JPH08507067A - HIV reverse transcriptase inhibitor - Google Patents

Abstract

  (57) [Summary] The novel compound of the present invention inhibits HIV reverse transcriptase, and can be used as a compound, a pharmaceutically acceptable salt, or a component of a pharmaceutical composition, as another antiviral agent, antiinfective agent, immunomodulator. , Useful in the prevention or treatment of HIV infection and the treatment of AIDS, with or without antibiotics or vaccines. Methods of treating AIDS and preventing or treating HIV infection are also disclosed.

Description

Detailed Description of the InventionInvention title HIV reverse transcriptase inhibitor   The present invention provides reverse transcriptase encoded by the human immunodeficiency virus (HIV). Related to a compound that inhibits For the prevention and treatment of HIV infection and acquired immunodeficiency as a result of HIV infection It is beneficial for the treatment of the syndrome (AIDS). The present invention also contains the above compounds Pharmaceutical compositions, as well as compounds of the present invention and other agents, may be used for AIDS and HIV viruses. It also relates to the method used to treat the infection.Background of the Invention   The retrovirus, called human immunodeficiency virus (HIV), has a progressive immune system. System destruction (acquired immune deficiency syndrome; AIDS) and central and peripheral nervous system degeneration It is the etiological agent of complex diseases including. This virus was formerly known as LAV, HTLV- Known as III or ARV. One of the usual features of retrovirus replication is A virus-encoded reverse transcriptase reverse transcribes the RNA genome, which Occasionally, a DNA copy of the HIV sequence is generated, which is essential for viral replication. This is an essential step. Some compounds, eg For example, azidothymidine or AZT is a reverse transcriptase inhibitor, and It is known to be an effective substance for treating a patient.   By HIV nucleotide sequencing, within one open reading framepolgene Is known to exist (L. Ratner et al.,Nature 313, p. 277, 1985). From the amino acid sequence homology,polSequence is reverse transcriptase , Have been proven to encode endonucleases and HIV proteases (H. Toh et al.,EMBO J.M. Four, P. 1267, 1985; D. Po wer, etc.Science 231, P. 1567, 1986; H. Pea rl, etc.,Nature 329, P. 351, 1987).   The compounds of the present invention are inhibitors of HIV reverse transcriptase. Moreover, the compound of the present invention Are effective without being bioactivated.Summary of the invention   Formula A as defined herein The novel compounds of This compound is also pharmaceutically acceptable as a compound Other antiviral agents, both as appropriate salts (where appropriate) and as ingredients of pharmaceutical compositions , Or in combination with antiinfectives, immunomodulators, antibiotics or vaccines Inhibition of HIV reverse transcriptase without prevention, prevention of HIV infection, treatment of HIV infection, And are useful in treating AIDS and / or ARC. Those who treat AIDS Methods, methods of preventing HIV infection, and methods of treating HIV infection are also disclosed.Detailed Description of the Invention and Preferred Embodiments   The present invention provides a compound of formula A, a combination of compounds of formula A, or a compound of formula A HIV reverse transcription fermentation involving pharmaceutically acceptable salts or esters of compounds Inhibition, prevention or treatment of HIV infection, and acquired as a result of HIV infection Involved in the treatment of immunodeficiency syndrome (AIDS). The compounds of the present invention have the structural formula A [In the formula X is -H, -Cl, -F, -Br, -NO₂, -CN, -OR², -NR²R², − NHSO₂-C_{1 to 3}Alkyl or -NHCO-C_{1 to 3}Alkyl, Y is -S (O)_n-Or-O-, wherein n is O, 1 or 2, R is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH, or       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            Aryl substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, or 4) Y is -S (O)_nOnly when -NR²R³And Z is 1) -C (= W) -NR²R³[Wherein W is = O, = S, = N-CN or = N- OR²]], 2) -COR^1a, 3) -COOR^1b, 4) -CR²R²-S (O)_n-R^1a[Where n is as defined above], 5) -CR²R²NHR^Four, 6) -CR²R²-CO-R^Five, 7) 1 or more       a) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       b) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 3}Alkyl, or 8) -CN And R¹Is 1) hydrogen, 2) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 3) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, or 4) Unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R^1aIs 1) Unsubstituted-C_{1 to 5}Alkyl, or 1 or more upper       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, or 4) C_{3 to 6}Cycloalkyl And R^1bIs 1) 1 or more       a) -C_{1 to 5}Alkoxy,       b) -OH,       c) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, or 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R²Is hydrogen or C_{1 to 3}Alkyl, R³Is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C unsubstituted or substituted with -OH_{1 to 5}Alkoxy,       c) -OH,       d) -OC (O) R⁷,       e) -COOR²,       f) not substituted or one or more            i) -C unsubstituted or substituted with one or more -OH_{1 ~Five} Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen,            v) -NO₂,            vi) -NR²R²,           vii) -NHCO-C₁~₃Alkyl, or          viii) -NHSO₂-C_{1 to 3}Alkyl            An aryl substituted with,       g) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) C_{1 to 3}Alkyl-NR²R²,            v) halogen,            vi) oxo,           vii) -NO₂,          viii) -NR²R²,            iX) -NHCO-C_{1 to 3}Alkyl, or            x) -NHSO₂-C_{1 to 3}Alkyl            A heterocycle substituted with,       h) -NR²R²Or       i) -C_{3 to 6}Cycloalkyl       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, 4) -C_{1 to 5}Alkoxy, 5) -OH, 6) -C_{3 to 6}Cycloalkyl, or 7) Hydrogen And R^FourIs 1) R¹, Or 2) -COR¹ And R^FiveIs 1) R¹, 2) -C_{1 to 5}Alkoxy, 3) -NHR¹, Or 4) Unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R⁶Is 1) hydrogen, 2) -COR¹, Or 3) -CONHR¹ And R⁷Is 1) unsubstituted aryl, or one or more -Cl, -Br, -OH, -OCH₃Or an aryl substituted with -CN, or 2) Unsubstituted-C_{1 to 5}Alkyl, or one or more -OH or- NR²R²-C substituted with_{1 to 5}Alkyl And Provided that X is -H, Y is -S-, and R is an unsubstituted phenyl. Yes, and R⁶Is -H, Z is -CH₂-SO-Ph, -COH, Or a pharmaceutically acceptable salt or ester thereof. Including.   One embodiment of the present invention is X is -H, -Cl or -F, Y is -S (O)_n−, R is -Ph, -tolyl, 3-Cl-phenyl, 2-pyridy Or 2-thiazolyl, R⁶Is -H, Z is -C (= W) -NR²R³, -COOR^1b, -COR^1a, -CR²R²-S (O )_n-R^1a, Or -C substituted with a heterocycle_{1 to 3}Is an alkyl, Includes more limited compounds of formula A.   One compound group within the range of the first specific example, X is -H or -Cl, Y is -S (O)_n−, R is -Ph, 1-tolyl, 3-Cl-phenyl or 2-thiazolyl, R⁶Is -H, Z is 1) -C (= W) -NR²R³[R in the formula²Is -H and W is = O, = S or = NCN], or 2) -CR²R²-SO-aryl [wherein the aryl group is unsubstituted or Or more than one C_{1 to 5}Substituted with alkyl] Is It is further limited to compounds.   Below this group of compounds, X is -Cl, Y is -S (O)_n−, n is 1 or 2, R is -Ph, 3-Cl-phenyl or 2-thiazolyl, R⁶Is -H, Z is -C (= W) -NR²R³[R in the formula²Is -H and W is = O, = S or = It is NCN] R³Is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C unsubstituted or substituted with -OH_{1 to 5}Alkoxy,       b) -OH,       c) -OC (O) R⁷,       d) not substituted or one or more            i) -C unsubstituted or substituted with one or more -OH_{1 ~Five} Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with,       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with, or       f) C_{3 to 6}Cycloalkyl       -C substituted with_{1 to 5}Alkyl, 2) an unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, 3) hydrogen, or 4) C_{3 to 6}Is a cycloalkyl, There is a more limited group of compounds.   In the second embodiment of the present invention, X is 1) -NR²R², 2) -NHSO₂-C_{1 to 3}Alkyl, and 3) -NHCO-C_{1 to 3}Alkyl Including compounds of formula A selected from:   In the third embodiment of the present invention, Z is -C (= W) -NR.²R³And R³Is 1) 1 or more       a) -NO₂,       b) -NR²R²,       c) -NHCO-C_{1 to 3}Alkyl, or       d) -NHSO₂-C_{1 to 3}Alkyl       C substituted with phenyl substituted with_{1 to 3}Alkyl, as well as 2) 1 or more       a) halogen,       b) oxo,       c) -NO₂,       d) -NR²R²,       e) -NHCO-C_{1 to 3}Alkyl, or       f) -NHSO₂-C_{1 to 3}Alkyl       C substituted with a heterocycle substituted with_{1 to 3}Alkyl Including compounds of formula A selected from:   In the fourth embodiment of the present invention, Y is -S (O)._n-, And R is -NR₂R₃Is Includes compounds of formula A.   The most preferable compounds of the present invention are the compounds 1 to 39 shown below.Compound 1 : N-ethyl-5-chloro-3-phenylthioindole-2-carboxamideCompound 2 : N-2-hydroxyethyl-5-chloro-3-phenylthioindole-2-ca RuboxamideCompound 3 : N-2-Methoxyethyl-5-chloro-3-phenylthioindole-2-cal VoxamideCompound 4 : N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-ca RuboxamideCompound 5 : N-4-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal VoxamideCompound 6 : N-3-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal VoxamideCompound 7 : N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-cal VoxamideCompound 8 : N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxa MidCompound 9 : N- [1- (2 (R) -hydroxypropyl)]-5-chloro-3-phenylthio Oindole-2-carboxamideCompound 10 : N- (2-pyridyl) methyl-5-chloro-3-phenylthioindole-2- CarboxamideCompound 11 : N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioi Ndol-2-carboxamideCompound 12 : N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindo 2-carboxamideCompound 13 : 5-chloro-3-phenylthioindole-2-carboxamideCompound 14 : N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole- 2-carboxamideCompound 15 : N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thio CarboxamideCompound 16 : 5-chloro-3-phenylthioindole-2-thiocarboxamideCompound 17 : 5-chloro-3-phenylsulfinylindole-2-carboxamideCompound 18 : 5-chloro-3-phenylsulfonylindole-2-carboxamideCompound 19 : N-[(1-methylimidazol-2-yl) methyl]- 3-phenylsulfonyl-5-chloroindole-2-carboxamideCompound 20 : N-[(1-methylimidazol-2-yl) methyl] -3-phenylsulfi Nyl-5-chloroindole-2-carboxamideCompound 21 : N-[(1-methylimidazol-4-yl) methyl] 3-phenylsulfonyl -5-chloroindole-2-carboxamideCompound 22 : N-[(1-methylimidazol-5-yl) methyl] -3-phenylsulfoni Lu-5-chloroindole-2-carboxamideCompound 23 : N-[(1-methylimidazol-2-yl) methyl] 3- (3-chloropheni Sulfonyl) -5-chloroindole-2-carboxamideCompound 24 : N- [2- (imidazol-4-yl) ethyl] -3-phenylsulfonyl-5 -Chloroindole-2-carboxamideCompound 25 : N- [2- (1-methylimidazol-4-yl) ethyl] -3-phenylsul Fonyl-5-chloroindole-2-carboxamideCompound 26 : N-cyclopropyl-5-chloro-3-phenylsulfonylindole-2-ca RuboxamideCompound 27 : N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-cal VoxamideCompound 28 : N- (3-pyridylmethyl) -3-phenylsulfonyl- 5-chloroindole-2-carboxamideCompound 29 : N- (4-pyridylmethyl) -5-chloro-3-phenylsulfinylindole Le-2-carboxamideCompound 30 : N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole -2-carboxamideCompound 31 : N- (3-methoxybenzyl) -5-chloro-3- (2- Thiazolyl) sulfonylindole-2-carboxamideCompound 32 : N-[(S) -1-phenyl-2-hydroxyethyl] -5-chloro-3-phen Nylsulfonylindole-2-carboxamideCompound 33 : N-[(R) -1-phenylethyl] -5-chloro-3-phenylsulfonyl group Ndol-2-carboxamideCompound 34 : N- (3-methylsulfonylaminobenzyl) -3-phenylsulfonyl-5- Chloroindole-2-carboxamideCompound 35 : N-cyano-5-chloro-3-phenylsulfonylindole-2-carboxy MidamideCompound 36 : 3-phenylsulfonyl-5-methylsulfonylaminoindole-2-carb XamideCompound 37 : 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamide ) -Methyl] pyridin-2 (1H) -oneCompound 38 : N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfoni Luindole-2-carboxamideCompound 39 : N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2- Carboxamide   The compounds of the present invention may have asymmetric centers and may be racemic, racemic mixtures, individual Can be produced as a diastereomer or enantiomer of any of the isomers. Forms are also included in the present invention.   Variable (eg aryl, heterocycle, R¹, R², R³Etc.) in any component, Alternatively, when two or more are present in formula A of the present invention, the definition is independent at each occurrence. There is. In addition, the combination of substituents and / or variables is a stable compound. Only those that lead to can be tolerated.   The term "alkyl", as used herein unless otherwise specified, refers to a specified number of carbon atoms. To include both branched and straight chain saturated aliphatic hydrocarbon groups having , And the term "alkoxy" refers to the stated number of carbon atoms attached through an oxygen bridge. Means an alkyl group having True spirit The terms "halogen" or "halo" as used in the detailed text mean fluorine, chlorine, bromine. And iodine.   The term “aryl” as used in the present specification, unless otherwise specified, means that each ring is a 7-membered ring or less. Is any stable monocyclic, bicyclic or tricyclic carbocycle which is at least 1 Rings shall mean those which are aromatic. Such aryl elements include , Phenyl, naphthyl, tetrahydronaphthyl, biphenyl and the like.   The terms "heterocycle" or "heterocycle" as used herein unless otherwise indicated. , A stable 5- to 7-membered monocyclic or a stable 8- to 11-membered bicyclic saturated or unsaturated heterocycle And a carbon atom and 1 to 3 heteroatoms selected from N, O and S With nitrogen and sulfur heteroatoms optionally oxidizable, and A nitrogen heteroatom means a heterocycle which may optionally be quaternized and is as defined above. Includes any two-membered ring formed by the fusion of a heterocycle defined as above with a benzene ring It A heterocycle is attached to any heteroatom or carbon atom that results in the creation of a stable structure. Can be combined. Examples of such heterocyclic members are piperidinyl, piperazinyl, 2 -Oxopiperazinyl, 2-oxopiperidinyl, 2- Oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-pipet Ridonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazole Zolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazi Nyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidi Nil, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinucli Dinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzene Zoimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzo Oxazolyl, furyl, tetrahydrofuryl, benzofuranyl, tetrahydropyr Ranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsul Includes phoxides, thiamorpholinyl sulfones and oxadiazolyls.   The following abbreviations are used in this specification.   Me: Methyl   Et: ethyl   Ph: Phenyl   BuLi: Butyl lithium   n-Bu₃P: tri-n-butylphosphine   LAH: lithium aluminum hydride   DMF: dimethylformamide   THF: tetrahydrofuran   Et₃N: triethylamine   MMPP: monoperoxyphthalic acid in the form of magnesium salt   BOP reagent: benzotriazol-1-yloxytris- (dimethylamino               ) Phosphonium hexafluorophosphate   mp or m. p. : Melting point   The present invention capable of forming a salt (in the form of a product soluble or dispersible in water or oil) The pharmaceutically acceptable salts of the novel compounds of the invention include the compounds, for example inorganic or Are the usual non-toxic salts or quaternary ammonium salts formed from organic acids or bases included. Examples of the above acid addition salts include acetate, adipate, alginate, and aspartate. Paraginate, benzoate, benzenesulfonate, bissulfate (bissul) fate), butyrate, citrate, camphorate, camphorsulfonate, cyclopenta N-propionate, digluconate, dodecyl sulfate, ethane sulfonate, phosphate Malate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate , Hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane Sulfonate, lactate, maleate, methanesulfonate, 2-naphthalene Sulfonate, nicotinate, oxalate, pamoate, pectate, Sulfate, 3-phenylpropionate, picrate, pivalate, propion Acid salt, succinate, tartrate, thiocyanate, tosylate and undecanoate Is included. The basic nitrogen-bearing groups can be replaced with methyl chloride, bromide and methyl iodide, ethyl, Lower alkyl halides such as ropyl and butyl; dimethyl sulfate, diethyl, Dialkyl sulphates such as dibutyl and diamyl; chlorinated, brominated and decyl iodide, laur Long-chain halides such as ril, myristyl and stearyl; benzyl bromide and fumes It can also be quaternized with substances such as aralkyl halides such as enetyl and others. It is possible. The present invention is, for example, C_{1 to 4}Easily to those skilled in the art, such as alkyl esters Also included are esters, including those recalled.   Schemes I-VIII for the preparation of the novel compounds of the invention are shown below. Table I-following the manufacturing scheme VII illustrates compounds that can be synthesized according to Schemes I-VIII. I is also the compound in the table and the specific substituents used in the production schemes for illustration. Is not limited by. The application of the following production scheme to specific compounds is described in the examples. To explain specifically.   The following Preparation Scheme I is a general route for synthesizing, for example, the compounds shown in Table I below. is there. Substituents used in Scheme I (eg If X, R, R¹Etc.) correspond to the substituents defined in Table I, while Scheme I is a feature of Table I. It is not limited by a given substituent or compound.   As shown in the manufacturing scheme I, Atkinson et al., Synthesis, pp. ． According to the normal procedure described in 480-481, 1988, commercially available indole -2-carboxylic acid (or 5-chloro, 5-fluoro or 5-methoxyin Dol-2-carboxylic acid) I in dimethylformamide at 0-60 ° C. Phenyl disulfide Treat with excess sodium hydride in the presence of any aryl disulfide. Profit The resulting product II is reacted with oxalyl chloride in refluxing chloroform for about 30 minutes to 1 hour. To produce the corresponding acid chloride, which is chloroform at 0-20 ° C. Reaction with a primary or secondary amine in to afford amide III. Or elsewhere The desired primary or secondary amine in a solvent such as dimethylformamide. And BOP reagent in the presence of triethylamine [benzotriazole-1 -Yloxytris- (dimethylamino) -phosphonium hexafluorophosphine The amide III can be formed directly from the product II by treatment with EDTA. This In step, other carboxyl groups such as 1,1'-carbonyl-diimidazole It is also possible to use a sexualizing reagent. 5-Chloro-3 (prepared as described below) -Saponification of ethyl benzylindole-2-carboxylate by methods well known to those skilled in the art. Gives 5-chloro-3-benzylindole-2-carboxylic acid, which is The material can be converted to the desired amide by the methods described for the synthesis of amide III.   The compounds shown in Table II below are generally synthesized as in Preparation Scheme I, except that At that time, as described in the following manufacturing scheme II And R²R³R instead of NH¹OH is used. The substituents used in Scheme II are specified in Table II. Corresponding to the specified substituents, Scheme II is defined by the specific substituents or compounds of Table II. Not limited.   As shown in Production Scheme II, 3-phenylthioindole-2-carboxylic acid II Was converted to the corresponding acid chloride with oxalyl chloride in refluxing chloroform and It can be reacted with an alcohol to form ester IV. (Also made In another operation (shown in scheme II), boron trifluoride etherate etc. as a catalyst N-phenylthioose in chloroform at room temperature in the presence of Lewis acid Ku Ia can be converted to IV by reacting with cinimide. Compound 5-chloro Ethyl-3-benzylindole-2-carboxylate is available from Inaba et al.Chem . Pharm. Bull. 24 , Pp. 1076-1082, 1976 Manufactured according to the operation.   The following Production Scheme III is a general route for synthesizing, for example, the compounds shown in Table III below. Is. The substituents used in Scheme III correspond to the substituents specified in Table III. III is not limited by the particular substituents or compounds in Table III.   As shown in Production Scheme III, commercially available ethyl indole-2-carboxylate (X Is a compound V) or ethyl 5-chloroindole-2-carboxylate ( Compound V), where X is -Cl, is added in excess of tetrahydrofuran in tetrahydrofuran at 0 ° C. Reduction with lithium aluminum hydride Got a call VI. Compound VI was added to tetrahydrofuran at 0 to 20 ° C. for 6 to 24 hours. Excessive amount of tri-n-butylphosphine and phenyl disulfide in orchid It was converted to sulfide VII by treatment with aryl disulfide. Su Ruffide VII was hydrogenated in dimethylformamide for 1-18 hours at 0-20 ° C. Reacted with sodium fluoride and aryl disulfides such as phenyl disulfide Then, bis-sulfide VIII is produced. Aryl disulfi not commercially available De is Orville G. LoweJ. Org. Chem. 40, Pp. Two Commercially available aryl mercaps according to the procedure described in 096-2098,1975. Obtained by oxidizing tan with dimethylsulfoxide and iodine. Compound If desired, product VIII can be prepared by methods well known to those skilled in the art, such as iodomethane. Hydrogenation in dimethylformamide at 0 ° C. in the presence of alkylating agents It can be N-alkylated to Compound IX by treatment with thorium. Then the compound Add VIII (or IX) to methanol or chloroform at 0 ° C for 30 minutes to 3 hours. 1 equivalent of monoperoxyphthalic acid in the form of a magnesium salt in methanol (MMPP) and m-chloroperoxy Treatment with a peracid such as benzoic acid gives mainly sulfoxide X.   The following Production Schemes IV-A and IV-B are shown, for example, in Tables IV-A and IV-B below. It is a general route to synthesize compounds. The devices used in Schemes IV-A and IV-B, respectively. The substituents correspond to the substituents respectively defined in Tables IV-A and IV-B, but are represented by the scheme IV- A and IV-B are limited by the specific substituents or compounds of Tables IV-A and IV-B. Not.   As shown in Production Scheme IV-A, 3-phenylthioindole-2-carboxyl Samide XI is refluxed for 6-24 hours To react with excess borane-dimethyl sulfide complex in hydrofuran It can be further reduced to the primary or secondary amine XII. Shown in Manufacturing Scheme IV-B As such, the primary amine XII-A was salified in chloroform in the presence of pyridine. It may be acylated with an acid chloride such as benzoyl to give amide XIII.   The following Preparation Scheme V, for example, synthesizes the compounds shown in Tables VA and VB below. It is a general route. The substituents used in Scheme V are defined in Tables VA and VB. Corresponding to the substituents, Scheme V is a specific substituent or compound of Tables VA and VB Not limited by.   As shown in Production Scheme V, commercially available 2-methylindole XIV was added to dimethylform Hydrogen in the presence of aryl disulfides such as phenyl disulfide Compound XV may be treated with sodium iodide. Compound XV was tested at −78 ° C. Conversion to the monovalent anion with n-butyllithium in trahydrofuran, This can be reacted with carbon dioxide to give the carboxylic acid ester XVI. Cal A divalent anion formed by the reaction of boric acid ester XVI with t-butyllithium Is monoacylated by reacting with an isocyanate such as phenyl isocyanate. This could be a mixture of product and diacylated product XVII (see Table VB). There Is otherwise obtained by reaction of the carboxylic acid ester XVI with t-butyllithium. The resulting divalent anion can be generated by methods well known to those skilled in the art, eg N-methoxy-N-methyl-furan-2-carbo prepared by the method described above). Keto by reacting with N-methoxy-N-methylamide such as xamide XVIII could be produced. The method described above is essentially as described in A. J. Katr itsky and K.K. Those used by Akutagawa to produce 2-indoleacetic acid Is the lawJ. Am. Che m. Soc. 108 , P. 6808, 1986.   The following Production Scheme VI is a general route for synthesizing, for example, the compounds shown in Table VI below. is there. The substituents used in Scheme VI correspond to the substituents specified in Table VI, while Scheme VI It is not limited by the particular substituents or compounds in Table VI.   As shown in Scheme VI, N-methoxy- (prepared by the method of Scheme I) N-methyl-3-phenylthioindole-2-carboxamide XIX (or N -Methoxy-N-methyl-5-chloro-3-phenylthioindole-2-cal Voxamide) at -78 ° C to 20 ° C for 18 to 48 hours in tetrahydrofuran Grignard reagents such as phenylmagnesium chloride (R¹Is not hydrogen) Reacting or reacting said XIX with other organometallic reagents well known to those skilled in the art To produce ketone XX.   The compounds shown in Table VII below are generally prepared by the methods shown in Production Schemes I-VI. 2- (2-benzoxazol-2-ylethyl), which can be synthesized by those skilled in the art. -3-Phenylthioindole (Compound XXIV) is an exception and the compound The composition is shown in the following production scheme VII.   As shown in Production Scheme VII, N-methoxy-N-methyl-3-phenylthio was used. Add indole-2-carboxamide XXI to tetra at 0-20 ° C for 2-4 hours. Aldehydes XXII reduced with lithium aluminum hydride in hydrofuran Can be Aldehyde XXII was converted to [(benzoxazol-2-yl) methyl] pho The olefin XXIII was reacted by reacting with the lithium salt of diethyl sulfonic acid. Could be generated. The olefin XXIII produced was placed in methanol under 1 atm of hydrogen. Hydrogenation in the presence of 10% palladium on charcoal gives compound XXIV.   The compound 5-chloro-2-cyano-3-phenylthioindole in Table VII is 5-chloro-3-phenylthioindole-2-thiocarboxamide can be prepared, for example, from H 2 g (OAc)₂Can be prepared by dehydrosulfurylation.   Y is -SO- or -SO₂Compounds of formula A which are-are well known to those skilled in the art. Using the method, Y is -S-₃Or vinegar M-chloroperoxybenzoic acid (MCPBA), periodate in a suitable solvent such as acid Sodium oxalate or hydrogen peroxide, or MeOH / H₂In a solvent such as O. It can be synthesized by treating with an appropriate oxidizing agent such as potassium sulfate. .   Y is -SO- or -SO₂Alternative Way to Synthesize Amide Derivatives of Formula A Is shown in Production Scheme VIII. Intermediate acid II [eg CHCl₃In m-chloroperu Xybenzoic acid (MCPBA)], and Y is —SO— or —SO₂An acid derivative X which is XV, which is the acid derivative XXV using the amide formation conditions shown in Scheme I. , Can be converted to the corresponding amide derivative XXVII. Another useful procedure is Oxidation of the intermediate ester IVa such that Y is -SO- or -SO₂Is an ester Intermediate XXVI which can be heated with ammonia or a primary amine. Reaction below converts to compound of formula XXVII.   The compounds of the present invention inhibit HIV reverse transcriptase, human immunodeficiency virus (HIV). ) For the prevention and treatment of infections and the treatment of pathological conditions such as AIDS as a result of said infections It is useful. Treatment of AIDS or prevention or treatment of HIV infection is AIDS and ARC (AIDS, both asymptomatic and asymptomatic) S-related complex), as well as treatment of actual or potential exposure to HIV. Defined to include, but not limited to. For example, the compounds of the present invention can be used for blood transfusion, organ transplantation, body fluid Replacement, bite wound, needle stick accident, or exposure to patient blood during surgery. It is useful in treating HIV infection when it may have been exposed to HIV.   The compounds of the present invention also relate to the production of antiviral compounds, and the compounds relating to the compounds. It is useful for cleaning. For example, the compounds of the present invention are more potent anti-inflammatory agents. Isolation of enzyme mutants is an excellent screening tool for irs compound Useful for. Moreover, the compounds of the present invention allow HIV reverse transcription of other antiviral drugs. Also useful for confirming or determining binding sites for enzymes, for example by competitive inhibition. It That is, the compounds of the present invention are commercial products to be sold for these uses.   Inhibits HIV reverse transcriptase, prevents or treats HIV infection, and prevents AIDS or Or for treating ARC, the compounds of the present invention are conventional non-toxic and pharmaceutically acceptable. Orally in the form of dosage unit formulations containing active carriers, adjuvants and excipients By parenteral (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques) By inhalation spray or from the rectum Can be administered.   That is, the present invention provides a method for treating HIV infection and AIDS, and HIV infection and AIDS. And a pharmaceutical composition for the treatment of AIDS. The treatment method according to the present invention is as described above. To a patient in need of such treatment with a pharmaceutical carrier and a therapeutically effective amount of a compound of the invention. Administering a pharmaceutical composition containing   The above pharmaceutical composition is an orally administrable suspension or tablet; nasal spray; Sterile injectable preparations for use as sterile injectable aqueous or oily suspensions; or It may be in the form of an agent.   When orally administered as a suspension, the above composition is well known in the field of formulation. Prepared according to the technique, with the composition containing microcrystalline cellulose for bulking and a suspension As an agent Alginic acid or sodium alginate, and methyl cellulose as a thickener , Sweeteners / flavours known to those skilled in the art may be included. Above as a quick release tablet The composition includes microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate. Cesium and lactose, and / or other excipients, binders, additives known to those skilled in the art. Amounts, disintegrants, diluents and lubricants may be included.   The compositions described above when administered by nasal spray or inhalation are well suited to the field of formulation. Prepared according to known techniques, the composition in this case is benzyl alcohol or Other suitable preservatives, bioavailability-enhancing absorption enhancers, fluorocarbons and / or the like. It may be prepared as a saline solution using other solubilizers or dispersants known to those skilled in the art. .   Injectable solutions or suspensions include mannitol, 1,3-butanediol, water Non-toxic and parenterally acceptable, such as Ringer's solution or isotonic sodium chloride solution Appropriate diluent or solvent, if possible, or synthetic mono- or diglyceride And suitable dispersions such as sterile non-volatile non-volatile oils including fatty acids such as oleic acid Alternatively, it may be prepared according to known techniques using wetting and suspending agents.   The above composition for rectal administration in the form of suppositories has the drug cocoa butter and synthetic Solid at room temperature, such as glyceride ester or polyethylene glycol A suitable non-irritating excipient that liquefies and / or dissolves in the rectal fossa to release the drug It can be prepared by mixing with.   The compound of the present invention is orally administered to human in divided doses of 1 to 100 mg / kg body weight. You can In the case of divided oral administration, one preferable dose range is 1 to 10 mg / kg body It is heavy. In divided oral administration, a dose range of 1 to 20 mg / kg body weight is also preferable. However, the particular dose level and frequency of administration for any particular patient may vary. , Activity of a specific compound used, metabolic stability of the compound and duration of action, age, body Weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combination, A variety of conditions, including the severity of the condition and the treatment the host is receiving It is understood that it depends on various factors.   The present invention is useful for HIV reverse transcriptase inhibitor compounds and the treatment of AIDS 1 Combinations with more than one drug are also provided. The compounds of the present invention are suitable for HIV reverse transcriptase inhibition. Other compounds that are harmful agents and / or HIV protease inhibitors Can be administered in combination with a compound. For example, a compound of the present invention is an effective amount of Pre-exposure and / or in combination with AIDS antivirals as shown in Table VIII below. Alternatively, it may be effectively administered after exposure.   HIV protease inhibitors for therapeutic use in combination with the compounds of the invention Of the above-mentioned conditions useful in the treatment or prevention of the above mentioned conditions are about 0 per day. ． 02g to 5.0 or 10.0g, 2 to 5 times that for oral administration is there. For example, an HIV protease inhibitor may be administered 1 to 3 times a day per 1 kg of body weight. HIV infection can be effectively treated when administered in an amount of 10 to 50 mg. But any Specific dosing levels and dosing frequencies for specific patients in Compound activity, metabolic stability and duration of action, age, body weight, general health Health status, sex, diet, mode and timing of administration, excretion rate, drug combination, weight of specific condition Understand that it depends on a variety of factors, including severity and the treatment the recipient is receiving To be done.   The dose of HIV reverse transcriptase inhibitor is therapeutically combined with the compound of the invention. If so, the doses specified above for the compounds of the invention will be similar.   The range of combinations of compounds of the present invention with AIDS antivirals is shown in Table VIII. In principle, the combination with any pharmaceutical composition useful for the treatment of AIDS It is understood that it also includes the combination.   The compounds in Table VIII are as follows: L-697,661 is 3-{[(4,7 -Dichloro-1,3-benzoxazol-2-yl) methyl] amino} -5- It is ethyl-6-methyl-pyridin-2 (1H) -one. L-696,229 Is 3- [2- (1,3-benzoxazol-2-yl) ethyl] -5-ethyl It is -6-methyl-pyridin-2 (1H) -one. L-735, 524 is Scientific name N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenyl Rumethyl-4 (S) -hydroxy-5- {1- [4- (3-pyridyl-tyl)- 2 (S) -N '-(t-butylcarboxamido) piperazinyl]} pentaneami Is an HIV protease inhibitor. L-738,372 is 6-chloro -4 (S) -cyclopropyl-3,4-dihydro-4-[(2-pyridyl) -e Tinyl] quinazolin-2 (1H) -one. L-738 and 872 are Nt- Butyl-1- {2 '-(R) -hydroxy-4'-phenyl-3' (S)-[3 "(R)-(1 '", 1' "-dioxo-2 '" (R) -methylethyl) tetra Hydrothienyloxycarbonylamino] -butyl} -4- [4 '-(2 "-ku Lolo-6 ″ -methyl) pyridylmethyl] -Piperazine-2 (S) -carboxamide.Reverse transcriptase assay   In this assay, dGTP and poly r (C) oligo d (G)₁₂~₁₈Km In value, recombinant HIV reverse transcriptase (HIV RT_R) (Or other RT) To acid-precipitating cDNA of tritiated deoxyguanosine-phosphate To measure the built-in. The inhibitors of the present invention suppress this incorporation.   10 μl of sterile distilled H stored in a tube₂O, 2.5 μl of test inhibitor and 10 μ 5nM purified HIV RT_RAnd 500 mM Tris-HCl (pH 8.2) , 300 mM MgCl₂And 1200 mM KCl, 10 mM DTT, 4 00 μg / ml poly r (C) / oligo d (G) [1.5 mg (25 U) poly r (C) -Oligo d (G) 1.5 ml sterile distilled H₂Dissolve in O and 400 Diluted to μg / ml] and 0.1 μCi / μl [³H] dGMP, 16 30 μl of reaction mixture containing equal amounts of 0 μM dGTP was added. mixture Were incubated at 37 ° C for 45 minutes.   After the incubation was complete, the tubes were cooled in ice for 5 minutes. 10 mM NaPP_iAdd ice-cold 13% TCA (200 μl) containing The mixture is incubated on ice for 30 minutes. Precipitated cDNA was pre-soaked Glass filter [TCA, NaPP_i] To recover by filtration. precipitation 1N HCl, 10 mM NaPP_iWash with.   The filter discs are then counted in a scintillation counter.   Under the above conditions, [dGTP] and poly r (C) / oligo d (G)₁₂~₁₈Is it Each shows a value approximately equal to the appropriate Km value. About 5,000-6,000 cpm [³ H] dGMP is incorporated into the acid-precipitating material. RT reaction is concentration and time dependent Is. DMSO (5% or less) does not affect enzyme activity. Compounds of the invention tested IC calculated for objects₅₀Values vary from about 3 nM to greater than 300 μM. Is. Most preferred compound IC₅₀The value is about 3 to about 35 nM.Suppression of virus spread A.Production of HIV infected MT-4 cell suspension   On day 0, MT cells with a concentration of 250,000 cells / ml were added to H 1: 2,000 dilution of IV-1 stock strain IIIb (final p24 concentration 125 pg / m l; 1% or less on day 1 and 25-100% on day 4 enough concentration to obtain infected cells Infected). Infection and proliferation of cells was performed using RPMI 1640 (Whita). ker BioProducts), 10% inactive fetal bovine serum, 4 mM gluta Min (Gibco Labs) and 1: 100 penicillin / streptomycin (Gibco Labs).   Mix the mixture with 5% CO₂Incubated overnight at 37 ° C in an atmosphere. B.Treatment with inhibitors   Stepwise 2-fold dilutions of compounds were made in cell culture medium. On the first day, 12 of the compound Aliquot 5 μl aliquots of 96-well microtiter cell culture plates in equal volumes of H 2 IV-infected MT-4 cells (50,000 / well) were added. 5% CO₂Atmosphere Incubation at 37 ° C under aeration was continued for 3 days. C.Virus spread measurement   Resuspend the sedimented cells using a multichannel pipettor and collect 125 μl. Another microtiter play by catching I moved to the inside. Plates were settled after cell sedimentation and the HIV p24 anti-antibody in the supernatant, which was carried out later, It was frozen in preparation for assay on the stock.   The concentration of HIV p24 antigen was determined by the enzyme immunoassay described below. Measured. An aliquot of p24 antigen to be measured was used to Added to microwells coated with monoclonal antibody. At this point and after The microwells were washed in another appropriate step that follows. Then biotinyl Antibodies specific for HIV were added, followed by the combined streptavidin (streptavidin). avidin) -horseradish peroxidase was added. Peroxidation added A color reaction occurs from hydrogen and the tetramethylbenzidine substrate. Color intensity is HI It is proportional to the concentration of V p24 antigen.   Cell culture inhibitory concentration of each compound (CIC₉₅) Is an untreated pair with p24 antigen production. Of infection, assessed by a reduction of> 95% in comparison with Defined as the concentration that resulted in greater than 95% spread inhibition. Invention tested Compound CIC₉₅Values range from about 3 to about 400 nM in preferred species, and Less than about 40 μM in seeds It turned out thatExample 1 N- (3-pyridylmethyl) -5-chloro-3-phenylthioindole-2- Manufacture of carboxamide Step A :5-chloro-3-phenylthioindole-2-carboxylic acid   Dilute sodium hydride (3.0 g; 60% dispersion in oil; 0.076 mol) To the suspension in tilformamide (125 ml) was added 5-chloroindole- 2-carboxylic acid (5.0 g; 0.0255 mol) and phenyl disulfide ( 6.1 g; 0.028 mol) was added. The reaction mixture under nitrogen at 50 ° C. overnight. Heated. The reaction mixture was cooled, and additional sodium hydride (1.8 g) and phenol were added. Nyl disulfide (3.6 g) was added and heating continued for 1 hour. The reaction mixture Upon cooling, the dimethylformamide was evaporated under vacuum. The residue is ethyl acetate and water Distributed to and. The aqueous layer was separated and the pH was adjusted to 1 with 10% hydrochloric acid. Vinegar aqueous phase Extract with ethyl acetate, wash the ethyl acetate extract with water and saturated brine, and wash with magnesium sulfate. Dehydrated with nesium. The crude product was recrystallized from ethyl acetate in hexane to give the standard Memorialization The product was obtained as an off-white solid.Step B :N- (3-pyridylmethyl) -5-chloro-3-phenylthioi Ndol-2-carboxamide   5-chloro-3-phenylthioindole-2-carboxylic acid (0.50 g; 1 ． 6 mmol), 3-aminomethylpyridine (0.35 g; 3.2 mmol) and And triethylamine (0.50 ml; 3.2 mmol) degassed dimethylphore Benzotriazol-1-yloxy was added to the solution in Lumamide (25 ml). Tris (dimethylamino) phosphonium hexafluorophosphate (0.73 g; 1.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The precipitate It was filtered off and the filter cake was washed thoroughly with water. The solid is 30% ethyl acetate in hexane Triturated, filtered and dried under vacuum at 60 ° C. for 72 hours. Mp2 the title compound Obtained as an off-white solid at 40-241 ° C. C_{twenty one}H₁₆ClN₃OS ・ 0.25H₂Analysis for O:   Calculated C 63.31; H 4.17; N 10.54.   Found C 63.34; H 4.06; N 10.71. NMR (DMSO-d₆): Δ 12.54 (1H, s), 8.91 (1H, s) t, J = 6 Hz), 8.51 (1H, s), 8.42 (1H, d, J = 5 Hz), 7 ． 58 (2H, m), 7.45 (1H, m), 7.25 (4H, m), 7.15 (1H, t, J = 7Hz), 7.04 (2H, d, J = 8Hz), 4.58 (2 H, d, J = 6 Hz).Example 2 Preparation of methyl 5-chloro-3-phenylthioindole-2-carboxylate   Under nitrogen, oxalyl chloride (0.70 ml; 9.6 mmol), 5-chloro- 3-Phenylthioindole-2-carboxylic acid (0.97 g; 3.2 mmol) Was added to a solution dissolved in chloroform (50 ml). Reaction mixture for 3 hours Reflux, cool and dry under vacuum. Dissolve the obtained solid in chloroform This was added to methanol at 0 ° C. The methanol was removed under vacuum and the crude The product was chromatographed on silica gel with 20% ethyl acetate in hexane. I hung it on Ruffy. The title compound was obtained as a solid with mp 193-196 ° C. C₁₆H₁₂ClNO₂Analysis of S:   Calculated C 60.47; H 3.81; N 4.42   Found C 60.09; H 3.50; N 4.67.Example 3 Production of ethyl 5-chloro-3-benzylindole-2-carboxylate   The title compound was converted to S. Inaba and othersChem. Pharm. Bull. 24, pp. Prepared according to the procedure described in 1076-1082,1976. Ben The title compound was obtained by recrystallisation from ZEN, pale yellow needles mp 196-197 ° C. Got it as a body. C₁₈H₁₆ClNO₂Analysis about:   Calculated C 68.90; H 5.13; N 4.46   Found C 68.64; H 5.10; N 4.56.Example 4 Preparation of 2-phenylsulfinylmethyl-3-phenylthioindole Step A :2-hydroxymethylindole   Add lithium aluminum hydride (2.0 g; 0.20 mol) to tetrahydrofuran. The suspension suspended in orchid (100 ml) was cooled to 0 ° C. with stirring under nitrogen. It was Ethyl indole-2-carboxylate (10.0 g; 0.052 mol) Add the solution of trahydrofuran dropwise and add the reaction temperature. The temperature was maintained at 0-5 ° C. After 1 hour, the reaction was saturated with sodium potassium tartrate solution. Stopped at. Filter the reaction mixture and wash the filter cake thoroughly with tetrahydrofuran. Clean Tetrahydrofuran was evaporated under vacuum and the residue was taken up in ethyl acetate and water. Distributed. The ethyl acetate solution was washed with water, saturated brine, and dried over magnesium sulfate. Watered, filtered and solvent removed. The title compound was obtained as a yellowish solid. NMR (CDCl₃): Δ 8.13 (1H, bs), 7.57 (1H, d, J = 8 Hz), 7.35 (1 H, d, J = 8 Hz), 7.26 (1 H, s), 7 ． 18 (1H, dt, J = 1, 8Hz), 7.10 (1H, dt, J = 1, 8H) z), 6.41 (1H, bs), 4.84 (2H, s).Step B :2-phenylthiomethylindole   2-Hydroxymethylindole (6.94 g; 0.047 mol) and fe Nyl disulfide (10.8 g; 0.049 mol) was added to tetrahydrofuran under nitrogen. It was dissolved in orchid (200 ml) and cooled to 0 ° C. Tri-n-butylphos Fin (11.7 ml; 0.047 mol) was added and the reaction mixture was stirred for 1 hour. did. Additional phenyl disulfide (1.5 g; 0.007 mol) and tri- n-Butylphosphine (5.1 ml; 0.020mo 1) was added and the reaction mixture was stirred at room temperature until the reaction was complete. Tetrahydrofuran Was removed under vacuum and the residue was purified by silica gel eluting with 5% ethyl acetate in hexane. Chromatography on the filter. The title compound, mp100-101.5 It was obtained as a colorless and transparent plate-shaped product at ℃. C_FifteenH₁₃Analysis of NS:   Calculated 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   Dilute sodium hydride (0.37 g; 60% dispersion in oil; 9.4 mmol). The suspension in tylformamide (50 ml) was cooled to 0 ° C. 2-pheny Add luthiomethylindole (1.5 g; 6.3 mmol) little by little and react The mixture was stirred at 0 ° C for 15 minutes. Phenyl disulfide (1.5 g; 6.9 m mol) was added and the reaction mixture was stirred at 20 ° C. for 6 hours. Stop the reaction with water, It was extracted with ethyl acetate. The organic extract is washed with water, saturated brine and washed with magnesia sulphate. Dehydrated with um. An oil remains after filtration and solvent evaporation, which oil %Ethyl acetate Purified by medium pressure chromatography on silica gel using. Compounding The product was obtained as an oil. C_{twenty one}H₁₇NS₂・ H₂O ・ 0.15C_FourH₈O₂Analysis about:   Calculated 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   3-phenylthio-2-phenylthiomethylindole (0.750 g; 2. 94 mmol) dissolved in methanol (100 ml) at 0 ° C. with stirring Cooled to. Magnesium monoperoxyphthalate in methanol (50 ml) Salt (0.908 g; 80% peracid) was added slowly dropwise. After this addition, the reaction mixture The mixture was stirred for another 30 minutes and then with 10% aqueous sodium thiosulfate solution (2 ml). The reaction was stopped. The methanol was removed under vacuum and the residue was partitioned between ethyl acetate and water. I arranged it. The organic phase is washed successively with water and saturated brine, then with magnesium sulfate. Dehydrated. Filtration was performed and the filtrate was concentrated under vacuum to give an oil, which was mixed with hexane. By chromatography on silica gel using 20 → 30% ethyl acetate in Was purified. The title compound Obtained as foam with mp 71-74 ° C. C_{twenty one}H₁7 NOS₂Exact mass of:   Calculated value 364.082982   Found 364.084549 NMR (DMSO-d₆): Δ 11.82 (1H, s), 7.50 (6H, m), 7.23 (1H, d, J = 8Hz), 7.15 (3H, m), 7.05 ( 2H, m), 6.90 (2H, m), 4.43 (1H, d, J = 13Hz), 4 ． 38 (1H, d, J = 13 Hz).Example 5 Preparation of 2-phenylcarboxamidomethyl-3-phenylthioindole Step A :3-phenylthioindole-2-carboxamide   3-Phenylthioindole-2-carboxylic acid in dimethylformamide (J ． G. Atkinson et al., Synthesis, pp. 480-481, 19 Manufactured according to the procedure described in 88) (4.01 g; 0.015 mol). Nia (large excess) and benzotriazol-1-yloxytris (dimethylacetate) Mino) phosphonium hexafluorophosphate (7.2 g; 0.016 mol) ) To the title compound N- (3-pyridylmethyl) Regarding the preparation of 5-chloro-3-phenylthioindole-2-carboxamide Was prepared according to the general procedure described in Example 1. The title compound was a pale yellow solid It was obtained.Step B :2-aminomethyl-3-phenylthioindole   3-Phenylthioindole-2-carboxamide (1.9 g; 7.1 mmo The tetrahydrofuran solution of 1) was cooled to 0 ° C. under nitrogen, and borane dimethylsulfur was added. The fido complex (7.1 ml; 0.070 mol) was treated as such. Reaction mixture Was refluxed for 7 hours, cooled to 0 ° C., and quenched with 10% hydrochloric acid. The pH of the solution Adjusted to 8 with 20% aqueous sodium hydroxide. Extract the reaction mixture with ethyl acetate The organic extract was washed with saturated brine and dried over magnesium sulfate. Marking The compound was obtained as a pale yellow oil.Step C :2-phenylcarboxamidomethyl-3-phenylthioindole Le   2-Aminomethyl-3-phenylthioindole (0.85 g; 3.3 mmo l) was dissolved in chloroform (15 ml) and this was cooled to 0 ° C. under nitrogen. Pyridine (2.7 ml; 33 mmo1), then benzoyl chloride (1.1 ml; 10 mmol) was added. The reaction mixture was stirred at 20 ° C. for 1 hour 10% hydrochloric acid was added. The layers were separated and the organic phase was washed with water, saturated sodium bicarbonate and Wash sequentially with saturated brine. Dehydrate the chloroform solution with magnesium sulfate, Filtered and evaporated to dryness. Use the oil obtained with 5% ethyl acetate in methylene chloride. Chromatography on silica gel. Mp64-6 of the title compound Obtained as a solid at 5 ° C. C_{twenty two}H₁₈N₂OS 0.2H₂Analysis for O:   Calculated C 73.00; H 5.08; N 7.74   Found C 72.93; H 5.02; N 7.66.Example 6 2- (N-phenylacetamido) -3-phenylthioindole and 2- (N -Phenylacetamido) -1- (phenylcarbamoyl) -3-phenylthio Manufacture of indole   2-Methyl-3-phenylthioindole (JG Atkinson et al. synthesis, pp. Manufactured according to the operation described in 480-481,1988. (Preparation) (0.50 g; 2.1 mmol) with anhydrous tetrahydrofuran Dissolved in a run and cooled to -78 ° C under nitrogen. n-butyllithium 2 ． A 5M hexane solution (0.83 ml) was added via syringe. carbon dioxide Was bubbled through the reaction mixture for several minutes. Unreacted carbon dioxide is a reaction mixture By freezing the product under high vacuum at liquid nitrogen temperature and warming to -78 ° C. Removed. Add 1.7 M hexane solution of t-butyllithium (1.35 ml) And the reaction mixture was stirred for 20 minutes. Fluorine in tetrahydrofuran (1.5 ml) Phenyl isocyanate (0.23 ml; 2.1 mmol) was added and the reaction mixture Was stirred overnight at 20 ° C. The reaction mixture was diluted with water and extracted with ethyl acetate. Existence The organic phase was washed with saturated brine and dried over magnesium sulfate. Filtration and solvent evaporation A tan oil remained afterwards. The crude product was converted into 15%, 20% and Chromatography on silica gel eluting sequentially with 40% ether. 2- (N-phenylacetamido) -3-phenylthioindole was added as mp66- Isolated as a solid at 68 ° C. C_{twenty two}H₁₈N₂OS analysis:   Calculated C 72.98; H 5.01; N 7.73   Found C 72.99; H 4.87; N 7.52.   The relatively later fraction is 2- (N-phenylacetamide) at mp 123-125 ° C. ) -1- (Phenylcarbamoyl) -3-phenylthioindole was included. C₂₉H_{twenty three}N₃O₂Analysis of S:   Calculated C 70.28; H 4.67; N 8.47.   Found C 70.37; H 4.61; N 8.34.Example 7 2- (2-oxo-2-furan-3-yl) ethyl-3-phenylthioindole Manufacturing Step A :N-methoxy-N-methylfuran-3-carboxamide   Furan-3-carboxylic acid (3.4 g; 0.030 mol), N, O-dimethyl Hydroxylamine hydrochloride (2.9 g; 0.030 mol), triethylamine (8.3 ml; 0.060 mol) and benzotriazol-1-yloxyto Lis (dimethylamino) phosphonium hexafluorophosphate (13.3 g 0.030 mol), the title compound was added to N- (3-pyridylmethyl) -5- Lolo-3-phenylthioindole-2-carboxa Prepared according to the general procedure described in Example 1 for the amide. NMR (DMSO-d₆): Δ 8.25 (1H, s), 7.75 (1H, s) ), 3.70 (3H, s), 3.22 (3H, s).Step B :2- (2-oxo-2-furan-3-yl) ethyl-3-phenyl Lucioindole   N-methoxy-N-methylfuran-3-carboxamide (0.32 g; 2.1 mmol) and 2-methyl-3-phenylthioindole (0.50 g; 2.1. mmol) from the title compound to give 2- (N-phenylacetamido) -3-phenyl Prepared according to the general procedure described in Example 6 for the preparation of ruthioindole. The crude product is chromatographed on silica gel with chloroform. It was The title compound was obtained as a pale yellow solid, mp 127-129 ° C. C₂₀H_FifteenNO₂Analysis of S:   Calculated C 72.05; H 4.54; N 4.20   Found C 72.08; H 4.57; N 4.24.Example 8 Preparation of 2-benzoyl-5-chloro-3-phenylthioindole Steve A:N-methoxy-N-methyl-5-chloro-3-phenylthioin Dole-2-carboxamide   5-Chloro-3-phenylthioindole-2-ca in dimethylformamide Rubonic acid (1.0 g; 3.30 mmol), N, O-dimethylhydroxylami Hydrochloride (0.64 g; 6.6 mmol), triethylamine (1.0 ml; 7 mmol) and benzotriazol-1-yloxytris (dimethylamino) From phosphonium hexafluorophosphate (1.64 g; 3.6 mmol) , The title compound was N- (3-pyridylmethyl) -5-chloro-3-phenylthioii According to the general procedure described in Example 1 for the preparation of ndol-2-carboxamide Manufactured.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 added to anhydrous tetrahydrofuran ( 5 ml) and cooled to -78 ° C under nitrogen. Phenyl chloride 2M tetrahydrofuran solution of rumagnesium (0.81 ml) through a syringe The reaction mixture was warmed to 20 ° C. overnight. Water and ethyl acetate in the reaction mixture Was added and then separated. The organic phase is water, 5% hydrochloric acid, saturated sodium bicarbonate, saturated It was washed with Japanese brine and dried over magnesium sulfate. Crude after filtration and solvent evaporation The product remained and the crude product was treated with silica gel using 10% ether in hexane. Chromatography on the filter. The title compound was solidified at mp 154-155 ° C. Got it as a body. C_{twenty one}H₁₄Analysis for ClNOS:   Calculated C 69.32; H 3.88; N 3.85.   Found C 68.61; H 3.83; N 3.83.Example 9 2- (2-benzoxazol-2-ylethyl) -3-phenylthioindole Manufacturing Step A :N-methoxy-N-methyl-3-phenylthioindole-2- Carboxamide   3-Phenylthioindole-2-carboxylic acid (1.0 g; 3.7 mmol) , N, O-Dimethylhydroxylamine hydrochloride (0.54 g; 5.5 mmol) , Trier Cylamine (1.5 ml; 11 mmol) and benzotriazol-1-yl Xytris (dimethylamino) phosphonium hexafluorophosphate (1. 64 g; 3.7 mmol) to give the title compound as N- (3-pyridylmethyl) -5. Example 1 for -chloro-3-phenylthioindole-2-carboxamide It was manufactured according to the procedure described in.Step B :3-phenylthioindole-2-carboxaldehyde   N-methoxy-N-methyl-3-phenylthioindole-2-carboxami (1.57 g; 5.26 mmol) in tetrahydrofuran (150 ml) It was allowed to thaw and it was cooled to 0 ° C. under nitrogen. 1M lithium aluminum hydride The solution of trahydrofuran (5.76 ml) was added slowly via syringe and The reaction mixture was stirred for a total of 1.5 hours. Ethyl acetate (30 ml) was added, followed by Saturated potassium sodium tartrate solution was added. Separate the layers and wash the organic phase with saturated brine. It was washed with in and dried over magnesium sulfate. After filtration and evaporation of the solvent the title compound Was obtained as a yellow solid.Step C :Trans-2- (2-benzoxazol-2-ylethenyl) -3-Phenylthioindole   Under nitrogen at −78 ° C. [(benzoxal-2-yl) -methyl] die Tylphosphonate (2.34 g; 8.68 mmol) was added to tetrahydrofuran (5 Solution of n-butyllithium in 2.5 M hexane (3. 47 ml) was added. The reaction mixture was stirred for 20 minutes and warmed to -20 ° C. Three -Phenylthioindole-2-carboxaldehyde (1.10 g; 4.34 m) (mol) in tetrahydrofuran (30 ml) was added and the reaction mixture was added. The mixture was stirred overnight at 20 ° C. Ethyl acetate and water were added and the layers were separated. Organic The layer was washed with saturated brine and dried over magnesium sulfate. 1: 1 crude product Trituration with hexane-ethyl acetate, which was collected by filtration. The title compound is m Obtained as a yellow solid at p260.degree. C_{twenty three}H₁₆N₂OS analysis:   Calculated 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-phenyl Lucioindole   Trans-2- (2-benzoxazol-2-ylethenyl) -3-phenyl Luthioindole (0.420 g; 1.14 mmol) in 1: 1 methanol- A solution of tetrahydrofuran (250 ml) dissolved in 10% palladium-carbon ( 100 mg) and stirred under 1 atm of hydrogen. To complete the reaction Additional catalyst was added as needed. The catalyst is removed by filtration and the filtrate is put under vacuum. Concentrated. The solid obtained was triturated with 10% ethyl acetate in hexane and filtered Recovered to give the title compound, mp 192-193 ° C. C_{twenty three}H₁₈N₂OS analysis:   Calculated C 72.80; H 5.04; N 7.38   Found C 72.78; H 4.95; N 7.45.Example 10 N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide production   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine To 2-aminomethylfuran The title compound was prepared. Dimethylformamide was removed under vacuum and the residue was 1: It was triturated with 1 ethyl acetate-hexane and filtered. Re-from acetonitrile Crystallization gave the title compound with mp 214 ° C. C₂₀H_FifteenClN₂O₂Analysis of S:   Calculated C 62.74; H 3.95; N 7.32   Found C 62.27; H 3.88; N 7.41. NMR (DMSO-d₆): Δ 12.55 (1H, s), 8.72 (1H, t) , J = 6 Hz), 7.55 (1 H, m), 7.54 (1 H, d, J = 8 Hz), 7.45 (1H, d, J = 2Hz), 7.15 (1H, tt, J = 7, 1Hz) , 7.08 (1H, s), 7.06 (1H, d, J = 8Hz), 6.35 (1H , M), 6.18 (1H, m), 4.56 (2H, d, J = 6 Hz).Example 11 N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxa Manufacture of mid   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 3-aminopyridine to produce the title compound. Dimethylformamide Removed under vacuum and triturated the residue with 1: 1 ethyl acetate-hexane which was filtered. did. Chromatograph on silica gel with 40% ethyl acetate in hexane. The title compound was obtained with mp 255-256 ° C. C₂₀H_FifteenClN₃OS analysis:   Calculated C 63.24; H 3.98; N 10.74   Found C 62.59; H 3.86; N 11.06. NMR (DMSO-d₆): Δ 12.72 (1H, s), 10.55 (1H, s) s), 8.85 (1H, d, J = 3 Hz), 8.35 (1H, dd, J = 5, 1) Hz), 8.14 (1H, dm, J_d= 8 Hz), 7.60 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2Hz), 7.40 (1H, dd, J = 9, 2Hz), 7.25 (2H, t, J = 7Hz), 7.16 (1H, m), 7.1 1 (2H, t, J = 7 Hz).Example 12 Of N-ethyl-5-chloro-3-phenylthioindole-2-carboxamide Manufacturing   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with ethylamine to produce the title compound. Dimethylformamide under vacuum The residue was triturated with 1: 1 ethyl acetate-hexane and filtered. Recrystallization from 2% methanol in ethyl acetate gave mp 210-211 ° C. The above compound was obtained. C₁₇H_FifteenClN₂OS-0.5H₂Analysis for O:   Calculated value C 60.08; H 4.74; N 8.24   Found C 60.00; H 4.18; N 8.52. NMR (DMSO-d₆): Δ 12.49 (1H, s), 8.31 (1H, t) , J = 6 Hz), 7.54 (1H, d, J = 9 Hz), 7.43 (1H, d, J = 2 Hz), 7.27 (3H, m), 7.15 (1H, tt, J = 7,2Hz) , 7. 07 (2H, m), 3.35 (4H, m), 1.06 (3H, t, J = 7Hz) .Example 13 N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-ca Production of ruboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 3-methoxybenzylamine to produce the title compound. Dimethyl form The amide was removed under vacuum and the residue was triturated with 1: 1 ethyl acetate-hexane, It was filtered. The title compound, mp 172 ° C, by recrystallization from acetonitrile Got C_{twenty three}H₁₉ClN₂O₂S ・ 0.3H₂Analysis for O:   Calculated C 64.48; H 4.61; N 6.54   Found C 64.41; H 4.38; N 6.75. NMR (DMSO-d₆): Δ 12.55 (1H, s), 8.80 (1H, m) ), 7.55 (1H, d, J = 8 Hz), 7.44 (1H, s), 7.25 (3 H, m), 7.15 (2H, m), 7.05 (2H, d, J = 7Hz), 6.8 0 (3H, m), 4.54 (2H, d, J = 6Hz).Example 14 N-2-Methoxyethyl-5-chloro-3-phenylthioindole-2-cal Voxamide production   Follow the procedure described in Step B of Example 1, except that The title compound was prepared by substituting 2-methoxyethylamine for aminomethylpyridine. It was Dimethylformamide was removed under vacuum and the residue was washed with 1: 1 ethyl acetate-hexane. Triturate with xanthan and filter to give the title compound, mp 216-217 ° C. C₁₈H₁₇ClN₂O₂S-0.25H₂Analysis for O:   Calculated C 59.17; H 4.83; N 7.67.   Found C 59.11; H 4.75; N 7.82. NMR (DMSO-d₆): Δ 12.54 (1H, s), 8.44 (1H, t) , J = 6 Hz), 7.54 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2Hz), 7.28 (3H, m), 7.17 (1H, t, J = 7Hz), 7. 10 (2H, m), 3.49 (2H, q, J = 6Hz), 3.37 (2H, t, J = 6 Hz), 3.16 (3H, s).Example 15 N-4-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide production   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 4-aminomethylpyridine to produce the title compound. Dimethylformua The amide was removed under vacuum and the residue was triturated with 1: 1 ethyl acetate-hexane, which Was filtered. Mp 228 to 229 ° C by recrystallization from acetonitrile. The compound was obtained. C_{twenty one}H₁₆ClN₃OS 0.2H₂Analysis for O:   Calculated C 63.45; H 4.16; N 10.57.   Found C 63.33; H 4.02; N 10.50. NMR (DMSO-d₆): Δ 12.56 (1H, s), 8.92 (1H, t , J = 6 Hz), 8.38 (1H, d, J = 4 Hz), 7.55 (1H, d, J = 8 Hz), 7.47 (1H, s), 7.31 (1H, dd, J = 8,2 Hz) , 7.25 (1H, d, J = 7Hz), 7.17 (2H, m), 7.05 (1H , D, J = 7 Hz), 4.58 (2H, d, J = 6 Hz).Example 16 N-2-hydroxyethyl-5-chloro-3-phenylthioindole-2-ca Production of ruboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 2-hydroxyethylamine to produce the title compound. Dimethyl form The amide was removed under vacuum and the residue was triturated with 1: 1 ethyl acetate-hexane, It was filtered. Chromatography on silica gel with 2% methanol in chloroform. By chromatography, the title compound was obtained with mp 222-223 ° C. C₁₇H_FifteenClN₂O₂S ・ 0.3H₂Analysis for O:   Calculated C 57.96; H 4.46; N 7.95.   Found C 57.99; H 4.26; N 7.90. NMR (DMSO-d₆): Δ 12.50 (1H, s), 8.46 (1H, m) ), 7.55 (1H, d, J = 9Hz), 7.45 (1H, d, J = 1Hz), 7.2 8 (3H, m), 7.17 (1H, t, J = 6Hz), 7.13 (2H, m), 485 (1H, t), 3.49 (1H, m), 3.43 (1H, m).Example 17 Preparation of 5-chloro-3-phenylthioindole-2-carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine And triethylamine were replaced with excess ammonia gas to produce the title compound. . Dimethylformamide and excess ammonia were removed under vacuum and the residue was converted to acetic acid. Partitioned between ethyl and 10% hydrochloric acid. The organic phase is water, 5% sodium hydroxide and saturated It was washed with brine and then dried over magnesium sulfate. Crude after filtration and evaporation A product was obtained, the crude product was converted to silica using 30% ethyl acetate in hexane. Chromatography on gel. The title compound was obtained as a white solid with mp 213-215 ° C. C_FifteenH₁₁ClN₂OS / 1 / 3H₂Analysis for O:   Calculated C 58.35; H 3.81; N 9.07.   Found C 58.33; H 3.64; N 9.11. NMR (DMSO-d₆): Δ 12.52 (1H, bs), 8.06 (1H, s), 7.76 (1H, s), 7.55 (1H, d, J = 9 Hz), 7.44 ( 1 H, s), 7.28 (3H, m), 7.15 (1H, t, J = 6Hz), 7.0 6 (2H, d, J = 8HZ).Example 18 Preparation of 5-chloro-3-phenylthioindole-2-thiocarboxamide   5-chloro-3-phenylthioindole-2-carboxamide (3.8 g; 12.5 mmol) and 2,4-bis (4-methoxyphenyl) -1,3-dithio A-2,4-diphosphetane-2,4-disulfide (Laweson reagent) (5.0 g; 12.5 mmol) dissolved in anhydrous THF (110 ml) Was refluxed under nitrogen for 16 hours. The solvent was removed under vacuum and the residue was taken up in hexane. Chromatography on silica gel with 10% ethyl acetate. Before The product obtained by chromatography was triturated with hexane to give a yellowish solid. Was collected and dried to give the title compound with mp 217 ° C (decomposition). C_FifteenH₁₁ClN₂Analysis of S:   Calculated C 56.50; H 3.48; N 8.79.   Found C 56.75; H 3.64; N 8.59. NMR (DMSO-d₆): Δ 12.22 (1H, s), 10.31 (1H, s) s), 9.48 (1H, s), 7.50 (1H, d, J = 8Hz), 7.39 ( 1 H, s), 7.25 (3H, m), 7.13 (1H, t, J = 7Hz), 7.0 1 (2H, d, J = 7 Hz).Example 19 N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thio Manufacture of carboxamide   Regarding 5-chloro-3-phenylthioindole-2-thiocarboxamide According to the procedure described, except that 5-chloro-3-phenylthioindole-2-car Voxamide was added to N-2-furanylmethyl-5-chloro-3-phenylthioindole. The title compound was prepared in place of le-2-carboxamide. The crude product was added to hexane Chromatography on silica gel with 3% ethyl acetate in. Standard The compound was obtained as a bright yellow solid, mp 143-144 ° C. C₂₀H_FifteenClN₂OS₂・ H₂Analysis for O:   Calculated C 57.61; H 3.62; N 6.72   Found C 57.56; H 3.58; N 6.52. NMR (DMSO-d₆): Δ 12.27 (1H, s), 10.73 (1H, s) s), 7.55 (2H, m), 7.39 (1H, s), 7.21 (4H, m), 6.98 (2H, d, J = 7Hz), 6.36 (2H, s), 4.96 (2H, s).Example 20 N- [1- (2 (R) -hydroxypropyl)]-5-ku Preparation of loro-3-phenylthioindole-2-carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced by 2 (R) -hydroxy-1-propylamine to produce the title compound. Dimethylformamide was removed under vacuum and the residue was first treated with 20% acetic acid in hexane. Triturated with ethyl then acetonitrile. Mp 202-203 ° C of the title compound Obtained as an off-white solid. C₁₈H₁₇ClN₂O₂S ・ 0.3H₂Analysis for O:   Calculated C 59.01; H 4.67; N 7.65.   Found C 58.91; H 4.59; N 7.50. NMR (DMSO-d₆): Δ 12.52 (1H, s), 8.45 (1H, t) , J = 5 Hz), 7.55 (1H, d, J = 8 Hz), 7.46 (1H, s), 7.25 (3H, m), 7.15 (3H, m), 4.89 (1H, d, J = 5H z), 3.74 (1H, m), 3.38 (1H, m), 3.23 (1H, m), 1.00 (3H, d, J = 6HZ).Example 21 N- (2-pyridyl) methyl-5-chloro-3-phenylthioindole-2- Manufacture of carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Replace with 2-pyridylmethylamine The title compound was prepared. Dimethylformamide was removed under vacuum and residue was collected. Triturated with 30% ethyl acetate in hexane, then acetonitrile. Compounding The product was obtained as a white solid with mp 209-210 ° C. C_{twenty one}H₁₆ClN₃OS analysis:   Calculated C 64.03; H 4.10; N 10.67   Found C 63.51; H 3.97; N 10.41. NMR (DMSO-d₆): Δ 12.58 (1H, s), 9.15 (1H, t) , J = 5 Hz), 8.46 (1H, d, J = 5 Hz), 7.66 (1H, t, J = 8 Hz), 7.57 (1H, d, J = 8 Hz), 7.50 (1H, s), 7. 25 (5H, m), 7.12 (3H, m), 4.68 (2H, d, J = 5Hz) .Example 22 N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioi Production of ndol-2-carboxamide Step 1 :Production of 4-cyano-2-methoxypyridine   D. Liebermann, N .; Rist, F.R. Grumbach, S .; Ca Is, M .; Moyeux and A.M. RouixBull. Soc. Chim. France 694 , 2-chloro-4-, prepared as described in US Pat. Cyanopyridine (1.25 g; 9.1 mmol) in sodium methoxide (0.58 g; 10.9 mmol) and refluxed for 30 minutes. Cool the reaction mixture and filter And the filtrate was concentrated in vacuo to give a crude product as an off-white solid. This The crude product of was chromatographed on silica gel with 20% ethyl acetate in hesan. I went to the graph. The title compound was obtained as a white powder.Step two :Production of 4-aminomethyl-2-methoxypyridine   Ethano of 4-cyano-2-methoxypyridine (0.55 g; 4.1 mmol) Solution in the presence of 10% palladium-charcoal (100 mg).₂Pressure 60 psi It was hydrogenated at After 3.5 hours, the catalyst was filtered by Super-Cel. Removed and the filtrate was evaporated to give the title compound as a foam.Step 3 :N- (3-methoxy-4-pyridylmethyl) -5-chloro-3- Production of phenylthioindole-2-carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine 4-aminomethyl-2-methoxy The title compound was prepared in place of pyridine. Remove dimethylformamide under vacuum And the crude product obtained was silica using 20 → 40% ethyl acetate in hexane. Purified by chromatography on gel. The title compound is mp227-2 Obtained as a white solid at 28 ° C. C_{twenty two}H₁₈ClN₃O₂Analysis of S:   Calculated C 62.33; H 4.28; N 9.91.   Found C 62.63; H 4.21; N 9.92. NMR (DMSO-d₆): Δ 12.58 (1H, s), 8.93 (1H), 8.37 (2H, d), 7.56 (1H, d), 7.47 (1H, s), 7.2 7 (3H, m), 7.18 (2H, m), 7.05 (2H, d), 4.59 (2 H, d), 3.30 (3H, s).Example 23 N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindo Production of ol-2-carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 3-hydroxymethylbenzylamine to produce the title compound. Dimethi Ruformamide was removed under vacuum and the resulting crude product was recrystallized from acetonitrile. Crystallized The title compound was obtained as a white solid with mp 229-230 ° C. C_{twenty two}H₁₇ClN₂O₂Analysis of S:   Calculated C 64.61; H 4.19; N 6.85.   Found C 64.20; H 4.09; N 6.85. NMR (DMSO-d₆): Δ 12.69 (1H, s), 10.33 (1H, s) s), 7.60 (3H, m), 7.49 (1H, s), 7.30 (4H, m), 7.15 (4H, m), 5.22 (1H, t, J = 7Hz), 4.50 (2H, d, J = 7 Hz).Example 24 N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole- Production of 2-carboxamide   Follow the procedure described in Example 1, Step B, except that 3-aminomethylpyridine Was replaced with 3-hydroxybenzylamine to produce the title compound. Dimethyl phor The muamide was removed under vacuum and the crude product obtained was treated with 10% meta in chloroform. Chromatography on silica gel with nol. The title compound is m Obtained as a white solid, p 214-216 ° C. C_{twenty two}H₁₇ClN₂O₂S ・ 0.3H₂Analysis for O:   Calculated C 63.77; H 4.04; N 6.76.   Found C 63.92; H 3.88; N 6.49. NMR (DMSO-d₆): Δ 12.55 (1H, s), 9.34 (1H, s) ), 8.75 (1H, t, J = 5Hz), 7.53 (1H, d, J = 8Hz), 7.45 (1H, s), 7.1 to 7.65 (4H, m), 7.06 (2H, d, J = 7H z), 7.01 (1H, t, J = 8Hz), 6.70 (1H, s), 6.62 ( 2H, m), 4.48 (2H, d, J = 5Hz).Example 25 5-chloro-3-phenylsulfonylindole-2-carboxamide (compound 18) Manufacturing   5-chloro-3-phenylthioindole-2-carboxamide (0.177 g; 0.584 mmol) was dissolved in 25 ml of chloroform, and this was heated to 0 ° C. Cooled. 50% by weight of m-chloroperoxybenzoic acid (503 mg; 1.46) mmol) was added and the reaction mixture was stirred at 200 ° C. for 6 hours. Natri thiosulfate A 10% aqueous solution of Um was added and the reaction mixture was vigorously stirred for 10 minutes. Separate layers The organic phase was washed with saturated sodium chloride and then dried over magnesium sulfate. . The crude product obtained is applied to silica gel eluting with 40% ethyl acetate in hexane. Chromatography on. The title compound was obtained as a white compound with mp 255-257 ° C. Obtained as a powder. NMR (300 MHz; DMSO-d₆): Δ 13.05 (1H, s), 8. 48 (1H, s), 8.25 (1H, s), 8.03 (2H, d, J = 8Hz) , 7.95 (1H, s), 7.60 (4H, m), 7.34 (1H, d, J = 8) Hz). C_FifteenH₁₁ClN₂O₃Analysis of S:   Calculated C 53.82; H 3.31; N 8.37   Found C 53.74; H 3.29; N 8.34.Example 26 5-chloro-3-phenylsulfinylindole-2-carboxamide (compound Manufacture of product 17)   5-Chloro-3-phenylthioindole-2-carboxamide (14.5m g; 0.048 mmol) in methanol (2 ml) at 0 ° C. And magnesium monoperoxyphthalic acid (85% peracid) (11.8 mg; 0 ． A solution of 024 mmol) dissolved in methanol (2 ml) was added dropwise. The reaction mixture was stirred at 20 ° C. for 4 hours. Add 10% aqueous solution of sodium thiosulfate The reaction mixture was stirred vigorously for 10 minutes. Remove the methanol under vacuum and leave The distillate was partitioned between ethyl acetate and water. Wash the ethyl acetate extract with brine and It was dehydrated with magnesium acid. The crude product obtained was added to 30% to 40% vinegar in hexane. Purified by column chromatography on silica gel with ethyl acidate . The title compound was obtained as a white solid. NMR (DMSO-d₆300 MHz): δ 12.53 (1H, s), 8. 35 (1H, br s), 8.08 (1H, br s), 7.83 (1H, d, J = 2 Hz), 7.71 (2H, d, J = 8 Hz), 7.52 (4H, m), 7 ． 30 (1H, dd, J = 9, 2Hz).Example 27 N- (2,6-difluorobenzyl) -5-chloro-3-phenylsulfonylyl Production of ndol-2-carboxamide Step A :5-chloro-3-phenylsulfonylindole-2-carvone acid   5-chloro-3-phenylthioindole-2-carboxylic acid (4.84 g; 0 ． 016 mol) in a suspension of chloroform (1,200 ml) 5% m-Chloroperoxybenzoic acid (12.5 g; 0.04 mol) was added. It was The mixture was stirred at room temperature for 40 hours. Filter to give the title compound as mp277 Obtained as a colorless solid at ˜280 ° C. (decomposition). Secondary recovery product during partial evaporation GotStep B :5-chloro-3-phenylsulfonylindole-2-carvone Acid and oxalyl chloride Products of reaction with   5-chloro-3-phenylsulfonylindole-2-carboxylic acid (5.04 g: 0.015 mol) in a suspension of chloroform (200 ml) Oxalyl chloride (3.81 g; 0.03 mol) was added. Catalytic amount of dimethyl After addition of formamide (0.1 ml), heat the mixture at a bath temperature of 60 ° C. for 50 minutes. did. The solid product with mp> 300 ° C. obtained after cooling, without further purification I used it directly. This product is symmetrical based on mass spectrum and NMR data While it is believed to be a dimer, the typical acid in the reaction with primary amines Behaves as chloride.Step C :N- (2,6-difluorobenzyl) -5-chloro-3-phenyl Lesulfonylindole-2-carboxamide   The “acid chloride equivalent” (0.354 g; 1.0 mmol) obtained in Step B was tested. The solution in trahydrofuran (10 ml) was cooled in an ice-acetone bath, 2,6-difluorobenzylamine (0.430 g; 3.0 mmol) was added to this. It was added dropwise. The temperature of the reaction mixture is adjusted to room temperature. It was warmed up and left overnight. Ethyl acetate and water were added for workup. Wash the ethyl acetate phase thoroughly with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine. did. After dehydration over magnesium sulphate and evaporation of the solvent the residue is washed with ethyl acetate. Slurry and filter to give the title compound, mp 274-280 ° C. C_{twenty two}H_FifteenClF₂N₂O₃S / 0.5H₂Analysis for O:   Calculated C 56.24; H 3.43; N 5.96   Found C 56.12; H 3.31; N 5.97. NMR (DMSO-d₆): Δ 13.06 (1H, s), 9.41 (1H, t) , J = 5.5 Hz), 7.95 (3H, m), 7.41 to 7.67 (m, 5H) , 7.34 (1H, dd, J = 9, 2Hz), 7.18 (2H, t, J = 8Hz) ), 4.64 (2H, d, J = 5.5Hz).Example 28 N- (4-pyridylmethyl) -5-chloro-3-phenylsulfinylindole Preparation of Le-2-carboxamide (Compound 29) Step A :5-chloro-3-phenylsulfinylindole-2-carb Production of acid   5-Chloro-3-phenylthioindole-2-carboxylic acid (2.14 g; 0 ． 007 mol) to chloroform 55% m-chloroperoxybenzoic acid in a suspension suspended in (600 ml). (2.32 g; 0.0074 mol) was added. The mixture becomes transparent for a while and then After that a solid appeared. After stirring overnight at room temperature, the title compound is filtered to give mp18. Obtained in pure form at 3-185 ° C.Step B :N- (4-pyridylmethyl) -5-chloro-3-phenylsulf Inylindole-2-carboxamide   5-chloro-3-phenylsulfinyl indo in anhydrous dimethylformamide -2-carboxylic acid (0.096 g; 0.3 mmol), triethylamine ( 0.061 g; 0.6 mmol) and 4-aminomethylpyridine (0.043 g) 0.4 mmol) in a mixture of benzotriazol-1-yloxytris (di Methylamino) phosphonium hexafluorophosphate (BOP reagent) (0. 155 g; 0.35 mmol) was added. Stir the mixture under nitrogen at room temperature for 3 days did. After evaporation, the residue was partitioned between ethyl acetate and water. Separate the ethyl acetate phase, It was washed with diluted hydrochloric acid. The acidic extract is neutralized with aqueous sodium bicarbonate and the product is vinegared. Extracted into ethyl acid. Ethyl acetate extraction Wash product thoroughly with aqueous sodium bicarbonate then brine and wash with magnesium sulfate. I dehydrated it. After evaporation a solid residue was obtained which was recrystallized from ethyl acetate Gave the title compound with mp 233-235 ° C. C_{twenty one}H₁₆ClN₃O₂Analysis of S:   Calculated C 61.54; H 3.93; N 10.25   Found C 61.39; H 3.95; N 10.36. NMR (DMSO-d₆): Δ 9.62 (1H, t, J = 6 Hz), 8.53 (2H, d, J = 6Hz), 7.80 (1H, d, J = 2Hz), 7.67 (2 H, m), 7.64 (2H, d, J = 9Hz), 7.44 to 7.54 (3H, m ), 7.33 (3H, m), 4.60 (2H, dq, J = 9.6Hz).Example 29 N-[(S) -1-phenyl-2-hydroxyethyl] -5-chloro-3-phen Preparation of Nylsulfonylindole-2-carboxamide (Compound 32)   Acid chloride dimer obtained in Step B of Example 27 cooled in an ice-acetone bath The product (0.354 g; 1.0 mmol) in tetrahydrofuran (10 ml) (S)-(+)-2-phenylglycinol (0.343 g; 2.5 mmol) solution was added. Allow the mixture to slowly warm to room temperature overnight I left it. Ethyl acetate And water were added. The ethyl acetate phase is diluted with dilute hydrochloric acid, water, saturated sodium bicarbonate and It was sequentially washed in. After dehydration over magnesium sulfate and evaporation, the product was Chroma on a 20 mm column containing 230-400 mesh silica gel. I went to the topography. Pure by elution with 40% ethyl acetate in methylene chloride The trendy title compound was obtained, which after evaporation was crystallized from ethyl acetate-hexane to give mp The title compound was obtained at 155-160 ° C. C_{twenty three}H₁₉ClN₂O_FourAnalysis of S:   Calculated C 60.72; H 4.21; N 6.16   Found C 60.33; H 4.13; N 6.16. NMR (DMSO-d₆): Δ 13.05 (1H, s), 9.52 (1H, d , J = 7.5 Hz), 7.95 to 8.48 (3 H, m), 7.26 to 7.68 ( 10H, m), 5.13 (1H, q, J = 7.5Hz), 5.07 (1H, t, J = 6 Hz), 3.75 (2H, d, J = 6 Hz).Example 30 N- (3-methoxybenzyl) -5-chloro-3- (2-thiazolyl) sulfoni Luindole-2-carboxamide (Compound 31) Step A :5-chloro-3- (2-thiazolyl) thioindole-2-cal Production of boric acid   The procedure of Step A of Example 1 is used, except that the phenyl disulfide is di- (2 -Thiazolyl) disulfide was obtained to give the title compound with mp 242-244 ° C. .Step B :5-chloro-3- (2-thiazolyl) sulfonylindole-2- Production of carboxylic acid   Using the procedure of Step A of Example 27, but with 5-chloro-3-phenylthio 5-chloro-3- (2-thiazolyl) thioindole with indole-2-carboxylic acid To give the title compound with mp 260-261 ° C.Step C :5-chloro-3- (2-thiazolyl) sulfonylindole-2 -The product of the reaction of a carboxylic acid and oxalyl chloride   Using the procedure of Example 27, Step B, except that 5-chloro-3-phenylsulfur is used. Fonylindole-2-carboxylic acid was added to 5-chloro-3- (2-thiazolyl) sulfur. Substituting honylindole-2-carboxylic acid to give a solid product with mp> 290 ° C., This was used directly in the next step.Step D :N- (3-methoxybenzyl) -5-chloro-3- (2-thiazo Rylsulfonyl)- Indole-2-carboxamide   The "acid chloride" product (0.1%) obtained in Step C, cooled in an ice-acetone bath. 81 g; 0.5 mmol) in a solution of tetrahydrofuran (5 ml) 3-Methoxybenzylamine (0.205 g; 1.5 mmol) was added. Mixed The mixture was allowed to warm to room temperature and then left overnight with stirring. Ethyl acetate And water were added. The separated ethyl acetate layer was washed with diluted hydrochloric acid, saturated sodium bicarbonate and And washed with brine. After dehydration (magnesium sulfate) and evaporation, reduce solid residue Amount of ethyl acetate. The title compound with mp 205-209 ° C. Obtained. C₂₀H₁₆ClN₃O_FourS₂Analysis about:   Calculated C 52.00; H 3.49; N 9.10.   Found C 51.88; H 3.42; N 9.07. NMR (DMSO-d₆): Δ 9.43 (1H, t, J = 6 Hz), 8.18 (1H, d, J = 3Hz), 8.02 (1H, d, J = 3Hz), 8.00 (1 H, d, J = 2 Hz), 7.58 (1 H, d, J = 8.5 Hz), 7.40 (1 H, dd, J = 8.5, 2 Hz), 7.28 (1 H, t, J = 8 Hz), 6.9 8 to 7.05 (2H, m), 6.85 (1H, dd, J = 8, 2.5Hz), 4 ． 54 (2H, d, J = 3.76 Hz).Example 31 5-chloro-3- (2-thiazolyl) sulfonyl indole Le-2-carboxamide   The "acid chloride" product of Step C of Example 30 (0.50 g; 1.4 mmol) ) Was dissolved in tetrahydrofuran (25 ml) at -10 ° C. Slowly added to a tetrahydrofuran solution saturated with ammonia. Reaction mixture Was allowed to stir overnight after gradually raising its temperature to room temperature. The solvent was evaporated After that, the residue was partitioned between ethyl acetate and water. Saturated sodium bicarbonate extract with ethyl acetate extract It was washed with barium and brine and dried over magnesium sulfate. Residue after evaporation of solvent The product was slurried with ethyl acetate, filtered and mp 292-294 ° C (decomposition) The title compound was obtained. C₁₂H₈ClN₃O₃S₂Analysis about:   Calculated C 42.17; H 2.36; N 12.29.   Found C 42.23; H 2.35; N 11.85. NMR (DMSO-d₆): Δ 8.39 (1H, br s), 8.34 (1H , Br s), 8.24 (1H, d, J = 3 Hz), 8.07 (1H, d, J = 3 Hz), 8.00 (1H, dd, J = 2, 0.6 Hz), 7.57 (1H, d d, J = 9, 0.6 Hz), 7.40 (1H, dd, J = 9, 2 Hz).Example 32 5-chloro-3-phenylsulfonylindole-2-thi Ocarboxamide   5-chloro-3-phenylsulfonylindole-2-carboxamide was added to 2, 4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan (Lawesson's reagent) and reacted according to the procedure of Example 18 to give the title compound. Obtained. Chromatographic purification on silica gel with 30% vinegar in methylene chloride Performed with ethyl acid followed by 50% ethyl acetate in methylene chloride. Pure The product had an mp of 207-210 ° C. C_FifteenH₁₁ClN₂O₂S₂Analysis about:   Calculated C 51.35; H 3.16; N 7.98.   Found C 50.84; H 3.08; N 8.04. NMR (DMSO-d₆): Δ 12.90 (1H, s), 10.71 (1H, s), 10.70 (1H, s), 8.0 to 8.6 (2H, m), 7.84 (1H) , D, J = 2 Hz), 7.54 to 7.66 (3 H, m), 7.46 (1 H, d, J = 8.5 Hz), 7.30 (1 H, dd, J = 8.5, 2 Hz).Example 33 Preparation of 3-phenylsulfonyl-5-chloroindole-2-carboxamide Step A :N- (phenylthio) succinimide   N-chlorosuccin, cooled in an ice bath under an inert atmosphere Of imide (3.34 g; 25 mmol) in anhydrous methylene chloride (30 ml) To the split solution, thiophenol (2.05 ml; 20 mmol) was added via a syringe. Was added. After stirring for 1 hour, additional N-chlorosuccinimide (0.40 g; 3 m mol) was added. After a total of 2.5 hours triethylamine (3.9 ml; 2 8 mmol) was added dropwise. Dilute the reaction mixture with methylene chloride within 15 minutes. , Wash the solvent with dilute hydrochloric acid, and then dehydrate the solvent (Na₂SO_Four), Filter with charcoal pad And evaporated. The residue was triturated with diethyl ether and the product was filtered Collect and mp115-116 ℃ (ReferenceJ. Org. Chem. 34, P. 51, Also in 1969, the title compound with mp 115-116 ° C) was obtained. This substance as it is used.Step B :3-phenylthio-5-chloroindole-2-carboxylic acid ethi Le   5-chloroindole-2-carbohydrate at ambient temperature under an inert gas atmosphere Ethyl acidate (698 mg; 3.1 mmol) and N- (phenylthio) succin The imide (683 mg; 3.3 mmol) was suspended in anhydrous methylene chloride (20 ml). Boron trifluoride ether was added to the suspended partial suspension. Ruride (0.12 ml; 1.0 mmol) was added. Reaction to completion It was monitored by lc (thin layer chromatography). After 2 hours, the reaction mixture was Diluted with loroform and NaHCO₃Neutralized with aqueous solution. The organic layer is dehydrated (N a₂SO_Four), Filtered through a charcoal pad and evaporated the solvent. Grind the residue with hexane And the product crystallized, mp 160-162 ° C. (mp 163-16 in Table II). The title compound (4 ° C.) crystallized out. This material was used as is.Step C :3-phenylsulfonyl-5-chloroindole-2-carvone Ethyl acid   Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642m g; 1.94 mmol) was dissolved in chloroform (35 ml), and m- Chloroperoxybenzoic acid (55% purity; 1.30 g; 4.1 mmol) Dissolve in Loform (20 ml) (Na₂SO_FourThen add the dehydrated solution dropwise. It was The progress of oxidation was monitored by tlc until completion. After 5 hours, the reaction mixture was Dilute with loroform and some methanol and add NaHCO 3 solution.₃Aqueous solution and N a₂CO₃It was washed with an aqueous solution. (N a₂SO_FourThe dried organic layer was filtered through a charcoal pad and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to give the title compound. Methylene chloride and diet Crystallization from chill ether gave analytically pure material with mp 201-202 ° C. Was obtained.¹ 1 H NMR (CDCl₃): Δ 9.63 (br s, 1H), 8.58 (t, 1H, J = 0.7 Hz), 8.07 (d, 2H, J = 7 Hz), 7.46 to 7. 56 (m, 3H), 7.40 (m, 2H), 4.39 (ABq, 2H, J = 7H z), 1.35 (t, 3H, J = 7 Hz). C₁₇H₁₄ClNO_FourAnalysis of S:   Calculated C 56.12; H 3.88; N 3.85.   Found C 55.91; H 3.95; N 3.91.Step D :3-phenylsulfonyl-5-chloroindole-2-carboxy Samide (Compound 18)   Ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate (5 96 mg; 1.64 mmol) in water containing ammonium chloride (28 mg) Suspended suspension in concentrated ammonium oxide aqueous solution (10 ml), with screw cap Heated at 100 ° C. for 3 hours in a sealed tube. Cool the sealed tube in an ice bath, thereby producing The product crystallized. The product is collected by filtration, rinsed with ice water and dried to mp 25 The title compound was obtained at 3-254 ° C.Example 34 N-[(imidazol-2-yl) methyl] -3-phenylsulfonyl-5-qua Production of loloindole-2-carboxamide   2-aminomethylimidazole dihydrochloride (J. Org. Chem. 43, P. 1603, 1978) (256 mg; 1.5 mmol) Was added to anhydrous tetraethylamine containing triethylamine (0.42 ml; 3.0 mmol). Suspended in hydrofuran (6 ml) and stirred for 1 hour at room temperature under inert atmosphere . Dimer acid chloride (see step B of Example 27) (179 mg; 0.25 mm ol), then additional triethylamine (0.07 ml; 0.5 mmol) was added. And the mixture was stirred for 12-20 hours. The mixture was diluted with water and the product was diluted with acetic acid. Extracted into chill. This organic layer is dehydrated (Na₂SO_Four), Filter and evaporate the solvent I let you. The residue was triturated with ethyl acetate to give the title compound. Re from hot ethyl acetate Crystallization gave an analytically pure product, mp 276-278 ° C.¹ 1 H NMR (DMSO-d₆): Δ 9.50 (br t, 1H, J = 5.4H) z), 8.07 (s, 1H), 8.05 (s, 1H), 8.00 (d, 1H, J = 1.2 Hz), 7.52 to 7.67 (m, 4H), 7.37 (dd, 1H, J = 1.5, 9 Hz), 7.03 (br s, 2H), 4.61 (d, 2H, J = 5.4 Hz). C₁₉H_FifteenClN_FourO₃Analysis of S:   Calculated C 55.00; H 3.64; N 13.50   Found C 54.67; H 3.36; N 13.37. Example 35N-[(1-methylimidazol-2-yl) methyl] -3-phenylsulfoni Preparation of le-5-chloroindole-2-carboxamide (compound 19) Step A :2-aminomethyl-1-methylimidazole   Lithium aluminum hydride (114 mg; 3.0 mmol) was suspended in anhydrous tetrahydrofuran (15 ml) to give a solid 1-methylimidazole-2-carboxamide (J. Org. Chem. 52, p. 4379, 1987) (185 mg; 1.5 mmol) One was added. The reaction mixture was stirred for 0.5 hours and then the temperature was raised for 3.5 hours at 50 ° C. Raised to. After cooling the reaction mixture in this way, Saturated Na₂SO_FourThe reaction was stopped by adding an aqueous solution (2 ml), and then powdery anhydrous Na₂SO_FourWas added. The resulting mixture was filtered to remove salts, -Aminomethyl-1-methylimidazole is tetrahydrofuran (about 25 ml) A non-aqueous solution dissolved in was obtained, and this solution was used as it was.Step B :N-[(1-methylimidazol-2-yl) methyl] -3-ph Phenylsulfonyl-5-chloroindole-2-carboxamide   The 2-aminomethyl-1-methylimidazole tetrahydrate cooled in an ice bath. Add the dimer indole acid chloride to the hydrofuran solution (see Step B of Example 27) ) (358 mg; 0.5 mmol) in anhydrous tetrahydrofuran (7 ml) The allowed solution was added dropwise. After 15 minutes triethylamine (0.2 ml; 1.4 mmol) and the reaction mixture is slowly warmed to room temperature over 12-20 hours. did. The reaction mixture was diluted with water and the product was taken up in 10% methanol in ethyl acetate. Extracted. Dehydrate the extract (Na₂SO_Four), Filtered through charcoal and evaporated the solvent. Vinegar residue Trituration with ethyl acid and recovery of the title compound by filtration. Hot methanol-acetic acid Recrystallization from chill gave analytically pure material, mp 273-275 ° C. It was¹ 1 H NMR (DMSO-d₆): Δ 9.48 (br t, 1H, J = 5 Hz) , 8.05 (d, 2H, J = 7Hz), 7.98 (d, 1H, J = 2Hz), 7 ． 52 to 7.67 (m, 4H), 7.35 (dd, 1H, J = 2, 9 Hz), 7 ． 18 (d, 1H, J = 1 Hz), 6.88 (d, 1H, J = 1 Hz), 4.6 6 (d, 2H, J = 5Hz), 3.71 (s, 3H). C₂₀H₁₇ClN_FourO₃Analysis of S:   Calculated C 56.00; H 4.00; N 13.06   Found C 55.77; H 3.97; N 13.41.   Decomposition by addition of 1 equivalent of HCl in ethanol to the above free base. A hydrochloride salt with an mp of 284-285 ° C. was obtained. C₂₀H₁₇ClN_FourO₃Analysis for S.HCl:   Calculated C 51.62; H 3.90; N 12.04   Found C 51.21; H 3.92; N 11.55.Example 36 According to another method, N-[(1-methylimidazol-2-yl) methyl] -3-ph Preparation of phenylsulfonyl-5-chloroindole-2-carboxamide   N-[(imidazol-2-yl) methyl] -3-phen Nylsulfonyl-5-chloroindole-2-carboxamide (Example 35) ( 42 mg; 0.1 mmol) of 1: 1 methanol-tetrahydrofuran (4 m l) in a partial suspension suspended in iodomethane (0.05 ml; 0.8 mmol ) Was added. The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure and N aHCO₃Aqueous solution was added and the product was extracted into ethyl acetate-methanol. Existence Dehydrate the machine layer (Na₂SO_Four), Filtered and the solvent was evaporated. Chromatograph the residue Purified by Ruffy and the product eluted with 3% methanol in chloroform . Combine appropriate fractions, evaporate the solvent and grind the residue with methylene chloride. To give pure product.Example 37 N- [2- (imidazol-4-yl) ethyl] -3-phenylsulfonyl-5 -Preparation of chloroindole-2-carboxamide (compound 24)   5-chloro-3-phenylsulfonylin cooled in an ice bath under an inert atmosphere Dole-2-carboxylic acid (see step A of Example 27) (336 mg; 0.5 carbonyldiimidazole (180 mg; 1.1 1 mmol) was added. After 0.5 hours, the yellow solution contained histamine (125 mg ; 1.12 mmol) was added. After 5 hours, the reaction mixture was diluted with water to give the product Was extracted into ethyl acetate. This organic layer is₃Wash with diluted aqueous solution and remove Water (Na₂SO_Four), Filtered through charcoal and evaporated the solvent. Chlorination of the obtained residue Trituration with methylene gave a crude product. By crystallization from hot ethyl acetate, mp2 The analytically pure title compound was obtained at 20-221.5 ° C.¹ 1 H NMR (DMSO-d₆): Δ 9.11 (br t, 1H, J = 5.4H) z), 8.00 (s, 1H), 7.98 (s, 1H), 7.95 (d, 1H, J = 2.1 Hz), 7.52 to 7.67 (m, 5H), 7.35 (dd, 1H, J = 2.1, 8.7 Hz), 6.94 (s, 1H), 3.60 (q, 2H, J = 7) ． 2 Hz), 2.83 (t, 2H, J = 7.2 Hz). C₂₀H₁₇ClN_FourO₃Analysis of S:   Calculated C 56.00; H 4.00; N 13.05   Found C 55.74; H 4.04; N 13.35.Example 38 N- (3-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole Production of le-2-carboxamide   3-Methoxybenzylamine (1.3 ml; 10 ml) cooled in an ice-acetone bath. (mmol) in a solution of anhydrous tetrahydrofuran (20 ml) and dimer Acid chloride (See Step B of Example 27) (1.77 g; 2.5 mmol) in anhydrous tetra A solution of hydrofuran (25 ml) was added dropwise. 12 reaction mixture Stir for -20 hours, then dilute with 10% methanol in ethyl acetate. Obtained The organic layer is washed with diluted hydrochloric acid and dehydrated (Na₂SO_Four), Filtered and evaporated the solvent . The residue was triturated with diethyl ether and a flocculent white raw I got a product. Recrystallisation from hot methanol-ethyl acetate, mp 203-2 The analytically pure title compound was obtained at 04 ° C.¹ 1 H NMR (DMSO-d₆): Δ 9.47 (br t, 1H, J = 6 Hz) , 8.03 (s, 1H), 8.01 (s, 1H), 7.94 (d, 1H, J = 2) ． 1 Hz), 7.63 (t, 1H, J = 6.9 Hz), 7.52 to 7.58 (m , 3H), 7.35 (dd, 1H, J = 2.1, 8.7 Hz), 7.29 (t, 1H, J = 7.8 Hz), 7.06 (s, 1H), 7.05 (d, 1H, J = 6) ． 6 Hz), 6.86 (dd, 1H, J = 2.7, 7.5 Hz), 4.57 (q , 2H, J = 6 Hz), 3.76 (s, 3H). C_{twenty three}H₁₉ClN₂O_FourAnalysis of S:   Calculated C 60.72; H 4.21; N 6.16   Found C 60.60; H 4.17; N 6.12.Example 39 N- (3-hydroxybenzyl) -3-phenylsulfoni Preparation of le-5-chloroindole-2-carboxamide   N- (3-methoxybenzyl) -3-phenylsulfonyl under an inert atmosphere -5-chloroindole-2-carboxamide (1.37 g; 3.0 mmol) Was dissolved in anhydrous methylene chloride (140 ml) and saturated with a solution of triodor in hexane. Boron bromide (1M; 10 ml; 10 mmol) was added. After stirring for 12 to 20 hours , The reaction mixture is NaHCO.₃It was neutralized by the addition of an aqueous solution. After 2 hours, the solution It was made weakly acidic by the addition of dilute hydrochloric acid. The precipitate is collected by filtration and then aqueous The filtrate of was extracted with ethyl acetate. The organic layer is dehydrated (Na₂SO_Four), Filtered and solvent Was evaporated. The residue was triturated with diethyl ether to give additional product. solid Were combined and crystallized from hot methanol-ethyl acetate, mp 273.5 The analytically pure title compound was obtained at ˜274.5 ° C.¹ 1 H NMR (DMSO-d₆): Δ 9.43 (t, 1H, J = 6 Hz), 8. 01 (s, 1H), 7.98 (s, 1H), 7.97 (d, 1H, J = 2.1H z), 7.63 (t, 1H, J = 6 Hz), 7.52 to 7.58 (m, 3H), 7.35 (dd, 1H, J = 2.1, 9 Hz), 7.17 (t, 1H, J = 7. 8 Hz), 6.89 (s, 1H), 6.86 (s, 1H), 6.84 (s, 1H) ), 6.70 (dd, 1H, J = 2.1, 8.4 Hz), 4.50 (d, 2H, J = 6 Hz). C_{twenty two}H₁₇ClN₂O_FourAnalysis of S:   Calculated C 59.93; H 3.89; N 6.36.   Found C 59.91; H 3.86; N 6.51.Example 40 N- (3-nitrobenzyl) -3-phenylsulfonyl-5-chloroindole -2- Production of carboxamide   Using the procedure described in Example 34, except 2-aminomethylimidazole dihydrochloride Replaced the salt with 3-nitrobenzylamine hydrochloride and therefore adjusted the amount of triethylamine. The title compound was obtained with mp 253-254 ° C. C_{twenty two}H₁₆ClN₃O_FiveAnalysis of S:   Calculated C 56.23; H 3.43; N 8.94   Found C 55.98; H 3.37; N 8.85.Example 41 N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole Preparation of 2-carboxamide (Compound 30)   N- (3-nitrobenzyl) -3-phenyi containing platinum oxide (70 mg) Rusulfonyl-5-chloroindole-2-carboxamide (353 mg; 75 mmo 1) dissolved in tetrahydrofuran (25 ml) and methanol (10 ml) The solution was hydrogenated at atmospheric pressure of hydrogen for 3 hours. The degassed solution is filtered to remove the catalyst. Removed and the solvent was evaporated. Triturate the residue with diethyl ether to give the title compound. It was Crystallization from acetonitrile gave analytically pure mp 247-249 ° C. The product was obtained.¹ 1 H NMR (DMSO-d₆): Δ 9.38 (t, 1H, J = 6 Hz), 7. 98 (s, 1H), 7.96 (d, 1H, J = 2.1 Hz), 7.53 to 7.6 0 (m, 4H), 7.35 (dd, 1H, J = 2.1, 9Hz), 7.02 (t , 1H, J = 7.5 Hz), 6.61 (s, 1H), 6.60 (d, 1H, J = 6 Hz), 6.50 (dd, 1H, J = 2.1, 8.1 Hz), 4.43 (d, 2H, J = 6Hz). C_{twenty two}H₁₈ClN₃O₃S / 0.25H₂Analysis for O:   Calculated C 59.45; H 4.20; N 9.46.   Found C 59.43; H 4.08; N 9.54.Example 42 N- (2-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole Production of le-2-carboxamide   Using the procedure described in Example 38, but using 3-methoxybenzylamine in 2-me. The title compound with mp 235-237 ° C. was obtained in place of toxybenzylamine.¹ 1 H NMR (DMSO-d₆): Δ 9.39 (t, 1H, J = 6 Hz), 7. 99 (d, 1H, J = 2.1 Hz), 7.95 (s, 1H), 7.93 (s, 1) H), 7.63 (t, 1H, J = 7.2 Hz), 7.50 to 7.57 (m, 3H) ), 7.29 to 7.44 (m, 3H), 7.06 (d, 1H, J = 7.5 Hz) , 6.97 (dt, 1H, J = 0.9, 7.2 Hz), 4.55 (d, 2H, J = 5.7 Hz), 3.85 (s, 3H). C_{twenty three}H₁₉ClN₂O_FourS ・ 0.2H₂Analysis for O:   Calculated value C 60.24; H 4.26; N 6.11   Found C 60.19; H 4.40; N 6.11.Example 43 N- (2-hydroxybenzyl) -3-phenylsulfonyl-5-chloroindo Production of ol-2-carboxamide   Use the procedure described in Example 39, except that the above 3-methoxy isomer is treated with 2-methoxy The title compound having mp 243 to 244.5 ° C. was obtained in place of the cis isomer (Example 42). .¹ 1 H NMR (DMSO-d₆): Δ 7.99 (d, 1H, J = 3 Hz), 7. 98 (s, 1H), 7.97 (s, 1H), 7.63 (t, 1H, J = 6Hz) , 7.51 to 7.57 (m, 3H), 7.33 to 7.38 (m, 2H), 7.1 4 (dt, 1H, J = 1.2, 7.8 Hz), 6.89 (d, 1H, J = 7.2) Hz), 6.81 (t, 1H, J = 7.2Hz), 4.52 (s, 2H). C_{twenty two}H₁₇ClN₂O_FourS ・ 0.2H₂Analysis for O:   Calculated C 59.44; H 3.95; N 6.30.   Found C 59.38; H 3.70; N 6.39.Example 44 N- (4-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole Production of le-2-carboxamide   Using the procedure described in Example 38, but using 3-methoxybenzylamine in 4-me. The title compound with mp 205-206 ° C was obtained in place of toxybenzylamine.¹ 1 H NMR (DMSO-d₆): Δ 9.42 (br t, 1H, J = 6 Hz) , 8.01 (s, 1H), 7.98 (s, 1H), 7.95 (d, 1H, J = 1 ． 8 Hz), 7.64 (t, 1H, J = 7.2 Hz), 7.52 to 7.58 (m , 3H), 7.33 to 7.40 (m, 3H), 6.95 (d, 2H, J = 9Hz. ), 4.51 (d, 2H, J = 6Hz), 3.76 (s, 3H). C_{twenty three}H₁₉ClN₂O_FourAnalysis of S:   Calculated C 60.72; H 4.21; N 6.16   Found C 60.59; H 4.14; N 6.11.Example 45 N- (4-hydroxybenzyl) -3-phenylsulfonyl-5-chloroindo Production of ol-2-carboxamide   Using the procedure described in Example 39, but changing the methoxy isomer to 4-methoxy The title compound having mp 249 to 250 ° C. was obtained in place of the substance (Example 44).¹ 1 H NMR (DMSO-d₆): Δ 9.35 (t, 1H, J = 6 Hz), 7. 95 to 7.99 (m, 3H), 7.62 (t, 1H, J = 6.9 Hz), 7.5 2 to 7.57 (m, 3H), 7.35 (dd, 1H, J = 1.8, 8.7 Hz) , 7.25 (d, 2H, J = 8.7 Hz), 6.76 (d, 2H, J = 8.1H) z), 4. 46 (d, 2H, J = 6 Hz). C_{twenty two}H₁₇ClN₂O_FourAnalysis of S:   Calculated C 59.93; H 3.89; N 6.36.   Found C 59.37; H 3.85; N 6.25.Example 46 N- (3-acetylaminobenzyl) -3-phenylsulfonyl-5-chloroi Production of ndol-2-carboxamide   N- (3-aminopropionate) containing acetic anhydride (0.05 ml; 0.5 mmol) ) -3-Phenylsulfonyl-5-chloroindole-2-carboxamido (Example 41) (176 mg; 0.4 mmol) in anhydrous tetrahydrofuran ( The solution dissolved in 7 ml) was stirred at room temperature for 16 hours. Dilute the reaction mixture with water , Extracted with ethyl acetate. The organic layer is dehydrated (Na₂SO_Four), Filtered through charcoal, solvent Was evaporated. The residue was triturated with methylene chloride and the solid was collected by filtration. The title compound of p249-250 degreeC was obtained.¹ 1 H NMR (DMSO-d₆): Δ 9.98 (br s, 1H), 9.39 ( v br s, 1H), 7.96 to 8.00 (m, 3H), 7.51 to 7.62 (M, 6H), 7.30 (t, 2H, J = 8Hz), 7.14 (d, 1H, J = 8 Hz), 4.53 (br s, 2H), 2.04 (s, 3H). C_{twenty four}H₂₀ClN₃O_FourAnalysis of S:   Calculated C 59.81; H 4.18; N 8.72.   Found C 59.41; H 4.09; N 8.62.Example 47 N- (3-methylsulfonylaminobenzyl) -3-phenylsulfonyl-5- Preparation of chloroindole-2-carboxamide (compound 34)   N- (3-aminobenzyl) -3-phenyl at room temperature under an inert atmosphere Sulfonyl-5-chloroindole-2-carboxamide (174 mg; 0.4 mmol) in anhydrous tetrahydrofuran (7 ml) and add methane Honyl chloride (0.035 ml; 0.45 mmol) and triethylamine ( 0.7 ml; 0.50 mmol) was added. The reaction process was continued for 20 hours. monitored by lc. During this period, twice the same amount of methanesulfonyl chloride and tri Ethylamine was added to complete the reaction with carboxamide. The reaction mixture Diluted with water, acidified with dilute hydrochloric acid and the product extracted into chloroform. This organic Dehydrate layer (Na₂SO_Four), Filter and evaporate the solvent Let The residue was purified by chromatography on silica gel. Black Elution with 1% methanol in chloroform gave the bis-sulfonylated product. This is due to the two methyl group resonances at δ 3.47 and 2.98 in NMR. So proved.   The above material was dissolved in dimethoxy ether (3 ml) and water (2 ml), To lithium hydroxide monohydrate (66 mg; 1.57 mmol) was added. Solution Heated at 60 ° C. for 2 hours. The cooled reaction mixture was acidified with dilute hydrochloric acid. 2-3 o'clock The title compound was crystallized by stirring for a while, which was collected by filtration and dried. Heat meta Analytically pure at mp 252-253 ° C. by recrystallisation from nol-ethyl acetate Different products were obtained.¹ 1 H NMR (DMSO-d₆): Δ 9.48 (br t, 1H, J = 5.4H) z), 8.01 (s, 1H), 7.98 (s, 1H), 7.95 (d, 1H, J = 1.8 Hz), 7.63 (t, 1H, J = 7.2 Hz), 7.52 to 7.58 (M, 3H), 7.33 to 7.38 (m, 2H), 7.27 (br s, 1H) , 7.23 (br d, 1H, J = 7.8 Hz), 7.15 (d, 1H, J = 7) ． 8 Hz), 4.55 (d, 2H, J = 5.4 Hz), 3.00 (s, 3H). C_{twenty three}H₂₀ClN₃O_FiveS₂Analysis about:   Calculated C 53.33; H 3.89; N 8.11   Found C 53.26; H 3.86; N 8.12.Example 48 N-benzyl-3-phenylsulfonyl-5-chloroindole-2-carboxy Manufacture of samide   Benzylamine (0.28 ml; 2.5 mmo, cooled in ice-acetone bath) 1) to a solution of anhydrous tetrahydrofuran (3 ml) in dimer acid chloride (actual Step B) of Example 27 (170 mg; 0.25 mmol) was treated with anhydrous tetrahydro A solution of furan (2 ml) was added dropwise. Reaction mixture at 12-20 o'clock It was left with stirring for a period of time during which the temperature rose to ambient temperature. Remove the solvent under vacuum It was removed and the residue was partitioned between ethyl acetate and water. Wash the ethyl acetate layer with brine , Dehydrated (Na₂SO_Four), The solvent was evaporated. The residue is ethyl acetate-methanol From above to give the analytically pure title compound, mp 249-251 ° C.¹ 1 H NMR (DMSO-d₆): Δ 9.47 (t, 1H, J = 6 Hz), 8. 02 (s, 1H), 8.00 (s, 1H), 7.95 (d, 1H, J = 2.1H z), 7.33 to 7.57 (m, 10H), 4.59 (d, 2H, J = 6Hz) . C_{twenty two}H₁₇ClN₂O₃Analysis of S:   Calculated C 62.19; H 4.03; N 6.59.   Found C 62.14; H 4.13; N 6.62.Example 49 N- (3-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole Preparation of 2-carboxamide (Compound 28)   Using the procedure of Example 48, but replacing benzylamine with 3-aminomethylpyridine. To give the title compound with mp 263-264 ° C. C_{twenty one}H₁₆ClN₃O₃Analysis of S:   Calculated C 59.22; H 3.79; N 9.87.   Found C 59.01; H 3.79; N 9.87.Example 50 N- (2-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole -2- Production of carboxamide   The procedure described in Example 48 is used, except that benzylamine is treated with 2-aminomethylpyrrole. Substitution of lysine gave the title compound with mp 250-251 ° C. C_{twenty one}H₁₆ClN₃O₃Analysis of S:   Calculated C 59.22; H 3.79; N 9.87.   Found C 59.04; H 3.73; N 10.06.Example 51 N- [2- (pyridin-4-yl) ethyl] -3-phenylsulfonyl-5-quat Production of loloindole-2-carboxamide   The procedure described in Example 48 is used, except that benzylamine is treated with 4- (2-aminoethanol). (Til) pyridine was obtained to give the title compound with mp 258-260 ° C. C_{twenty two}H₁₈ClN₃O₃Analysis of S:   Calculated value C 60.07; H 4.12; N 9.55   Found C 59.68; H 3.84; N 9.30.Example 52 N- (2-hydroxyethyl) -3-phenylsulfonyl-5-chloroindole Production of le-2-carboxamide   The procedure described in Example 48 is used, except that benzylamine is treated with 2-hydroxyethyl. The title compound with mp 198-200 ° C was obtained in place of luamine. C₁₇H_FifteenClN₂O_FourAnalysis of S:   Calculated C 53.90; H 3.99; N 7.39   Found C 54.09; H 3.94; N 7.25.Example 53 N-ethyl-3-phenylsulfonyl-5-chloroindole-2-carboxa Manufacture of mid   Using the procedure described in Example 48, but replacing benzylamine with ethylamine. Gave the title compound with mp 259-260 ° C. C₁₇H_FifteenClN₂O₃Analysis of S:   Calculated C 56.28; H 4.17; N 7.72.   Found C 56.07; H 4.11; N 7.73.Example 54 N-[(2-chloropyridin-4-yl) methyl] -3-phenylsulfonyl- Preparation of 5-chloroindole-2-carboxamide   Using the procedure described in Example 35, Step B, except that 2-aminomethyl-1- Replace methylimidazole with 2-chloro-4-aminomethylpyridine to give mp26 The title compound was obtained at 3-265 ° C. C_{twenty one}H_FifteenCl₂N₃O₃Analysis of S:   Calculated C 54.79; H 3.28; N 9.13   Found C 54.38; H 3.18; N 9.03.Example 55 N-cyclopropyl-5-chloro-3-phenylsulfonylindole-2-ca Production of ruboxamide (compound 26)   The procedure described in Example 48 was used, except that benzylamine was treated with cyclopropylamine. To give the title compound with mp 242-243 ° C. C₁₈H_FifteenClN₂O₃Analysis of S:   Calculated C 57.68; H 4.03; N 7.47   Found C 57.40; H 3.94; N 7.43.Example 56 N- (cyclopropylmethyl) -3-phenylsulfonyl-5-chloroindole Production of le-2-carboxamide   Using the procedure described in Example 48, but using benzylamine as the cyclopropyl methyl ester. The title compound with mp 232-234 ° C. was obtained in place of ruamine. C₁₉H₁₇ClN₂O₃Analysis of S:   Calculated C 57.88; H 4.50; N 7.11   Found C 57.92; H 4.34; N 7.09.Example 57 3- (4-chlorophenylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Replacing Fido with bis (4-chlorophenyl) disulfide, mp275-277 This gave the title compound at ° C. C_FifteenH_TenCl₂N₂O₃Analysis of S:   Calculated C 48.79; H 2.73; N 7.59   Found C 48.23; H 2.84; N 7.91.Example 58 3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Replacing Fido with bis (3-chlorophenyl) disulfide, mp272-273 This gave the title compound at ° C. C_FifteenH_TenCl₂N₂O₃Analysis of S:   Calculated C 48.79; H 2.73; N 7.59   Found C 48.39; H 2.70; N 7.44.Example 59 3- (3,5-dichlorophenylsulfonyl) -5-chloroindole-2-ca Production of ruboxamide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Replacing Fido with bis (3,5-dichlorophenyl) disulfide, mp258- The title compound was obtained at 260 ° C. C_FifteenH₉Cl₃N₂O₃Analysis of S:   Calculated C 44.63; H 2.25; N 6.94.   Found C 44.49; H 2.24; N 7.04.Example 60 3- (2-chlorophenylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Use the procedure described in Example 33, except that thiophenol was replaced with 2-chlorothiophene. The title compound with mp 267 ° C. was obtained in place of the nor. C_FifteenH_TenCl₂N₂O₃Analysis of S:   Calculated C 48.79; H 2.73; N 7.59   Found C 48.69; H 2.73; N 7.62.Example 61 3- (pyridin-2-ylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Using the procedure described in Examples 30 and 31, except that the di (2 -Thiazolyl) disulfide replaced with bis (pyridin-2-yl) disulfide Gave the title compound with mp 244-246 ° C. C₁₄H_TenClN₃O₃Analysis of S:   Calculated value C 50.08; H 3.00; N 12.51   Found C 50.31; H 3.00; N 12.55.Example 62 3- (pyridin-3-ylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Fido was replaced with bis (pyridin-3-yl) disulfide and mp300 ° C (decomposition) ) Was obtained. FAB mass spectrum: m / e = 336 (M + 1)Example 63 3- (Pyridin-4-ylsulfonyl) -5-chloroindole-2-carboxy Manufacture of samide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Fido as bis (pyridin-4-yl) Instead of disulfide, the title compound with mp> 260 ° C. (decomposition) was obtained. FAB mass spectrum: m / e = 336 (M + 1)Example 64 3-[(1-Methylimidazol-2-yl) sulfonyl] -5-chloroindo Production of ol-2-carboxamide   Using the procedure described in Examples 30 and 31, but with di (2-thiazolyl) disul Replace Fido with bis (1-methylimidazol-2-yl) disulfide and mp The title compound was obtained at 255-256 ° C (decomposition). C₁₃H₁₁ClN_FourO₃Analysis of S:   Calculated value C 46.09; H 3.27; N 16.54.   Found C 46.02; H 3.28; N 16.27.Example 65 N- (3-methoxybenzyl) -3- (3-chlorophenylsulfonyl) -5- Production of chloroindole-2-carboxamide   Using the procedure described in Example 38, except 3- (phenylsulfonyl) -5-qua Loroindole-2-carboxylic acid The conventional dimer acid chloride was added to 3- (3-chlorophenylsulfonyl) -5-chloroin Instead of dimer acid chloride derived from dol-2-carboxylic acid, mp225-226.5 This gave the title compound at ° C. C_{twenty three}H₁₈Cl₂N₂O_FourAnalysis of S:   Calculated C 56.45; H 3.71; N 5.73   Found C 56.52; H 3.70; N 5.83.Example 66 N- (3-hydroxybenzyl) -3- (3-chlorophenylsulfonyl) -5 -Production of chloroindole-2-carboxamide   Using the procedure described in Example 39, N- (3-methoxybenzyl) -3- (3- Chlorophenylsulfonyl) -5-chloroindole-2-carboxamide Methylation gave the title compound with mp 230-231 ° C. C_{twenty two}H₁₆Cl₂N₂O_FourAnalysis of S:   Calculated C 55.58; H 3.39; N 5.89   Found C 55.59; H 3.36; N 5.66.Example 67 N-[(1-methylimidazol-2-yl) methyl]- 3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxy Production of samide (compound 23)   Using the procedure described in Example 35, except 3- (phenylsulfonyl) -5-qua The dimer acid chloride derived from loroindole-2-carboxylic acid was treated with 3- (3-chlorophene). Nylsulfonyl) -5-chloroindole-2-carboxylic acid derived dimer acidification The title compound with mp 232-234 ° C. was obtained. C₂₀H₁₆Cl₂N_FourO₃Analysis of S:   Calculated C 51.84; H 3.48; N 12.09   Found C 51.46; H 3.38; N 11.78.Example 68 2-carboxamide-5-chloroindole-3-cyclopropylsulfonami Manufacturing Step A :2-carbethoxy-5-chloro-1-phenylsulfonylin Dole-3-sulfonic acid   2-carboethoxy-5-chloro-1-phenylsulfonylindole (7. 28 g; 20.0 mmol) was added to acetic anhydride (10 ml) and anhydrous dichloromethane ( 50 ml) The solution dissolved in was stirred and concentrated sulfuric acid (2.50 ml; 90 mmo1) was added to it. It was added dropwise at 0 ° C over 5 minutes. The resulting tan solution is brought to RT (room temperature) Warm up and after 3 hours pour onto ice and extract the mixture with ethyl acetate. Ethyl acetate layer Washed with brine, dried (Na₂SO_Four), Evaporate under vacuum to obtain a syrup It was The residual acetic anhydride was removed azeotropically with toluene (3 x 50 ml) and the residue was Crystallized from dichloromethane. Evaporate the dichloromethane under vacuum to give the title The compound was obtained as a tan powder.¹ 1 H NMR (DMSO-d₆): Δ 1.33 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.44 (dd, J = 8.9 and 2. 2Hz, 1H), 7.63 (t, J = 7.6Hz, 2H), 7.73 (t, J = 7.4 Hz, 1 H), 7.77 (d, J = 2.2 Hz, 1 H), 7.96 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H).Step B :2-carbethoxy-5-chloro-1-phenylsulfonylin Dole-3-cyclopropylsulfonamide   2-Carboethoxy-5-chloro-1-phenylsulphonyl group at 0 ° C. Ndol-3-sulfonic acid (1.505 g; 3.39 mmol) with anhydrous dichloro Stir the solution dissolved in methane (15 ml) and add it to oxalic chloride. (0.90 ml; 10.3 mmol) was added. Add DMF (2 drops), The solution was warmed to room temperature. Add more DMF (1 drop) and heat the reaction mixture to reflux. Let it flow. After 2 hours the solution was cooled and evaporated under vacuum to give a tan solid chloride powder. I got Lefonil. This material was dissolved in dichloromethane (15 ml) and mixed with it. Clopropylamine (0.94 ml; 13.56 mmol) and pyridine (0. 5 ml) was added. The solution is heated to reflux, cooled after 15 minutes, ethyl acetate Diluted with 1M HCl solution, washed with sodium hydrogen carbonate solution and brine, Dehydrated (Na₂SO_Four), And evaporated under vacuum to give a gum. Methanol (5 ml) Was added to give a colorless solid, the mixture was stirred and heated to reflux for 5 minutes. I let you. The solid is filtered off at low temperature, washed with cold methanol (3 x 5 ml) and vacuum dried. Dried to give the title compound as colorless crystals, mp 189-191 ° C.¹ 1 H NMR (CDCl₃): Δ 0.61 (m, 4H), 1.48 (t, J = 7) ． 1 Hz, 3 H), 2.26 (m, 1 H), 4.58 (q, J = 7.1 Hz, 2 H), 5.06 (br s, 1H), 7.42 (dd, J = 9.0 and 2.0H). z, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.66 (t, J = 7. 5 Hz, 1 H), 7.97 (d, J = 9.0 Hz, 1 H), 7.98 (d, J = 2.0 Hz, 1 H), 8.09 (d, J = 7.6 Hz, 2 H).Step C :2-carboxamide-5-chloroindole-3-cyclopropyi Lesulfonamide   2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3- Cyclopropylsulfonamide (0.42 g; 0.870 mmol) 2: 1: A mixture of 1 with 10% potassium hydroxide solution-methanol-THF (20 ml). Heat to reflux to give a clear tan solution. After refluxing for 0.5 hours, cool the solution Then, the mixture was concentrated under vacuum to a volume of 1/2. Acidify the solution with 1M HCl The resulting mixture was extracted with ethyl acetate, washed with brine, dried (Na₂ SO_Four), And evaporated under vacuum to give a gum. This crude product was mixed with 2% sodium hydroxide. And was acidified with 1M HCl. The solid material is collected by filtration Wash with 1M HCl solution and dry in vacuo to give 3-cyclopropylsulfone. Mido-5-chloroindole-2-carboxylic acid was obtained. This acid is treated with anhydrous dichlorometh The suspension, suspended in tan (10 ml), was stirred and to this was added oxalyl chloride (0. 58 ml; 6.65 mmol) and DMF (1 drop) were added. 1 hour at room temperature After that, heat the mixture for 1 hour Refluxed, cooled, and evaporated in vacuo to give a tan solid. Acetone solid (10 ml) and suspended in 9: 1 ammonium hydroxide-acetone solution (20 ml) was added. After 15 minutes, the solution was evaporated under vacuum to bring its volume to 2 m. l, the residue was acidified with 1M HCl solution and the mixture was extracted with ethyl acetate . The ethyl acetate layer was washed with a sodium hydrogen carbonate solution, dehydrated (Na₂SO_Four),true Evaporated under air. Flash chromatograph the resulting tan solid on silica. Raffy (dry loading; methanol gradient 2 → 10% methanol-chloroform) Of the title compound as colorless crystals of mp 236-238 ° C. (Crystallized from ethyl acetate-hexane).¹ 1 H NMR (DMSO-d₆): Δ 0.40 (m, 4H), 2.07 (m, 1) H), 7.35 (dd, J = 8.7 and 2.1 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1 H), 8.01 (d, J = 1.7 Hz, 1 H), 8.10 (d , J = 2.1 Hz, 1H), 8.22 (br s, 1H), 8.47 (br s) , 1H).Example 69 Preparation of 2-carboxamide-5-chloroindole-3-phenylsulfonamide Construction Step A :2-carbethoxy-5-chloro-1-phen Nylsulfonylindole-3-phenylsulfonamide   In the method outlined in Step B of Example 68, 2-carbethoxy-5- Aniline to loro-1-phenylsulfonylindole-3-sulfonyl chloride (0.63 ml; 6.91 mmol) and flash column on silica Chromatography (dry loading; ethyl acetate gradient 20 → 30% ethyl acetate -Eluted with hexane) to give the title compound as colorless crystals.¹ 1 H NMR (CDCl₃): Δ 1.47 (t, J = 7.1 Hz, 3H), 4. 58 (q, J = 7.1 Hz, 2H), 6.74 (br s, 1H), 7.11 ( m, 5H), 7.31 (dd, J = 9.0 and 2.2 Hz, 1H), 7.51 ( t, J = 8.1 Hz, 2H), 7.57 (d, J = 1.7 Hz, 1H), 7.6 5 (t, J = 7.5 Hz, 1H), 7,87 (d, J = 9.0 Hz, 1H), 7 ． 99 (d, J = 7.6 Hz, 2H).Step B :5-chloro-3-phenylsulfonamide indole-2-cal Boric acid   2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3- Phenylsulfonamide (0.39 g; 0.75 mmol) was added in 2: 1: 1 10 % Sodium hydroxide solution-methanol-THF (20 ml) And after 2 hours acidify the solution with 1M HCl and the resulting mixture with ethyl acetate. Extract, wash with brine, dry (Na₂SO_Four), Glass evaporated under vacuum Got Dichloromethane (5 ml) was added to give a colorless solid and the mixture was Stir and heat to reflux for 5 minutes. The solid is filtered off at low temperature and cold dichlorometa After washing with water and vacuum drying, the title compound was obtained as colorless crystals.¹ 1 H NMR (DMSO-d₆): Δ 7.28 (t, J = 7.1 Hz, 1H), 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, 1H), 7.86 (d, J = 8) ． 8 Hz, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 10.25 (br   s, 1H).Step C :2-carboxamide-5-chloroindole-3-phenylsul Honamide   At 0 ° C, 5-chloro-3-phenylsulfonamide indole-2-carb Rubonic acid (123 mg; 0.35 mmol) was dissolved in anhydrous THF (3 ml) The solution was stirred and added to it oxalyl chloride (0.087 ml; 1.00 mmol). And DMF (1 drop) were added. After 1 hour at room temperature, the solution was evaporated under vacuum. Gave a tan solid. Dissolve the solid in acetone (1 ml) and add 9: 1 water Ammonium oxide-acetone solution (2 ml) was added. 0.5 hours later, Evaporation under vacuum gave a gum which was dissolved in ethyl acetate and treated with 1M HCl and Wash with brine, dehydrate (Na₂SO_Four), Evaporated under vacuum. Obtained yellowish brown Flash column chromatography on silica of dry solids (dry loading; acetic acid Ethyl gradient-eluting with 70% ethyl acetate-hexane). , Colorless compound with mp 225 to 227 ° C (crystallized from dichloromethane) Got as.¹ 1 H NMR (DMSO-d₆): Δ 7.00 (m, 3H), 7.17 (t, J = 7.3 Hz, 2H), 7.30 (dd, J = 8.8 and 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H) ), 8.21 (br s, 1H), 8.28 (br s, 1H), 10.34 ( brs, 1H).Example 70 2-carboxamide-5-chloroindole-3-methyl (phenyl) sulfone Amide production Step A :2-carbethoxy-5-chloro-1-phenylsulfonylin Dole-3-methyl (phenyl) sulfonamide   In the method outlined in Example 68 Step B Ruboethoxy-5-chloro-1-phenylsulfonylindole-3-sulfoni N-methylaniline was added to the chloride and flash column chromatography on silica was performed. Matography (dry loading; ethyl acetate gradient 10 → 30% ethyl acetate After elution with xane) the title compound is obtained as colorless crystals (from dichloromethane-hexane). Crystallization).¹ 1 H NMR (CDCl3): δ 1.46 (t, J = 7.1 Hz, 3H), 3 ． 30 (s, 3H), 4.55 (q, J = 7.1Hz, 2H), 6.69 (d, J = 2.0 Hz, 1 H), 7.11 (d, J = 7.0 Hz, 2 H), 7.26 ( m, 4H), 7.54 (t, J = 7.6Hz, 2H), 7.66 (t, J = 7. 4 Hz, 1 H), 7,87 (d, J = 8.8 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 2H).Step B :5-chloro-3-methyl (phenyl) sulfonamidoindole -2-carboxylic acid   2: 1: 1 10% NaOH in the method outlined in Example 69, Step B. Thorium solution-methanol-THF [20 ml; RT (room temperature) for 14 hours, At reflux temperature for 5 minutes] in 2-carbethoxy-5-chloro-1-phenyl Lesulfonylindole-3-methyl (phenyl) sulfonamide (0.39 g 0.75 mmol), whereby the title compound (ethyl acetate or Crystallization) was obtained.¹ 1 H NMR (DMSO-d₆): Δ 3.26 (s, 3H), 7.03 (d, J = 2.2 Hz, 1H), 7.21 (m, 6H), 7.46 (d, J = 8.8 Hz , 1H).Step C :2-carboxamide-5-chloroindole-3-methyl (phen Nyl) sulfonamide   In the method outlined in Example 69, Step C, 5-chloro-3-methyl (phenyl) Starting from phenyl) sulfonamidoindole-2-carboxylic acid on silica Flash column chromatography (dry loading; 2% methano in chloroform) Of the title compound after purification by colorless crystals (mp 240-242 ° C). Crystallized from ethyl acetate).¹ 1 H NMR (DMSO-d₆): Δ 3.13 (s, 3H), 7.06 (d, J = 2.1 Hz, 1H), 7.09 (m, 2H), 7.23 (dd, J = 8.8) 2.1 Hz, 1H), 7.26 (m, 3H), 7.48 (d, J = 8.8Hz) , 1H), 8.01 (br s, 1H), 8.06 (br s, 1H).Example 71 N- [2- (1-methylimidazol-4-yl) ethyl] -3-Phenylsulfonyl-5-chloroindole-2-carboxamide (Compound Manufacture of thing 25)   Under the conditions of Example 37, 3-phenylsulfonyl-5-chloroindole-2 Reaction of the carboxylic acid with 1-methylhistamine gives the title compound.Example 72 N- [2- (3-methylimidazol-4-yl) ethyl] -3-phenylsul Preparation of phonyl-5-chloroindole-2-carboxamide   Under the conditions of Example 37, 3-phenylsulfonyl-5-chloroindole-2 Reacting the carboxylic acid with 3-methylhistamine at mp 257-258.5 ° C. The title compound was obtained.Example 73 N-[(imidazol-4-yl) methyl] -3-phenylsulfonyl-5-chloro Production of loloindole-2-carboxamide   Under the conditions of Example 34, the dimer acid chloride (Step B of Example 27) was treated with 4-acetic acid. Reaction with minomethylimidazole gives the title compound.Example 74 N- [3- (imidazol-1-yl) propyl] -3-phenylsulfonyl- Preparation of 5-chloroindole-2-carboxamide   Under the conditions of Example 37, 3-phenylsulfonyl-5-chloroindole-2 Reacting a carboxylic acid with 1- (3-aminopropyl) imidazole to give mp21 The title compound was obtained at 6-217.5 ° C.Example 75 3-phenylsulfonyl-5-methylsulfonylaminoindole-2-carb Production of xamide (compound 36) Step A :3-phenylsulfonyl-5-nitroindole-2-carboxy Samide   5-nitroindole-2-carboxylic acid under the conditions of Step B of Example 33 ethyl(J. Amer. Chem. Soc. 80, P. 4621, 1958) Reacted with N- (phenylthio) succinimide and then also the sulfonyl product The product is obtained by carrying out oxidization (step C) so that it is heated under pressure and pressure. Can be converted to the title compound with ammonium hydroxide.Step B :3-phenylsulfonyl-5-aminoindole-2-carboxy Samide   Under the conditions of Example 41, 3-phenylsulfonyl-5-nitroindole-2 -Reaction of carboxamide with hydrogen gives the title compound.Step C :3-phenylsulfonyl-5-methylsulfonylaminoindo Le-2-carboxamide   Under the conditions of Example 47, 3-phenylsulfonyl-5-aminoindole-2 -Reaction of carboxamide with methanesulfonyl chloride gave the title compound. Be done.Example 76 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamide ) Methyl] -pyridin-2 (1H) -one (Compound 37) Step A :N- (2-methoxy-4-pyridylmethyl) -5-chloro-3- Phenylsulfonylindole-2-carboxamide   Under the conditions of Example 27, Step C, Example 27, Step B, "acid chloride The "mer" product was treated with 2-methoxy-4-pi Reaction with lysylmethylamine gives the title compound.Step B :4-[(5-chloro-3-phenylsulfonylindole-2- Carboxamido) methyl] -pyridin-2 (1H) -one   N- (2-methoxy-4-pyridylmethyl) at temperatures from 0 ° C to room temperature Chloride 5-chloro-3-phenylsulfonylindole-2-carboxamide When reacted with boron tribromide in methylene according to the procedure described in Example 39, the title compound is obtained. The compound is obtained.Example 77 N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfoni Production of Luindole-2-carboxamide Step A :2-amino-4-aminomethylpyridine   2-Aminopyridine-4-carbonitrile (L.W. Deady et al.,Aust . J. Chem. 35 , P. 2025, 1982), 2-amino-3-amino D. for the production of methylpyridine. E. FIG. Operations such as Beattie (J. Med. C hem. 20 , P. 718, 1977) to give the title compound by catalytic reduction.Step B :N- (2-amino-4-pyridylmethyl) -5-chloro-3-ph Phenylsulfonylindole-2-carboxamide   2-Amino-4-aminomethylpyridine was obtained in Step B of Example 27. When the dimer acid chloride was reacted according to the procedure of Step C of Example 27, the title compound was obtained. The thing is obtained.Example 78 N- (2-aminothiazol-4-ylmethyl) -5-chloro-3-phenyls Preparation of Lefonylindole-2-carboxamide   The dimer acid chloride obtained in Step B of Example 27 was treated with 2-aminothiazole- 4-ylmethylamine (Chem. Ab. 58, 4534, 1962) and implementation Reaction under the conditions of Step C of Example 27 gives the title compound.Example 79 N-cyano-5-chloro-3-phenylsulfonylindole-2-carboxy Preparation of Mid-amide (Compound 35) Step A :5-chloro-3-phenylsulfonylindole-2-carboni Trill   5-chloro-3-phenylsulfonylindole-2-carboxamide was added to D ． A. Claremon and B.I. T. Phillips (Tetrahedr on Lett. 29 , P. 2155, 1988). Methyl (carboxysulfamoyl) triethylammo in orchid (THF) solvent The title compound was obtained by reacting with an inner salt of nium hydroxide (Burgess reagent). obtain.Step B :Ethyl 5-chloro-3-phenylsulfonylindole-2-ca Ruboximi date   5-chloro-3-phenylsulfonylindole-2-carbonitrile, salt React with ethanol saturated with hydrogen hydride at 0-10 ° C for 7 days. By evaporation to dryness The title compound is obtained as the hydrochloride salt. Dissolve the reaction mixture in excess ice-cold ice-cold Addition to the solution and extraction of the product with chloroform gives the title compound in the form of the free base. can get.Step C :N-Cyano-5-chloro-3-phenylsulfonylindole- 2-carboximide-amide   Ethyl 5-chloro-3-phenylsulfonylindole -2-Carboximidate was combined with an equimolar amount of cyanamide in anhydrous methanol (K. R. Huffman and F.H. C. Schaefer,J. Org. Chem. 2 8 , P. 1812, 1963). Solvent after 30-60 minutes Was removed and the residue was purified by silica gel chromatography to give the title compound. obtain.Example 80 N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-cal Production of voxamide (compound 27)   Using the procedure of Example 48, but replacing benzylamine with cyclobutylamine To give the title compound.Example 81 N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2- Production of carboxamide (compound 39)   Use the procedure of Example 28, Step B, but without the 4-aminomethylpyridine. Substitute for chloropropylamine to give the title compound.Example 82 N-[(1-methylimidazol-2-yl) methyl]-3-phenylsulfinyl-5-chloroindole-2-carboxamide (compound Manufacturing of thing 20)   Using the procedure of Step B of Example 28, but using 2-aminomethylpyridine in 2 Substitute for -aminomethyl-1-methylimidazole to give the title compound.Example 83 N-[(1-methylimidazol-4-yl) methyl] -3-phenylsulfoni Le-5-chloroindole-2-carboxamide (Compound 21) and N-[(1 -Methylimidazol-5-yl) methyl] -3-phenylsulfonyl-5-qua Production of loloindole-2-carboxamide (compound 22) Step A :N-[(imidazol-4 (or 5) -yl) methyl] -3- Phenylsulfonyl-5-chloroindole-2-carboxamide   Using the procedure of Example 34, but adding 2-aminomethylimidazole dihydrochloride to 4 Substituting (or 5) -aminomethylimidazole dihydrochloride for the title compound.Step B :N-[(1-methylimidazol-4-i ) Methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxy Samide; N-[(1-methylimidazol-5-yl) methyl] -3-phenyl Sulfonyl-5-chloroindole-2-carboxamide   Using the procedure of Example 36, except that N-[(imidazol-2-yl) methyl] -3-Phenylsulfonyl-5-chloroindole-2-carboxamide was added to N- [(Imidazol-4 (or 5) -yl) methyl] -3-phenylsulfonyl -5-Chloroindole-2-carboxamide is obtained to obtain each of the title compounds. This These compounds were obtained in pure form by chromatography on silica gel. Be done.Example 84 N-[(R) -1-phenylethyl] -5-chloro-3-phenylsulfonyl group Preparation of Ndol-2-carboxamide (Compound 33)   Using the procedure of Example 29, except that (S)-(+)-2-phenylglycinol Was replaced with (R)-(+)-α-methylbenzylamine and the title compound at mp 149 ° C was used. I got a thing. C_{twenty three}H₁₉ClN₂O₃S / 0.15C₂H_FourO₂・ 0.15H₂Analysis for O:   Calculated C 62.32; H 4.54; N 6.16   Found C 62.39; H 4.54; N 6.01.¹ 1 H NMR (DMSO-d₆): Δ 3.06 (1H, s), 9.43 (1H, s) d, J = 8 Hz), 7.94 to 8.02 (3H, m), 7.46 to 7.67 (6 H, m), 7.25 to 7.42 (4H, m), 5.21 (1H, q, J = 7Hz ), 1.53 (3H, d, J = 7 Hz).Example 85 N-[(1-ethylimidazol-2-yl) methyl] -3-phenylsulfoni Preparation of le-5-chloroindole-2-carboxamide   Using the procedure described in Example 35, except 2-aminomethyl-1-methyl imidazole Replace sol (step A) with 2-aminomethyl-1-ethylimidazole and m The title compound of p204-205.5 degreeC was obtained.   The foregoing description teaches the principles of the invention and provides examples for illustration. Although shown, implementations of the present invention are subject to any ordinary variations and modifications which do not depart from the scope of the following claims. It is understood to include adaptations and modifications and their equivalents.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI A61K 31/44 9454-4C 31/535 ADY 9454-4C C07D 209/30 8217-4C 209/42 8217-4C 401 / 06 209 7602-4C 401/12 209 7602-4C 403/12 209 7602-4C 405/06 209 7602-4C 405/12 207 7602-4C 413/06 209 7602-4C 417/12 209 7602-4C (81 ) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI) , CM, GA, GN, ML, MR, NE, SN, TD, TG), AU, BB, BG, BR, BY, CA, CN, CZ, FI, HU, JP, KR, KZ, LK, LV. ， G, MN, MW, NO, NZ, PL, RO, RU, SD, SK, UA, UZ (72) Inventor Sitkarone, Terence M. USA, Pennsylvania 18041, East Greenville, Township Woods Road 3124 (72) Inventor Saari, Walfred S. United States, Pennsylvania 19446, Lancedale, Wagon Wheel Lane 1740 (72) Inventor Way, Zyon Es United States, Pennsylvania 19438, Harleysville, Tanglewood Wed Lee 208 (72) Inventor Greenley, William J.A. USA, New Jersey 07666, Tenetsk, Heritsk Avenyu 115 (72) Inventor Barani, Sletscheu Kay United States, Pennsylvania 19440, Hutfield, Denbay Drive 2813 (72) Inventor Goldman, Mark E. United States, California, 92130, San Diego, Corte de la Juanda 4372 (72) Inventor Hoffman, Jacob M. Giunia United States, Pennsylvania 19446 , Lancedale, Kipling Court, 1160 (72) Inventor Luma, William C. Giunia, United States, Pennsylvania 18073, Pensberg, Newman Road M.R. 1 1447 (72) Inventor Huff, Jojoel Earl USA, Pennsylvania 19437, Guined Valley, Slade Drive 825 (72) Inventor Rouney, Clarence S. USA, Pennsylvania 19490, Worcester, Hitzcory Hill Drive 2902 (72) Inventor Sanderson, Filipps・ E USA, pen Sylvania 19118, Philadelphia, West Glover's Lane, 129 (72) Inventor Theohalides, Anthony Day USA, Pennsylvania 19446, Lancedale, Sitzpriter Way 417

Claims (1)

[Claims] 1. Formula A [In the formula X is -H, -Cl, -F, -Br, -NO₂, -CN, -OR², -NR²R², − NHSO₂-C_{1 to 3}Alkyl or -NHCO-C_{1 to 3}Alkyl, Y is -S (O)_n-Or-O-, wherein n is 0, 1 or 2, R is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH, or       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            Aryl substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, or 4) Y is -S (O)_nOnly when -NR²R³And Z is 1) -C (= W) -NR²R³[Wherein W is = O, = S, = N-CN or = N- OR²]], 2) -COR^1a, 3) -COOR^1b, 4) -CR²R²-S (O)_n-R^1a[Where n is as defined above], 5) -CR²R²NHR^Four, 6) -CR²R²-CO-R^Five, 7) 1 or more       a) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       b) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 3}Alkyl, or 8) -CN And R¹Is 1) hydrogen, 2) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 3) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, or 4) Unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R^1aIs 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, or 4) C_{3 to 6}Cycloalkyl, R^1bIs 1) 1 or more       a) -C_{1 to 5}Alkoxy,       b) -OH,       c) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with, or       d) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen,       e) -CN,       f) -NO₂Or       g) -NR²R²       An aryl substituted with, or 3) an unsubstituted heterocycle, or one or more       a) not substituted or one or more            i) -OH, or            ii) -C_{1 to 5}Alkoxy            -C substituted with_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R²Is hydrogen or C_{1 to 3}Alkyl, R³Is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C unsubstituted or substituted with -OH_{1 to 5}Alkoxy,       c) -OH,       d) -OC (O) R⁷,       e) -COOR²,       f) not substituted or one or more            i) -C unsubstituted or substituted with one or more -OH_{1 ~Five} Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen,            v) -NO₂,            vi) -NR²R²,           vii) -NHCO-C_{1 to 3}Alkyl, or          viii) -NHSO₂-C_{1 to 3}Alkyl          An aryl substituted with, g) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) C_{1 to 3}Alkyl-NR²R²,            v) halogen,            vi) oxo,           vii) -NO²,          viii) -NR²R²,            ix) -NHCO-C_{1 to 3}Alkyl, or            x) -NHSO₂-C_{1 to 3}Alkyl            A heterocycle substituted with,       h) -NR²R²Or            i) -C_{3 to 6}Cycloalkyl       -C substituted with_{1 to 5}Alkyl, 2) unsubstituted aryl, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       An aryl substituted with, 3) an unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, 4) -C_{1 to 5}Alkoxy, 5) -OH, 6) -C_{3 to 6}Cycloalkyl, or 7) Hydrogen And R^FourIs 1) R¹, Or 2) -COR¹ And R^FiveIs 1) R¹, 2) -C_{1 to 5}Alkoxy, 3) -NHR¹, Or 4) Unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with And R⁶Is 1) hydrogen, 2) -COR¹, Or 3) -CONHR¹ And R⁷Is 1) unsubstituted aryl, or one or more -Cl, -Br, -OH, -OCH₃Or an aryl substituted with -CN, or 2) Unsubstituted-C_{1 to 5}Alkyl, or one or more -OH or- NR²R²-C substituted with_{1 to 5}Alkyl And Provided that X is -H, Y is -S-, and R is an unsubstituted phenyl. Yes, and R⁶Is -H, Z is -CH₂-SO-Ph, -COH, No.] or a pharmaceutically acceptable salt or ester thereof. 2. X is -H, -Cl or -F, Y is -S (O)_n−, R is -Ph, -tolyl, 3-Cl-phenyl, 2-pyridy Or 2-thiazolyl, R⁶Is -H, Z is -C (= W) -NR²R³, -COOR^1b, -COR^1a, -CR²R²-S (O )_n-R^1a, Or -C substituted with a heterocycle_{1 to 3}Characterized by being an alkyl The compound according to claim 1, wherein 3. X is -H or -Cl, Y is -S (O)_n−, R is -Ph, -tolyl, 3-Cl-phenyl or 2-thiazolyl, R⁶Is -H, Z is 1) -C (= W) -NR²R³[R in the formula²Is -H and W is = O, = S or = NCN], or 2) -CR²R²-SO-aryl [wherein the aryl group is unsubstituted or Or more than one C_{1 to 5}Substituted with alkyl] The compound according to claim 2, wherein 4. X is -Cl, Y is -S (O)_n−, n is 1 or 2, R is -Ph, 3-Cl-phenyl or 2-thiazolyl, R⁶Is -H, Z is -C (= W) -NR²R³[R in the formula²Is -H and W is = O, = S or = It is NCN] R³Is 1) Unsubstituted-C_{1 to 5}Alkyl, or one or more       a) -C unsubstituted or substituted with -OH_{1 to 5}Alkoxy,       b) -OH,       c) -OC (O) R⁷,       d) not substituted or one or more            i) -C unsubstituted or substituted with one or more -OH_{1 ~Five} Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            An aryl substituted with,       e) not substituted or one or more            i) -C_{1 to 5}Alkyl,            ii) -C_{1 to 5}Alkoxy,           iii) -OH,            iv) halogen, or            v) -NR²R²            A heterocycle substituted with, or       f) C_{3 to 6}Cycloalkyl       -C substituted with_{1 to 5}Alkyl, 2) an unsubstituted heterocycle, or one or more       a) -C_{1 to 5}Alkyl,       b) -C_{1 to 5}Alkoxy,       c) -OH,       d) halogen, or       e) -NR²R²       A heterocycle substituted with, 3) hydrogen, or 4) C_{3 to 6}Cycloalkyl The compound according to claim 3, wherein 5. X is 1) -NR²R², 2) -NHSO₂-C_{1 to 3}Alkyl, and 3) -NHCO-C_{1 to 3}Alkyl The compound of claim 1, wherein the compound is selected from: 6. Z is -C (= W) -NR²R³And R³Is 1) 1 or more       a) -NO₂,       b) -NR²R²,       c) -NHCO-C_{1 to 3}Alkyl, or       d) -NHSO₂-C_{1 to 3}Alkyl       C substituted with phenyl substituted with_{1 to 3}Alkyl, and 2) 1 or more       a) halogen,       b) oxo,       c) -NO₂,       d) -NR²R²,       e) -NHCO-C_{1 to 3}Alkyl, or       f) -NHSO₂-C_{1 to 3}Alkyl       C substituted with a heterocycle substituted with_{1 to 3}Alkyl The compound of claim 1, wherein the compound is selected from: 7. Y is -S (O)_n-, And R is -NR²R³Claims characterized in that The compound according to 1. 8. N-ethyl-5-chloro-3-phenylthioindole-2-carboxami De, N-2-hydroxyethyl-5-chloro-3-phenylthioindole-2-ca Ruboxamide, N-2-Methoxyethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-ca Ruboxamide, N-4-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-3-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxa Mid, N- [1- (2 (R) -hydroxypropyl)]-5-chloro-3-phenylthio Oindole-2-carboxamide, N- (2-pyridyl) methyl-5-chloro-3-phenylthioindole-2- Carboxamide, N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioi Ndol-2-carboxamide, N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindo 2-carboxamide, 5-chloro-3-phenylthioindole-2-carboxamide, N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole- 2-carboxamide, N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thio Carboxamide, 5-chloro-3-phenylthioindole-2-thiocarboxamide, 5-chloro-3-phenylsulfinylindole-2-carboxamide, and 5-chloro-3-phenylsulfonylindole-2-carboxamide A compound selected from among the above, or a pharmaceutically acceptable salt or ester thereof. 9. N-ethyl-5-chloro-3-phenylthioindole-2-carboxami De, N-2-hydroxyethyl-5-chloro-3-phenylthioindole-2-ca Ruboxamide, N-2-Methoxyethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-ca Ruboxamide, N-4-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-3-pyridylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-cal Voxamide, and N-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxa Mid A compound selected from among the above, or a pharmaceutically acceptable salt or ester thereof. 10. N- [1- (2 (R) -hydroxypropyl)]-5-chloro-3-phen Nylthioindole-2-carboxamide, N- (2-pyridyl) methyl-5-chloro-3-phenylthioindole-2- Carboxamide, N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioi Ndol-2-carboxamide, N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindo 2-carboxamide, 5-chloro-3-phenylthioindole-2-carboxamide, N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole- 2-carboxamide, N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thio Carboxamide, and 5-chloro-3-phenylthioindole-2-thiocarboxamide A compound selected from among Salt or ester. 11.5-Chloro-3-phenylsulfinylindole-2-carboxamide ,as well as 5-chloro-3-phenylsulfonylindole-2-carboxamide A compound selected from the following or a pharmaceutically acceptable salt thereof. 12. N-[(1-methylimidazol-2-yl) methyl] -3-phenyls Lefonyl-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-2-yl) methyl] -3-phenylsulfi Nil-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-4-yl) methyl] -3-phenylsulfoni Lu-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-5-yl) methyl] -3-phenylsulfoni Lu-5-chloroindole-2-carboxamide, N-[(1-methylimidazol-2-yl) methyl]- 3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxy Samide, N- [2- (imidazol-4-yl) ethyl] -3-phenylsulfonyl-5 -Chloroindole-2-carboxamide, N- [2- (1-methylimidazol-4-yl) ethyl] -3-phenylsul Phonyl-5-chloroindole-2-carboxamide, N-cyclopropyl-5-chloro-3-phenylsulfonylindole-2-ca Ruboxamide, N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-cal Voxamide, N- (3-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole -2-carboxamide, N- (4-pyridylmethyl) -5-chloro-3-phenylsulfinylindole Le-2-carboxamide, N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole -2-carboxamide, N- (3-methoxybenzyl) -5-chloro-3- (2-thiazolyl) -sulfo Nilindol-2-carboxami De, N-[(S) -1-phenyl-2-hydroxyethyl] -5-chloro-3-phen Nylsulfonylindole-2-carboxamide, N-[(R) -1-phenylethyl] -5-chloro-3-phenylsulfonyl group Ndol-2-carboxamide, N- (3-methylsulfonylaminobenzyl) -3-phenylsulfonyl-5- Chloroindole-2-carboxamide, N-cyano-5-chloro-3-phenylsulfonylindole-2-carboxy Midamide, 3-phenylsulfonyl-5-methylsulfonylaminoindole-2-carb Xamide, 4-[(5-chloro-3-phenylsulfonylindole-2-carboxamide ) -Methyl] pyridin-2 (1H) -one, N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfoni Luindole-2-carboxamide, as well as N-cyclopropyl-5-chloro-3-phenylsulfi Nilindole-2-carboxamide A compound selected from among the above, or a pharmaceutically acceptable salt or ester thereof. 13. Compound N-[(1-methylimidazol-2-yl) methyl] -3-phen Nylsulfonyl-5-chloroindole-2-carboxamide or a pharmaceutical thereof Acceptable salt. 14. An effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition having the function of inhibiting HIV reverse transcriptase. 15. An effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. Having or preventing HIV infection, or treating AIDS or ARC A pharmaceutical composition useful for.