CA2156420A1 - Inhibitors of hiv reverse transcriptase - Google Patents

Abstract

Novel indole compounds inhibit HIV reverse transcriptase, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Description

WO 94/19321 215 ~ ~ 2 ~ PCT/US94/01694 TITLE OF THE INVENTION
IN~BITORS OF HIV REVERSE TRANSCRIPTASE

s This application is a continuation-in-part of co-pending application U.S. Serial No. 07/866,765 filed April 9, 1992, which itself is a continuation-in-part of application U.S. Serial No. 07/832,260 filed February 7, 1992 and now ~b~ndoned, which itself was a contiml~tion-in-part of application U.S. Serial No. 07/756,013, filed September 6, 1991, now ~b~n~iQned.
The present invention is concerned with compounds which inhibit the reverse transcriptase encoded by human i~ odeficiency ViIUS (HIV) or ph~ ceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the tre~tm~nt of the resulting acquired ;,....-...-e deficiency syndrome (AIDS). It also relates to pharmaceutical compositions cont~inin~ the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV.

BACKGROUND OF THE INVENTION
A retrovirus design~ted hllm~n immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immlme system (acquired immlme 2s deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-m, or ARV. A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step 30 in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and simil~r diseases, e.g., azidothymidine or AZT.
Nucleotide sequencing of HIV shows the presence of a ~1 gene in one open re~ding frame [Ratner, L. et ah, Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the -21~642o ~1 sequence encodes reverse transcriptase, an endonuclease and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, ~, 1567 (1986); Pearl, L.H. et al., Nature ~2, 351 (1987)].
The compounds of this invention are inhibitors of HIV
reverse transcriptase. Furthermore, the compounds of the present invention do not require bioactivation to be effective.

BREF DESCRIPTION OF THE ~VENTION
Novel compounds of formula A:
X~ .

\R6 as herein defined, are disclosed. These compounds are useful in the inhibition of HIV reverse transcriptase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS
and/or ARC, either as compounds, ph~ ceutically acceptable salts 20 (when al,~ro~"ate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, ;,.-.-..~,.omodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
2s DETAILED DESCRIPTION OF THE INVENTION AND
PREFERRED EMBODIMENTS
This invention is concerned with the compounds of formula A described below, combinations thereof, or pharmaceutically 30 acceptable salts or esters thereof, in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired i"-.~ e deficiency syndrome (AIDS). The compounds of this invention include those with structural formula A:

2 ~ 5 6 4 2 ~ PCT/US94/01694 wherein X is -H, -Cl, -F, -Br, -NO2, -CN, -oR2, -NR2R2, -NHSO2-Cl 3alkyl, or -NHCO-Cl 3alkyl;
Y is S()n or -O-, wherein n is zero, 1 or 2;
Ris 1) -C1 salkyl, unsubstituted or substituted with one or more of:
a) -C1 salkyl, b) -Cl ~aLkoxy, c) -OH, or d) aryl, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, 2) aryl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstituted or sul,sliluled with one or more of:
i) -OH or ii) -Cl salkoxy, ~, b) -Cl salkoxy, 3 o c) -OH, d) halogen, or e) -NR2R2 3) heterocycle, unsubstituted or substituted with one or more of:

21~iS~?O

a) -Cl salkyl, unsubstituted or substituted wi~ one or more of:
i) -OH or ii) -Cl salko~y, b) -Cl salko~y, c) -OH, d) halogen, or e) -NR2R2, or 4) -NR2R3, provided that Y is ~S(O)n~;
zis W, wherein W is O, S, -N-CN, or -N-OR2, 2) -COR1a, 3) -COOR1b, 4) -CR2R2-s(o)n-R 1 a, wherein n is defined above, S) -CR2R2NHR4, 6) -CR2R2-Co-R5, 7) -Cl 3alkyl substituted wi~ one or more of:
a) aryl, unsubstituted or substituted with one or more of:
i) -Cl saLkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or WO 94/19321 % l ~; 6 4 2 ~ PCT/US94/01694 - v) -NR2R2, or b) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salko~y, iii) -OH, iv) halogen, or v) -NR2R2, or 8) -CN;

Rl is 1 ) hydrogen, - 2) -Cl salkyl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, b) -Cl salkoxy, c) -OH, d) aryl, unsubstituted or substituted with one or more 20 of:
i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or 2s v) -NR2R2, or e) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salkoxy, 3 0 iii) -OH, iv) halogen, or v) -NR2R2, or 3) aryl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstitl-te~ or substituted with one or more of:

21~6420 i) -OH or ii) -Cl salkoxy, b) -C1 salko~y, c) -OH, d) halogen, e) -CN, f) -NO2, or g) -NR2R2; or 4) heterocycle, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstituted or subsliluled with one or more of:
i) -OH or ii) -Cl_5alkoxy, b) -Cl salkoxy, c) -OH, d) halogen, or g) -NR2R2;

Rla is 1 ) -Cl salkyl, unsubstituted or substituted with one or more of:
a) -Cl salkyl, b) -Cl salkoxy, c) -OH, d) aryl, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, or e) heterocycle, unsubstituted or substituted with one or more of:

WO 94/19321 215 o 4 2 ~ PCT/US94/01694 Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, or 2) aryl, unsubstituted or sul,sliluted with one or more of:
a) -Cl salkyl, unsubstituted or subs~ led with one or more of:
i) -OH or ii) -Cl salkoxy, b) -Cl salkoxy, c) -OH, d) halogen, e) -CN, f) -NO2, or g) -NR2R2;
3) heterocycle, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstituted or substituted with one or more of:
i) -OH or ii) -Cl salkoxy, b) -Cl saLkoxy, or 2S C) -OH, d) halogen, or e) -NR2R2, or 4) C3 6cycloalkyl;

30 Rlb iS
1) -Cl salkyl subs~ ed with one or more of:
a) -C1 saLkoxy, b) -OH, c) aryl, unsubstituted or substituted with one or more of:

~1564~0 i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, or d) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2~
2) aryl, unsubstituted or subs~iluled with one or more of:
a) -C1 salkyl, unsubstituted or substituted with one or more of:
i) -OH or ii) -Cl salkoxy, b) -Cl salkoxy, c) -OH, d) halogen, e) -CN, f) -NO2, or g) -NR2R2; or 3) heterocycle, unsubstituted or substituted with one or more of:
a) -Cl salkyl, unsubstituted or subsliluled with one or more of:
i) -OH or ii) -Cl saLkoxy, b) -Cl salko~y, c) -OH, d) halogen, or e) -NR2R2;

WO 94/19321 ~ 1 5 ~S ~ 2 ~ PCT/US94/01694 _ 9 _ - R2is hydrogenorCl 3aLkyl;

R3 is 1) -C1 salkyl, unsubstituted or substituted with one or more of:
a) -C1 salkyl, b) -Cl saLkoxy, unsu~sliluted or substituted with -OH, c) -OH, d) -oC(o)R7;
e) -COOR2 f) aryl, unsubstituted or substituted with one or more of:
i) -Cl salkyl, unsubstituted or substituted with one or more of -OH, ii) -Cl salkoxy, iii) -OH, iv) halogen, v) -N2, vi) -NR2R2 vii) -NHCO-C 1 3alkyl, or viii) -NHS02-Cl 3aLkyl, g) heterocycle, unsubstituted or substituted with one or more of:
2s i) -Cl saLkyl, ii) -Cl salkoxy, iii) -OH, iv) C1 3alkyl-NR2R2, v) halogen, 3 o vi) oxo, vii) -N2~
viii) -NR2R2 ix) -NHCO-Cl 3aLkyl, or x) -NHS02-Cl 3alkyl, h) -NR2R2, i) -C3 6cycloalkyl, 2) aryl, unsubstituted or substituted with one or more of:
a) -Cl saL~yl, b) -Cl salko~y, c) -OH, d) halogen, or e) -NR2R2, 3) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, 4) -Cl salkoxy, 5) -OH, 6) -C3 6cycloalkyl, or 7) hydrogen;

R4 is 1) Rl or 2) -CORl;

R5 is 1) Rl, 2) -Cl salkoxy, 3) -NHRl, or 4) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl salkyl, ii) -Cl salko~y, - ~ 21~6420 - iii) -OH, iv) halogen, or v) -NR2R2;

R6 is 1 ) hydrogen, 2) -COR1, 3) -CONHR1;

R7 is 1 ) aryl, unsubsliluled or substituted with one or more of -Cl, -Br, -OH, -OCH3, or-CN, or 2) -Cl salkyl, unsubstituted or substituted with one or more of -OH or -NR2R2; and with the proviso that when X is -H, Y is -S, R is unsubstituted phenyl and R6 is -H, Z is not -CH2-SO-Ph, -COH, \ J or \~ ;

or a pharmaceutically acceptable salt or ester thereof.

One embodiment of this invention encompasses compounds of Formula A further limited to:
30 X iS -H, -Cl or -F;
Y is -S()n~;
R is -Ph, -tolyl, 3-CI-phenyl, 2-pyridyl or 2-thiazolyl;
R6 is -H; and WO 94/19321 ~ PCT/US94/01694 ~1~6420 zis -fj-NR2R3 -COOR1b -COR1a, W

-CR2R2-S(O)n-R1a or -Cl 3alkyl sul,~liluled with heterocycle.

One class of compounds within the first embodiment is further limited to compounds wherein X is -H or -Cl;
Y is -S()n~;
R is -Ph, -tolyl, 3-Cl-phenyl or 2-thiazolyl;
R6 is -H; and zis 1 ) -fi-NR2R3 W, wherein R2 is -H and W is -O, -S or -NCN, or 2) -CR2R2-SO-aryl, wherein the aryl group is unsub~liluled or substituted with one or more of Cl salkyl.

A sub-class of compounds within ~is class is fi~er limited to compounds wherein 2s X is -Cl;
Y is -S()n~;
n is 1 or 2;
R is -Ph, 3-Cl-phenyl or 2-thiazolyl;
R6 is -H;
Zis -f~ NR2R3 W, wherein R2 is -H, and W is -O, -S or -NCN; and 2 ~

- R3 is 1) -Cl saL~yl, unsubstituted or substituted with one or more of a) -Cl salkoxy, unsubstituted or substituted with -OH, b) -OH, c) -oc(o)R7~
d) aryl, unsubstituted or substituted with one or more of:
i) -Cl saLkyl, unsub~liluled or substituted with one or more of -OH, ii) -Cl salkoxy, iii) -OH, iv) halogen, or V) -NR2R2, e) heterocycle, unsubstituted or substituted with one or more of:
i) -Cl saL~yl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, or f) C3 6cycloalkyl, 2) heterocycle, unsulusliluled or substituted with one or more 2s of:
i) -C1 salkyl, ii) -Cl salkoxy, iii) -OH, iv) halogen, or v) -NR2R2, 3) hydrogen, or 4) C3-6 cycloalkyl.

~lS6 ~2~

A second embodiment of ~is invention encompasses compounds of formula A wherein X is selected from the group consisting of:
1 ) -NR2R2, 2) -NHS02-Cl 3alkyl, and 3) ` -NHCO-Cl 3alkyl.

A third embotlimP-nt of this invention encompasses compounds of formula A wherein Z is -Ijj-NR2R3 W

and R3 is selected from the group consisting of:
1 ) C1 3aLkyl sub~liluled with phenyl wherein phenyl is substituted with one or more of:
a) -NO2, b) -NR2R2, c) -NHCO-Cl 3alkyl or d) -NHS02-Cl 3alkyl, and 2) Cl 3alkyl substituted with heterocycle, wherein heterocycle is substituted with one or more of:
a) halogen, b) oxo, c) -NO2, d) -NR2R2, e) -NHCO-Cl 3alkyl, or f) -NHS02-Cl 3alkyl.

30A fourth embodiment of this invention encompasses compounds of formula A wherein Y is ~S(O)n- and R is -NR2R3.
The most preferred compounds of this invention are compounds 1 ~rough 39, shown below.

_ ~156~29 - Compound 1:
SPh N-e~yl-5-chloro-3 -phenylthioindole-2-carboxamide Compound 2:
SPh Cl~ NHCH2CH20H

N-2-hydroxyethyl-5 -chloro-3 -phenylthioindole-2-carboxamide 20 Compound 3:
SPh Cl~_ ~.NHCH2CH20CH3 H O

N-2-methoxyethyl-5 -chloro-3 -phenylthioindole-2-carboxamide WO 94/19321 ~ 1 5 ~ o PCT/US94/01694 Compound 4:

SPh o N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-carboxamide Compound 5:

Cl~ NI1 N-4-pyridylmethyl-S -chloro-3 -phenylthioindole-2-carboxamide Compound 6:
SPh N
CI~NHJ~

N-3 -pyridylmethyl-5 -chloro-3 -phenylthioindole-2-carboxamide WO 94/19321 2 1 ~ G 4 2 0 PCT/US94/01694 - Compound 7:
SPh Cl~ N--~3 N-2-furanylmethyl-5 -chloro-3 -phenylthioindole -2-carboxamide Compound 8:
SPh Cl~"NH~

N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxarnide 20 Compound 9:

S-Ph CI~NH

H o N-[ 1 -(2(R)-hydro~ypropyl)]-5-chloro-3-phenyl-thioindole-2-carboxamide WO 94/19321 ~ ~. PCT/US94/01694 ~1 5~;~2~

Compound 10:
S-Ph Cl~ NHCH2~

N-(2-pyridyl)methyl-5-chloro-3 -phenylthioindole-2-carboxamide Compound 11:
S-Ph OCH3 Cl~,NHCH2~N

N-(3 -methoxy~-pyridyl)methyl -5 -chloro -3 -phenylthioindole-2-carboxamide Compound 12:
S-Ph CH20H

Cl~NHCH2~

N-(3 -hydroxymethyl)benzyl-5-chloro-3-phenylthioindole -2-30 carbo~amide ~6~2~

- Compound 13:
S-Ph Cl~[" NH2 S -chloro-3 -phenylthioindole-2-carboxamide Compound 14:
S-Ph OH

Cl ~ N HC H2 H o N-(3-hydro~ybenzyl)-5-chloro-3-phenylthioindole-2-carboxamide 20 Compound 15:

S-Ph C~ ~NHcH

2s H S

N -2-furanylmethyl-5 -chloro-3 -phenylthioindole-2-thiocarboxamide WO 94/lg321 PCT/US94/01694 6 ~ 2 i~

Compound 16:
S-Ph Cl~" NH2 5-chloro-3-phenyl~ioindole-2-thiocarbox~mide Compound 17:

\
S-Ph Cl~NH2 H o 20 5-chloro-3-phenylsulfinylindole-2-carboxamide Compound 18:
o 0~ 11 2s CI~NH2 H O

3 5-chloro-3-phenylsulfonylindole-2-carbo~mide.

- 2l~6~2a Compound 19:

S Cl~0~,NHCH2~/ ~

N-[(l -methylimidazol-2-yl)methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide Compound 20:
Cl~, NHCH

N-[(1 -methylimidazol-2-yl)methyl]-3-phenylsulfinyl-5-chloroindole-2-carboxamide W O 94/19321 ~ ~ 5 6 4 2 0 PCTrUS94/01694 Compound 21:
o ~ NHCH2~-~N

N-[(1 -methylimidazol-4-yl)methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide Compound 22:
O

O=S' CI~NHCH

N-[(1-methylimidazol-5-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide 2~ ~642~

Compound 23:
Cl ~

Cl~NHCH2~ ~

N-[(1-methylimidazol-2-yl)methyl]-3-(3-chlorophenyl-sulfonyl)-5-chloroindole-2-carboxamide Compound 24:

~[~NHCH2CH2~q 25 N-[2-(imidazol~-yl)ethyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide -WO 94/19321 . PCT/US94/01694 21~6~2~

Compound 25:

s Cl~NHCH2CH2 N-[2-(1 -methylimi~1~7ol-4-yl)ethyl] -3-phenylsulfonyl-S-chloroindole-2-carboxamide Compound 26:

\\ Ph Cl~ NH~

N-cyclopropyl-S -chloro-3-phenylsulfonylindole-2-carboxamide 6~2~

- Compound 27:

\\ Ph CI~NH~

N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-carboxamide Compound 28:

\\ Ph Cl ~; NHCH2~;~

N-(3 -pyridylme~yl)-3 -phenylsulfonyl-5-chloroindole-2-carboxamide 2 ~

Compound 29:

Cl~ NHCH2~N

o N-(4-pyridylme~yl)-5-chloro-3-phenylsulfinylindole-2-carboxamide Compound 30:

~O~NHCH2~NH2 N-(3-aminobenzyl)-3-phenylsulfonyl-5 -chloroindole-2-carboxamide WO 94/19321 2 1 5 ~ ~ 2 ~ PCT/US94/01694 Compound 31:
O S
O=S~N
s CI~NHCH2--Q

N-(3 -methoxybenzyl)-5-chloro-3 -(2-thiazolyl)sulfonyl-indole-2-carboxamide Compound 32:
O

~ CH,OH

N-[(S)- 1 -phenyl-2-hydroxyethyl] -5-chloro-3 -phenylsulfonylindole-2-carboxamide Compound 33:
o o=~ ~h ><~

N-[(R)- 1 -phenylethyl] -5-chloro-3-phenylsulfonylindole-2-carboxamide Compound 34:
o ~ ~ ;NHCH2 ~ lNHSO2CHj N-(3-methylsulfonylaminobenzyl)-3 -phenylsulfonyl-S-chloroindole-2-carboxamide WO 94/19321 ~ 3 PCT/US94/01694 Compound 35:

Cl~ 2 N-cyano-5 -chloro-3-phenylsulfonylindole -2-carboximid-amide Compound 36:
O

CH3SO2NH ~NH2 3-phenylsulfonyl-5 -methylsulfonylaminoindole-2-carboxamide wo 94/19321 PCT/US94/01694 ~ S~2~

Compound 37:
o C ~ NHCH2~N--H

4-[(5-chloro-3 -phenylsulfonylindole-2-carboxamido)-methyl]pyridin-2(1H)-one Compound 38:
lS

Cl~NHCH2~N

N-(2-amino-4-pyridylmethyl)-5-chloro-3-phenylsulfonyl-indole-2-carboxamide, and WO 94/19321 ~ .1 5 ~ 4 2 ~ PCT/US94/01694 ~ompound 39:
- Ph S Cl~ NH <

N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide.

The compounds of the present invention may have asymmetric cellters and occur as racemates, racemic mixtures, 5 individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
When any variable (e.g., aryl, heterocycle, R1, R2, R3, etc.) occurs more than one time in any constituent or in formula A of this invention, its definition on each occurrence is independent of its 20 definition at eve y other oc~ ce. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic 2s hydrocarbon groups having the specified number of carbon atoms;
"aLkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Halogen" or "halo" as used herein, means fluoro, chloro, bromo and iodo.
- As used herein, wi~ exceptions as noted, "aryl" is intended 30 to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, biphenyl.

WO 94/19321 PCTtUS94tO1694 ~15642G

The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered monocyclic or stable 8- to 1 l-membered bicyclic heterocyclic ring which is either saturated 5 or lms~tllrated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaterni7ed, and including any bicyclic group in which any of the above-defined o heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, 15 pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, ben7imidazolyl, thi~di~70yl, benzopyranyl, 20 benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, benzofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, ~iamorpholinyl sulfoxide, thiamorpholinyl sulfone, and ox~di~7.01yl.
Further abbreviations that may appear in this application are as follows:
Me methyl Et ethyl Ph phenyl BuLi butyllithium n-Bu3P tri-n-butyl phosphine LAH lil~.;l.,,l ~ll.. i.-.. -. hydride DMF dimethylformamide THF tetrahydrofuran Et3N tri-ethyl~mine MMPP monoperoxyphthalic acid, m~nesium salt WO 94/19321 2~ ~z5 6 4 2 0 PCT/US94/01694 BOP-reagent ben_otria_ol- 1 -yloxytris-(dimethyl-amino)phosphonium hexafluorophosphate mp or m.p. melting point The ph~rm~ceutically-acceptable salts of the novel compounds of this invention that are capable of salt formation (in the forrn of water- or oil- soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts of these o compounds, which are formed, e.g., from inorganic or organic acids or bases. F.~mples of such acid addition salts include ~cet~te, adipate, ~lgin~te, aspartate, ben70~te, ben7~nesulfonate, bissulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, 15 glycerophosphate, hemisulfate, heptanoate, hex~no~te, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the 20 basic nitrogen-co.~t~ ig groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;
and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Esters are also encompassed by the present invention, and include those which would readily occur to the skilled artisan, for example, Cl~ alkyl esters.
Schemes I-VIII for pr~il~g the novel con~l,out~ds of ~is invention are presented below. Tables I - VII which follow the schemes - 3 o illustrate the compounds that can be synthesized by Schemes I-VIII, but Schemes I - VIII are not limiterl by the compounds in the tables nor by - any ~li.;.llar substituents employed in the sch~mes for illustrativepurposes. The examples specifically illustrate the application of the following schPmes to specific compounds.

2156~2~

Scheme I, below, is a general route for synthesizing, e.g., the compounds shown in Table I, infra. The substituent groups (e.g., X, R, Rl, etc.) employed in Scheme I correspond to the substituent groups as 5 de~lned in Table I, but Scheme I is not limite~l by the defined substit~ t~ or compounds of Table I.

SCHEME I

SPh X~ NaH, PhSSPh X~--CO2H

1 ) (co)2cl2~
CHCI3, ~ BOP-reagent, or R2R3NH, DMF
2) R2R3NH

SPh x~N\R32 As shown in Scheme I, commercially available indole-2-carbo~ylic acid (or 5-chloro, 5-fluoro or 5-methoxyindole-2-carbo~ylic acid) I is treated with an excess of sodium hydride in dimethyl-formamide in the presence of an aryl disulfide such as phenyldisulfide at 0C to 60C, according to the general procedure described by Atkinson, et al., in Synthesis, p. 480-481 (1988). The resulting product II is reacted with oxalyl chloride in refluxing chloroform for about 30 WO 94/19321 2 ~ ~ 6 ~ 2 0 PCT/US94/01694 - millu~es to 1 hour to produce the corresponding acid chloride which is then reacted with a primary or secondary amine in chlorofo.lll at 0C to 20C to give the amide m. Alternatively, amide m can be produced g directly from II by treatment with BOP reagent (benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate) in the presence of the desired primary or secondary amine and triethyl~mine, in a solvent such as dimethyl-form~mide. Other carboxyl group activating reagents such as l,l'-c~l,ollyl-diimidazole can also be used for this step. Saponification of ethyl 5-chloro-3-benzylindole-2-carboxylate (prepared as described below) by methods f~mili~r to those skilled in ~e art, yields 5-chloro-3-benzylindole-2-carboxylic acid, which can be converted to the desired amides in the m~nner described for the synthesis of arnides m.
The compounds shown in Table II infra, are generally synthesized as in Scheme I, except R1OH is used in place of R2R3NH, as depicted in Scheme II below. The substituent groups employed in Scheme II correspond to the substituent groups as defined in Table II, but Scheme II is not limited by the defined substituents or compounds of 20 Table II.

WO 94/19321 : PCT/US94/01694 2:1 5 ~ 4 ? U

SCHEME II

X"~N C07H 2) R10H ~OR
H H o Il IV

/ PhS-N
,~

~OR1 BF3-Et20/CHCI3 As shown in Scheme II, 3-phenylthioindole-2-carboxylic acid II can be converted to the corresponding acid chloride with oxalyl chloride in refluxing chloroform, and reacted with an alcohol to give the ester IV. In an alternative procedure, Ia may be converted to IV by reaction with N-phenylthio-succinimide in chloroform at room 2s ten.l,eldture with a Lewis acid, such as boron trifluoride etherate, as catalyst (as shown in Scheme II). The con-yound ethyl 5-chloro-3-benzylindole-2-carboxylate was ylc~&~ed according to the procedure described by Inaba, et ah, in Chem. Pharm. Bull., 24, p. 1076-1082 (1 976).
Scheme m, below, is a general route for synthesizing, e.g., the compounds shown in Table m, infra. The substituent groups employed in Scheme m correspond to the substituent groups as defined in Table m, but Scheme m is not limited by the defined substituents or compounds of Table m.

WO 94/19321 2 ~ 3 ~ 4 ~ G PCT/US94/01694 scHEME m X~--C0 C H LAH X~CH20H

V Vl n-Bu3P X~ CH2SPh o PhSSPh,THF ~NH PhSSPh, DMF

SPh SPh X~CH2SPh X~CH2SPh ~Llll X Rx is H or CH3) NaH

CH31, DMF / MMPP

SPh X~CH2SPh IX

As shown in Scheme m commercially available ethyl indole-2-carboxylate (compound V wherein X is -H) or ethyl 5-chloroindole-2-carbo~ylate (compound V wherein X is -Cl), was reduced to the primary alcohol VI with an e~cess of li~liu~il aluminum hydride in tetrahydrofuran at 0C. Compound Vl was converted to the sulfide VII by treatment with an excess of tri-n-butylphosphine and an WO 94/19321 . PCT/US94/01694 ~6 ~120 aryldisulfide such as phenyl-disulfide in tetrahydrorul~u. at 0C to 20C
for 6-24 hours. Reaction of sulfide VII with sodium hydride, an aryldisulfide such as phenyldisulfide, in dimethylformamide at 0C to 5 20C for 1 to 18 hours produces bis-sulfide vm. Aryl disulfides which were not commercially available were obtained by oxidation of the commercially available aryl merc~tal- with dimethyl sulfoxide and iodine, according to the procedure described by Orville G. Lowe in L
Or~. Chem.. 40, p. 2096-2098 (1975). Compound vm can be N-aL~ylated, if desired, by methods f~mili~r to those trained in the art, e.g., by treatment with sodium hydride in dimethylfonn~mide at 0C in the presence of an alkylating agent such as iodomethane, to give compound IX. Thereafter, compound vm (or IX) is treated with one equivalent of peracid such as monoperoxyphthalic acid, magnesium salt 15 (MMPP), or meta-chloroperoxy-benzoic acid in methanol or chloroform-methanol at 0C for 30 mimltes to 3 hours, to give predomin~tely sulfoxide X.
Schemes IV-A and IV-B, below, show a general route for synthesizing, e.g., the compounds shown in Tables IV-A and IV-B, 20 infra. The substituent groups employed in Schemes IV-A and IV-B, respectively, correspond to the substituent groups as defined in Tables IV-A and IV-B, respectively, but Schemes IV-A and IV-B are not limited by the defined substituents or compounds of Tables IV-A and IV-B.

WO 94/19321 ,2~1 5 6 4 2 ~ PCT~S94/01694 SCHEME IV-A

SPh SPh ~ BH, DMS
¦ `~ NHRl 3 ~ `~CH2NHR
--N T~ THF A ~ N
H o H
Xl 2~11 SCHEME IV-B

SPh 1I SPh H
pyridinc. CHCI3 ~CH2NCR

XII-A 2~Lll As shown in Scheme IV-A, 3-phenylthioindole-2-carboxamides XI can be reduced to primary or secondary amines XII
by reaction with an excess of borane-dimethylsulfide complex in 2s reflu~ing tetrahydrofuran for 6-24 hours. As shown in Scheme IV-B, the ~lill-aly amine XII-A can be acylated with an acid chloride, such as benzoyl chloride, in chloroform in the presence of pyridine, to give the amide XIII.
- Scheme V, below, is a general route for synthesizing, e.g., 30 the compounds shown in Table V-A and Table V-B, infra. The substituent groups employed in Scheme V correspond to the substituent groups as defined in Tables V-A and V-B, but Scheme V is not limited by the defined substituents or compounds of Tables V-A and V-B.

- ~1S6~2~

SCHEME V

s ~CH3 NaH, PhSSPh~CH

o 1 ) n-BuLi 2) CO2 SPh SPh 1) t-BuLi ~CH3 XvlllH O 3 ~ CO2Li _ _ 1 ) t-BuLi 2) R1-NCO/H+

SPh ~ e XVII

WO 94/19321 2 ~ 5 ~ PCT/US94/01694 - As shown in Scheme V, commercially available 2-methyl-indole XIV can be treated with sodium hydride in dimethylform~mide - in the presence of an aryldisulfide such as phenyldisulfide to give 5 compound XV. Compound XV can be converted to the monoanion with n-butyl-li~hiull- in tetrahydrorul~l at -78C, and then reacted with carbon dioxide to give carboxylate XVI. The dianion formed by the reaction of XVI with t-butyllitl~ n could be reacted with an isocyanate, such as phenyliso-cyanate, to give a mi~ture of monoacylated product and diacylated product XVII (see Table V-B). Alternatively, the dianion fonned by the reaction of XVI with t-butyllithium could be reacted with an N-methoxy-N-methyl amide such as N-methoxy-N-methyl-furan-2-carboxamide (prepared in a manner f~mili~r to those skilled in the art, e.g., by the methods described in Scheme 1) to produce ketones xvm. The methodology described above is essentially that used by A. J. Katritsky and K. ~hlt~g~wa to prepare 2-indoleacetic acids, and is published in J. Am. Chem. Soc.. 108, 6808 (1986).
Scheme VI, below, is a general route for synthesizing, e.g., the compounds shown in Table VI, infra. The substituent groups 20 employed in Scheme VI correspond to the substituent groups as defined in Table VI, but Scheme VI is not limited by the defined substituents or compounds of Table VI.

SCHEME VI

SPh SPh 3 -78Cto20C ~R
2~ 2Q~
As shown in Scheme VI, N-methoxy-N-methyl-3-phenyl-thioindole-2-carboxamide XIX (or N-methoxy-N-methyl-5-chloro-3-phenyl~ioindole-2-carboxamide) (prepared as in Scheme 1) can be reacted with Grignard reagents (wherein Rl is not hydrogen) such as WO 94tl9321 PCT/US94/01694 4 2 ~

phenylm~nesium chloride, in tetrahyrodrofuran at -78C to 20C for 18-48 hours, or XIX can be reacted with other organometallic reagents well known in the art to one of ordinary skill, to produce ketones XX.
The compounds shown in Table VII infra, can generally be synthesized by those of ordinary skill in the art according to methods described in Sçhemçs I through VI, with the exception of 2-(2-benzoxazol-2-ylethyl)-3-phenyl~ioindole (compound XXIV), the synthesis of which is described below in Scheme VII.

SCHEME VII

SPh SPh 5~OCH -0C to 20C ~CH0 XXII

2eq.
THF ~_N

O

2s SPh SPh H2, CH30H ~
N~-- ~ Pd/C ~ N~ N
H 0y~/ ~ H 0_~
\~/ XXIII \~/

As shown in Scheme VII, N-methoxy-N-methyl-3-phenylthioindole-2-carbo~mille XXI can be reduced to aldehyde XXII
with lilhiuln ~ .., hydride in tetrahyd~fur~l at 0C to 20C for 2-4 hours. Aldehyde XXII could be reacted wi~ the li~ ll salt of WO 94/19321 ~15 6 4 ;~ C PCT/US94/01694 - [(benzoxal-2-yl)methyl]diethyl-phosphonate to produce olefin XXIII, which is then hydrogenated in the presence of 10% palladium on charcoal in methanol under one atmosphere of hydrogen to give 5 compound XXIV.
The compound 5-chloro-2-cyano-3-phenylthioindole in Table VII can be prepared by dehydro-sulfurization of 5-chloro-3-phenyl-thioindole-2-thiocarboxamide with, e.g., Hg(OAc)2.
Using methods well-known to those skilled in the art, compounds of formula A where Y is -SO- or -SO2- can be synthesized by treatment of compounds where Y is -S- with a suitable oxidizing agent such as, for example, meta-chloroperoxybenzoic acid (MCPBA), sodium periodate or hydrogen peroxide in an a~ro~liate solvent such as MeOH, CHCl3 or acetic acid, or potassium persulfate in a solvent 15 such as MeOHlH2O.
Alternative routes to amide derivatives of forrnula A where Y = -SO- or -S02- are shown in Scheme vm. Intermediate acid II can be oxidized (with for example meta-chloroperoxybenzoic acid (MCPBA) in CHCl3) to the Y = -SO- or -SO2- acid derivative XXV
20 which can then be converted to the corresponding arnide derivatives XXVII employing the amide forming conditions indicated in Scheme I.
In another useful sequence, interm~ te ester IVa can be oxidized to the Y = -SO- or -S02- ester intenne~i~te XXVI which on reaction with ammonia or a primary amine with heating is converted to compounds of 25 formula XXVII.

2 ~ 0 SCHEME vm SPh S X~ H2O2/HOAc ~ 5~ h S(O)nPh See SCHEME I
X~ C~o N R2R3 lS H
XXVII
~NR2R3 \

SPh S()nPh 20 X~l H2O2/HOAc X~CO2Et ~B H
XXVI

WO 94/19321215 6 4 ;~ O PCT/US94/01694 ~ `_ TABLE I

Y-Ph s X~N/ RR3 X Y R2 R3 m.p.

H S H CH2Ph 179-181C
- l 5 H S H Ph 194-196C
H S H n-C4Hg 161 -163C
H S H CH2CH2Ph 147-149C
Cl S CH3 OCH3 57-59C

Cl S H ~) 255-256C

Cl S H nC3H7 210-212C

Cl S H --CH2~ 240-241 C

Cl S H {~ 255-256C

TABLE I. Cont'd X Y R2 R3 m.p.

F S H ~ 239-241 C

Cl S H ~OH 232-233C

Cl CH~ H --CH~ 243-244C

Cl S H ~ 221 C

Cl S H --CH2~ 21 4C

Cl S HCH2CH2CH2OH 21 5C

Cl S H ~OCH3 229C

Cl S H CH3 220-221 C

WO 94/19321 ~ 4 2 ~ PCT/US94/01694 TABLE I. Cont'd X Y R2 R3 m.p.

Cl S H CH2CH2CH2OCH3 170-171C

Cl S H CH2~OCH3 1 84C

Cl S H CH2~ 259-260C
lS NH (HCI salt) Cl S H CH2CH2--N~N 256C
\=/ (HCI salt) Cl S H CH(CH3)2 193-1 94C

Cl S CH3 Ph 191-1 92C

Cl S H CH2CH2CH2N(CH3)2 229-230C
(HCI salt) WO 94/19321 ` PCT/US94/01694 4 2 t3 TABLE I. Cont'd X Y R2 R3 m.p.
s Cl S HC2H5 210-211 C

Cl S H Ph 245-246C

Cl S HCH2~ 1 72C

Cl S HCH2CH2CHz--N O 162-164C

Cl S HCH2 A 219-21 9.5C

Cl S HCH2Ph 222C

Cl S H CH2~OCH3 1 98C

Cl S H CH2CH2OCH2CH2OH 161.5-162.5C

_ 215~;~20 - TABLE I. Cont'd X Y R2 R3 m.p.
Cl S H ~OH ~300C

Cl S H CH2CH2OCH3 216-217.5C

Cl S H CH2CH2Oc2Hs 165.5-167C

Cl S H CH2~ 182-183C

Cl S H CH2~ 201C

Cl S H CH2CI HCH3 205C
OH
,~
Cl S H --CH2~N 228-229C

Cl S H CH2CH2OH 222-223.5C

Cl S H CH2~CH2N~ 151-152C

- so TABLE I~ Cont'd X Y- R2 R3 m.p.

Ci S H OCH3 179-180C

l o Cl S H CH2OH 153-154C
o l 5 Cl S H CH2COC2Hs 215-215.2C

Cl S H CH3 168-169C

OH
Cl S H _CH2"~` 202-203C

Cl S H - CH2~ 209-210C

Cl S H - CH2CH2CH2 - N~N HCI 188-189C

OH
Cl S H - CH2~ 201 -206C

Cl S H - ~CHCH2CH3 138-139C

WO 94119321 2 1 S 6 4 2 ~ PCTIUS94/01694 TABLE I. Cont'd - X Y R2 R3 m.p.

Cl S H _ 137.5-1 39C

OH
Cl S H --CH2CHCH2OH 219-221 C

Cl S H ~ ~CH~ 208-21 0C

Cl S H --CH~ 223-226C

Cl S H ~ ~CH~ 223-226C

Cl S H --CH~ 208-21 0C

Cl S H --CH2~N 227-228C

2156~12~

TABLE I. Cont'd X Y R2 R3 m.p.
Cl S CH20H 229 230C
- CH2~

~=~
Cl S H--CH2~) 217-219C

- OH
Cl S H--CH2~ 214-21 6C

OH
Cl S H--CH2~ 193-1 95.5C
` 20 ~

Cl S H - H 213-21 5C

Cl SO2 H H 255-257C

3 0 Cl so2 H--CH2~ 249-251 C

WO 94/19321 21 5 6 4 2 ~ PCT/US94/01694 TABLE I. Cont'd X Y R2 R3 m.p.

Cl so2 H - CH2CH2OH 1 98-200C

Cl so2 H --CH2~N

l 5 Cl S2 H - CH2~3 212-21 5C

Cl S2 H --CH2~N 21 1-21 5C

Cl so2 H --CH2~3F 275-278C

Cl so2 H --CH2~ 265-270C

Cl Cl S2 CH3~ 1 49C

-~15~

TABLE I. Cont'd X Y R2 R3 m.p.

Cl SO2 H ~ \ ~ 175C

Cl SO2 H --CH2~N 278-281C

WO 94tl9321 ~ PCT/US94/01694 - TABLE II

X~OR~ b X Y R R1b m.p.
H S Ph CH3 179-180C

H S ~ CH3 195-1 97C

OCH3 S Ph CH3 211-21 2C

Cl S Ph CH3 193-1 96C

Cl S Ph CH2Ph 154-1 55C

Cl S Ph C2H5 163-164C

Cl CH2 Ph C2H5 196-1 97C

3 F S Ph C2H5 1 49C

WO 94/19321 _ PCT/US94/01694 ~ ~ ~ G42~

TABLE m S-R

~N ~;
R ()n x X R R~ n Rx m.p.

H Ph Ph 1 H 71-74C

H Ph Ph 0 H

H Ph Ph 2 H 168-1 69C

H ~ Ph 1 H 166-1 67C

H ~CH3 Ph 1 H 164.5-166.5C

OCH3 Ph Ph 1 H 70-80C

H ~ Ph 1 H 171.5-1 72.5C

H Ph Ph 0 CH3 98-99C

-- 2156~2~

- ~7 -- TABLE m. Cont'd X R R1a n Rx m.p.

H Ph Ph 1 CH3 177-1 78C

l 0 H Ph~OCH3 1 H

H PhCH3 1 H 164-1 68C

H Ph ~ 0 H ---H Ph~--CH3 H

H Ph ~-CH3 H

H Ph ~ 1 H ---H Ph`~1 H _ 21 56~2~

TABLE m. Cont'd X R R1a n Rx m.p.

H Ph ~ 1 H ---0 H Ph ~}> 1 H 138-1 40C

H Ph ~OH 0 H --H Ph ~ ~OH 1 H 219-220C

Cl Ph Ph 1 H 158-1 62C

OH
H Ph ~ 1 H ---WO 94/19321 215 ~ 4 2 ~ PCT/US94/01694 _ 59 _ TABLE IV-A

SPh s ~CH2NHR1 NH

R1 m.p.

-CH2Ph 199-201 C
-Ph 167-1 70C
-n-C4Hg 177-1 79C
-H

TABLE IV-B

SPh H

~CH2N ICIR
H O
2s R1 m.p.

-CH3 ~--- -Ph 64-65C

21~6~2(~

TABLE V-A

SPh X~CH2lCIR5 X R5 R6 m.p.

H -CH2Ph H

l 5 H -Ph H 154-1 55C

H -CH3 H 101.5-1 03.5C

H ~ H 87-90C
o H ~D H 127-1 29C
Cl -OC2H5 H 99-1 03C

WO 94/19321 215 ~ 4 2 ~ PCT/US94101694 TABLE V-B

SPh s X~CH~ICINHR

X R1 R6 m.p.

H -Ph H 66-68C

H -Ph-IClNHPh 123-125C

2 a TABLE VI

Y-Ph S X~o~ R 1 a X YR1a m.p.

Cl S -Ph 154-155C

Cl S-CH2Ph 219-220C

H S -Ph 121.5-123.5C

H S ~CI 142-149C

Cl S-C2H5 196-197C

Cl S ~CI 214-215C

Cl S -CH3 178C

Cl CH2 -Ph 161 -163C
Cl SO2 cyclopropy 224-226C
Cl SO2 -C2H5 226-227C

Cl SO2 -CH3 184-187.5C

WO 94/19321 ~ 1 ~ 6 4 ~ ~ PCT/US94/01694 - TABLE VII

SPh X~Rx N~R6 X Rx R6 m.p.

l 5 H -CH3 - IlNHPh 157-159C

H -CH3 - IlPh 124-125C

H -CH2CH2Ph H 117-120.5C
N ~
H --CH2CH2~/ ,I~d H 92-193C

Cl -CN H 172-174C

~ NHCH2~ H 143-144C

I l (decomp.) ~69?~

The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by the human immlmodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HrV infection: AIDS, ARC
(AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HrV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are also useful in the preparation and execution of screening for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establichin~ or determining the binding site of other antivirals to HIV reverse transcriptase e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
For inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS or ARC, the compounds of the present invention may be ~-lminictered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inh~l~tion spray, or rectally, in dosage unit formulations cont~ining conventional non-toxic ph~rm~celltiç~lly-acceptable carriers, adjuvants and vehicles.
Thus, in accordance with the present invention there is further provided a method of treating and a ph~rm~ceutical composition for treating HIV infection and AIDS. The treatment involves ~lminictering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
These pharmaceutical compositions may be in the form of orally-~lmini~trable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
When ~tlmini~tered orally as a suspension, these compositions are l ~aled according to techniques well-known in the art of ph~rm~ceutical form~ tion and may contain microcryst~lline 0 cellulose for impa~ting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enh~ncer, and sweetners/flavonng agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, m~gnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When ~dmini~tered by nasal aerosol or inh~l~tion, these compositions are ~lel)a~d according to techniques well-known in the art of pharmaceutical formulation and may be ~lepa ed as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or di~e~sillg agents known in the art.
The injectable solutions or suspensions may be form~ tt-d according to known art, using suitable non-toxic, parenterally-2s acceptable diluents or solvents, such as m~nnitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable disye.~ing or wetting and suspen~lin~ agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally ~lmini~tered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-illiLati~g excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.

WO 94tl9321 PCTtUS94/01694 2~5~42~ -The compounds of this invention can be ~tlmini~tered orally to hnm~n~ in a dosage range of l to 100 mg/kg body weight in divided doses. One preferred dosage range is 1 to l0 mg/kg body weight orally in divided doses. Another ~lefelled dosage range is 1 to 20 mg/kg body weight orally in divided doses. It wiIl be understood, however, that the specific dose level and frequency of dosage for any particular p~ti~nt may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of ~rlmini~tration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS. The compounds of this invention can be ~tlmini~tered in combination with other compounds that are HIV reverse transcriptase inhibitors, and/or with compounds that are HIV protease inhibitors. For example, the compounds of this invention may be effectively ~lmini~tered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, such as those in the following Table vm.
When used in a combination tre~tment with compounds of the instant invention, dosage levels of HIV protease inhibitors of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five time higher. For example, infection by HrV is effectively treated by the ~-lminictMtion of from 10 to 50 milligrams of the HIV protease inhibitor per kilogram of body weight from one to three times per day.
It will be understood, however, that the speci~lc dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of ~tlmini~tration, rate of excretion, drug combination, the severity WO 94/19321 2 1 S 6 4 2 ~ PCT/US94/01694 ~ _ .

- of the particular condition, and the host undergoing therapy.
Dosages of HIV reverse transcriptase inhibitors, when used in a combination tre~tment with compounds of the instant invention, are s comparable to those dosages specified above for the instant compounds.
It will be understood that the scope of` combinations of the compounds of this invention with AIDS antivirals is not limited by Table VIII but includes in principle any combination with any pharma-ceutical composition useful for the treatment of AIDS.

TABLE VIII

Dru Name Manufacturer Indication ddI Bristol-Myers AIDS, ARC
Dideoxyinosine (New York, NY) Dideoxycytidine; Hoffman-La Roche AIDS, ARC
ddC (Nutley, NJ) Zidovudine; AZT Burroughs Wellcome AIDS, adv, ARC
(Rsch. Triangle Park, pediatric AIDS, NC) Kaposi's sarcoma, asymptomatic HIV
infection, less severe HIV disease, neurological involvement, in combination with other therapies L-697,661 Merck AIDS, ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.

- .

WO 94/19321 ~ d PCT/US94/01694 TABLE VIII (Cont'd) Drute Name Manufacturer Indication L-696,229 Merck AIDS~,ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.

L-735,524 Merck AIDS, ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.

L-738,372 Merck AIDS, ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.

L-738,872 Merck AIDS, ARC, (Rahway, NJ) asymptomatic HIV
positive, also in combination with AZT.
Compounds of Table VIII are the following: L-697,661 is 3-([(4,7-dichloro-1,3-benzoxazol-2-yl)-methyl]-amino)-5-ethyl-6-methyl-pyridin-2(1H)-one; L-696,229 is 3-[2-(1,3-benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one; L-735,524 is an HIV
protease inhibitor with the chemical name N-(2(R)-hydroxy-1(S)-30 indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)piperazinyl))pent~ne~mide; L-738,372 is 6-chloro-4(S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)-ethynyl)-quinazolin-2(1H)-one; L-738,872 is N-tert-butyl-1-[2'-(R)-hydroxy-4'-phenyl-3'(S)-[3 "(R)-[1 "',1 "'-dioxo-2"'(R)-methylethyl]tetrahydro-thienyloxycarbonylamino] -butyl] -4-[4'-(2" -chloro-6 "-methyl)pyridyl-WO 94/19321 2 ~ ~ 6 ~ PCT/US94/01694 methyl] -piperazine-2(S)-carboxamide.

REVERSE TRANSCRIPTASE ASSAY
The assay measures the incorporation of tritiated deoxy-guanosine monophosphate by recombinant HIV reverse transcriptase (HIV RTR) (or other RT) into acid-precipitable cDNA at the Km values of dGTP and poly r(C)-oligo d(G)12 18. The inhibitors of the present invention inhibit this incorporation.
Thirty ~L of a reaction mixhlre cont~inin~ equal volumes of: 500 mM Tris-HCl (pH 8.2), 300 mM MgCl2, 1200 mM KCl, 10 mM
DTT, 400 ~g/mL poly r(c)-oligo d(G) [~ &~d by dissolving 1.5 mg (25 U) poly r(C)-oligo d(G) in 1.5 ml sterile distilled H2O and diluting to 400 ~lg/ml], 0.1 IlCi/~ll [3H] dGTP, 160 ~M dGTP, was added to 10 ~ll sterile distilled H20, 2.5 ~ll of potential inhibitor and 10 ~L of 5 nM
purified HIV RTR in tubes. The mixture was incubated at 37C for 45 mimltes.
After incubation is complete, the tubes were cooled in ice for5 ~ ltes. Ice-cold 13% TCA cont~ining 10mMNaPPi (200 are added and the ~ ule incubated on ice for 30 mimltes. The precipitated cDNA is removed by filtration using presoaked glass filters [TCA, NaPPi]. The precipitate is then washed with lN HCl, 10 mM
NaPPi-The filter discs are then counted in a scintill~tion counter.
Under these conditions [dGTP] and poly r(C)-oligo d(G)12 18 each are approximately equal to the ~r~liate Km value.
Approximately 5-6,000 cpm of [3H] dGMP are incorporated into acid-precipitable material. The RT reaction is concentration- and time-dependent. DMSO (up to 5%) does not affect enzyme activity.
3 o Calc~ te-l IC50 values for the tested compounds of this invention vary from about 3 nM to more than 300 ~lM. The IC50 values of the most preferred compounds range from about 3 nM to about 35 nM.

21~6~20 INHIBll ION OF VIRUS SPREAD

A. r~e~a-dtion of HIV-infected MT-4 Cell Suspension MT cells were infected at Day O at a concentration of 250,000 per ml with a 1:2000 dilution of HIV-1 strain IIIb` stock (final 125 pg p24/ml; sufficient to yield < 1% infected cells on day 1 and 25-100% on day 4). Cells were infected and grown in the following me~ m RPMl 1640 (Whin~ker BioProducts), 10% inactivated fetal 0 bovine serum, 4 mM glul~l..i..ç (Gibco Labs) and 1:100 Penicillin-Streptomycin (Gibco Labs).
The mix~re was incubated ovemight at 37C in 5% CO2 atmosphere.

lS B. Treatment with Inhibitors Serial two-fold dilutions of compound were prepared in cell culture medium. At Day 1, aliquots of 125 111 of compound were added to equal volumes of HIV-infected MT~ cells (50,000 per well) in a 96-well microtiter cell culture plate. Incubation was continued for 3 days at 37C in 5% CO2 atmosphere.

C. Measurement of Virus Spread Using a multich~nnel pipettor, the settled cells were resuspended and a 125 ,ul haIvested into a separate microtiter plate.
25 After the settling of the cells, the plates were frozen for subsequent assay of the ~uye...~t~nt for HIV p24 antigen.
The conce--l-dtion of HIV p24 antigen was measured by an enzyme ;.--....oassay, described as follows. Aliquots of p24 antigen to be measured were added to microwells coated with a monoclonal 30 antibody specific for HIV core antigen. The microwells were washed at this point, and at other a~l,ro~.iate steps ~at follow. Biotinylated HIV-specific antibody was then added, followed by conjllg~te~ streptavidin-horseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to ~e concentration of HIV p24 antigen.

WO 94/19321 215642 ~ PCT/US94/01694 The cell culture inhibitory concentration (ClCgs) for each compound is defined as that concentration which inhibited by greater than 95% the spread of infection, as assessed by a greater than 95%
reduction in p24 antigen production relative to untreated controls. The tested compounds of the present invention were found to have CICgs values r~nging from about 3 nM to about 400 nM for preferred species, and up to about 40 IlM for others.

Preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthioindole-2-carboxamide Step A: 5-Chloro-3-phenylthioindole-2-carbo~ylic acid To a suspension of sodium hydride (3.0 g, 60% dispersion in oil, 0.076 mol) in dimethylfonn~mi(le (125 mL) was added 5-chloroindole-2-carbo~ylic acid (5.0 g, 0.0255 mol) and phenyldi-sulfide (6.1 g, 0.028 mol). The reaction was he~te-l under nitrogen at 50C overnight. The reaction was cooled, and additional sodium hydride (1.8 g) and phenyldisulfide (3.6 g) were added and heating continued for 1 h. The reaction was cooled and the dimethylformamide tille-l in vaCuo. 'rhe residue was partitioned between ethyl acetate and water. The aqueous layer was separated and the pH ad~usted to pH1 with 10% aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the ethyl ~Get~te e~tract was washed with water and saturated brine, and dried over m~gnesium sulfate. The crude product was recryst~lli7ed from ethyl acetate in hexane to afford the title compound as an off-white solid.
Step B: N-(3-pyridylmethyl)-5-chloro-3-phenylthioindole-2-carboxamide Benzotria_ol- 1 -yloxytris(dimethylamino)phosphonium hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5-chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 rnmol), 3-WO 94/19321 2 1 5 6 ~ 2 ~ PCT/US94/01694 aminomethylpyridine (0.35 g, 3.2 mmol) and triethyl~mine (0.50 mL, 3.2 mmol) in degassed dimethylfonn~mide (25 mL). The reaction was stirred at room temperature overni~ht. The precipitated product was s filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60C in vacuo for 72 h. The title compound was obtained as an off-white solid, mp 240-241C.
Analysis calculated for C2lHl6clN3os-o.25 H20:
C, 63.31; H, 4.17; N, 10.54 Found: C, 63.34; H, 4.06; N, 10.71 NMR (DMSO-d6): ~ 12.54 (lH, s), 8.91 (lH, t, J=6 Hz), 8.51 (lH, s), 8.42 (lH, d, J=S Hz), 7.58 (2H, m), 7.45 (lH, m), 7.25 (4H, m), 7.15 (lH, t, J=7 Hz), 7.04 (2H, d, J=8 Hz), 4.58 (2H, d, J=6 Hz).

Preparation of Methyl 5-chloro-3-phenylthioindole-2-carboxylate Oxalyl chloride (0.70 mL, 9.6 mmol) was added to a solution of 5-chloro-3-phenylthioindole-2-carboxylic acid (0.97 g, 3.2 mmol) in chloroform (50 mL) under nitrogen. The reaction was refluxed for 3 h, cooled and reduced to dryness in vacuo. The resulting solid was dissolved in chloroform and added to methanol at 0C. The methanol was removed in vacuo and the crude product chromato-graphed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained as a solid, mp 193-196C.
Analysis calculated for C16H12ClN2S
C,60.47;H,3.81;N,4.42 Found: C, 60.09; H, 3.50; N, 4.67 Preparation of Ethyl 5-chloro-3-benzylindole-2-carboxylate The title compound was prepared according to the procedure described by Inaba, S., et al., Chem. Pharm. Bull., 24, 1076-1082 (1976). Recryst~11i7~tion from ben~ene gave the title compound as WO94/19321 ~ A~ 3 :~, 2~ PCT/US94/01694 pale yellow needles, mp 196-197C.
Analysis calculated for C18H16ClN2 C, 68.90; H, 5.13; N, 4.46 Found: C, 68.64; H, 5.10; N, 4.56 Preparation of 2-Phenylsulfinylmethyl-3-phenylthioindole o Step A: 2-Hydroxymethylindole A suspension of lithium alllmimlm hydride (2.0 g, 0.20 mol) in tetrahydrofuran (100 mL) was cooled with stirring to 0C
under nitrogen. A solution of ethyl indole-2-carboxylate (10.0 g, 0.052 mol) in tetrahydrofuran was added dropwise, m~ t~ ing the reaction ~m~e,ature between 0-5C. After 1 h, the reaction was quenched with saturated sodium potassium tartrate solution. The reaction was filtered and the filter cake washed well with tetrahydroruldll. The tetrahydro-furan was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water, 20 saturated brine, dried over magnesium sulfate, ~lltered and freed of solvent. The title compound was obtained as a yellowish solid.
NMR (CDCl3): ~ 8.18 (lH, bs), 7.57 (lH, d, J=8 Hz), 7.35 (lH, d, J=8 Hz),7.26(1H,s),7.18(1H,dt,J=1,8 Hz),7.10(1H,dt,J=1,8Hz), 6.41 (lH, bs), 4.84 (2H, s).
Step B: 2-Phenylthiome~ylindole 2-Hydroxymethylindole (6.94 g, 0.047 mol) and phenyldisulfide (10.8 g, 0.049 mol) were dissolved in tetrahydrofuran (200 mL) and cooled to 0C under nitrogen. Tri-n-butylphosphine 30 (11.7 mL, 0.047 mol) was added and the reaction stirred for 1 h.
Additional phenyldisulfide (1.5 g, 0.007) and tri-n-butylphosphine (5.1 mL, 0.20 mol) was ~ e~l, and the reaction stirred at room temperature until complete. The tetrahydrofuran was removed in vacuo and the residue chromatographed on silica gel eluting with 5% ethyl acetate in hexane. The title compound was obtained as clear colorless plates, mp WO 94/19321 21 5 6 ~ 2 a PCT/US94/01694 100-101.5C.
AI~alysis calculated for C1sH13NS
C, 75.27, H, 5.47, N, 5.85 Found: C, 74.52, H, 5.39, N, 5.95 Step C: 3-Phenylthio-2-phenylthiomethylindole A suspension of sodium hydride (0.37 g 60% dispersion in oil, 9.4 mmol) in dimethylform~mide (50 mL) was cooled to 0C.
2-Phenylthiomethylindole (1.5 g, 6.3 mmol) was added portionwise, and lO the reaction stirred at 0C for 15 min. Phenyldisulfide (1.5 g, 6.9 mmol) was added and the reaction stirred at 20C for 6 h. The reaction was quenched with water and e~tracted with ethyl ~cet~te. The organic extract was washed with water, saturated brine and dried over m~gnPsium sulfate. Filtration and evaporation of solvent left an oil which was purified by medium pressure chromatography on silica gel using 5% ethyl ~cet~te in hexane. The title compound was obtained as an oil.
Analysis calculated for C2lHl7Ns2-H2o-o.l5-c4H8o2 C, 68.50; H, 5.33; N 3.60 Found: C, 68.40; H, 4.65; N, 3.86 Step D: 2-Phenylsulfinylmethyl-3-phenylthioindole A solution of 3-phenylthio-2-phenylthiomethylindole (0.750 g, 2.94 mmol) in methanol (100 mL) was cooled to 0C with stirring. Monoperoxyphthalic acid m~nesium salt (0.908 g, 80%
peracid) in methanol (50 mL) was added slowly dropwise. After addition, the reaction was stirred an additional 30 min., then quenched with 10% aqueous sodium thiosulfate (2 mL). The methanol was removed in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed successively with water and saturated brine, then dried over m~nesium sulfate. Filtration and concentration of the filtrate in vacuo gave an oil which was purified by chromatography on silica gel using 20-30% ethyl ~cet~te in hexane.
The title compound was obt~inP-l as a foam, mp 71-74C.
Exact mass calculated for C21H17NOS2: 364.082982.

WO 94/19321 2 1 ~ ~ 4 2 ~ PCT/US94/01694 Found: 364.084549.
NMR (DMSO-d6) â 11.82 (lH, s), 7.50 (6H, m), 7.23 (lH, d, J=8 Hz), - 7.15 (3 H, m) 7.05 (2H, m) 6.90 2H, m), 4.43 (lH, d, J=13 Hz), 4.38 5 (lH, d, J=13 Hz).

P~ al ~tion of 2-Phenylcarboxamidomethyl-3 -phenylthioindole Step A: 3-Phenythioindole-2-carboxamide The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (~ aled according to the procedure described by Atkinson, J.G. et al., Synthesis, p. 480-481 (1988), (4.01 g, 0.015 mol), 15 ammonia (large e~cess), and benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorphosphate (7.2 g, 0.016 mol) in dimethylform~mide according to the general procedure described in Fx~mple 1 for the ~r~a ation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide. The title compound was obtained as a pale 20 yellow solid.
Step B: 2-Aminomethyl-3-phenylthioindole A solution of 3-phenylthioindole-2-carboxamide (1.9 g, 7.1 mmol) in tetrahydror~ was cooled under nitrogen to 0C and treated 25 with neat boranetlime.thylsulfide complex (7.1 mL, 0.070 mol). The reaction was reflu~ed for 7 h, cooled to 0C and qll~nclletl with 10%
aqueous hydrochloric acid. The solution was adjusted to pH 8 with 20%
aqueous sodium hydro~ide. The reaction was e~tracted with ethyl ~cet~te and the organic e~tract washed with saturated brine, and dried 3 o over m~pnesium sulfate. The title compound was obtained as a pale yellow oil.

Step C: 2-Phenylcarboxamidomethyl-3-phenylthioindole 2-Aminomethyl-3-phenylthioindole (0.85 g, 3.3 mmol) was dissolved in chloroform (15 mL) and cooled under nitrogen to 0C.

2 ~ 0 Pyridine (2.7 mL, 33 mmol) was added, followed by benzoyl chloride (1.1 mL, 10 mmol). The reaction was stirred at 20C for 1 h and 10%
aqueous hydrochloric acid added. The layers were separated and the 5 organic phase washed successively with water, saturated sodium bicarbonate and saturated brine. The chloroform solùtion was dried over m~gn~sium sulfate, filtered and evaporated to dryness. The resulting oil was chromatographed on silica gel with 5% ethyl acetate in methylene chloride. The title compound was obtained as a solid, mp 64-65C.
Analysis calculated for C22H18N2OS 0 2 H2O
C, 73.00; H, 5.08; N, 7.74 Found: C, 72.93; H, 5.02; N, 7.66 15Preparation of 2-(N-Phenylacetamido)-3-phenyl-thioindole and 2-(N-Phenylacetamido)- 1 -(phenyl-carbamoyl)-3-phenylthioindole 2-Methyl-3-phenylthioindole (0.50 g, 2.1 mmol) (prepared according to the procedure described by Atkinson, J. G., et aL, 20 Synthesis, p. 480-481 (1988), was dissolved in dry tetrahydrofuran and cooled under nitrogen to -78C. A solution of n-butyllithium in hexane (0.83 mL, 2.5 M) was added via syringe. Carbon dio~ide was bubbled into the reaction mixture over a period of several minlltes; unreacted carbon dioxide was removed by freezing the reaction at liquid nitrogen 25 tenl~elature under high vacuum and warming to -78C. A solution of t-butylli~iunl in hexane was added (1.35 mL, 1.7 M) and the reaction stirred for 20 min. Phenylisocyanate (0.23 mL, 2.1 mmol) in tetrahydrofuran (1.5 mL) was added and the reaction stirred at 20C
oven~ight. The reaction was diluted with water and extracted with ethyl 30 ~cet~te. The organic phase was washed with saturated brine and dried over magnesium sulfate. Filtration and evaporation of solvent left an amber oil. The crude products were chromatographed on silica gel eluting successively with 15%, 20%, and 40% ether in hexane. 2~
Phenylacetamido)-3-phenylthioindole was isolated as a solid, mp 66-68C.

WO 94/19321 21~6 4 2 0 PCT/US94/01694 `~. ., Analysis calculated for C22H 1 gN2OS
C, 72.98; H, 5.01; N, 7.73 Found: C, 72.99; H, 4.87; N, 7.52 Later fractions contained 2-(N-phenylacetamido)-1-(phenylc~-13allloyl3-3-phenyl~ioindole, mp 123-125C.
Analysis calculated for C29H23N302S
C, 70.28, H, 4.67, N, 8.47 Found: C, 70.37, H, 4.61; N, 8.34 Preparation of 2-(2-Oxo-2-furan-3-yl)ethyl-3-phenylthioindole Step A: N-Methoxy-N-methylfuran-3-carboxamide The title compound was prepared from furan-3-carboxylic acid (3.4 g, 0.030 mol), N,O-dimethylhydroxyl~mine hydrochloride hydrochloride (2.9 g, 0.û30 mol) triethyl~mine (8.3 mL, 0.060 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (13.3 g, 0.030 mol) according to the general procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide .
NMR (DMSO-d6) ~ 8.25 (lH, s), 7.75 (lH, s), 3.70 (3H, s), 3.22 (3H, s).

Step B: 2-(2-Oxo-2-furan-3-yl)ethyl-3-phenylthioindole The title compound was ~ ~ed from N-methoxy-N-methylfuran-3-carboxamide (0.32 g, 2.1 mmol), and 2-methyl-3-phenylthioindole (0.50 g, 2.1 mmol) according to the general procedure described in Example 6 for the preparation of 2-(N-phenylacetamido)-3-phenyl-thioindole. The crude product was chromatographed on silica gel with chloroform. The title compound was obtained as a pale yellow solid, mp 127-129C.
Analysis calculated for C20H15N2S
C, 72.05; H, 4.54; N, 4.20 Found: C, 72.08; H, 4.57; N, 4.24 -Preparation of 2-Benzoyl-5-chloro-3-phenylthioindole Step A: N-Methoxy-N-methyl-5-chloro-3-phénylthioindole-2-carboxamide The title compound was prepared from 5-chloro-3-phenyl-thioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethyl-o hydroxyl~mine hydrochloride (0.64 g, 6.6 mmol), triethyl~mine (1.0mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylform~mi~e according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.
Step B: 2-Benzoyl-5-chloro-3-phenylthioindole N-Methoxy-N-methyl-5 -chloro-3-phenylthioindole-2-carboxamide (0.24 g, 0.69 mmol) was dissolved in dry tetrahydrofuran 20 (5 mL) and cooled to -78C under nitrogen. A solution of phenylm~gnesium chloride in tetrahydrofuran (0.81 mL, 2M) was added via syringe and the reaction warmed to 20C overnight Water and ethyl ~cet~te were added to the reaction and then separated. The organic phase was washed with water, 5% aqueous hydrochloric acid, 2s saturated sodium bicarbonate, saturated brine, and dried over m~ sium sulfate. Filtration and evaporation of solvent gave the clude product which was chromatographed on silica gel with 10% ether in hexane. The title compound was obtained as a solid, mp 154-155C.
Analysis calculated for C21H14ClNOS
C, 69.32; H, 3.88; N, 3.85 Found: C, 68.61; H, 3.83; N, 3.83 WO 94/19321 2`1 ~ ~ 4 2 ~ PCT/US94/01694 Preparation of 2-(2-Benzoxazol-2-ylethyl)-3-phenylthioindole StepA: N-Methoxy-N-methyl-3-phenylthioindole-2-~;a~ lide The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxyl~min~o hydrochloride (0.54 g, 5.5 mmol), triethyl~mine (1.5 mL, 11 mmol) o and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.7 mmol) according to the procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.

lS Step B: 3-Phenylthioindole-2-carboxaldehyde N-Methoxy-N-methyl-3 -phenylthioindole-2-carboxamide (1.57 g, 5.26 mmol) was dissolved in tetrahydroruldn (150 mL) and cooled to 0C under nitrogen. A solution of lithium aluminum hydride in tetrahydroru-dn (5.76 mL, lM) was added slowly via syringe and the 20 reaction stirred a total of 1.5 h. Ethyl acetate (30 mL) was added, followed by saturated sodium potassium tartrate solution. The layers were separated and the organic phase washed with saturated brine and dried over m~gnesium sulfate. Filtration and evaporation of solvent gave the title compound as a yellow solid.

Step C: trans-2-(2-Benzoxazol-2-ylethenyl)-3-phenylthioindole n-Butylli~hil.... in he~ne (3.47 mL, 2.5 M) was added to a solution of [(benzoxal-2-yl)-methyl]diethylphosphonate (2.34 g, 8.68 mmol) in tetrahydrorul~l (50 mL) at -78C under nitrogen. The 30 reaction was stirred for 20 min., and warmed to -20C. A solution of 3-phenylthioindole-2-carboxaldehyde (1.10 g, 4.34 mmol) in - tetrahydrofuran (30 mL) was added and the reaction stirred at 20C
ovemight. Ethyl acetate and water were added and the layers separated.
The organic layer was washed with saturated brine and dried over m~gnesium sulfate. The cIude product was triturated with 1:1 hexane 21~120 ethyl acetate and collected by filtration. The title compound was obtained as a yellow solid, mp 260C.
Analysis calculated for C23H16N2S
C,72,32;H,4.58;N,7.33 Found: C, 72.41; H, 4.50; N, 7.44 Step D: 2-(2-Benzoxazol-2-ylethyl)-3-phenylthioindole A solution of trans-2-(2-benzoxazol-2-ylethenyl)-3-phenylthioindole (0.420 g, 1.14 mmol) in 1:1 methanol/tetrahydrorulan lO (250 mL) was stirred under 1 atmosphere of hydrogen in the presence of 10% p~ m on charcoal (100 mg). Additional catalyst was added as needed to drive the reaction to completion. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. The resulting solid was triturated with 10% ethyl ~cet~te in hexane and lS collected by filtration to afford the title co~ ound, mp 192-193C.
Analysis calculated for C23H18N2S
C, 72.80; H, 5.04; N, 7.38 Found: C, 72.78; H, 4.95; N,7.45 Preparation of N-2-Furanylmethyl-5-chloro-3-phenylthioindole-2-carboxamide The title compound was lJl~ar~,d according to the procedure described in Example 1, Step B, e~cept subslil..li..,e 2-aminomethylfuran for 3-aminomethylpyridine. The dimethylformamide was removed in vacuo, and the residue triturated with 1 :1 ethyl acetate-hP~ne and filtered. Reclyst~11i7~tion from acetonitrile gave the title compound, mp 214C.
Analysis calculated for C20H15CIN22S
C, 62.74; H, 3.95; N, 7.32 Found: C, 62.27; H, 3.88; N,7.41 NMR (DMSO-d6): ~ 12.55 (lH, s), 8.72 (lH, t, J=6 Hz),7.55 (1H, m), 7.54 (lH, d, J=8 Hz), 7.45 (lH, d, J=2 Hz),7.15 (lH, tt, J=7,1 Hz), 7.08 (lH, s), 7.06 (lH, d, J= 8 Hz), 6.35 (lH, m), 6.18 (lH, m), 4.56 (2H, d, J=6 Hz).

5 Preparation of N-3-Pyridyl-5-chloro-3-phenylthioindole-2-carboxamide The title compound was yl~ed according to the procedure described in Example 1, Step B, except subsl;l..li..g 3-aminopyridine for 3-aminomethyl-pyridine. The dimethylformamide was removed in vacuo, and the residue triturated with 1:1 ethyl acetate-hexane and filtered. Chromatography on silica gel with 40% ethyl acetate in hexane gave the title compound, mp 255-256C.
Analysis calculated for C20H15ClN3S
C, 63.24; H, 3.98; N, 10.74 Found: C, 62.59; H, 3.86; N, 11.06 NMR (DMSO-d6): ~ 12.72 (lH, s), 10.55 (lH, s), 8.85 (lH, d, J=3 Hz), 15 8.35 (lH, dd, J=5, 1 Hz), 8.14 (lH, dm, Jd=8 Hz), 7.60 (lH, d, J=9 Hz), 7.48 (lH, d, J=2 Hz), 7.40 (lH, dd, J=9, 2 Hz), 7.25 (2H, t, J=7 Hz), 7.16 (lH, m), 7.11 (2H, t, J=7 Hz).

Preparation of N-Ethyl-5-chloro-3-phenylthioindole-2-carboxamide The title compound was prepared according to the procedure described in F.x~mple 1, Step B, except sub~
ethyl~mine for 3-aminomethylpyridine. The dimethylfo~n~mide was 25 removed in vacuo, and the residue triturated with 1:1 ethyl acetate-hexane and ~lltered. Recryst~lli7~tion from 2% methanol in ethyl acetate gave the title compound, mp 210-211C.
Analysis calculated for C17H15ClN2OS-0 S H20 - C, 60.08; H, 4.74; N, 8.24 30 Found: C, 60.00; H, 4.18; N, 8.52 NMR (DMSO-d6): ~ 12.49 (lH, s), 8.31(1H, t, J=6 Hz), 7.54 (lH, d, J=9 Hz), 7.43 (lH, d, J= 2 Hz), 7.27 (3H, m), 7.15 (lH, tt, J=7, 2 Hz), 7.07 (2H, m), 3.35(4H, m), 1.06 (3H, t, J=7 Hz).

WO 94/19321 21 5 6 ~ 2 ~ PCT/US94/01694 Preparation of N-3-Metho~ybenzyl-5-chloro-3-phenylthioindole-2-carboxamide The title compound was prepared according to the procedure described in F.x~mple 1, Step B, except subs~ 3-methoxybenzylamine for 3-amino-methylpyridine. The dimethyl-formamide was removed in Yacuo~ and the residue triturated with 1:1 ethyl acetate-hexane and filtered. Recryst~11i7~tion from acetonitrile gave the title compound, mp 172C.
Analysis calculated for C23H19ClN22S- 3 H20 C, 64.48; H, 4.61; N, 6.54 Found: C, 64.41; H, 4.38; N, 6.75 NMR (DMSO-d6): ~ 12.55 (lH, s), 8.80 (lH, m), 7.55 (lH, d, J=8 Hz), 7.44 (lH, s), 7.25 (3H, m), 7.15 (2H, m), 7.05 (2H, d, J=7 Hz), 6.80 (3H, m), 4.54 (2H, d, J=6 Hz).

Preparation of N-2-Methoxyethyl-5-chloro-3-phenyl-thioindole-2-carboxamide The title compound was prepared according to the procedure described in E~ample 1, Step B, except sul,s~ 2-2s methoxyethyl~min~ for 3-amino-methylpyridine. The ~lim~thyl-fo~mide was removed in vacuo, and the residue t~ ated with 1:1 e~yl acetate-he~ane and filtered to give the title compound, mp 216-217C.
Analysis calculated for C18H17ClN22S: 0-25 H2O
C,59.17;H,4.83;N,7.67 Found: C, 59.11; H, 4.75? N, 7.82 NMR (DMSO-d6): ~ 12.54 (lH, s), 8.44 (lH, t, J=6 Hz), 7.54 (lH, d, J=9 Hz), 7.48 (lH, d, J=2 Hz), 7.28 (3H, m), 7.17 (lH, t, J=7 Hz), 7.10 (2H, m), 3.49 (2H, q, J=6 Hz), 3.37 (2H, t, J=6 Hz), 3.16 (3H, s).

WO 94/19321 21 5 6 ~ 2 ~ PCT/US94/01694 EXAMPLE lS

- ~e~a ation of N-4-Pyridylmethyl-5-chloro-3-phenyl-thioindole-2-carbo~amide The title compound was l~lcl~al~d according to the procedure described in ~mple 1, Step B, except su~s~ g 4-aminomethylpyridine for 3-amino-methylpyridine. The dimethylform~mide was removed in vacuo, and the residue triturated with 1 :1 ethyl acetate-hexane and filtered. Recryst~11i7~tion from acetonitrile gave the title compound, mp 228-229C.
Analysis calculated for C2lHl6clN3os: 0-2 H2O
C, 63.45; H, 4.16; N, 10.57 Found: C, 63.33; H, 4.02; N, 10.50 NMR (DMSO-d6): ~ 12.56 (lH, s), 8.92 (lH, t, J= 6 Hz), 8.38 (lH, d, lS J=4 Hz), 7.55 (lH, d, J=8 Hz), 7.47 (lH, s), 7.31 (lH, dd, J=8, 2 Hz),7.25 (lH, d, J=7 Hz), 7.17 (2H, m), 7.05 (lH, d, J=7 Hz), 4.58 (2H, d, J=6 Hz).

Plcyal~tion of N-2-Hydroxyethyl-S-chloro-3-phenylthioindole-2-carboxamide The title compound was ~le~a~cd according to the procedure described in P.x~mple 1, Step B, except subs~ 2-hydroxyethyl~mine for 3-amino-methylpyridine. The dimethyl-fonn~mide was removed in vacuo, and the residue triturated with 1:1 ethyl acetate-h~x~n~- and filtered. Chromatography on silica gel with 2% methanol in chloroform gave the title compound, mp 222-223C.
Analysis calculated for C17H15ClN202S: 0.3 H20 C, 57.96; H, 4.46; N, 7.95 Found: C, 57.99; H, 4.26; N, 7.90 NMR (DMSO-d6): ~ 12.50 (lH, s), 8.46 (lH, m), 7.55 (lH, d, J=9 Hz), 7.45 (lH, d, J=1 Hz), 7.28 (3H, m), 7.17 (lH, t, J=6 Hz), 7.13 (2H, m), 4.85 (lH, t), 3.49 (lH, m), 3.43 (lH, m).

W O 94/19321 PCTrUS94/01694 2 ~

Preparation of 5-Chloro-3-phenylthioindole-2-carbo~amide The title compound was prepared accordillg to the procedure described in F~mple 1, Step B, except ~ul~slilulil~g an excess of ammonia gas for 3-aminomethylpyridine and triethyl~mine. The dimethylformamide and excess ammonia were removed in vacuo and the residue partitioned between ethyl ~cet~te and 10% hydrochloric o acid. The organic phase was washed with water, 5% sodium hydroxide and saturated brine, and then dried over m~n~sium sulfate. Filtration and evaporation gave a crude product which was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a white solid mp 213-215C.
Analysis calculated for ClsH11ClN2OS-1/3H2O
C,S8.35;H,3.81;N,9.07 Found: C, 58.33; H, 3.64; N, 9.11 NMR (DMSO-d6): ~ 12.52 (lH, bs), 8.06 (lH, s), 7.76 (lH, s), 7.55 (lH, d, J=9 Hz), 7.44 (lH, s), 7.28 (3H, m), 7.15 (lH, t, J=6 Hz), 7~06 (2H, d, J=8 Hz).

Pl~yalalion of S-Chloro-3-phenylthioindole-2-thiocarboxamide A solution of S-chloro-3-phenylthioindole-2-carboxamide (3.8 g, 12.5 mmol) and [2,4-bis(4-methoxyphenyl3-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (5.0 g, 12.5 mmol) in dry THF (110 mL) was reflu~ed under nitrogen for 16 h. The solvent was removed in vacuo and the residue chromatographed on silica gel with 10% ethyl acetate in hexane. The chromatographed product was 30 lliluldted with hexane and the yellowish solid collected and dried to give the title compound, mp 217C (decomposed).
Analysis calculated for ClSH11ClN2S
C, 56.50; H, 3.48; N, 8.79 Found: C, 56.75; H, 3.64; N, 8.59 NMR (DMSO-d6): ~ 12.22 (lH, s), 10.31 (lH, s), 9.48 (lH, s), 7.50 WO 94/19321 2 15 ~ 4 2 ~ PCT/US94/01694 _ (lH, d, J=8 Hz), 7.39 (lH, s), 7.25 (3H, m), 7.13 (lH, t, J=7 Hz), 7.01 (2H, d, J=7 Hz).

Preparation of N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thiocarboxamide The title compound was l,lel,~ed according to the o procedure described for 5-chloro-3-phenyl-thioindole-2-thiocarboxamide except subsliluling N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-carbo~amide for 5-chloro-3-phenylthioindole-2-carboxamide. The crude product was chromatographed on silica gel with 3% ethyl acetate in hexane. The title compound was obtained as a bright yellow solid, mp 143-144C.
Analysis calculated for C2oHlsclN2os2-H2o C, 57.61; H, 3.62; N, 6.72 Found: C, 57.56; H, 3.58; N, 6.52 NMR (DMSO-d6): ~ 12.27 (lH, s), 10.73 (lH, s), 7.55 (2H, m), 7.39 (lH, s), 7.21 (4H, m), 6.98 (2H, d, J=7 Hz), 6.36 (2H, 4.96 (2H, s).

Preparation of N-[1-(2(R)-hydroxypropyl)]-5-chloro-3-phenylthio-indole-2-carboxamide The title compound was l~lG~alGd according to the procedure described in F.x~mrle 1, Step B, except sub~lilulillg 2(R)-hydroxy-l-propyl~min~ for 3-amino-methylpyridine. The dime~ylfomlamide was removed in vacuo and the residue triturated first with 20% ethyl ~ret~te in hexane then by acetonitrile. The title 30 compound was obtained as an off-white solid, mp 202-203C.
Analysis calc~ e~l for Cl8H17ClN22S--3 H20 C, 59.01; H, 4.67; N, 7.65 Found: C, 58.91; H, 4.59; N, 7.50 NMR (DMSO-d6): ~ 12.52 (lH, s), 8.45 (lH, t, J=5 Hz), 7.55 (lH, d, J=8 Hz), 7.46 (lH, s), 7.25 (3H, m), 7.15 (3H, m), 4.89 (lH, d, J=5 Hz), 21~ 86-3.74 (lH, m), 3.38 (lH, m), 3.23 (lH, m), 1.00 (3H, d, J=6 Hz).

5 Preparation of N-(2-pyridyl)methyI-S-chloro-3-phenylthioi~dole-2-~carboxamide The title compound was prepared accordillg to the procedure described in Example 1, Step B, except sub~ 2-pyridylmethylamine for 3-aminomethylpyridine. The dimethyl-o form~mi~e was removed in vacuo and the residue triturated first with30% ethyl acetate in hexane, then with acetonitrile. The title compound was obtained as a white solid, mp 209-210C.
Analysis calc~ teA for C21H16ClN3OS
C, 64.03; H, 4.10; N, 10.67 l5 Found: C, 63.51; H, 3.97; N, 10.41 NMR (DMSO-d6): o 12.58 (lH, s), 9.15 (lH, t, J=S Hz), 8.46 (lH, d, J=S Hz), 7.66 (lH, t, J=8 Hz), 7.57 (lH, d, J=8 Hz), 7.50 (lH, s), 7.25 (5H, m), 7.12 (3H, m), 4.68 (2H, d, J=5 Hz).

Preparation of N-(3-methoxy-4-pyridyl)methyl-S-chloro-3-phenyl-thioindole-2-carboxamide 25 Step 1: Preparation of 4-cyano-2-methoxypyridine A solution of 2-chloro-4-cyanopyridine (1.25 g, 9.1 mmol), prepared as described by D. Libenn~nn, N. Rist, F. Grumbach, S. Cals, M. Moyeux and A. Rouaix, Bull. Soc. Chim. France, 694 (1958), in methanol was treated with sodium me~oxide (0.58 g, 10.9 30 mmol) and refluxed for 30 ~ es. The reaction mixture was cooled, ~lltered and the filtrate concentrated in vacuo to obtain the clude product as an off-white solid. The clude product was chromatographed on silica gel with 20% ethyl ~cet~te in hexane. The title compound was obtained as a white powder.

~1~642~

Step2: Preparation of 4-aminomethyl-2-methoxypyridine A solution of 4-cyano-2-methoxypyridine (0.55 g, 4.1 mmol) in ethanol was hydrogen~te-l at 60 psi H2 in the presence of 10%
Pd/C (100 mg). After 3.5 h the catalyst was removed by filtration ~rough Super-Cel and the filtrate evaporated to give the titre compound~
as a foam.

Step 3: Preparation of N-(3-methoxy-4-pyridylmethyl)-5-chloro-3-o phenylthioindole-2-carboxamide The title compound was prepared according to the procedure described in Example 1, Step B, except subslilutillg 4-aminomethyl-2-methoxypyridine for 3-aminomethylpyridine. The dimethylforrn~mide was removed in vacuo and the crude product purified by chromatography on silica gel with 2040% ethyl acetate in hexane. The title compound was obtained as a white solid, mp 227-228C.
Analysis calc~ tecl for C22H1gClN3O2S
C, 62.33; H, 4.28; N, 9.91 Found: C, 62.63; H, 4.21; N, 9.92 NMR (DMSO-d6): ~ 12.58 (lH, s), 8.93 (lH), 8.37 (2H, d), 7.~6 (lH, d), 7.47 (lH, s), 7.27 (3H, m), 7.18 (2H, m), 7.05 (2H, d), 4.59 (2H, d), 3.30 (3H, s).

Preparation of N-(3-hydroxymethyl)benzyl-5-chloro-3-phenylthio-indole-2-carboxamide The title compound was prepared according to the - procedure described in F.x~mple 1, Step B, except sulJ~ ulil.g 3-30 hydroxymethylbenzyl~mine for 3-amino-methylpyridine. The dimethylforrn~mide was removed in vacuo and the crude product recryst~lli7e~ from acetonitrile. The title compound was obtained as a white solid, mp 229-230C.

21~2~

Analysis calc~ te~l for C22H17C1N22S
C,64.61;H,4.19;N,6.85 Found: C, 64.20; H, 4.09; N, 6.85 NMR (DMSO-d6): o 12.69 (lH, s), 10.33 (lH, s), 7.60 (3H, m), 7.49 S ~1-~ s~ 7.30 (4H,-m), 7.15 (AH, m), 5.22 (lH, t, J=7 Hz), 4.50 (2H, d, l=7 Hz).

Preparation of N-(3 -hydro~ybenzyl)-5-chloro-3 -phenylthioindole-2-carboxamide The title compound was prepared according to the procedure described in Example 1, Step B, except subs~ 3-hydroxybenzyl~mine for 3-aminomethyl-pyridine. The dimethyl-formamide was removed in vacuo and the crude product was chromatographed on silica gel with 10% methanol in chloroform. The title compound was obtained as a white solid, mp 214-216C.
Analysis calculated for C22Hl7clN2o2s-o.3 H2O
C, 63.77; H, 4.04; N, 6.76 Found: C, 63.92; H, 3.88; N, 6.49 NMR (DMSO-d6): ~ 12.55 (lH, s), 9.34 (lH, s), 8.75 (lH, t, J=5 Hz), 7.53 (lH, d, J=8 Hz), 7.45 (lH, s), 7.1-7.65 (4H, m), 7.06 (2H, d, J=7 Hz), 7.01 (lH, t, J=8 Hz), 6.70 (lH, s), 6.62 (2H, m), 4.48 (2H, d, J=5 Hz).

Preparation of S-Chloro-3-phenylsulfonylindole-2-carbo~amide (Compound 18) 3 0 5-Chloro-3-phenylthioindole-2-carbo~amide (0.177 g, 0.584 mmol) was dissolved in 25 mL chloroform and cooled to 0C.
50% by weight meta-chloro~elo~ybenzoic acid (503 mg, 1.46 mmol) was added and the reaction stirred at 20C for 6 hours. A 10% aqueous solution of sodium ~iosulfate was added and the reaction vigorously stirred for 10 ..,i....tes. The layers were separated and the organic phase WO 94/19321 21 5 ~ 4 ~ O PCT/US94/01694 washed with saturated sodium chloride then dried over magnesium sulfate. The crude product was chromatographed over silica gel eluting with 40% ethyl acetate in he~ane. The title compound was obtained as a white powder, mp 255-257C.
NMR (300 MHz, DMSO-d6~- ~ 13.05~ (lH,s), 8.48(1H,s), 8.25~1H,s), 8.03(2H,d,J=8 Hz), 7.95(1H,s), 7.60(4H,m), 7.34(1H,d,J=8 Hz).
Analysis calculated for Cl5Hl lClN23S
C, 53.82; H, 3.31; N, 8.37 Found: C, 53.74; H, 3.29; N, 8.34 Preparation of 5-Chloro-3-phenylsulfinylindole-2-carboxamide (Compound 17) A solution of m~gnesium monoperoxyphthalic acid (85%
peracid) (11.8 mg, 0.024 mmol) in methanol (2 mL) was added dropwise to a solution of 5-chloro-3-phenylthioindole-2-carboxamide (14.5 mg, 0.048 mmol) in methanol (2 mL) at O~C. The reaction was stirred at 20C for 4 hours. A solution of 10% aqueous sodium 20 thiosulfate was added and the reaction stirred vigorously for 10 lules. Methanol was removed in vacuo and the residue partitioned between ethyl ~cet~te and water. The ethyl acetate extract was washed with brine and dried over m~nesium sulfate. The crude product was purified by column cllrulllatography on silica gel with 30-40% ethyl 25 ~cet~te in hexane. The title compound was obt~ine~l as a white solid.
NMR (DMSO-d6, 300 MHz) ~ 12.53(1H, s), 8.35(1H,br s), 8.08(1H,br s), 7.83(1H,d,l=2 Hz), 7.71(2H,d,l=8 Hz), 7.52(4H,m), 7.30(1H,dd,J=9,2 Hz).

W O 94/19321 ~ PCTrUS94/01694 ~1 ~6~2~

Preparation of N-(2,6-difluorobenzyl)-5-chloro-3-phenyl-sulfonyl-5~ indole-2-carboxamide Step A: 5-chloro-3-phenylsulfonylindole-2-carboxylic acid To a suspension of 5-chloro-3-phenylthio-indole-2-carbo~ylic acid (4.84 g, 0.016 mol) in chloroform (1200 mL) was added 55% m-chloroperoxybenzoic acid (12.5 g, 0.04 mol). The mixture was allowed to stir at room temperature for 40 hours.
Filtration afforded the title compound as a colorless solid, mp 277-280C (dec). On partial evaporation a second crop of product was obtained.

Step B: Product of reaction of 5-chloro-3-phenyl-sulfonylindole-2-carboxylic acid with oxalyl chloride To a suspension of 5-chloro-3-phenylsulfonyl-indole-2-carboxylic acid (5.04 g, 0.015 mol) in chloroform (200 mL) was added oxalyl chloride (3.81 g, 0.03 mol). After addition of a catalytic amount of dimethylformamide (0.1 mL) the mixtllre was h~te-l at a bath temperature of 60C for 50 min~ltes. After cooling, the solid product, mp >300C, was utilized directly without further purification. While based on mass spectral and NMR data, this product appears to be a symmetrical dimer, it behaves as a typical acid chloride in reactions with primary ~mines.

Step C: N-(2,6-difluorobenzyl)-5-chloro-3-phenyl-sulfonylindole-2-carboxamide 2,6-Difluorobenzylamine (0.430 g, 3.0 mmol) was added dropwise to the solution of the "acid chloride equivalent" from Step B
(0.354 g, 1.0 mmol) in tetrahydrofuran solution (10 mL) cooled in an ice-acetone bath. The reaction mixture was allowed to warm to room tempelalure and left overnight. For work-up, ethyl acetate and water were ~ le~ The ethyl acetate phase was washed well with dilute WO 94tlg321 ~ 1 5 ~ ~ 2 ~ PCT/US94/01694 hydrochloride acid, saturated aqueous sodium bicarbonate, and brine.
Mer dIying over m~gnesium sulfate and evaporation of the solvent, the residue was slurried with ethyl acetate and filtered to give the title compound, mp 274-280C.
Analysis calculated for C22Hl5clF2N2o3s-o~5H2o C, 56.24; H, 3.43; N, 5.96 Found: C, 56.12; H, 3.31; N, 5.97 NMR (DMSO-d6) o 13.06 (lH, s), 9.41 (lH, t, J=S.SHz), 7.95 (3H, m), 7.41-7.67 (m, 5H), 7.34 (lH, dd, J=9, 2Hz), 7.18 (2H, t, J=8Hz), 4.64 (2H, d, J=5.5Hz).

Pre~,a~ation of N-(4-pyridylmethyl)-5-chloro-3-phenyl-sulfinylindole-15 2-carboxamide (29) Step A: Preparation of 5-chloro-3-phenylsulfinyl-indole-2-carboxylic acid To a suspension of 5-chloro-3-phenylthioindole-2-20 carboxylic acid (2.14 g, 0.007 mol) in chloroform (600 mL) was added55% m-chloropero~ybenzoic acid (2.32 g, 0.0074 mol). The n~i~ur~
cleared briefly and then solids appeared. After stirring overnight at room temperature, the title compound was obt~in~l in pure form on filtration, mp 183-185C.

Step B: N-(4-pyridylmethyl)-5-chloro-3-phenylsulfinylindole-2-carboxamide To a mi~ture of 5-chloro-3-phenylsulfinylindole-2-carboxylic acid (0.096 g, 0.3 mmol), triethyl~mine (0.061 g, 0.6 30 mmol), 4-aminomethylpyridine (0.043 g, 0.4 mmol) in dry dimethylfo~mide was added benzotriazol-l-ylo~ytris(dimethyl-amino)phosphonium he~afluorophosphate (BOP reagent) (0.155 g, 0.35 mmol). The mi~tu~ was stirred at room temperature under nitrogen for three days. Following evaporation, the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was separated WO 94/19321 ` PCT/US94/01694 215~4 æ~

and washed with dilute hydrochloric acid. The acidic extract was neutralized with aqueous sodium bicarbonate and the product extracted into ethyl acetate. The ethyl acetate extract was washed well with 5 aqueous sodium bicarbonate, then brine, and dried over m~nesium sulfate. Evaporation afforded a soIid residue which was recryst~lli7ed from ethyl acetate to give the title cGnllJoulld, mp 233-235C.
Analysis calc~ te~l for C21H16ClN32S
C, 61.54; H, 3.93; N, 10.25 Found: C, 61.39; H, 3.95; N, 10.36 10 NMR (DMSO-d6) o 9.62 (lH, t, J=6 Hz), 8.53 (2H, d, J=6Hz), 7.80 (lH, d, J=2 Hz), 7.67 (2H, m), 7.64 (2H, d, J=9 Hz), 7.44-7.54 (3H, m), 7.33 (3H, m), 4.60 (2H, dq, l=9, 6 Hz).

Preparation of N-[(S)-1-phenyl-2-hydroxyethyl]-5-chloro-3-phenyl-sulfonylindole-2-carboxamide (32) To a solution of the acid chloride dimer product from Example 27, Step B, (0.354 g, 1.0 mmol) in tetrahydrofuran (10 mL), 20 cooled in an ice-acetone bath, was added a solution of (S)-(+)-2-phenylglycinol (0.343 g, 2.5 mmol). The ~ u~e, after w~nnin~
gradually to room ~enl~elature, was allowed to sit overnight. Ethyl ~et~te and water were ~-1de-1 The ethyl ~cet~te phase was washed successively with dilute hydrochloric acid, water, saturated sodium 25 bicarbonate and brine. After drying over m~n~sium sulfate and evaporation, the product was chromatographed on a 20 mm column co.~ 6 inches of 230-400 mesh silica gel. Elution with 40% ethyl ~çet~te-methylene chloride gave pure title compound which, after evaporation, was crystallized from e~yl acetate-he~ane to give the title 30 compound, mp 155-160C.
Analysis calculated for C23Hl9CIN24S
C, 60.72; H, 4.21; N, 6.16 Found: C, 60.33; H, 4.13; N, 6.16 NMR (DMSO-d6): o 13.05 (lH, s), 9.52 (lH, d, J=7.5 Hz), 7.95-8.48 WO 94/19321 21 S g 4 2 0 PCT/US94101694 (3H, m), 7.26-7.68 (lOH, m), 5.13 (lH, q, J=7.5 Hz), 5.07 (lH, t=6 Hz), 3.75 (2H, 6Hz).

N-(3 -methoxybenzyl)-S-chloro-3 -(2-thiazolyl)sulfonyl-indole-2-carboxamide (31) o Step A: Preparation of S-Chloro-3-(2-thiazolyl)thioindole-2-carboxylic Acid Using the procedure of F.x~mrle 1, Step A, but sub~liluling di-(2-thiazolyl)disulfide for phenyl-lic~ de, there was obtained the title compound, mp 242-244C.

Step B: Preparation of S-Chloro-3-(2-thiazolyl)-sulfonylindole-2-carboxylic Acid Using the procedure of F.x~mple 27, Step A, but sub~ ulillg S-chloro-3-(2-thiazolyl)thioindole-2-carboxylic acid for 5-20 chloro-3-phenylthioindole-2-carboxylic acid, there was obtained the title compound, mp 260-261C.

Step C: Product of Reaction of S-Chloro-3-(2-thiazolyl)sulfonyl-indole-2-carboxylic Acid with Oxalyl Chloride 2s Using the procedure of Fx~mrle 27, Step B, but sul,slilulillg S-chloro-3-(2-thiazolyl)sulfonylindole-2-carboxylic acid for S-chloro-3-phenylsulfonylindole-2-carboxylic acid, there was obtained a solid product, mp>290C, which was ~tili7ed directly in the next step.

Step D: N-(3-medloxybenzyl)-S-chloro-3-(2-thiazolyl-~ulfonyl)-indole -2-carboxamide To a solution of the 'acid chloride' product from Step C
(0.181 g, 0.5 mmol) in tetrahydrofuran (5 mL), cooled in an ice-acetone bath, was added 3-methoxybenzyl~mine (0.205 g, l.S mmol).
The mi~lu-e was allowed to warm to room temperature and then was 21~; 12~

left overnight with stirring. Ethyl acetate and water were added. The e~yl acetate layer, after separation, was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and brine. After drying (magnesium sulfate) and evaporation, the solid residue was allowed to stand in a small volume of ethyl acetate. Filtration gave the title product, mp 205-209C.
Analysis calc~ te~l for C20H16ClN34S2 C, 52.00, H, 3.49, N, 9.10 Found: C, 51.88, H, 3.42, N, 9.07 o (DMSO-d6) ~ 9.43 (lH, t, J=6 Hz), 8.18 (lH, d, J=3 Hz), 8.02 (lH, d, J=3 Hz), 8.00 (lH, d, J=2 Hz), 7.58 (lH, d, J=8.5 Hz), 7.40 (lH, dd, J=8.5, 2 Hz), 7.28 (lH, t, J=8 Hz), 6.98-7.05 (2H, m), 6.85 (lH, dd, J=8, 2.5 Hz), 4.54 (2H, d, J=3.76 Hz).
l 5 EXAMPLE 31 5 -Chloro-3 -(2-thiazolyl)sulfonylindole-2-carboxamide A solution of the 'acid chloride' product of Example 30, Step C, (0.50 g, 1.4 mmol) in tetrahydloru~ (25 mL) was added 20 slowly to a solution of tetrahydrofuran saturated with ammonia at -10C. The reaction mi~ture was allowed to warm gradually to room tempelalule and then was stirred overnight. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water.
The e~yl acetate e~tract was washed wi~ saturated sodium bicarbonate 25 and bnne, and dried with m~gnesium sulfate. After evaporation of solvent, the residue was slurried in e~yl acetate and filtered to give the title compound, mp 292-294C (dec).
Analysis calculated for C12H8ClN33S2 C, 42.17; H, 2.36; N, 12.29 30 Found: C, 42.23; H, 2.35; N, 11.85 NMR (DMSO-d6) ~ 8.39 (lH, br s), 8.34 (lH, br s), 8.24 (lH, d, J=3 Hz), 8.07 (lH, d, J=3 Hz), 8.00 (lH, dd, J=2, 0.6 Hz), 7.57 (lH, dd, J=9, 0.6 Hz), 7.40 (lH, dd, J=9, 2Hz).

2 !L ~ ~ 4 2 ~

5-Chloro-3-phenylsulfonylindole-2-thiocarboxamide Reaction of 5-chloro-3-phenylsulfonylindole-2-carboxamidè with 2,4-bis~4-met~o~yphenyl)-1,3-dithia-2,4-diphosphetane (Lawesson's reagent) according to the procedure of Example 18 gave the title compound. Clllomatographic purification on silica gel was carried out using 30% ethyl acetate-methylene chloride, followed by 50% ethyl acetate-methylene chloride. The pure product had mp 207-210C.
Analysis calculated for C15Hl lClN22S2 C,51.35;H,3.16;N,7.98 Found: C, 50.84; H, 3.08; N, 8.04 NMR (DMSO-d6) ~ 12.90 (lH, s), 10.71 (lH, s), 10.70 (lH, s), 8.0-8.6 5 (2H, m), 7.84 (lH, d, J=2Hz), 7.54-7.66 (3H, m), 7.46 (lH, d, J=8.5Hz), 7.30 (lH, dd, J=8.5, 2Hz).

20 Preparation of 3-phenylsulfonyl-5-chloroindole-2-carboxamide Step A: N-(phenylthio)succinimide To a partial solution of N-chlorosucci~ lide (3.34 g, 25 mmol) in dry methylene chloride (30 mL), cooled in an ice bath and 25 under an inert atmosphere, was added thiophenol (2.05 mL, 20 mmol) via syringe. After stirring for 1 hour, additional N-chlorosuccinimide (0.40 g, 3 mmol) was ~ e~l. After 2.5 hours total, triethyl~mine (3.9 mL, 28 mmol) was added dropwise. Within 15 mimltes the reaction mixtllre was ~lil-lte~l with methylene chloride, ~e solvent washed wi~
30 dilute aq. HCl and the solvent then dried ~a2SO4), filtered through a pad of charcoal and evaporated. The residue was triturated with diethyl ether and the product collected by filtration to yield the title compound mp 115-116C [lit. mp 115-116C, J. Org. Chem.. 34, 51 (1969)]. This material was used as is.

2~ ~42~

Step B: Ethyl 3-phenylthio-5-chloroindole-2-carboxylate To a partial suspension of ethyl 5-chloroindole-2-carboxylate (698 mg, 3.1 mmol) and N-(phenylthio)succi~ nide (683 mg, 3.3 mmol) in anhydrous methylene chloride (20 mL) at ambient tempe~lule under-an inert gas atmosphere was added boron trifluoride etherate (0.12 mL, 1.0 mmol). The reaction was monitored by tlc (thin layer chromatography) until complete. After 2 hours, the reaction was diluted with chloroform and neutralized with aq. NaHCO3. The organic layer was dried (Na2S04)j filtered through a pad of charcoal, and the solvents evaporated. The residue was triturated with hexanes as the product crystallized out to yield the title product, mp 160-162C [see Table II, mp 163-164C]. This material was used as is.

Step C: Ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642 mg, 1.94 mmol) was dissolved in chloroform (35 mL) and a dried (Na2SO4) solution of m-chloro~ero~ybenzoic acid (55% pure, 1.30 g, 4.1 mmol) in chloroform (20 mL) was added dropwise. The progress of the oxidation was monitored by tlc until complete. After 5 hours, the reaction was diluted with chloroform and some methanol and the solution washed with aq. NaHCO3 and aq. Na2CO3. The dried (Na2SO4) organic layer was filtered through a pad of charcoal and the solvents removed under reduced pressure. The residue was triturated with diethyl ether to yield the product. Cryst~11i7~tion from methylene chloride and diethyl ether gave analytically pure material, mp 201-202C.
lH NMR (CDC13) ~ 9.63 (br s, lH), 8.58 (t, lH, J=0.7 Hz), 8.07 (d, 2H, J=7 Hz), 7.46-7.56 (m, 3H), 7.40 (m, 2H), 4.39 (ABq, 2H, J=7 Hz), 0 1.35 (t, 3H, J=7 Hz).
3 Analysis calculated for C17H14ClN04S
C, 56.12; H, 3.88; N, 3.85 Found: C, 55.91; H, 3.95; N, 3.91 WO 94/19321 ~3 ~ 2 ~ PCT/US94/01694 Step D: 3-Phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 18) A suspension of ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate (596 mg, 1.64 mmol) in aqueous conc. ammonium hydroxide (10 mL) co--t?i-~ g ammonium chloride (28 mg) was heated at 100C for 3 hours in a sealed screw-top tube. The sealed tube was cooled in an ice bath as product cryst~lli7e!1 out. The product was o collected by filtration, rinsed with ice water, and dried to give the product, mp 253-254C.

Preparation of N-[(imidazol-2-yl)methyl]-3-phenyl-sulfonyl-5-chloroindole-2-carboxamide A suspension of 2-aminomethylimidazole dihydrochloride (256 mg, 1.5 mmol) [prepared as described in J. OrP. Chem.. 43, 1603 (1978)] in dry tetrahydroru~ul (6 mL) cont~inin~ triethyl~min~o (.42 20 mL, 3.0 mmol) was stirred at room temperature under an inert atmosphere for one hour. The dimeric acid chloride (179 mg, 0.25 mmol) [see Example 27, Step B] was ~d~ed, followed by additional triethyl~mine (0.07 mL, 0.5 mmol) and the mi~lre was stirred for 12-20 hours. The ~ Lule was diluted with water and the product 25 extracted into ethyl ~cet~te. This organic layer was dried (Na2SO4), filtered, and the solvents evaporated. The residue was triturated with ethyl acetate to give the product. Recryst~11i7~tion from hot ethyl acetate gave analytically pure product, mp 276-278C.
lH NMR (DMSO-d6) ~ 9.50 (br t, lH, J=5.4 Hz), 8.07 (s, lH), 8.05 30 (S, lH), 8.00 (d, lH, J=1.2 Hz), 7.52-7.67 (m, 4H), 7.37 (dd, lH, J=1.5, 9 Hz), 7.03 (br s, 2H), 4.61 (d, 2H, J=5.4 Hz).
Analysis calculated for ClgHlsClN4O3S
C, 55.00; H, 3.64; N, 13.50 Found: C, 54.67; H, 3.36; N, 13.37 WO 94/19321 ,~ PCT/US94/01694 Preparation of N-[(l-methylimidazol-2-yl)methyl]-3-phenylsulfonyl-5-5 chloroindole-2-carboxamide (19) Step A: 2-Aminomethyl-l-methylimidazole To a suspension of lilhiulll al.l.~ hydride (114 mg, 3.0-mmol) in dry tetrahydrofuran (15 mL) at room temperature in an inert atmosphere was added solid 1-methylimidazole-2-carboxamide (185 mg, 1.5 mmol) [l~le~a~ed according to J. Or~. Chem., 52, 4379 (1987)] in portions. After stirring the reaction llli~lule for 0.5 hour, the temperature was raised to 50C for 3.5 hours. After cooling this reaction, satd. aq. Na2SO4 (2 mL) was added to quench reaction and 15 then powdered anhyd. Na2SO4. Filtration of this mi~tlllre to remove salts gave a dry solution of 2-aminomethyl-1-methyl-imidazole in tetrahydro~u~ (~25 mL) which was used as is.

Step B: N-[(l-methylimidazol-2-yl)methyl]-3-phenyl-sulfonyl-5-2 0 chloroindole-2-carboxamide A solution of the dimeric indole acid chloride (see Example 27, Step B) (358 mg, 0.5 mmol) in dry tetrahydrofuran (7 mL) was added dropwise to the above solution of 2-aminomethyl-1-methyl-imidazole in tetrahydror~ l, which was cooled in an ice bath. After 15 min. triethyl~mine (0.2 mL, 1.4 mmol) was added and the reaction .,.ixl~..e slowly warmed to room temperature over 12-20 hours. The reaction was ~lilllte~l with water and the product e~tracted into 10%
methanol/ethyl ~cet~te. The e~tract was dried (Na2S04), filtered through charcoal, and the solvents evaporated. The residue was 30 ~ ated with ethyl ~cet~te and the product collected by filtration.
Recryst~11i7~tion from hot methanol/ethyl acetate gave analytically pure material, mp 273-275C.
lH NMR (DMSO-d6) o 9.48 (br t, lH, J=5 Hz), 8.05 (d, 2H, J=7 Hz), 7.98 (d, lH, J=2 hz), 7.52-7.67 (m, 4H), 7.35 (dd, lH, J=2, 9 Hz), 7.18 215~420 _ 99 _ (d, lH, J=1 Hz), 6.88 (d, lH, J=l Hz), 4.66 (d, 2H, J=5 Hz), 3.71 (s, 3H).
Analysis calculated for C20H17ClN43S
C, 56.00; H, 4.00; N, 13.06 s Found: C, 55.77; H, 3.97; N, 13.41 The hydroc~hloride salt was obtained by addition of one equivalent of ethanolic HCl to the free base, mp 284-285C with decomposition.
Analysis calculated for C20H17ClN43S-C, 51.62; H, 3.90: N, 12.04 Found: C, 51.21; H, 3.92; N, 11.55 15 Alternate Preparation of N-[(l-methylimidazol-2-yl)-methyl] 3-phenylsulfonyl-5 -chloroindole-2-carboxamide To a partial suspension of N-[(imi~701-2-yl)-methyl] 3-phenylsulfonyl-S-chloroindole-2-carboxamide (Example 35) (42 mg, 0.1 mmol) in 1:1 methanoVtetrahydrofuran (4 mL) was added 20 iodomethane (.05 mL, 0.8 mmol). The reaction was stirred for three days at room tempelalule. The solvents were removed under reduced pressure, aq. NaHCO3 added and the product extracted into ethyl acetate/methanol. The organic layer was dried (Na2SO4), filtered, and the solvents evaporated. The residue was purified by chromatography 25 and the product eluted with 3% methanoVchloroform. A~l~.~liate fractions were combined, the solvents ev~olated, and ~e residue u~ated with me~ylene chloride to give pure product.

Preparation of N-[2-(imidazol4-yl)ethyl]-3-phenyl-sulfonyl-5-chloro-indole-2-carboxamide (24) Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a solution of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid (Example 27, Step A) (336 mg, 0.5 mmol) cooled in an ice bath under an inert WO 94/19321 2 I 5 64 ~ o PCT/US94/01694 atmosphere. After 0.5 hours, hist~mine (125 mg, 1.12 mmol) was added to the yellow solution. After S hours the reaction was diluted with water and the product extracted into ethyl ~cet~te. This organic layer was washed with dilute aq. NaHCO3, dried (Na2SO4), filtered through charcoal and the solvents evaporated. Tii~ ation of this residue with methylene chloride gave the crude product. Cryst~11i7~tion from hot ethyl ~cet~te gave analytically pure product, mp 220-221.5C.
H NMR (DMSO-d6) ~ 9.11 (br t, lH, J=5.4 Hz), 8.00 (s, lH), 7.98 o (s, lH), 7.95 (d, lH, J=2.1 Hz), 7.52-7.67 ~m, SH), 7.35 (dd, lH, J=2.1, 8.7 Hz), 6.94 (s, lH), 3.60 (q, 2H, J=7.2 Hz), 2.83 (t, 2H, J=7.2 Hz).
Analysis calculated for C20H17ClN43S
C, 56.00; H, 4.00; N, 13.05 Found: C, 55.74; H, 4.04; N, 13.35 Preparation of N-(3-methoxybenzyl)-3-phenylsulfonyl-S-chloroindole-2-carboxamide A solution of dimeric acid chloride (Example 27, Step B) 20 (1.77 g, 2.5 mmol) in dry tetrahydrofu.a" (25 mL) was added dropwise to a solution of 3-methoxybenzyl~mine (1.3 mL, 10 mmol) in dry tetrahydrorul~l (20 mL) cooled with an ice acetone bath. The reaction was stiITed for 12-20 hours and then ~ teA with 10% methanol/ethyl ~cet~te. This organic layer was washed with dilute HCl, dried 25 (Na2so4)~ filtered, and the solvents evaporated. The residue was triturated with diethyl ether to give flocculent white product.
Recryst~11i7~tion from hot m~th~novethyl acetate gave analytically pure product, mp 203-204C.
lH NMR (DMSO-d6) ~ 9.47 (br t, lH, J=6 Hz), 8.03 (s, lH), 8.01 30 (S, lH), 7.94 (d, lH, J=2.1 Hz), 7.63 (t, lH, J=6.9 Hz), 7.52-7.58 (m, 3H), 7.35 (dd, lH, J=2.1, 8.7 Hz), 7.29 (t, lH, J=7.8 Hz), 7.06 (s, lH), 7.05 (d, lH, J=6.6 Hz), 6.86 (dd, lH, J=2.7, 7.5 Hz), 4.57 (q, 2H, J=6 Hz), 3.76 (s, 3H).

WO 94/19321 2 ~; 6 !~! 2 0 PCT/US94/01694 Analysis calculated for C23H1gClN2O4S
C, 60.72; H, 4.21; N, 6.16 Found: C, 60.60; H, 4.17; N, 6.12 Preparation of N-(3-hydro~ybenzyl)-3-phenylsulfonyl-S-chloroindole-2-carboxamide To a saturated solution of N-(3-methoxybenzyl) 3-o phenylsulfonyl-5-chloroindole-2-carboxamide (1.37 g, 3.0 mmol) in dry methylene chloride (140 mL) under an inert atmosphere was added boron tribromide in hexane (1 M, 10 mL, 10 mmol). After stirring for 12-20 hours, the reaction was neutralized by addition of aq. NaHCO3.
After two hours, the solution was made weakly acidic by addition of 15 dilute HCl. The preci~ilated product was collected by filtration and then the aqueous filtrate extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the solvent evaporated. The residue was triturated with diethyl ether to give additional product. The solids were combined and crystallized from hot methanoVethyl acetate to give 20 analytically pure product, mp 273.5-274.5C.
lH NMR (DMSO-d6) ~ 9.43 (t, lH, J=6 Hz), 8.01 (s, lH), 7.98 (s, lH), 7.97 (d, lH, J=2.1 Hz), 7.63 (t, lH, J=6 Hz), 7.52-7.58 (m, 3H), 7.35 (dd, lH, J=2, 1, 9 Hz), 7.17 (t, lH, J=7.8 Hz), 6.89 (s, lH), 6.86 (s, lH), 6.84 (s, lH), 6.70 (dd, lH, J=2.1, 8.4 Hz), 4.50 (d, 2H, J=6 Hz).
25 Analysis calculated for C22H17ClN24S
C,59.93;H,3.89;N,6.36 Found: C, S9.91; H, 3.86; N, 6.51 Preparation of N-(3-nitrobenzyl)-3-phenylsulfonyl-S-chloroindole-2-carboxamide Using the procedure described in Example 34, except for subslilu~ g 3-nitrobenzylamine hydrochloride for 2-aminomethyl-imidazole dihydrochloride and adjusting the amount of triethylarnine 21 56~20 accordingly, the title compound was obt~in~l, mp 253-254C.
Analysis calc~ te~l for C22H16ClN3OsS
C, 56.23; H, 3.43; N, 8.94 Found: C, 55.98; H, 3.37; N, 8.85 Preparation of N-(3-aminobenzyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide (30) - lO A solution of N-(3-nitrobenzyl) 3-phenyl-sulfonyl-5-chloroindole-2-carboxamide (353 mg, 0.75 mmol) in tetrahydrofuran (25 mL) and methanol (10 mL) co.-t~ g pl~i.,.. oxide (70 mg) was hydrogenated with an atmospheric pressure of hydrogen for 3 hours.
The deg~se-l solution was filtered to remove catalyst and the solvents evaporated. The residue was triturated with diethyl ether to give the product. Cryst~11i7~tion from acetonitrile gave analytically pure product, mp 247-249C.
lH NMR (DMSO-d6) o 9.38 (t, lH, J=6 Hz), 7.98 (s, lH), 7.96 (d, lH, J=2.1 Hz), 7.53-7.60 (m, 4H), 7.35 (dd, lH, J=2.1, 9 Hz), 7.02 (t, lH, 20 J=7.5 Hz), 6.61 (s, lH), 6.60 (d, lH, J=6 Hz), 6.50 (dd, lH, J=2.1, 8.1 Hz), 4.43 (d, 2H, J=6 Hz).
Analysis calculated for C22Hl8clN3o3s-o.2sH2o C, 59.45; H, 4.20; N, 9.46 Found: C, 59.43; H, 4.08; N, 9.54 Preparation of N-(2-methoxybenzyl)-3-phenylsulfonyl-5-chloroindole-2-carbo~amide Using the procedure described in F.x~mple 38, except sul,~liluli.,p 2-methoxybenzyl~min~ for 3-metho~ybenzyl~min~, the title compound was obt~ine~l, mp 235-237C.
lH NMR (DMSO-d6) ~ 9.39 (t, lH, J=6 Hz), 7.99 (d, lH, J=2.1 Hz), 7.95 (s, lH), 7.93 (s, lH), 7.63 (t, lH, J=7.2 Hz), 7.50-7.57 (m, 3H), 7.29-7.44 (m, 3H), 7.06 (d, lH, J=7.5 Hz), 6.97 (dt, lH, J=0.9, 7.2 Hz), WO 94/19321 21~ 6 ~ 2 ~ PCT/US94/01694 4.55 (d, 2H, J=5.7 Hz), 3.85 (s, 3H).
Analysis calc~ te~l for C23Hl9clN2o4s-o.2H2o C, 60.24; H, 4.26; N, 6.11 Found: C, 60.19; H, 4.40; N, 6.11 Preparation of N-(2-hydroxybenzyl)-3-phenylsulfonyl-S-chloroirldole-2-carboxamide o Using the procedure described in F.x~mple 39, except subslilulillg the 2-me~oxy isomer (Example 42) for the 3-methoxy isomer described, the title compound was obtained, mp 243-244.5C.
lH NMR (DMSO-d6) ~ 7.99 (d, lH, J=3 Hz), 7.98 (s, lH), 7.97 (s, lH), 7.63 (t, lH, J=6 Hz), 7.51-7.57 (m, 3H), 7.33-7.38 (m, 2H), 7.14 5 (dt, lH, J=1.2, 7.8 Hz), 6.89 (d, lH, J=7.2 Hz), 6.81 (t, lH, J=7.2 Hz), 4.52 (s, 2H).
Analysis calculated for C22H17C~N24S- 2H20 C, 59.44; H, 3.95; N, 6.30 Found: C, 59.38; H, 3.70; N, 6.39 Preparation of N-(4-methoxybenzyl)-3-phenylsulfonyl-S-chloroindole-2-carboxamide Using the procedure described in Example 38, except sub~lilutillg 4-methoxybenzyl~mine for 3-methoxy~l~yl~mine, the title compound was obtained, mp 205-206C.
lH NMR (DMSO-d6) ~ 9.42 (br t, lH, J=6 Hz), 8.01 (s, lH), 7.98 (s, lH), 7.95 (d, lH, J=1.8 Hz), 7.64 (t, lH, J=7.2 Hz), 7.52-7.58 30 (m, 3H), 7.33-7.40 (m, 3H), 6.95 (d, 2H, J=9 Hz), 4.51 (d, 2H, J=6 Hz), 3.76 (s, 3H).
Analysis calculated for C23Hl9ClN24S
C, 60.72; H, 4.21, N, 6.16 Found: C, 60.59; H, 4.14; N, 6.11 WO 94/19321 . ~ 4 2 ~ PCT/US94/01694 Preparation of N-(4-hydro~ybenzyl)-3-phenylsulfonyl-5-chloroindole-2-carbo~amide Using the procedure described in Example 39, e~cept subs~ g the 4-metho~y isomer (Fx~mrle 44) for the metho~y isomer described, the title compound was obtained, mp 249-250C.
H NMR (DMSO-d6) ~ 9.35 (t, lH, J=6 Hz), 7.95-7.99 (m, 3H), 7.62 (t, lH, J=6.9 Hz), 7.52-7.57 (m, 3H), 7.35 (dd, lH, J=1.8, 8.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 6.76 (d, 2H, J=8.1 Hz), 4.46 (d, 2H, J=6 Hz).
Analysis calculated for C22H17CIN24S
C, 59.93; H, 3.89; N, 6.36 Found: C, 59.37; H, 3.85; N, 6.25 Preparation of N-(3-acetylaminobenzyl)-3-phenyl-sulfonyl-5-chloro-indole-2-carboxamide A solution of N-(3-aminobenzyl) 3-phenyl-sulfonyl-5-20 chloroindole-2-carboxamide (Example 41) (176 mg, 0.4 mmol) in dry tetrahydroru,~n (7 mL) co.lt~ g acetic anhydride (0.05 mL, 0.5 mmol) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with ethyl ~t~et~te. The organic layer was dried (Na2SO4), filtered through charcoal, and the solvents 25 evaporated. The residue was triturated ~,vith methylene chloride and the solid collected by filtration to give the product, mp 249-250C.
lH NMR (DMSO-d6) ~ 9.98 (br s, lH), 9.39 (v br s, lH), 7.96-8.00 (m, 3H), 7.51-7.62 (m, 6H), 7.30 (t, 2H, J=8 Hz), 7.14 (d, lH, J=8 Hz), 4.53 (br s, 2H), 2.04 (s, 3H).
30 Analysis calc~ te-l for C24H20CIN304S
C, 59.81; H, 4.18; N, 8.72 Found: C, 59.41; H, 4.09; N, 8.62 WO 94/19321 21~ ~ 4 ~ ~ PCTIUS94/01694 Preparation of N-(3-methylsulfonylaminobenzyl)-3-phenyl-sulfonyl-5-chloroindole-2-carboxamide (34) To a solution of`N-(3-aminobenzyl) 3-phenyl-sulfonyl-5-chloroindole-2-carboxamide (174 mg, 0.4 mmol) in dry tetrahydro-furan (7 mL) at room temperature under an inert atmosphere was addedmethanesulfonyl chloride (.035 mL, .45 mmol) and triethyl~mine (0.7 mL, .50 mmol). Over a period of 20 hours, the reaction progress was monitored by tlc. Additional equivalents of methanesulfonyl chloride and triethyl~mine were added twice over this period to obtain complete reaction with the carboxamide. The reaction was diluted with water, acidified with dilute HCl, and the product extracted into chloroform.
This organic layer was dried (Na2SO4), filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel.
Elution with 1% methanol/chloroform gave the bis-sulfonylated product as evidenced by two methyl group resonances in the NMR at ~ 3.47 and 2.98.
This material was dissolved in dimethoxyether (3 mL) and water (2 mL) and lithium hydroxide monohydrate (66 mg, 1.57 mmol) was added. The solution was heated at 60C for two hours. The cooled reaction was acidified with dilute HCl. Upon stirring for 2-3 hours, the product cryst~lli7e~ out and was collected by filtration and dried.
Recryst~11i7~tion from hot meth~novethyl ~cet~te gave analytically pure product, mp 252-253C.
H N~R (DMSO-d6) ~ 9.48 (br t, lH,J=5.4 Hz),8.01(s,lH),7.98(s, lH),7.95 (d, lH,J=1.8 Hz),7.63 (t, lH,J=7.2Hz),7.52-7.58(m,3H), 7.33-7.38 (m, 2H),7.27 (br s, lH),7.23 (br d, lH,J=7.8 Hz),7.15 (d, lH,J=7.8 Hz),4.55 (d, 2H,J=5.4 Hz),3.00(S,3H).

Analysis calculated for C23H20ClN3O5S2 C, 53.33; H, 3.89; N, 8.11 Found: C, 53.26; H, 3.86; N, 8.12 Pl~alation of N-benzyl-3-phenylsulfonyl-5-chloroindole-2-carboxamide A solution of the dimeric acid chloride (Example 27, Step B) (170 mg, 0.25 mmol) in dry tetrahydroruldll (2 mL) was added dropwise to a solution of benzyl~minç (.28 mL, 2.5 mmol) in dry tetrahydrorul~ul (3 mL) cooled in an ice/acetone bath. The reaction llli~lUl~ was left to stir for 12-20 hours as the temperature rose to ambient. The solvents were removed under vacuum and the residue 15 partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), and the solvent evaporated. The residue was crystallized from ethyl ~cet~te/methanol to give analytically pure product, mp 249-251C.
lH NMR (DMSO-d6) ~ 9.47 (t, lH, J=6 Hz), 8.02 (s, lH), 8.00 (s, lH), 20 7.95 (d, lH, J=2.1 Hz), 7.33-7.57 (m, 10 H), 4.59 (d, 2H, J=6 Hz).
Analysis calculated for C22H17ClN23S
C, 62.19; H, 4.03; N, 6.59 Found: C, 62.14; H, 4.13; N, 6.62 Preparation of N-(3-pyridylmethyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide (28) Using the procedure in F.x~mple 48, except subsl;l~.l;.-g 3-30 aminomethylpyridine for benzylamine, the title compound was obtained, mp 263-264C.
Analysis calculated for C21H16ClN33S
C, 59.22; H, 3.79; N, 9.87 Found: C, 59.01; H, 3.79; N, 9.87 WO 94/19321 2 1 5 6 4 2 ~ PCT/US94/01694 P~a~dtion of N-(2-pyridylmethyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide Using the procedure described in P.~mple 48, e~cept sub~ ;..g 2-aminomethylpyridine for benzyl~mine, the title compound was obtained, mp 250-251C.
Analysis calculated for C21H16ClN33S
C, 59.22; H, 3.79; N, 9.87 o Found: C, 59.04; H, 3.73; N, 10.06 Preparation of N-[2-(pyridin4-yl)ethyl]-3-phenyl-sulfonyl-5- .
lS chloroindole-2-carboxamide Using the procedure described in Example 48, except subslilulillg 4-(2-aminoethyl)pyridine for benzyl~minP, the title compound was obt~ine~, mp 258-260C.
Analysis calculated for C22H18CIN303S
C, 60.07; H, 4.12; N, 9.55 Found: C, 59.68; H, 3.84; N, 9.30 25 Preparation of N-(2-hydroxyethyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide Using the procedure described in F.~mple 48, except sub~ g 2-hydro~yethyl~min~ for benzyl~minP, ~e title compound was obt~in~l, mp 198-200C.
Analysis calculated for C17H1sClN2O4S
C, 53.90; H, 3.99; N, 7.39 Found: C, 54.09; H, 3.94; N, 7.25 .
~ I S ~

Preparation of N-ethyl-3-phenylsulfonyl-5-chloroindole-2-carboxamide Using the procedure described in Example 48, except SUI;JS~ Ig ethyl~mine for benzyl~ ;..e, the title compound was -obtained, mp 259-260C.
Analysis calculated for C17H15ClN23S
C,56.28;H,4.17;N,7.72 Found: C, 56.07; H, 4.11; N, 7.73 Preparation of N-[(2-chloropyridin-4-yl)methyl]-3-phenylsulfonyl-5-~ chloroindole-2-carboxamide Using the procedure described in Example 35, Step B, except sub~lil..li..~ 2-chloro-4-~minomethyl-pyridine for 2-~minomethyl-l-methylimidazole, the title compound was obtained, mp 263-265C.
Analysis calculated for C21H15Cl2N33S
C, 54.79; H, 3.28; N, 9.13 Found: C, 54.38; H, 3.18; N, 9.03 2 5 Pl e~al ation of N-cyclopropyl-5-chloro-3-phenylsulfonyl-indole-2-carboxamide (26) Using the procedure described in Fx~mple 48, e~cept sulJslilu~ g cyclopropyl~mine for benzyl~mine, the title compound was obtained, mp 242-243C.
Analysis calculated for C18H15ClN23S
C, 57.68; H, 4.03; N, 7.47 Found: C, 57.40; H, 3.94; N, 7.43 WO 94/19321 ~ 4 2 0 PCT/US94/01694 Preparation of N-(cyclopropylmethyl)-3-phenylsulfonyl-S-chloroindole-2-carboxamide Using ~e procedure described in Example 48, except subslil.l~ cyclopropylme~yl~mine for benzyl~mine, the title compound was obt~in~-l, mp 232-234C.
Analysis calculated for C19H17ClN23S
C, 57.88; H, 4.50; N, 7.11 o Found: C, 57.92; H, 4.34; N, 7.09 P~a~ation of 3-(4-chlorophenylsulfonyl)-5-chloro-indole-2-15 carboxamide Using the procedure described in Fx~mple 30 and 31, except sub~lillllillg bis(4-chlorophenyl)disul~de for di(2-thiazolyl)-disulfide, the title compound was obt~ine~l, mp 275-277C.
Analysis calculated for ClSH10C12N203S
C, 48.32; H, 2.81; N, 7.51 Found: C, 48.23; H, 2.84; N, 7.91 25 Preparation of 3-(3-chlorophenylsulfonyl)-5-chloro-indole-2-carboxamide Using the procedure described in F.x~mple 30 and 31, except sub~lil..li.-~ bis(3-chlorophenyl)disullSde for di(2-thiazolyl)-disulfide, ~e title compound was obt~ine~l, mp 272-273C.
Analysis calculated for ClSH10C12N203S
C, 48.79; H, 2.73; N, 7.59 Found: C, 48.39; H, 2.70; N, 7.44 21 56~2~

Preparation of 3-(3,5-dichlorophenylsulfonyl)-S-chloro-indole-2-carboxamide Using the procedu~e described in F~mple 30 and 31~
except sulJslilulillg bis(3,5-dichlorophenyl)-disulfide for di(2-thiazolyl)-disulfide, the title compound was obt~in~-~l, mp 258-260C.
Analysis calculated for ClsHgCl3N2O3S
C, 44.63; H, 2.25; N, 6.94 o Found: C, 44.49; H, 2.24; N, 7.04 Preparation of 3-(2-chlorophenylsulfonyl)-S-chloro-indole-2-15 carboxamide Using the procedure described in F.x~mple 33, except sub~lil..l;.~g 2-chlorothiophenol for thiophenol, the title compound was obtained, mp 267C.
Analysis calculated for C15H10Cl2N23S
C, 48.79; H, 2.73; N, 7.59 Found: C, 48.69; H, 2.73; N, 7.62 25 Preparation of 3-(pyridin-2-ylsulfonyl)-5-chloroindole-2-carboxamide Using the procedure described in F.x~mrle 30 and 31, except subslil.~li..g bis(pyridin-2-yl)disulfide for di(2-thiazolyl)-disulfide, the title compound was obt~in~l, mp 244-246C.
Analysis calculated for C14H10ClN33S
C, 50.08; H, 3.00; N, 12.51 Found: C, 50.31; H, 3.00; N, 12.55 ~6~9Q

Preparation of 3-(pyridin-3-ylsulfonyl)-5-chloroindole-2-carboxamide 5Using the procedure described in Example 30 and 31, except ~ubslil..li..g bis(pyridin-3-yl)disulfide for di(2-thiazolyl)-disulfide, the title compound was obtained, mp 300C dec.
FAB mass spectrum: m/e = 336 (M+1) Preparation of 3-(pyridin-4-ylsulfonyl)-5-chloroindole-2-carboxamide Using the procedure described in Example 30 and 31, except subslilu~ g bis(pyridin4-yl)disulfide for di(2-thiazolyl)-disulfide, the title compound was obt~ine!l, mp>260C dec.
FAB mass spectrum: m/e = 336 (M+1) 20 Preparation of 3-[(1-methylimidazol-2-yl)sulfonyl]-5-chloroindole-2-carboxamide Using the procedure described in Example 30 and 31, except subs~ i..g bis(1-methylimidazol-2-yl)-disulfide for di(2-thiazolyl)disulfide, the title compound was obt~ine~, mp 255-2S6C dec.
Analysis calculatedforC13H11clN4O3s C, 46.09; H, 3.27; N, 16.54 Found: C, 46.02; H, 3.28; N, 16.27 30 Preparation of N-(3-methoxybenzyl-3-(3-chlorophenylsulfonyl)-5-chloroindole-2-carboxamide Using the procedure described in Example 38, except subsliLu~ g the dimeric acid chloride derived from 3-(3-cniorophenylsulfonyl)-5-chloroindole-2-carboxylic acid for that derived from 3-(phenyl-sulfonyl)-5-chloroindole-2-carboxylic acid, the title 2~56~2~

compound was obtained, mp 225-226.5C.
Analysis calculated for C23H18C12N24S
C, 56.45; H, 3.71; N, 5.73 Found: C, 56.52; H, 3.70; N, 5.83 s Preparation of N-(3-hydroxybenzyl)-3-(3-chlorophenylsulfonyl)-5-chloroindole-2-carboxamide o Using the procedure described in F.x~mple 39, N-(3-methoxybenzyl)-3-(3-chlorophenylsulfonyl)-5-chloroindole-2-carbo~amide was demethylated to obtain the title compound, mp 230-231C.
Analysis calculated for C22H16C12N24S
S C, 55.58; H, 3.39; N, 5.89 Found: C, 55.59; H, 3.36; N, 5.66 20 Preparation of N-[( l -methylimidazol-2-yl)methyl]-3-(3-chloro-phenylsulfonyl)-5-chloroindole-2-carboxamide (23) Using the procedure described in F.~mple 35, except for substituting the dimeric acid chloride derived from 3-(3-chlorophenyl-sulfonyl)-5-chloroindole-2-carboxylic acid for that derived from 3-2s (phenylsulfonyl)-5-chloroindole-2-carboxylic acid, the title compound was obtained, mp 232-234C.
Analysis calculated for C20H16C12N43S
C, 51.84; H, 3.48; N, 12.09 Found: C, 51.46; H, 3.38; N, 11.78 WO 94/19321 ~15 ~ PCT/US94/01694 Preparation of 2-carbo~amido-5-chloroindole-3-cyclo-propyl-5 sulfonamide Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-sulfonic acid Concentrated sulfuric acid (2.50 ml, 90 mmol) was added dropwise over 5 min at 0C to a stirred solution of 2-carboethoxy-5-chloro-1-phenylsulfonylindole (7.28 g, 20.0 mmol) in acetic anhydride (10 ml) and dry dichloromethane (50 ml). The resulting tan solution was warmed to RT (room temperature) and after 3 hours was poured onto ice and the mi~ re was e~tracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (Na2S04) and evaporated in vacuo to a syrup. Residual acetic anhydride was removed by a_eotroping with toluene (3 x 50 ml), and the residue was cryst~lli7e(1 from dichloromethane. The dichloromethane was evaporated in vacuo to give the title compound as a tan powder:
20 lH NMR (d6 DMSO) ~ 1.33 (t, J=7.1 Hz, 3H), 4.33 (q, J=7.1 Hz, 2H), 7.44 (dd, J=8.9 and 2.2 Hz, lH), 7.63 (t, J=7.6 Hz, 2H), 7.73 (t, J=7.4 Hz, lH), 7.77 (d, J=2.2 Hz, lH), 7.96 (d, J=8.9 Hz, lH), 8.00 (d, J=7.6 Hz, 2H).

25 Step B: 2-Carboethoxy-5-chloro-1-phenylsulfonyl-indole-3-cyclopropylsulfonamide Oxalyl chloride (0.90 ml, 10.3 mmol) was added to a stirred solution of 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-sulfonic acid (1.505 g, 3.39 mmol) in dry dichloromethane (15 ml) at 30 0C. DMF (2 drops) was added and the solution was warmed to room temperature. More DMF (1 drop) was added and the reaction was - heated to reflux. After 2 hours, the solution was cooled and evaporated in vacuo to give the sulfonylchloride as a tan solid. This was dissolved in dichloromethane (15 ml) and cyclopropyl~min~ (0.94 ml, 13.56 mmol) and pyridine (0.5 ml) were ~d(lecl. The solution was heated to 5~fl~ J

reflux and after 15 min was cooled, r~ te~l with ethyl acetate and was washed with 1 M HCl solution, sodium hydrogen c~bollate solution and brine, dried (Na2S04) and evaporated in vacuo to a gum. Methanol (5 ml) was added to give a colorless solid, and the mixture was stirred and 5 h~te~l to reflux for 5 min. The solids were filtered cold, w~.chin~ with cold methanol (3xS ml), and were dried in vacuo to give the title compound as colorless crystals: mp 189-191C;
H NMR (CDCl3) o 0.61 (m, 4H), 1.48 (t, J=7.1 Hz, 3H), 2.26 (m, lH), 4.58 (q, J=7.1 Hz, 2H), 5.06 (br s, lH), 7.42 (dd, J=9.0 and 2.0 Hz, lH), 7.54 (t, J=7.6 Hz, 2H), 7.66 (t, J=7.5 Hz, lH), 7.97 (d, J=9.0 Hz, lH), 7.98 (d, J=2.0 Hz, lH), 8.09 (d, J=7.6 Hz, 2H).

Step C: 2-Carboxamido-5-chloroindole-3-cyclopropyl-sulfonamide A ...i,~ re of 2-carboethoxy-5-chloro-1-phenyl-sulfonyl-indole-3-cyclopropylsulfonamide (0.42 g, 0.870 mmol) and 2:1:1 10%
potassium hydroxide solution/methanolm~ (20 ml) was heated to reflux to give a clear tan solution. After 0.5 hour reflux the solution was cooled and was concentrated in vacuo to 1/2 volume. The solution 20 was acidified with 1 M HCl, and the resulting ~ e was extracted with ethyl ~cet~te, washed with brine, dried (Na2S04) and evaporated in vacuo to a gum. The crude product was dissolved in 2% sodium hydroxide solution which was acidified with 1 M HCl. The solid material was collected by filtration, washed with 1 M HCl solution, and 2s dried in vacuo to give 3-cyclopropylsulfonamido-5-chloroindole-2-carboxylic acid. Oxalyl chloride (0.58 ml, 6.65 mmol) and DMF
(1 drop) were added to a stirred suspension of the acid in dry dichloromethane (10 ml). After 1 hour at room tem~eldluIe the lu~ was he~e~l to reflux for 1 hour, cooled and evaporated in 30 vacuo to a tan solid. The solid was suspended in acetone (10 ml) and 9:1 ammonium hydroxide/acetone solution (20 ml) was ~ e~l~ After 15 min the solution was eva~oldted in vacuo to 2 ml in volume and the residue was acidified with 1 M HCl solution and the mixture was e~tracted with ethyl acetate. The ethyl acetate layer was washed with sodium hydrogen carbonate solution, dried (Na2S04) and evaporated in W0 94/lg321 ?., ~ 2 a PCT/US94/01694 ,.

vacuo. The resulting tan solid was purified by flash chromatography on silica (dry loaded, eluting with a chlorofo~n/methanol gradient, 2-10%
methanol), to give the title compound as colorless c~rstals (from ethyl acetate/he~anes): mp236-238C;
lH NM~. (d6 DMSO) ~ 0.40 (m, 4H), 2.07 (m, lH), 7.35 (dd, J=8.7 and 2.1 Hz, lH), 7.56 (d, J=8.7 Hz, lH), 8.01 (d, J=1.7 Hz, lH), 8.10 (d, J=2.1 Hz, lH), 8.22 (br s, lH), 8.47 (br s, lH).

Preparation of 2-carboxarnido-S-chloroindole-3-phenyl-sulfonamide Step A: 2-Carboethoxy-S-chloro-l-phenylsulfonylindole-3-phenylsulfonamide In the manner olltline~ in F.x~mple 68, Step B, ~niline (0.63 ml, 6.91 mmol) was added to 2-carboethoxy-S-chloro-l-phenyl-sulfonylindole-3-sulfonylchloride to give, after flash column chromatography on silica (dry loaded, eluting with an ethyl acetate/he~anes gradient, 20-30% ethyl acetate) the title compound as colorless crystals;
lH NMR (CDCl3) ~ 1.47 (t, J=7.1 Hz, 3H), 4.58 (q, J=7.1 Hz, 2H), 6.74 (br s, lH), 7.11 (m, SH), 7.31 (dd, J=9.0 and 2.2 Hz, lH), 7.51 (t, J=8.1 Hz, 2H), 7.57 (d, J=1.7 Hz, lH), 7.65 (t, J=7.5 Hz, lH), 7.87 (d, J=9.0 Hz, lH), 7.99 (d, J=7.6 Hz, 2H).

Step B: S-Chloro-3-phenylsulfonamidoindole-2-carboxylic acid 2-Carboethoxy-S-chloro- 1 -phenylsulfonylindole-3-phenylsulfonamide (0.39 g, 0.75 mmol) was dissolved in 2:1:1 10%
- 30 sodium hydroxide solution/methanoUI~lF (20 ml) and after 2 hours the solution was acidified with 1 M HCl, and the resulting ."i~lll.e was e~tracted with ethyl ~cet~te, washed with bnne, dried ~a2SO4) and evaporated in vacuo to a glass. Dichloromethane (S ml) was added to give a colorless solid, and the mixture was stirred and heated to reflux for S min. The solids were filtered cold, washing with cold dichloro-WO 94/19321 2 ~ ~ ~? 4 2 0 PCT~S94/01694 methane, and were dried in vacuo to give the title compound as colorless crystals;
lH NMR (d6 DMSO) ~ 7.28 (t, J=7.1 Hz, lH), 7.4 (d, J=7.2 Hz, 2H), 7.51 (t, J=7.1 Hz, 2H), 7.72 (dd, J=8.8 and 2.1 Hz, lH), 7.86 (d, J=8.8 Hz, lH), 8.43 (d, J=2.1 Hz, lH), 10.25 (br s, lH).

Step C: 2-Carboxamido-5-chloroindole-3-phenyl-sulfonamide Oxalyl chloride (0.087 ml, 1.00 mmol) and DMF (1 drop) were added to a stirred solution of 5-chloro-3-phenylsulfonamido-indole-2-carbo~ylic acid (123 mg, 0.35 mmol) in dry THF (3 ml) at 0C. After 1 hour at room t~ erature the solution was evaporated in vacuo to give a tan solid. The solid was dissolved in acetone (1 ml) and 9:1 ammonium hydroxide/acetone solution (2 ml) was ~ le-l After 0.5 hours the solution was evaporated in vacuo to a gum which was dissolved in ethyl acetate, washed with 1 M HCl and brine, dried (Na2SO4) and evaporated in vacuo. The resulting tan solid was purified by flash column chromatography on silica (dry loaded, eluting with an ethyl acetate/he~n~s gr~lient, 20-70% ethyl acetate) to give the title compound as colorless crystals (from dichloromethane); mp 225-227C:
lH NMR (d6 DMSO) ~ 7.00 (m, 3H), 7.17 (t, J=7.3 Hz, 2H), 7.30 (dd, J=8.8 and 2.0 Hz, lH), 7.48 (d, J=8.8 Hz, lH), 7.93 (d, J=2.0 Hz, lH), 8.21 (br s, lH), 8.28 (br s, lH), 10.34 (br s, lH).

cl ~ation of 2-carbo~amido-5-chloroindole-3-methyl-(phenyl)-sulfon-amide 30 Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-methyl(phenyl)sulfonamide In the manner olltlin~ in F.x~mple 68, Step B, N-methyl-~niline was added to 2-carboethoxy-5-chloro-1-phenyl-sulfonylindole-3-sulfonylchloride to give, after flash column chromatography on silica (dry loaded, eluting with an ethyl ~cet~te/hexanes gradient, 10-30%

WO 94/19321 ,~ ~ 5 ~ 4 2 ~ PCT/US94/01694 ethyl acetate) the title compound as colorless crystals (from dichloromethane/hexanes);
lH NMR (CDC13) ~ 1.46 (t, J=7.1 Hz, 3H), 3.30 (s, 3H), 4.55 (q, J=7.1 Hz, 2H), 6.69 (d, J=2.0 Hz, lH), 7.11 (d, J=7.0 Hz, 2H), 7.26 (m, 4H), 7.54 (t, l=7.6 Hz, 2H), 7.66 (t, J=7.4 Hz, lH), 7.87 (d, J=8.8 Hz, lH), 8.08 (d, J-7.6 Hz, 2H).

Step B: 5-Chloro-3-methyl(phenyl)sulfonamidoindole-2-carboxylic acid In the m~nner olltlin~l in Example 69, Step B, 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-methyl-(phenyl)-sulfonamide (0.39 g, 0.75 mmol) was hydrolysed in 2:1:1 10% sodium hydroxide solution/methanol~IF (20 ml, 14 h at RT (room telnpelature) followed by 5 min at reflux), to give the title compound (from ethyl acetate);
lH NMR (d6 DMSO) ~ 3.26 (s, 3H), 7.03 (d, J=2.2 Hz, lH), 7.21 (m, 6H), 7.46 (d, J=8.8 Hz, lH).

Step C: 2-Carboxamido-5-chloroindole-3-methyl(phenyl)-sulfonamide In the m~nn~r outlined in Example 69, Step C, starting with 5-chloro-3-methyl(phenyl)sulfonamidoindole-2-carboxylic acid, and after purification by flash column chromatography on silica (dry loaded, eluting with 2% meth~nouchloroform)~ the title compound was obtained as colorless crystals (from ethyl acetate); mp 240-242C.
1H NMR (d6 DMSO) ~ 3.13 (s, 3H), 7.06 (d, J=2.1 Hz, lH), 7.09 (m, 2H), 7.23 (dd, J=8.8 and 2.1 Hz, lH), 7.26 (m, 3H), 7.48 (d, J=8.8 Hz, lH), 8.01 (br s, lH), 8.06 (br s, lH).

Preparation of N-[2-(1-methylimidazol~-yl)ethyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide (25) Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic WO 94/19321 ~ 1 5 6 ~ 2 a PCT/US94/01694 acid with 1-methylhistamine under the conditions of F.x~mple 37 provides the title compound.

P~e~al~tion of N-[2-(3-methylimidazol-4-yl)ethyl]-3-phenylsulfonyl-5 -chloroindole-2-carbo~amide Reaction of 3-phenylsulfonyl-S-chloroindole-2-carboxylic acid with 3-methylhist~min~ under the conditions of Example 37 gave the title compound, mp 257-258.5C.

lS Pl~yal~tion of N-[(imi~7ol-4-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carbo~amide Reaction of the dimeric acid chloride (F.x~mple 27, Step B) with 4-aminomethylimidazole under the conditions of F.x~mple 34 provides the title compound.

Preparation of N-~3-(imidazol-1-yl)propyl]-3-phenylsulfonyl-5-chloroindole-2-carbo~amide Reaction of the 3-phenylsulfonyl-S-chloroindole-2-carboxylic acid with 1-(3-aminopropyl)-imidazole under the conditions of Example 37 gave the title compound, mp 216-217.5C.

Preparation of 3-phenylsulfonyl-S-methylsulfonylamino-indole-2-carboxamide (36) Step A: 3-Phenylsulfonyl-S-nitroindole-2-carboxamide Reaction of ethyl S-n.lloil~dole-2-carboxylate (J. Amer.

~ ~ 2 ~

Chem. Soc. 80, 4621 (1958)) with N-(phenyl-thio)succinimide under the conditions of Example 33, Step B, followed by oxidation to the sulfonyl product (Step C) provides a product which may be converted to the title compound with ammonium hydroxide at elevated te.l,l,e~ture and pressure.

Step B: 3-Phenylsulfonyl-5-aminoindole-2-carboxamide Reduction of 3-phenylsulfonyl-S-l~ ,dole-2-carbox-o amide with hydrogen under the conditions of Example 41 provides the title compound.

Step C: 3-Phenylsulfonyl-5-methylsulfonylaminoindole-2-carboxamide Reaction of 3-phenylsulfonyl-S-aminoindole-2-carboxamide with methanesulfonyl chloride under the conditions of Example 47 provides the title compound.

Preparatlon of 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamido)-methyllpyridin-2( 1 H)-one (37) Step A: N-(2-methoxy-4-pyridylmethyl)-S-chloro-3-phenyl-2 5 sulfonylindole-2-carboxamide Reaction of the 'acid chloride dimer' product of Example 27, Step B, with 2-methoxy-4-pyridylmethyl~mine under the conditions of Example 27, Step C, provides the title compound.

Step B: 4-[(S-Chloro-3-phenylsulfonylindole-2-carboxamido)-methyll -pyridin-2( 1 H)-one Reaction of N-(2-methoxy-4-pyridylmethyl)-5-chloro-3-phenylsulfonylindole-2-carboxamide with boron tribromide in methylene chloride at 0C to room tempel~lule, according to the procedure described in Example 39, provides the title compound.

~1~642~

5 Preparation of N-(2-amino-4-pyridylmethyl)-5-chloro-3-phenyl-sulfonylindole-2-carboxamide (38) Step A: 2-Amino-4-aminomethylpyridine 2-Aminopyridine-4-carbonitrile (L.W. Deady et ah, Aust.
o 1. Chem., 35, 2025 (1982)) is reduced catalytically according to the procedure of D.E. Beattie et al. for the preparation of 2-amino-3-aminomethyl pyridine (J. Med. Chem., 20, 718, (1977)) to give the title compound.

Step B: N-(2-Amino-4-pyridyl~nethyl)-5-chloro-3-phenylsulfonyl-indole -2-carboxamide Reaction of 2-amino-4-aminomethylpyridine with the dimeric acid chloride from Fx~mple 27, Step B, according to the procedure of Example 27, Step C, provides the title compound.

Preparation of N-(2-aminothiazol-4-ylmethyl)-5-chloro-3-phenyl-sulfonyl-indole-2-carboxamide 2s Reaction of the dimeric acid chloride from Example 27, Step B, with 2-aminothiazol-4-ylmethyl~mine (Chem. Ab. 58, 4534 (1962)) under the conditions of F.x~mple 27, Step C, provides the title compound.

4 2 (3 Preparation of N-cyano-5-chloro-3-phenylsulfonylindole-2-carbox-5 imid-amide (35) Step A: 5-Chloro-3-phenylsulfonylindole-2-carbonitrile 5-Chloro-3-phenylsulfonylindole-2-carboxamide reacts with methyl (carboxysulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent) in tetrahydrofiuan (IHF) solvent as described by D.A. Claremon and B.T. Phillips (Tetrahedron Lett., ~2, 2155 (1988)) to provide the title compound.

Step B: Ethyl 5-chloro-3-phenylsulfonylindole-2-carboximidate 5-Chloro-3-phenylsulfonylindole-2-call,o~ ileis allowed to react with ethanol saturated with hydrogen chloride at 0-10C for 7 days. Evaporation to dryness affords the title compound as a hydrochloride salt. The title compound is obtained as a free base by ~dclin.~ the reaction ~ e to an ice cold solution of excess potassium 20 carbonate and extracting the product with chloroform.

Step C: N-Cyano-5-chloro-3-phenylsulfonylindole-2-carboximid-amide Ethyl 5-chloro-3-phenylsulfonylindole-2-car~oximidate is 2s reacted with an equimolar amount of cyanamide in absolute meth~nol (according to the procedure of K.R. Hllffm~n and F.C. Schaefer (~.
Org. Chem.. 28, 1812 (1963)). After 30-60 ~ tes the solvent is removed and the residue purified by silica gel chromatography to afford the title compound.

2~ 20 Preparation of N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-carboxamide (27) Using the procedure of Example 48 but sub~li~..li..~
cyclobutyl~mine for benzyl~min~, there is obtained the title compound.

Preparation of N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide (39) Using the procedure of Example 28, Step B, but sub~lilulillg cyclopropyl~mine for 4-aminomethylpyridine, there is obtained the title compound.

Preparation of N-[(1-methylimidazol-2-yl)methyl]-3-phenylsulfinyl-5-20 chloroindole-2-carboxamide (20) Using the procedure of Fx~mple 28, Step B, but subsl it..l i..g 2-aminomethyl-1 -methylimi~7ole for 4-aminomethyl-pyridine, there is obtained the title compound.

2s ~le~ tion of N-[(1-methylimidazol-4-yl)methyl-3-phenylsulfonyl-5-chloroindole-2-carbo~amide (21) and N-[(1-methylimidazol-5-yl)me~yll-3-phenylsulfonyl-5-chloroindole-2-carboxamide (22) Step A: N-[(Imidazol-4(or 5)-ylmethyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide Employing the procedure of F.x~mple 34, but substituting 4(or 5)-aminomethylimidazole dihydrochloride for 2-aminomethyl-imidazole dihydrochloride, there is obtained the title compound.

~ G42~

Step B: N-[(1-methylimidazol-4-yl)methyl]-3-phenylsulfonylindole-f 5-chloroindole-2-carboxa~ide; N-[(1-methylimi~1~7Ol-5-yl)methyll-3-phenylsulfonyl-5-chloroindole-2-carboxamide Employing the procedure of E~ample 36, but sub~
N-[(imidazol-4(or 5)-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide for N-[(imidazol-2-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, there is obtained each of the title compounds which are obtained pure by chromatography on silica gel.

r~epa~ation of N-[(R)-1-phenylethyl]-5-chloro-3-phenylsulfonyl-indole-2-carboxamide (33) Employing the procedure of Example 29, but substitlltin~
(R)-(+)-a-methylbenzyl~mine for (S)-(+)-2-phenylglycinol, there was obtained the title compound, mp 149C.
Analysis calculated for C23H1gC1N2O3S-0.15 C2H4O2-0.15H2O
C, 62.32; H, 4.54; N, 6.16 Found: C,62.39;H,4.54;N,6.01 lH NMR (DMSO-d6) o 3.06 (lH, s); 9.43 (lH, d, J=8Hz); 7.94-8.02 (3H, m); 7.46-7.67 (6H, m); 7.25-7.42 (4H, m); 5.21 (lH, q,J =7Hz);
1.53 (3H, d, J=7Hz).

r~a dlion of N-[(1-ethylimirl~7O1-2-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carbo~amide Using ~e procedure described in F~mrle 35, e~cept 30 sub~ ulil~g 2-aminomethyl-1-ethylimidazole for the 2-aminomethyl-1-methylimidazole (Step A), the title compound was obtained, mp 204-205.5C.

While the foregoing specification teaches the pnnciples of the present invention, with examples provided for the purpose of 1 2 ~

illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations, and modifications, as come wi~in the scope of the following claims and its equivalents.

Claims (6)

WHAT IS CLAIMED IS:

1. A compound selected from the group consisting of:
N-[(1-methylimidazol-2-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-2-yl)methyl]-3-phenylsulfinyl-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-4-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-5-yl)methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-2-yl)methyl]-3-(3-chlorophenylsulfonyl)-5-chloroindole-2-carboxamide, N-[2-(imidazol-4-yl)ethyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-[2-(1-methylimidazol-4-yl)ethyl]-3-phenyl-sulfonyl-5-chloroindole-2-carboxamide, N-cyclopropyl-5-chloro-3-phenylsulfonylindole-2-carboxamide, N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-carboxamide, N-(3-pyridylmethyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-(4-pyridylmethyl)-5-chloro-3-phenylsulfinyl-indole-2-carboxamide, N-(3-aminobenzyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-(3-methoxybenzyl)-5-chloro-3-(2-thiazolyl)-sulfonylindole-2-carboxamide, N-[(S)-1-phenyl-2-hydroxyethyl]-5-chloro-3-phenylsulfonylindole-2-carboxamide, N-[(R)-1-phenylethyl]-5-chloro-3-phenylsulfonyl-indole-2-carboxamide, N-(3-methylsulfonylaminobenzyl)-3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-cyano-5-chloro-3-phenylsulfonylindole-2-carboximidamide, 3-phenylsulfonyl-5-methylsulfonylaminoindole-2-carboxamide, 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamido)-methyl]pyridin-2(1H)-one, N-(2-amino-4-pyridylmethyl)-5-chloro-3-phenyl-sulfonylindole-2-carboxamide, and N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide, or a pharmaceutically acceptable salt or ester thereof.

2. The compound N-[(1-methylimidazol-2-yl)-methyl]-3-phenylsulfonyl-5-chloroindole-2-carboxamide, or a pharmaceutically acceptable salt thereof.

3. A method of inhibiting HIV reverse transcriptase, comprising administering to a mammal an effective amount of a compound of Claim 1.

4. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS or ARC, comprising administering to a mammal an effective amount of a compound of Claim 1.

5. A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS or ARC, comprising an effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier.