2CH3 benzyl 4067 -C02CH2CH3 phenethyl 4068 -C02CH2CH3 -CHZCH2-cycPr 4069 -COZCHZCH3 -C=C-CH3 4070 -C02CH2CH3 -C-=C-CF3 4071 -C02CH2CH3 -~C-Et 4072 -C02CH2CH3 -~C-iPr 4073 -COZCH2CH3 -C~-cycPr 4074 -C02CH2CH3 -C~-1-(Me)cycPr 4075 -C02CH2CH3 -C.C-CH=CH2 4076 -COZCH2CH3 -CH=CH-CH3 4077 -C02CH2CH3 -CH=CH-CF3 4078 -C02CH2CH3 -CH=CH-Et 4079 -C02CH2CH3 -CH=CH-iPr 4080 -C02CH2CH3 -CH=CH-cycPr 4081 -C02CH2CH3 -CH=CH-CH=CH2 4082 -C02CH2CH3 -CH2-C-=C-CH3 4084 -COzCH2CH3 -CHZ-C=C-Et 4085 -C02CH2CH3 -CH2-C-d-iPr 4086 -C02CHZCH3 -CHZ-C~-cycPr 4087 -C02CHZCH3 -CH2-C=-C-CH=CH2 4089 -C02CH2CH3 -CH2-CH=CH-CH3 4090 -C02CH2CH3 -CHZ-CH=CH-CF3 4091 -C02CHZCH3 -CHZ-CH--CH-Et 4092 -C02CH2CH3 -CH2_~~H-iPr 4093 -C02CH2CH3 -CH2_~~-cycPr 4094 -C02CH2CH3 -CH2-CH=CH-CH=CHZ

4095 -COZCH2CH3 -CH2-CH--C(CH3)2 4096 -COZCH2CH3 -CH=CH-CH2-cycPr 4097 -C02CH(CH3)2 n-butyl 4098 -C02CH(CH3)2 benzyl 4099 -C02CH(CH3)2 phenethyl 4101 -C02CH(CH3)2 -CH2CH2-cycPr 4102 -C02CH(CH3)2 -CSC-CH3 4103 -CO2CH(CH3)2 -C$C-CF3 4104 -C02CH(CH3)2 -C=-C-Et 4105 -C02CH(CH3)2 -~-iPr 4106 -C02CH(CH3)2 -~-cycPr 4107 -CO2CH(CH3)2 -C=C-1-(Me)cycPr 4108 -C02CH ( CH3 ) -~-~=~2 4109 -C02CH(CH3)2 -CH=CH-CH3 4110 -C02CH(CH3)2 -CH=CH-CF3 4111 -C02CH(CHg)2 -CH=CH-Et 4112 -C02CH(CH3)2 -CH=CH-iPr 4113 -C02CH(CH3)2 -CH=CH-cycPr 4114 -C02CH(CH3)2 -CH=CH-CH=CH2 4115 -C02CH(CH3)2 -CH2-C=C-CH3 4116 -C02CH(CH3)2 -CH2-C$C-CF3 4117 -C02CH(CH3)2 -CH2-C=C-Et 4118 -C02CH(CH3)2 -CH2-C~C-iPr 4119 -CO2CH(CH3)2 -CH2-C=C-cycPr 4120 -C02CH(CH3)2 -CH2-CSC-CH=CH2 4121 -C02CH(CH3)2 -CH2-CH=CH2 4122 -CO2CH(CH3)2 -CH2-CH=CH-CH3 4123 -C02CH (CH3 ) 2 -CH2-CH~Fi-CF3 4124 -C02CH(CH3)2 -CH2-CH=CH-Et 4125 -C02CH(CH3)2 -CH2-CH=CH-iPr 4126 -CO2CH(CH3)2 -CH2-CH=CH-cycPr 4127 -C02CH (CH3 ) 2 -CH2-CH~FI-CH=CH2 4128 -CO2CH(CH3)2 -CH2-CH=C(CH3)2 4129 -C02CH(CH3)2 -CH=CH-CH2-cycPr 4130 -CO2C(=CH2)CH3 n-butyl 4131 -C02C(=CH2)CH3 benzyl 4132 -CO2C(=CH2)CH3 phenethyl 4133 -C02C(=CH2)CH3 -CH2CH2-cycPr 4134 -C02C(=CH2)CH3 4135 -C02C(=CH2)CH3 -C=C-CF3 4136 -C02C(=CH2)CH3 -C=C-Et 4137 -C02C(=CH2)CH3 -~C-iPr 4138 -C02C(=CH2)CH3 -C._C-cycPr 4139 -C02C(=CHZ)CH3 -C~-1-(Me)cycPr 4140 -C02C(=CH2)CH3 -~C-CH=CH2 4141 -C02C(=CH2)CH3 -CH--CH-CH3 4142 -COZC(=CH2)CH3 -CH=CH-CF3 4143 -COZC(=CH2)CH3 -CH=CH-Et 4144 -C02C(=CH2)CH3 -CH=CH-iPr 4145 -C02C(=CHZ)CH3 -CH--CH-cycPr 4146 -COZC(=CH2)CH3 -CH=CH-CH=CHZ

4147 -C02C(=CH2)CH3 -CH2-CSC-CH3 4148 -COZC(=CH2)CH3 -CH2-~C-CF3 4149 -C02C(=CH2)CH3 -CHZ_CsC-Et 4150 -C02C(=CHZ)CH3 -CH2-CSC-iPr 4151 -C02C(=CH2)CH3 -CHZ-~-cycPr 4152 -C02C(=CH2)CH3 -CH2-C-~-CH=CH2 4153 -C02C(=CH2)CH3 -CH2-CH=CHZ

4154 -C02C(=CH2)CH3 -CH2-CH=CH-CH3 4155 -C02C(=CH2)CH3 -CH2-CH=CH-CF3 4156 -C02C(=CH2)CH3 -CH2-CH=CH-Et 4157 -C02C(=CH2)CH3 -CH2-CH=CH-iPr 4158 -C02C(=CH2)CH3 -CH2-CH=CH-cycPr 4159 -COzC(=CHZ)CH3 -CHZ-CH--CH-CH=CH2 4160 -C02C(=CH2)CH3 -~2-CH=C(CH3)2 4161 -C02C(=CH2)CH3 -CH=CH-CHZ-cycPr 4162 -C(=0)-cycPr n-butyl 4163 -C(=O)-cycPr benzyl 4164 -C(=O)-cycPr phenethyl 4165 -C(=O)-cycPr -CH2CH2-cycPr 4166 -C(=O)-cycPr _ 4167 -C(=O)-cycPr -~-CF3 4168 -C (=O) -cycPr -~C-Et WO 00/00478 PC'f/US99/14395 4169 -C(=0)-cycPr -CSC-iPr 4170 -C(=0)-cycPr -C._C-cycPr 4171 -C(=O)-cycPr -C=-C-1-(Me)cycPr 4172 -C(=0)-cycPr -CSC-CH=GH2 4173 -C(=0)-cycPr -CH=CH-CH3 4174 -C (=O) -cycPr -CH~Ii-CF3 4175 -C (=O) -cycPr -~=~-Et 4176 -C(=O)-cycPr -CH=CH-iPr 4177 -C(=O)-cycPr -~~-cycpr 4178 -C(=0)-cycPr -~~-CH=CH2 4179 -C(=0)-cycPr -CH2_~C_CH3 4180 -C(=O)-cycPr -CH2-C._C-CF3 4181 -C(=0)-cycPr -CHz-CSC-Et 4182 -C(=O)-cycPr -CH2-C=_C-iPr 4183 -C(=O)-cycPr -CH2-CSC-cycPr 4184 -C(=O)-cycPr -CH2-CSC-CH=CH2 4185 -C(=O)-cycPr -CH2-CH=CH2 4286 -C(=O)-cycPr -CH2-CH=CH-CH3 4187 -C(=O)-cycPr -CH2-CH=CH-CF3 4188 -C(=O)-cycPr -CH2-CH=CH-Et 4189 -C(=0)-cycPr -CH2-CH=CH-iPr 4190 -C(=0)-cycPr -CH2-CH=CH-cycPr 4191 -C(=0)-cycPr -CH2-CH=CH-CH=CH2 4192 -C(=0)-cycPr -CH2-CH=C(CH3)2 4193 -C(=0)-cycPr -CH=CH-CH2-cycPr *Unlessotherwise noted, stereochemistry is (+/-) and in R2, all double bonds are trans.

Utilitv The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV
inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV
infection and associated diseases. The compounds of formula (I) 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 (I) 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 HN 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 would be indicative of the presence of HIV reverse transcriptase and HIV virus.
As used herein "ug" denotes microgram, "mg" denotes milligram, "g" denotes gram, "uL" denotes microliter, "mL"
denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "uM" denotes micromolar, "mM" denotes millimolar, "r" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, MO.
HIV RNA Assav DNA Plasmids and in vitro RNA transcriptss Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 2989, 5, 577. The plasmid was linearized with Bam 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 extrac.:ion, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at -70°C. The concentration of RNA was determined from the A26o.
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 3') 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 H~2.
Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, CA.).
The pol reporter probe (5' CTGTCTTACTTTGATAAAACCTC 3') was complementary to nucleotides 2403-2425 of HX82. The gag WO 00!00478 PCT/US99/14395 reporter probe (5' CCCAGTATTTGTCTACAGCCTTCT 3') was complementary to nucleotides 950-973 of H~2. 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 1984, 12, 387). The reporter probes were prepared as 0.5 ~.iM
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 uM stocks in water.
Streptavidin coated nla-PS:
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 10% FC5 for MT-4 cells, 2 mM z-glutamine and 50 ug/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 ~..alls and stored as aliquots at -70°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 106/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°C.
HIV Rt~lA 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 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°C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 uL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe aad 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 20.) 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 ul 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°C, the plate was again washed 6 times.
Immobilized alkaline phosphatase activity was detected by addition of 100 uL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific, in buffer 8(2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl2, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37°C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.
~~»~~rP based compound evaluation in HIV-l infected MT-2 Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum I7~fS0 concentration of 2%. 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 uL) 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°C in a COz incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 uL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 uL.
Eight wells per plate were left uninfected with 50 uL 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 uL of medium/well was removed from the HIV infected plates. Thirty seven uL 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 uL of this diluted mixture was transferred to~a strept;,ridin 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 ICgp value (concentration of compound required to reduce the HIV RNA
level by 90~) for dideoxycytidine (ddC) of 0.2 ug/mL. ICgp values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (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, ICgo 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 IC9o for ddC, determined in each assay run, should be between 0.1 and 0.3 ug/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 IC9p was found to be less than 20~.iM.
Compounds of the present invention have been found to have an ICgp less than 20uPt.
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 w~oPette.
HTV-1 RT Assay Materials and Methods This assay measures HIV-1 RT RNA dependent DNA
polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:
Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.
Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAF) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Read:
The template primer Poly (rA) oligo (dT)12-18 and dTTP
were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/ml and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 ul/aliquot, dTTP at 9 ul/aliquot) and frozen at -20 C.
The 3H dTTP (2.5 mCi/ml in 10 mM Tricine at pH 7.6;
specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 ul in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50~
glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 ul/microfuge tube (58 uCi) and frozen at -20 C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT
buffer (80 mM KC1, 50 mM Tris HC1, 12 mM MgCl2, 1 mM DTT, 50 pM EGTA, 5 mg/ml BSA, 0.01 Triton-X 100, pH 8.2) and aliquoted at 10 ul/microfuge tube (10 Units/10 ul). One aliquot (enough for a assays) was diluted further to 10 Units/100 ul and aliquoted into 8 tubes (1.25 Units/12.5 ul).
All aliquots were frozen at -70 C.
The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 Eun pore size diethyl amino ethyl cellulose (DEAF) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 ul /well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.
HIV-1 RT Assav:
The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was WO 00/004'78 PCT/US99/14395 diluted with RT buffer (containing 5 mg/ml BSA) to a concentration of 0.05 Units/10 ul or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/ml respectively. The inhibitor and substrate mixture were diluted With RT buffer containing no HSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at -20 C after use. A
Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 uM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 uM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 uM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 ~,iM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 ug/ml of Poly (rA) oligo (dT)12-18 and 12.5 ~tM of dTTP
(58 pCi 3H dTTP). The final substrate concentrations were 2.5 ug/ml and 5 P.M respectively.
Using the Beckman Instruments Biomek robot, 10 ul of HIV-1 RT was combined with 20 ul of inhibitor in a 96 well U
bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 ul of the substrate mixture was added to each well to initiate the reaction (total volume was 50 ul). The reactions were incubated at 37 C and terminated after 45 minutes.
For method 1, 200 ul of an ice-cold solution of 13%
trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 ml/wash) with 1 N HC1 and 10 mM
sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 ml of Beckman Ready Flow III

scintillant was added, and the vials were counted for radioactivity for 1 minute.
For method 2, the assay was terminated with the addition of 175 ul/well of 50 mM EDTA at pH 8Ø Then 180 ul of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAF filter disks. Each well was washed 3 times with 200 ul of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8Ø 50 ul of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.
The ICSp values are calculated with the equation:
ICSp = [Inh]/(1/fractional activity - 1);
where the fractional activity = RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the ICSp values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The ICSp values in this range (generally 2 values) were averaged. A compound was considered active if its ICSp was found to be less than 60u1K.
Compounds of the present invention have been found to have an ICSO less than 60uM.
~roteinBindina 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 l~IRTIs 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-1-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 (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound 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-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 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.

Dosaae 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, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with 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 Z5 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.
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-fozins 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, 50 mg of cellulose, and 6 mg magnesium stearic.
.loft Gelatin Cag~g~
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, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.
Appropriate coatings may be applied to increase palatability or delay absorption.
Suspension 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, U.S.P., and 0.025 mg of vanillin.
Injectable 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 conanonly used techniques.
Combination of comDOnen (a) 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 (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.
Components (a) and (b) 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 (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the revserse order. If component (b) contains more that one agent, e.g:, one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order.
When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) 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 (b) 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 (a) and (b) 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 (b) 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 (b).
By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80$ 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.
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 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 release polymer, 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 (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b) .

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 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 force 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 (a) and one or more compounds of component (b), 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 (a) and component (b) 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 (a) and component (b), 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, 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.

Claims (18)

WHAT IS CLAIMED AS NEW AND DESIRED TO BE SECURED BY LETTER
PATENT OF UNITED STATES IS;

1. A compound of Formula (I):
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is O or S;
W is N or CR3 ;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
C f is cyclopropyl or C1-3 alkyl substituted with 3-7 halogen;
provided that the number of W, X, Y, and Z which are N, is zero, one or two;
R1 is selected from:
-CO2R12, -COR12, -SO2R12, -SOR12, -CONHR12, -(CHR7)p CHR7R8, - (CHR7)p pCH=CR7R8 , -(CHR7)p C~C-R8, -C1-6 alkyl substituted with 0-3 R11, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R2 is selected from:

-CH=CR7R8, -C~C-R8, -CH=CHCHR7R8, -(CHR7)pCHR7R8, -(CHR7)pCH=CR7R8, -(CHR7)pC~C-R8, -C1-4 alkyl substituted with 0-3 R11, -(CH2)pphenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R3 is selected from:
H, F, Cl, Br, I, -OH, OCF3, -CN, NO2, CHO, C(=O)CH3, C(=O)CF3, C(=O)NH2. C(=O)NHCH3, NR7R7a, NR7C (=O ) OR7b , C (=O ) OR7 , SR7 , S (=O ) R7 , SO2R7 , SO2NHR7 , NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10 R4 is selected from:
H, F, Cl, Br, I, -OH, OCF3, -CN, NO2, CHO, C (=O) CH3, C (=O)CF3, C (=0)NH2, C (=O)NHCH3, NR7R7a, NR7C (=O) OR7b, C (=O) OR7, SR7, S (=O) R7, SO2R7, SO2NHR7, NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;

alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring, said carbocyclic ring being aromatic or nonaromatic, said carbocyclic ring being substituted with 0-2 R10;
alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms atoms selected from the group consisting of N, O, and S, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 R10;
R5 is selected from H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to ~rm a 5-7 membered carbocyclic ring, said carbocyclic ring being aromatic or nonaromatic, said carbocyclic ring being substituted with 0-2 R10;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms atoms selected from the group consisting of N, O, and S, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 R10;
R6 is selected from:
H, OH, F, Cl, Br, I, OCF3, -CN, NO2, CHO, C(=O)CH3, C(=O)CF3, C(=O)NH2, C(=O)NHCH3, NR7R7a, NR7C(=O)OR7b, C(=O)OR7, SR7, S(=O)R7, SO2R7, SO2NHR7, NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R7, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R7b, at each occurrence, is methyl, ethyl, propyl, or butyl;
R8, at each occurrence, is selected from:
H, F, Cl, Br, I, CH(-OCH2CH2O-), C1-4 haloalkyl, C1-6 alkyl substituted wit~ 0-3 R11, C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R10, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, CN, NR7R7a, and C (=O) CH3;
R11, at each occurrence, is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(=O)CH3, C(=O)NH2;

R12, at each occurrence, is selected from C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10, -(CH2)p phenyl substituted with 0-2 R10, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, 2, and 3;
provided, if, simultaneously, each of W, X, Y, and Z are carbon, then R2 is not unsubstituted C1-4 alkyl.

2. A compound according to Claim 1 of Formula (II):
wherein:
A is O or S;
C f is -CF3, -CF2CF3, or -CF2CF2CF3;
R1 is selected from:
-CO2R12 , -COR12 , -SO2R12 , -SOR12 , -CONHR12, - (CHR7) pCHR7R8, - (CHR7)p CH=CR7R8, - (CHR7)pC~C-R8, - C1-6 alkyl substituted with 0-3 R11 - (CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R2 is selected from:
-CH=CR7R8, -C~C-R8, -CH=CHCHR7R8, -(CHR7)pCHR7R8, -(CHR7)pCH=CR7R8, -(CHR7)pC~C-R8, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R3 is selected from:
H, F, Cl, Br, I, -OH, OCF3, -CN, NO2, CHO, C (=O) CH3, C(=O)CF3, C(=O)NH2, C(=O)NHCH3, NR7R7a, NR7C(=O)OR7b, C(=O)OR7, SR7, S(=O)R7, SO2R7, SO2NHR7, NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11 C2-3 alkenyl, C2-3 alkynyl, C1-3 alkox~, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R4 is selected from:
H, F, Cl, Br, I, -OH, OCF3, -CN, NO2, CHO, C(=O)CH3, C(=O)CF3, C(=O)NH2, C(=O)NHCH3, NR7R7a, NR7C(=O)OR7b, C(=O)OR7, SR7, S(=O)R7, SO2R7, SO2NHR7, NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-, -O-CH2-CH2-O-, or -CH=CH-CH=CH-;
R5 is selected from H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-, -O-CH2-CH2-O-, or -CH=CH-CH=CH-;
R6 is selected from:
H, OH, F, Cl, Br, I, OCF3, -CN, NO2, CHO, C(=O)CH3, C(=O)CF3, C(=O)NH2, C (=O)NHCH3, NR7R7a, NR7C(=O)OR7b, C(=O)OR7, SR7, S(=O)R7, SO2R7, SO2~ R7, NR7SO2R7b, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R7, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;;
R7b, at each occurrence, is methyl, ethyl, propyl, or butyl;

R8, at each occurrence, is selected from:
H, F, Cl, Br, I, CH(-OCH2CH2O-), C1-4 haloalkyl, C1-6 alkyl substituted with 0-3 R11, C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R10, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, CN, NR7R7a, and C(=O)CH3;
R11, at each occurrence, is selected from OR7, CN, F, C1, Br, I, N02. NR7R7a, CHO, C (=O)CH3, C(=O)NH2;
R12, at each occurrence, is selected from C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10 -(CH2)p phenyl substituted with 0-2 R10, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, 2, and 3.

3. A compound according to Claim 2, wherein:

A is O or S;
C f is -CF3, -CF2CF3, or -CF2CF2CF3;
R1 is selected from:
-CO2R12, -COR12, -SO2R12, -SOR12, -CONHR12, - (CHR7)p CHR7R8, - (CHR7)p CH=CR7R8, - (CHR7)p C~C-R8, -C1-5 alkyl substituted with 0-3 R11, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R2 is selected from:
-CH=CR7R8, -C~C-R8, -CH=CHCHR7R8, -(CHR7)p CHR7R8, -(CHR7)p CH=CR7R8, -(CHR7)p C~C-R8, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R3 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3. -SCH3, -S(=O)CH3, -SO2CH3, -SO2NHCH3, -NHSO2CH3, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, R4 is selected from:
H, F, Cl, Br, I, -OH, OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -C(=O)NH2. -C(=O)NHCH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2. -N(CH2CH3)2, -NHC(=O)OCH3, -NHC(=O)OCH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3, -S(=O)CH2CH3, -SO2H, -SO2CH3, -SO2CH2CH3, -SO2NHCH3, -SO2NHCH2CH3, -NHSO2CH3, -NHSO2CH2CH3, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, alternatively, R3 and R4, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-, -O-CH2-CH2-O-, or -CH=CH-CH=CH-;
R5 is selected from H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
alternatively, R4 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form -O-CH2-O-, -O-CH2-CH2-O-, or -CH=CH-CH=CH-;
R6 is selected from:
H, F, C1, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C (=O) CF3 , -C (=O)NH2, -C (=O) NHCH3 , -NH2 , -NHCH3 , -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -SCH3, -S(=O)CH3, -SO2CH3, -SO2NHCH3, -NHSO2CH3, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, R7, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;;
R8, at each occurrence, is selected from:

H, F, C, Br, I, CH(-OCH2CH2O-), C1-4 haloalkyl, C1-6 alkyl substituted with 0-3 R11 C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R10, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, CN, NR7R7a, and C (=O) CH3;
R11, at each occurrence, is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(=O)CH3, C(=O)NH2;
R12, at each occurrence, is selected from C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10, -(CH2)p phenyl substituted with 0-2 R10, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, 2, and 3.

4. A compound according to Claim 3, wherein:
A is O;

C f is -CF3 or -CF2CF3;
R1 is selected from:
-CO2R12, -COR12 , -SO2R12, -(CHR7) p CHR7R8, -(CHR7)p CH=CR7R8, - (CHR7) p C~C-R8, -C1-5 alkyl substituted with 0-3 R11, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R2 is selected from:
-CH=CR7R8, -C~C-R8, -CH=CHCHR7R8, -(CHR7)p CHR7R8, -(CHR7)p CH=CR7R8, -(CHR7)p C~C-R8, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R3 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2. -CHO. -C(=O)CH3, -C(=O) CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3, R4 is selected from:
H, F, Cl, Br, I, -OH, OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3. -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -CF3, -CH3, -CH2CH3. -OCH3, and -OCH2CH3;
R5 is selected from H, F, Cl, Br, I, -OH, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R6 is selected from:

H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R7, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R8, at each occurrence, is selected from:
H, F, Cl, Br, I, CH(-OCH2CH2O-), C1-4 haloalkyl, C1-4 alkyl substituted with 0-3 R11, alkenyl, C3-6 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R10, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and C(=O)CH3;
R11, at each occurrence, is selected from OR7, CN, F, Cl, Br, I, NO2, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, CHO. C(=O)CH3, C(=O) NH2;
R12, at each occurrence, is selected from C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl, -(CH2)pphenyl substituted with 0-2 R10, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, and 2.

5. A compound according to Claim 4 of Formula (III) wherein:
R1 is selected from:
-CF3, -CF2H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2C(CH3)3, -CH2CH2CH(CH3)CH3, -CH(=CH2)CH3, -CH2CH=CH2, -CH2-CH=C(CH3)2, -CH2-C-CH, -CH2-C~CCH3, -CH2Ph, -cycPr, -CH2cycPr, -CH2CH2cycPr, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, -CO2CH2CH2CH2CH3, -CO2CH(CH3)2, -CO2CH2CH(CH3)2, -CO2CH2Ph, -CO2cycPr, -CO2CH2cycPr, -CO2CH2CH=CH2, -SO2CH2CH3, -SO2CH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2, and -COCH2cycPr;
R2 is selected from:
benzyl, phenethyl, -CH2CH2cycPr, -C~C-CH3, -C~C-CF3, -C~C-Et, -C~C-iPr, -C~SC-cycPr, -C~C-1-(CH3)cycPr, -C~C-CH=CH2, -C~C-C(=CH2)CH3, -CH=CH-CH3, -CH=CH-CF3, -CH=CH-Et, -CH~CH-iPr, -CH=CH-cycPr, -CH=CH-CH=CH2, -CH2-C~C-CH3, -CH2-C~C-CF3, -CH2-C~C-Et, -CH2-C~C-iPr, -CH2-C~C-cycPr, -CH2-C~C-CH=CH2, -CH2-CH=CH2, -CH2-CH=CH-CH3, -CH2-CH=CH-CF3, -CH2-CH=CH-Et, -CH2-CH=CH-iPr, -CH2-CH=CH-cycPr, -CH2-CH=CH-CH=CH2, -CH2-CH=C(CH3)2, and -CH=CH-CH2-cycPr;
R3 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -C(=O)CH3, -C(=O)CF3, -NH2. -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3. -OCH3, and -OCH2CH3, R4 is selected from:
H, F, Cl, Br, I, -OH, OH, -OCF3, -CN, -NO2, -C(=O)CH3, -C(=O)CF3, -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R3 is selected from H, F, and Cl; and R6 is selected from:
H, F, Cl -OH, -OCF3, -CF3, -CH3, and -OCH3.

6. A compound according to Claim 2, wherein the compound is selected from:
4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(methyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(methyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
3-(allyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-guinoxalin-2(1H)-one;
4-(benzyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylmethyl)-3-(allyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(propargyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(allyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(cyclopropylmethyl)-3-(n-butyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

6-(chloro)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(isobutyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(cyclopropylmethyl)-3-(phenethyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(allyl)-3-(phenethyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(methoxy)-4-(cyclopropylmethyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(methoxy)-4-(allyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl; ~,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylmethyl)-3-(1-propynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(allyl)-3-(1-propynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(propen-2-yl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isobutoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(n-butoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(allyloxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(benzyloxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(n-propylsulfonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(phenylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(neopentyl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(2-propynyl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(cyclopropylcarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(ethylsulfonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
4-(isopropylsulfonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;

4-(methoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(chloro)-4-(propen-2-yl-oxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(2H)-one;
6-(fluoro)-4-(ethoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one;
6-(fluoro)-4-(isopropoxycarbonyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one; and 6-(fluoro)-4-(propen-2-yl-oxycarboxyl)-3-(2-cyclopropylethynyl)-3-(trifluoromethyl)-3,4-dihydro-quinoxalin-2(1H)-one.

7. A compound according to Claim 1 of Formula (IIb), wherein:
A is O or S;
W is N or CR3;
X is N or CR4;

Y is N or CR5 Z is N or CR6;
C f is -CF3-, -CF2CF3, or -CF2CF2CF3;
provided that one or two of W, X, Y, and Z are N;
R1 is selected from:
-CO2R12, -COR12, -SO2R12, -(CHR7)pCHR7R8, -(CHR7)pCH=CR7R8, -(CHR7)pC~C-R8, -C1-5 alkyl substituted with 0-3 R11, -(CH2)pphenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R2 is selected from:
-CH=CR7R8, -C~C-R8, -CH=CHCHR7R8, -(CHR7)pCHR7R8.
-(CHR7)pCH=CR7R8, -(CHR7)pC~C-R8, -(CH2)p phenyl substituted with 0-3 R10, and -(CH2)p(C3-5 cycloalkyl);
R3 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3, R4 is selected from:
H, F, Cl, Br, I, -OH, OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;

R5 is selected from H, F, Cl, Br, I, -OH, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R6 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -CHO, -C(=O)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3. -CH3, -CH2CH3, -OCH3. and -OCH2CH3;
R7, at each occurrence, is selected from H, methyl, ethyl, propyl, and butyl;
R8, at each occurrence, is selected from:
H. F. Cl, Br. I, CH(-OCH2CH2O-), C1-4 haloalkyl, C1-4 alkyl substituted with 0-3 R11, C2-4 alkenyl, C3-6 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting of pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl;
R9, at each occurrence, is selected from D, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, and F;
R10, at each occurrence, is selected from OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, CN, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and C(=O)CH3;
R11, at each occurrence, is selected from OR7, CN, F, Cl, Br, I. NO2, -NH2. -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, CHO, C (=O) CH3, C (=O) NH2;
R12, at each occurrence, is selected from C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-3 heteroatoms selected from the group consisting pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl, -(CH2)p phenyl substituted with 0-2 R10, and -(CH2)p(C3-5 cycloalkyl); and p, at each occurrence, is selected from 0, 1, and 2.

8. A compound according to Claim 7 of Formula (IIIb) wherein:
R1 is selected from:
-CF3, -CF2H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2C(CH3)3, -CH2CH2CH(CH3)CH3, -CH(=CH2)CH3, -CH2CH=CH2, -CH2-CH=C(CH3)2, -CH2-C~CH, -CH2-C~CCH3, -CH2Ph, -cycPr, -CH2cycPr, -CH2CH2cycPr, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3. -CO2CH2CH2CH2CH3, -CO2CH(CH3)2, -CO2CH2CH(CH3)2, -CO2CH2Ph, -CO2cycPr, -CO2CH2cycPr, -CO2CH2CH=CH2, -SO2CH2CH3, -SO2CH(CH3)2, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2, and -COCH2cycPr;
R2 is selected from:
benzyl, phenethyl, -CH2CH2cycPr, -C~C-CH3, -C~C-CF3, -C~C-Et, -C~C-iPr, -C~C-cycPr, -C~C-1-(CH3)cycPr, -C~C-CH=CH2, -C~C-C(=CH2)CH3, -CH=CH-CH3, -CH=CH-CF3, -CH=CH-Et, -CH=CH-iPr, -CH=CH-cycPr, -CH~H-CH=CH2, -CH2-C~C-CH3, -CH2-C~C-CF3, -CH2-C~C-Et, -CH2-C~C-iPr, -CH2-C~C-cycPr, -CH2-C~C-CH=CH2, -CH2-CH=CH2, -CH2-CH=CH-CH3, -CH2-CH=CH-CF3, -CH2-CH~CH-Et, -CH2-CH=CH-iPr, -CH2-CH=CH-cycPr, -CH2-CH=CH-CH=CH2, -CH2-CH=C(CH3)2, and -CH=CH-CH2-cycPr;
R3 is selected from:
H, F, Cl, Br, I, -OH, -OCF3, -CN, -NO2, -C(=O)CH3, -C(=O)CF3, -NH2, -NHCH3, -N(CH3)2, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3, R4 is selected from:
H, F, Cl, Br, I, -OH, OH, -OCF3, -CN, -NO2, -C(=O)CH3, -C(=O)CF3, -C(=O)NH2, -C(=O)NHCH3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)OCH3, -C(=O)OCH3, -CF3, -CH3, -CH2CH3, -OCH3, and -OCH2CH3;
R5 is selected from H, F, and Cl; and R6 is selected from:
H, F, Cl -OH, -OCF3, -CF3, -CH3, and -OCH3.

9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to one of Claims 1-8.

10. A method for treating HIV infection, comprising:
administering to a host in need of such treatment a therapeutically effective amount of a compound according to one of Claims 1-8, or a pharmaceutically acceptable salt form thereof.

11. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound according to one of Claims 1-8; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV
protease inhibitors.

12. A method according to Claim 11, wherein, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

13. A method according to Claim 11, wherein, the HIV
reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, efavirenz, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

14. A method according to Claim 13, wherein the HIV
reverse transcriptase inhibitor is selected from AZT, rescriptor, efavirenz, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

15. A method according to Claim 14, wherein, the HIV
reverse transcriptase inhibitor is AZT.

16. A method according to Claim 14, wherein, the HIV
reverse transcriptase inhibitor is efavirenz.

17. A method according to Claim 14, wherein, the protease inhibitor is indinavir.

18. A compound according to Claim 1 of Formula (Ia) or (Ib) or a stereoisomer or pharmaceutically acceptable salt form thereof.