HK1110597A - Indole derivatives as inhibitors of soluble adenylate cyclase - Google Patents
Indole derivatives as inhibitors of soluble adenylate cyclase Download PDFInfo
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Description
Technical Field
The present invention relates to inhibitors of soluble adenylate cyclase, their production and their use in the production of contraceptives (pharmaceutical agents).
Background
There are many modern methods of contraception available to women; for male birth control, however, very few methods are available (condoms and sterilization). It is very necessary to develop a new safe drug for male birth control. In this connection, the infertility caused by "male pills" should be completely reversible and as effective as existing methods available to women. Infertility should take effect relatively rapidly and be continued for as long a time as possible. Such a method of contraception should not have any side effects; in this connection, these may be non-hormonal preparations in addition to hormonal preparations. Modulation of the activity of the enzyme important in oocyte fertilization, soluble adenylate cyclase (sAC), is a possible starting point. This enzyme is expressed primarily in testicular stem cells and is present in mature sperm.
In 1999, authors Levin and Buck (Proc. Natl. Acad. Sci. U.S. 96 (1): 79-84) have been able to purify and clone isoforms of sAC from rat spermary.
Bicarbonate stimulates the rat recombinase. Through antibodies, the catalytic domain of the enzyme can be demonstrated to be located in the testis, sperm, kidney and choroid plexus. These disclosures are the subject of application WO01/85753, issued in the United states (US 6544768).
Isolated polynucleotide sequences encoding human sAC isoforms, isolated sAC polypeptides and test systems by means of which substances capable of inhibiting the activity of sAC can be identified are claimed in WO01/21829(Conti et al). The use of these substances for reducing the number of motile sperm cells in a reversible manner and the possibility of their use as a male birth control drug is disclosed.
The John Herr panel presented isolation and characterization of human sAC isoforms derived from sperm. In WO02/20745, in addition to nucleic acids, test systems which code for sAC are claimed, with the aid of which substances which can modulate the expression or activity of human sAC can be identified. These compounds may selectively inhibit the activity of, for example, sAC; thereby causing the sperm cells to lose their ability to fertilize the oocyte. Thus, these sAC inhibitors are useful as non-hormonal contraceptives.
However, known sAC inhibitors show particular problems: catechol estrogens (T.Braun, Proc Soc Exp Biol Med 1990, (1): 58ff) and gossypol (K.L.Olgiati Archbiochem Biophys 1984, 231 (2): 411ff) are toxic in nature, while adenosine analogues only exert a very weak inhibitory effect (M.A.Brown and E.R.Casillas J Androl1984, 5: 361 ff). Recombinant human sAC Inhibitors (IC) as described by Zippin et al (J.H.Zippin et al J Cell Biol 2004, 164 (4): 527ff)50< 10. mu. mol) in a certain amountMore effective in extent.
To be able to obtain drugs that can be used in male birth control, there is an increasing need for substances that are capable of reversibly, rapidly and successfully causing infertility.
Disclosure of Invention
The above objects are achieved by the preparation of compounds of the general formula I and their isomers, diastereomers, enantiomers and salts which overcome the known disadvantages and exhibit improved properties, i.e. good efficacy, good solubility and stability:
wherein
R1Represents hydrogen, halogen, CF3Optionally multiply saturated (polysaturated) and optionally multiply substituted C3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl radicalOr C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents C which is optionally substituted in one or more positions in the same or different manner by halogen, optionally substituted in one or more positions1-C6-alkyl or C1-C6Acyl or by C1-C6Alkoxy, hydroxy, cyano, CO2-(C1-C6Alkyl), N- (C)1-C6-alkyl groups)2、CO-NR4R5Or by CF3Substituted C6-C12-aryl, representing optionally halogen, optionally in one or more positions, in the same or different manner, by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, hydroxy, cyano, CO2-(C1-C6Alkyl), N- (C)1-C6-alkyl groups)2、CO-NR4R5Or by CF3Substituted C5-C12-heteroaryl or represents halogen, CF, optionally in one or more positions, in the same or different manner3Hydroxy, cyano, CO2-(C1-C6Alkyl), C1-C6Alkyl radical, C1-C6-acyl, N- (C)1-C6-alkyl groups)2、CO-NR4R5Or C1-C6-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, optionally substituted in one or more positions in the same or different manner by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents optionally desiredC substituted by radicals1-C6-an alkyl group,
R5represents hydrogen, optionally substituted in one or more positions in the same or different manner by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5-to 8-membered ring which together may contain further heteroatoms, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents a nitrogen atom or a nitrogen atom,
n represents 0 to 4.
The compounds of the present invention inhibit soluble adenylate cyclase and prevent sperm capacitation and are therefore used for male birth control.
Alkyl is in each case defined as straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl.
Alkoxy is in each case defined as straight-chain or branched alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy and hexoxy (hexoxy).
Acyl is in each case defined as a straight-chain or branched radical, for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and benzoyl.
Cycloalkyl is defined as a monocycloalkyl ring such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Cycloalkyl groups may contain one or more heteroatoms, such as oxygen, sulfur and/or nitrogen, in place of carbon atoms. Preference is given to those heterocycloalkyl having from 3 to 6 ring atoms. Ring systems in which the ring may optionally contain one or more possible double bonds are defined, for example, as cycloalkenyl, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl or cycloheptenyl, whereby the connection to double and single bonds can be effected.
Halogen is defined in each case as fluorine, chlorine, bromine or iodine.
In all cases, the aryl group contains 6 to 12 carbon atoms and may, for example, be benzo-fused. For example, the following aryl groups may be mentioned: phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, fluorenyl (florenyl), anthracenyl and the like.
Heteroaryl groups contain in each case 5 to 16 ring atoms and may contain one or more identical or different heteroatoms such as oxygen, sulfur or nitrogen instead of carbon atoms in the ring and may be monocyclic, bicyclic or tricyclic and furthermore may be benzo-fused in each case.
For example, mention may be made of:
thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl (quinolyl), isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like, and benzo derivatives thereof; or a quinolyl (quinolyl), isoquinolyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxacycloheptenyl (oxapinyl), etc.
Heteroaryl groups may in each case be benzo-fused. For example, thiophene, furan, oxazole, thiazole, imidazole, pyrazole and their benzo derivatives may be mentioned as 5-membered heteroaromatic ring compounds, and pyridine, pyrimidine, triazine, quinoline, isoquinoline and their benzo derivatives may be mentioned as 6-membered heteroaromatic ring compounds.
Heteroatoms are defined as oxygen, nitrogen or sulfur atoms.
Physiologically compatible salts of organic and inorganic bases, if acid radicals are included, are suitable as salts, for example readily soluble alkali metal and alkaline earth metal salts, and also N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, Sovak base (Sovakbase) and 1-amino-2, 3, 4-butanetriol.
Physiologically compatible salts of organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, and the like, are suitable if a basic group is included.
Particular preference is given to those compounds of the general formula (I) and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, halogenPlain, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl orCF is3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogenOptionally at one or more positions in the same or different ways by C1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents any ofC substituted in the desired manner1-C6-an alkyl group,
R4and R5A 5-to 8-membered ring which together may contain further heteroatoms, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
Particular preference is given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo or-O-CF3、-SO2-CH3And in the para-position,
R3represents the following group
R4Represents hydrogen or- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x represents sulfonylRadical, carbonyl or represent CH2The radical(s) is (are),
y represents a carbonyl group or represents (CH)2)nThe radical(s) is (are),
z represents nitrogen or represents
And
n is 1 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, tert-butyl, cyano, bromine or represents-O-CF3or-SO2-CH3，
R2Represents tert-butyl, cyano, bromo, or represents-O-CF3or-SO2-CH3And are and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents optionally in one or more positions, the same or differentBy halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo, or-O-CF3or-SO2-CH3And in the para position, and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl groups optionally interrupted by oxygen, sulfur or nitrogen in one or more positions in the same or different manner, orEpenesulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12-aryl, or represents optionally in one or more positionsBy halogen, C, in the same or different ways1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5 to 8 membered ring which may contain other hetero atoms in common, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents a nitrogen atom or a nitrogen atom,
n represents 0 to 4.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo, or represents-O-CF3or-SO2-CH3And in the para position, and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen or represents- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x represents sulfonyl, carbonyl or CH2The radical(s) is (are),
y represents carbonyl, hydrogen, or (CH)2)nThe radical(s) is (are),
z represents nitrogen or represents
And
n represents 1 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl-yl, or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents the following groups:
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5 to 8 membered ring which may contain other hetero atoms in common, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo or represents-O-CF3or-SO2-CH3And in the para position, and
R3represents the following groups:
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or cyano radicalsSubstituted C6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
x represents sulfonyl, carbonyl or CH2，
Y represents a carbonyl group or represents (CH)2)n，
Z represents nitrogen or represents
And
n represents 1 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3-alkyl radical、C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen or- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
Preference is also given to those compounds of the formula I and their isomers, diastereomers, enantiomers and salts, in which
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen or represents
And
n represents 0 to 2.
The following compounds according to the invention are particularly preferred:
1.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide
2.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-3-ylamide
3.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclohexanamide
4.4-tert-butyl-N- [ 3-phenyl-2- (pyrrolidine-1-carbonyl) -1H-indol-5-yl ] -benzenesulfonamide
4-tert-butyl-N- [2- (morpholine-4-carbonyl) -3-phenyl-1H-indol-5-yl ] -benzene-sulfonamide
6.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
7.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
8.5- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
9.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
10.5- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
11.5- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
12.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
13.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
14.5- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
15.5- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-phenylamide
16.5- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
17.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide
18.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide
19.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
20.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide
21.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridine (pyrindin) -4-ylamide
22.5- (4-tert-butylbenzylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide
5- (4-tert-Butylcarbonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
24.5- (4-tert-Butylsulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
25.5- (4-tert-Butylsulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
26.5- (4-tert-Butylsulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
27.5- (4-tert-Butylsulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
28.5- (4-tert-Butylsulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
29.5- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
30.5- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid pyridin-4-ylamide
31.5- (4-tert-Butylsulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
32.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
33.5- (4-tert-Butylsulfonylamino) -3- (4-hydroxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
34.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
35.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxypropyl) amide
36.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxyethyl) amide
37.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
38.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxy-1-methylethyl) amide
39.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
40.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
41.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (1-methylpiperidin-4-yl) amide
5- (4-tert-Butylsulfonylamino) -3- (4-N, N-dimethylamino-phenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
43.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
44.5- (4-tert-Butylsulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
45.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
46.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
47.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-acetylamino) amide
48.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
49.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
50.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
51.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
52.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
53.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
54.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
55.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
56.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
57.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
58.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
59.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
60.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
61.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
62.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
63.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid piperidin-4-ylamide
64.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carbonyl ] -piperidine-1-carboxylic acid tert-butyl ester
65.5- (4-tert-butyl-phenylsulfonyl-amino) -3-naphthalen-1-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
66.5- (4-tert-butyl-phenylsulfonyl-amino) -3-m-tolyl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
67.5- (4-tert-butyl-phenylsulfonyl-amino) -3-thiophen-2-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
68.5- (4-tert-butyl-phenylsulfonyl-amino) -3-thiophen-3-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
69.3-benzofuran-2-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
70.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (5-chloro-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
71.5- (4-tert-butyl-phenylsulfonyl-amino) -3-furan-2-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
72.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-fluoro-4-methoxy-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
73.3-benzo [1, 3] dioxol-5-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
74.3- (4-acetyl-phenyl) -5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
3- (3-acetyl-phenyl) -5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
76.3-benzo [ b ] thiophen-2-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
77.3-benzo [ b ] thiophen-3-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
78.5- (4-tert-butyl-benzenesulfonylamino) -3- (5-methyl-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
79.3- [5- (4-tert-butyl-phenylsulfonyl-amino) -2- (2-morpholin-4-yl-ethylcarbamoyl) -1H-indol-3-yl ] -benzoic acid methyl ester
80.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2-fluoro-3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
81.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-chloro-4-methyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
82.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 4-dimethoxy-pyrimidin-5-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
83.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 5-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
84.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 4-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
85.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 3-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
86.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 6-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
87.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-hydroxy-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
88.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-hydroxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
89.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-fluoro-4-methylphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
90.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-trifluoromethyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
91.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-cyanomethyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
5- (4-tert-butyl-phenylsulfonyl-amino) -1H, 1 'H- [3, 4' ] biindole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
93.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-cyano-4-fluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
94.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2-fluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
95.5- (4-tert-butyl-benzenesulfonylamino) -3- (3, 4-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
96.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-cyano-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
97.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-cyano-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
98.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-methyl-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
99.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-chloro-phenyl) -amide
100.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-isoxazol-5-yl) -amide
101.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-fluoro-phenyl) -amide
102.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-fluoro-phenyl) -amide
103.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (6-methyl-pyridin-2-yl) -amide
104.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-carbamoyl-pyridin-2-yl) -amide
105.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-hydroxy-phenyl) -amide
106.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxy-phenyl) -amide
107.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methoxy-phenyl) -amide
108.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methoxy-phenyl) -amide
109.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-chloro-phenyl) -amide
110.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-dimethylamino-phenyl) -amide
111.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-chloro-pyridin-2-yl) -amide
112.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid p-tolylamide
113.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid pyrazin-2-ylamide
114.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-cyano-phenyl) -amide
115.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-isothiazol-5-yl) -amide
116.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-bromo-phenyl) -amide
117.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-carbamoyl-phenyl) -amide
118.5- (4-tert-butyl-benzenesulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-pyridin-2-yl) -amide
119.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-chlorophenyl) -amide
120.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-methyl-2H-pyrazol-3-yl) -amide
121.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid quinolin-5-ylamide
122.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid quinolin-6-ylamide
123.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 6-dichloro-pyridin-4-yl) -amide
124.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-fluoro-phenyl) -amide
125.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methyl-pyridin-4-yl) -amide
126.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-fluoro-pyridin-4-yl) -amide
127.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-pyridin-4-yl) -amide
128.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-bromo-pyridin-4-yl) -amide
129.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 3-dihydroxy-propyl) -amide
130.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-oxo-tetrahydro-thiophen-3-yl) -amide
131.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (2-oxo-imidazolidin-1-yl) -ethyl ] -amide
132.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 2-diethoxy-ethyl) -amide
133.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-ethoxy-propyl) -amide
134.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-isopropoxy-propyl) -amide
135.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-morpholin-4-yl-propyl) -amide
136.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-diethylamino-propyl) -amide
137.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-dimethylamino-propyl) -amide
138.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (furan-2-ylmethyl) -amide
139.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methylsulfanyl-ethyl) -amide
140.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-diethylamino-ethyl) -amide
141.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -amide
142.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-piperidin-1-yl-ethyl) -amide
143.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-pyrrolidin-1-yl-propyl) -amide
144.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-phenethyl-amide
145.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxy-1-methyl-ethyl) -amide
146.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-2-ylmethyl) -amide
147.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-3-ylmethyl) -amide
148.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-4-ylmethyl) -amide
149.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-diethylamino-1-methyl-butyl) -amide
150.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-imidazol-1-yl-ethyl) -amide
151.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-benzylamide
152.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 2, 2-trifluoro-ethyl) -amide
153.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-methoxy-benzylamide
154.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclopentamide
155.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-butyl) -amide
156.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (4-methyl-piperazin-1-yl) -propyl ] -amide
157.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (4-hydroxy-phenyl) -ethyl ] -amide
158.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (4-chloro-phenyl) -ethyl ] -amide
159.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-cyclopropylamide
160.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclohexylmethyl-amide
161.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (tetrahydro-furan-2-ylmethyl) -amide
162.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (thien-2-ylmethyl) -amide
163.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-fluoro-benzylamide
164.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-thiophen-2-yl-ethyl) -amide
165.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyrrolidin-1-yl-ethyl) -amide
166.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-methyl-benzylamide
167.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (1-ethyl-pyrrolidin-2-ylmethyl) -amide
168.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyridin-3-yl-ethyl) -amide
169.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 3-chloro-benzylamide
170.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (3-chlorophenyl) -ethyl ] -amide
171.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((R) -2-hydroxy-1-phenyl-ethyl) -amide
172.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (2-methyl-piperidin-1-yl) -propyl ] -amide
173.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-phenyl-propyl) -amide
174.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-carbamoyl-ethyl) -amide
175.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (5-methyl-1H-pyrazol-4-yl) -propyl ] -amide
176.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methyl-cyclohexyl) -amide
177.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((S) -2-methoxy-1-methyl-ethyl) -amide
178.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclopropylmethyl-amide
179.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-carbamoylmethyl-amide
180.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cycloheptylamide
181.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((R) -2-methoxy-1-methyl-ethyl) -amide
182.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (furan-3-ylmethyl) -amide
183.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 3-fluoro-benzamide
184.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-methyl-pyrazin-2-ylmethyl) -amide
185.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyridin-2-yl-ethyl) -amide
186.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-phenoxy-ethyl) -amide
187.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-benzimidazol-1-yl-ethyl) -amide
188.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-imidazol-1-yl-propyl) -amide
189.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (1-benzyl-piperidin-4-yl) -amide
190.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -amide
191.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amide
192.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid methyl- (2-morpholin-4-yl-ethyl) -amide
Detailed Description
The compounds of the invention inhibit soluble adenylate cyclase, for example in the case of male contraception, on which their action is based.
Adenylate cyclase is an effector molecule of one of the most commonly used signal transduction methods; they synthesize the second messenger molecule cyclic adenosine monophosphate (cAMP) from Adenosine Triphosphate (ATP) cleaved pyrophosphate (PP). cAMP mediates many cellular responses to a large number of neurotransmitters and hormones. Soluble, sperm-specific adenylyl cyclase (sAC, human mRNA sequence (genebank) NM — 018417, human gene ADCY X) is one of ten described adenylyl cyclases in the human genome. In this case, sAC displays several distinct properties that differ from other adenylate cyclases. Unlike all other adenylate cyclases, sAC is stimulated by the concentration of bicarbonate in its surrounding medium rather than by the G-protein. sAC is devoid of any transmembrane region in its amino acid sequence; it cannot be inhibited by forskolin, can be stimulated more strongly by manganese than by magnesium, and shows only low sequence homology with other adenylate cyclases (catalytic domains I and II of sAC share ≦ 26% identity in the amino acid plane with other adenylate cyclases).
In particular, T.Braun et al (1975, PNAS 73: 1097ff) described for the first time the manganese-dependent activity of sAC in rat sperms and sperms. Okamura et al (1985, J.biol. Chem260(17)9699ff) demonstrated that the substance stimulating sAC activity in porcine semen is bicarbonate. It also demonstrated that bicarbonate-stimulated AC activity was detectable only in rat testis and sperm but not other tissues. Buck and Levin research groups purified from rat testis and sequenced sAC for the first time (J.Buck et al 1999 PNAS 96: 79ff, WO 01/85753). The expected properties (e.g., the ability to stimulate bicarbonate and magnesium) are confirmed by recombinantly expressed proteins (Y.Chen et al 2000Science 289: 625 ff).
Data on the distribution of sAC mRNA and the bicarbonate-stimulated activity of sAC can indicate testis-and sperm-specific expression of the enzyme (M.L. Sinclair et al 2000 Mol reprodDevelop 56: 6 ff; N.Okamura et al 1985, J.biol.chem260(17)9699 ff; J.Buck et al 1999 PNAS 96: 79 ff). In this case, sAC mRNA is expressed in testis only at a later stage, when the gametes Develop into sperm, and not in somatic cells (M.L. Sinclair et al 2000 Mol Reprod Defelop 56: 6 ff).
There are many pharmacological studies on sAC function in mammalian sperm. Sperm must be prepared for this function before they penetrate the zona pellucida of the egg so as to subsequently fuse with the egg membrane of the egg. The process of sperm capacitation has been quite well studied. Capacitated sperm are distinguished by a change in the form of movement and the ability to undergo an acrosome reaction process upon appropriate stimulation (release of a hydrolase which is presumed that the sperm is intended to penetrate the zona pellucida). Sperm capacitation can be performed in vivo and in vitro, i.a., based on an increase in bicarbonate concentration in the medium (P.E.Visconti G.S.Kopf (1998) biol Reprod 59: 1 ff; E.de Lamirande et al 1997 Mol Hum Reprod 3 (3): 175 ff). Sperm capacitation can also be stimulated by the addition of suitable membrane-penetrating cAMP analogues to stimulate db-cAMP, for example, and inhibitors that inhibit their degradation (IBMX, for example). The expected dependence of the sAC sperm function was only recently confirmed by gene deletion models, so-called knockout mice (g. esposito et al 2004 PNAS 101 (9): 2993 ff). Male mice that lack the sAC gene show normal spermatogenesis, but are unable to give birth. The sperm has a motility defect and cannot fertilize an egg. These animals showed no other defects or abnormal findings corresponding to the postulated function of the sAC group (j.h. zippin et al 2003 FASEB 17: 82 ff).
sAC has a unique sequence and only low homology to other somatic adenylate cyclases. It is the only adenylate cyclase present in mammalian sperm, the activity of which is essential for sperm motility and capacitation. specific inhibitors of sAC therefore represent an important possibility to modulate male fertility.
Medicaments comprising at least one compound according to claims 1 to 3 are therefore the subject of the present invention.
The use of the compounds of claims 1 to 3 is also a subject of the present invention.
For the use of the compounds of the invention as medicaments, the medicaments should take the form of pharmaceutical preparations which, in addition to the active ingredients for enteral or parenteral administration, comprise suitable pharmaceutically, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. In addition, they optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure, or buffers. These pharmaceutical preparations are also the subject of the present invention.
In particular, injection solutions or suspensions of the active compounds in aqueous solution in polyhydroxyethoxylated castor oil are particularly suitable for parenteral administration.
Surface-active adjuvants such as salts of bile acids or animal or vegetable phospholipids and mixtures thereof and liposomes or their components can also be used as carrier systems.
Tablets, coated tablets or capsules containing talc and/or a hydrocarbon excipient or binder such as lactose, corn starch or potato starch are particularly suitable for oral administration. Administration may also be carried out in the liquid state, such as a juice with optional addition of sweeteners.
Such enteral, parenteral and oral administration are also subjects of the present invention.
The dosage of the active ingredient may vary depending on the method of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the like. The daily dose is 0.5-1000mg, preferably 50-200mg, wherein the dose can be administered as a single dose administered at one time or divided into 2 or more daily doses.
The compounds of formula I of the present invention are, i.a., excellent inhibitors of soluble adenylate cyclase. Soluble adenylate cyclase inhibitors result in a decrease in cAMP signal. cAMP levels determine the monitoring of processes that play an important role in cell proliferation, cell differentiation and apoptosis. Diseases determined by reduced cAMP levels, such as cancer, can be modulated by soluble adenylate cyclase inhibitors. This modulation can have both prophylactic and therapeutic effects on patients suffering from this disease. Diseases such as cancer, which are accompanied by increased cell proliferation, are currently treated by treatments such as radiotherapy and chemotherapy. These methods are not specific and have high potential side effects. It is therefore advantageous to prepare new substances that directly attack a specific target site. Substances which modulate cAMP production by inhibiting soluble adenylate cyclase are the subject of the present invention. Thus, for example, abnormal cell proliferation can be reduced or inhibited by modulating or inhibiting cAMP production. By applying the substance of the present invention, soluble adenylate cyclase can be inhibited; resulting in a reduction in cell proliferation. The subject of the invention is medicaments for the treatment of diseases comprising at least one compound of the general formula I and medicaments with suitable formulation substances (formulaion substances) and excipients. These diseases are therefore characterized in that they are caused by a disturbance in the metabolism of the second messenger cAMP.
Reducing the concentration of cAMP by inhibiting soluble adenylate cyclase enables the preparation of drugs useful for modulating sperm capacitation. The subject of the present invention is the use of the substances of the invention for reducing or inhibiting the fertility of male gametes mediated by the reduction or inhibition of the soluble adenylyl cyclase activity and the resulting sperm acquisition.
Fertilization of eggs can be prevented by administering an effective amount of a substance that results in the inhibition of cAMP production. The use of compounds of the general formula I for the production of non-hormonal contraceptives is also a subject of the present invention.
If the preparation of the starting compound is not described, the starting compound is known or can be prepared analogously to the methods described herein or to known compounds. All reactions described herein can also be carried out in parallel reactors (parallel reactors) or by combined operation processes (combinatorial operating processes).
The isomer mixtures are separated into the enantiomers or E/Z isomers according to customary methods such as crystallization, chromatography or salt formation.
The preparation of the salts can be carried out in a customary manner by mixing a solution of the compounds of the formula I with an equal or excess amount of a base or acid, optionally in solution, and isolating the precipitate or treating the solution (work up) in a customary manner.
Preparation of the Compounds of the invention
The following examples illustrate the preparation of the compounds of general formula (I) according to the invention without limiting the scope of the claimed compounds to these examples.
The compounds of the general formula (I) according to the invention can be prepared as described below.
An operation guide 1: amide coupling:
the carboxylic acid (1.0 eq) was dissolved in N, N-Dimethylformamide (DMF) (10ml/1mmol) and mixed with N- [ (dimethylamino) -1H-1, 2, 3-triazolo [4, 5-b ] pyridin-1-ylmethylene ] -N-methylhexafluorophosphate methylammonium (Methylethanaminiumhexafluoro phosphate) -N-oxide (HATU) (1.1 eq) and the amine to be coupled (1.0 eq). Then, ethyldiisopropylamine (1.1 eq) was added thereto at 0 ℃ and the mixture was stirred at room temperature for 22 hours. Then, the mixture was mixed with ice water (35ml/1mmol of carboxylic acid) and stirred at room temperature for 30 minutes. The precipitated crystals were aspirated and dried in air. The product is either used in the next reaction without additional purification or purified chromatographically.
An operation guide 2: reduction of nitro group:
the nitro compound (1.0 eq) was introduced into methanol (10ml/lmmol) and water (0.03ml/lmmol), mixed with ammonium formate (5 eq) and catalytic amount of palladium on carbon (10%) and refluxed at 90 ℃ for 3 hours. Then, aspirate over Celite and wash again with boiling methanol. After removal of the solvent, the residue was mixed with water (7ml/mmol of amide), and the precipitated crystals were aspirated. If no crystals were formed, the aqueous phase was extracted with ethyl acetate or dichloromethane. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. Then, the solvent was removed under reduced pressure.
An operation guide 3: coupling with arylsulfonyl chloride:
the prepared amine (1.0 eq) was dissolved in DMF (10ml/1mmol), mixed with ethyldiisopropylamine (1.5 eq) and arylsulfonyl chloride (1.0 eq) at 0 ℃ and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue purified by chromatography.
An operation guide 4: bromination:
ethyl 5-nitroindole-2-carboxylate (1.0 eq) was dissolved in tetrahydrofuran (5ml/1mmol) and mixed with N-bromosuccinimide (1.0 eq). After 30 minutes water was added and after 20 minutes the precipitated crystals were aspirated. If no crystals were formed, the aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. After removal of the solvent, the residue is purified by chromatography.
An operation guide 5: saponification:
the ester compound (1.0 eq) was mixed with 19 eq of 1M sodium hydroxide in ethanol/water (1/1). After 6 hours at room temperature, the ethanol was removed under reduced pressure, diluted with water and adjusted to pH 2 with 10% aqueous sulfuric acid. The precipitated crystals were then aspirated.
An operation guide 6: coupling with an aryl boronic acid:
3-Bromoindole-2-carboxylate (1.0 equiv.) is suspended with arylboronic acid (1.5 equiv.) in toluene/ethanol 1: 1(40ml/1mmol ester) and mixed with 1M sodium carbonate solution (2.5 equiv.) and lithium chloride (2.8 equiv.). After addition of tetrakis (triphenylphosphine) -palladium (0.08 eq), the reaction mixture was refluxed for 8 hours. After cooling to room temperature, it was diluted with ethyl acetate (70ml/1mmol of ester) and after 10 minutes it was aspirated through Celite. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. The residue was purified by chromatography after removal of the solvent.
Example 1: 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide
Following reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with cyclopropylamine (0.105ml, 1.5mmol) according to guide 1, 445mg (93%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide were obtained, which was used in the following reaction without purification.
Following reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide (445mg, 1.39mmol) with ammonium formate (438mg, 6.95mmol) in the presence of palladium on carbon (44mg) according to operating manual 2, 289mg (72%) of 5-amino-3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.28-0.36(m，2H)，0.60-0.68(m，2H)，2.72(m，1H)，5.00(br，2H)，6.60-6.68(m，2H)，7.15(d，1H)，7.22-7.38(m，2H)，7.40-7.50(m，4H)，11.19(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide (145mg, 0.5mmol) with 4-tert-butylbenzenesulfonyl chloride (116mg, 0.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 190mg (78%) of the 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-cyclopropylamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.32-0.37(m，2H)，0.59-0.65(m，2H)，1.25(s，9H)，2.67-2.76(m，1H)，7.02(dd，1H)，7.10(s，1H)，7.25(d，2H)，7.31-7.36(m，2H)，7.40-7.45(m，2H)，7.51-7.59(m，5H)，9.79(s，1H)，11.66(s，1H)。
Example 2: 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-3-ylamide
Following reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with 3-aminopyridine (141mg, 1.5mmol) according to guide 1, 494mg (93%) of the pyridine-3-ylamide-5-nitro-3-phenyl-1H-indole-2-carboxylic acid product was obtained and used without further purification in the following reaction.
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid pyridin-3-ylamide (494mg, 1.39mmol) with ammonium formate (435mg, 6.90mmol) in the presence of palladium on carbon (49mg) according to operating manual 2, 257mg (72%) of the 5-amino-3-phenyl-1H-indole-2-carboxylic acid pyridin-3-ylamide product was obtained.
NMR(300 MHz，DMSO-d6)：δ 4.98(br，2H)，6.70-6.78(m，2H)，7.23(d，1H)，7.30-7.38(m，2H)，7.40-7.58(m，4H)，8.00(d，1H)，8.25(dd，1H)，8.64(d，1H)，9.75(s，1H)，11.49(s，1H)。
After reaction (128mg, 0.39mmol) with 4-tert-butylbenzenesulfonyl chloride (90mg, 0.39mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 140mg (68%) of pyridin-3-ylamide 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylate product were obtained.
NMR(300 MHz，DMSO-d6)：δ 1.26(s，9H)，7.09(dd，1H)，7.19(s，1H)，7.34-7.43(m，7H)，7.54(d，2H)，7.60(d，2H)，7.95-7.97(m，1H)，8.27(d，1H)，8.65(s，1H)，9.86(s，1H)，9.98(s，1H)，11.97(s，1H)。
Example 3: 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-cyclohexanamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with cyclohexylamine (149mg, 1.5mmol) according to operating manual 1, 504mg (93%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid cyclohexanamide product was obtained, which was used in the following reaction without further purification.
Following the protocol 2, 367mg (79%) of the 5-amino-3-phenyl-1H-indole-2-carboxylic acid cyclohexylamide product was obtained after reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid cyclohexylamide (504mg, 1.39mmol) with ammonium formate (438mg, 6.95mmol) in the presence of palladium on carbon (50 mg).
NMR(300MHz，DMSO-d6)：δ 0.92-1.16(m，3H)，1.18-1.31(m，2H)，1038-1.55(m，3H)，1.62-1.76(m，2H)，3.61-3.78(m，1H)，4.82(br，2H)，6.58-6.74(m，3H)，7.1 8(d，1H)，7.32-7.40(m，1H)，7.43-7.54(m，4H)，11.25(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid cyclohexanamide (183mg, 0.55mmol) with 4-tert-butylbenzenesulfonyl chloride (128mg, 0.55mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 231mg (79%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclohexanamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.98-1.09(m，3H)，1.19-1.32(m，11H)，1.50-1.53(m，3H)，1.66-1.70(m，2H)，3.65-3.74(m，1H)，6.97-7.06(m，3H)，7.29-7.48(m，6H)，7.51(d，2H)，7.57(d，2H)，9.79(s，1H)，11.71(s，1H)。
Example 4: 4-tert-butyl-N- [ 3-phenyl-2- (pyrrolidine-1-carbonyl) -1H-indol-5-yl ] -benzenesulfonamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with pyrrolidine (0.124mg, 1.5mmol) according to guide 1, 430mg (85%) of 5-nitro-3-phenyl-1H-indol-2-yl) pyrrolidin-1-yl-methanone product was obtained and used in the following reaction without further purification.
Following reaction of 5-nitro-3-phenyl-1H-indol-2-yl) pyrrolidin-1-yl methanone (430mg, 1.28mmol) with ammonium formate (404mg, 6.41mmol) in the presence of palladium on carbon (43mg) according to guide 2, 255mg (65%) of 5-amino-3-phenyl-1H-indol-2-yl) pyrrolidin-1-yl methanone product was obtained.
NMR(300MHz，DMSO-d6)：δ 1.44-1.60(m，2H)，1.62-1.78(m，2H)，2.84(t，2H)，3.41(t，2H)，4.90(br，2H)，6.61(dd，1H)，6.88(d，1H)，7.12(d，1H)，7.22-7.30(m，1H)，7.38-7.50(m，4H)，11.25(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indol-2-yl) pyrrolidin-1-yl methanone (128mg, 0.42mmol) with 4-tert-butylbenzenesulfonyl chloride (98mg, 0.42mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 160mg (76%) of 4-tert-butyl-N- [ 3-phenyl-2- (pyrrolidine-1-carbonyl) -1H-indol-5-yl ] -benzenesulfonamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 1.24(s，9H)，1.49-1.55(m，2H)，1.65-1.73(m，2H)，2.81(t，2H)，3.41(t，2H)，7.01(dd，1H)，7.24-7.34(m，5H)，7.42-7.46(m，2H)，7.54(d，2H)，7.60(d，2H)，9.85(s，1H)，11.72(s，1H)。
Example 5: 4-tert-butyl-N- [2- (morpholine-4-carbonyl) -3-phenyl-1H-indol-5-yl ] -benzene-sulfonamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with morpholine (0.131mg, 1.5mmol) according to operating manual 1, 487mg (92%) of the morpholin-4-yl- (5-nitro-3-phenyl-1H-indol-2-yl) -methanone product is obtained, which is used in the following reaction without further purification.
After reaction of morpholin-4-yl- (5-nitro-3-phenyl-1H-indol-2-yl) -methanone (487mg, 1.39mmol) with ammonium formate (438mg, 6.95mmol) in the presence of palladium on carbon (49mg) according to the operating manual 2, 393mg (88%) of the (5-amino-3-phenyl-1H-indol-2-yl) -morpholin-4-yl methanone product is obtained.
NMR(300MHz，DMSO-d6)：δ 2.78-3.70(m，8H)，4.70(br，2H)，6.63(dd，1H)，6.82(d，1H)，7.12(d，1H)，7.29-7.51(m，5H)，11.30(s，1H)。
After reaction of (5-amino-3-phenyl-1H-indol-2-yl) -morpholin-4-ylmethanone (196mg, 0.61mmol) with 4-tert-butylbenzenesulfonyl chloride (142mg, 0.61mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 280mg (88%) of 4-tert-butyl-N- [2- (morpholine-4-carbonyl) -3-phenyl-1H-indol-5-yl ] -benzenesulfonamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 1.24(s，9H)，2.75-3.10(br，4H)，3.30-3.60(br，4H)，7.02(dd，1H)，7.21-7.30(m，5H)，7.42-7.61(m，6H)，9.85(s，1H)，11.78(s，1H)。
Example 6: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (1.0g, 3.54mmol) with N, N-dimethylethylenediamine (312mg, 3.54mmol) according to guide 1, 557mg (44%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide were obtained, which was used in the following reaction without further purification.
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide (557mg, 1.58mmol) with ammonium formate (498mg, 7.90mmol) in the presence of palladium on carbon (87mg) in accordance with operating manual 2, 386mg (75%) of the 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ 2.03(s，6H)，2.21(t，2H)，3.24(q，2H)，4.95(br，2H)，6.55(d，1H)，6.64(dd，1H)，6.86(t，1H)，7.17(d，1H)，7.34-7.50(m，5H)，11.25(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide (229mg, 0.71mmol) with 4-tert-butylbenzenesulfonyl chloride (165mg, 0.71mmol), purification by chromatography (silica gel, dichloromethane/methanol (0-10% methanol)) according to operating manual 3, 300mg of the solid was dissolved in dichloromethane and washed with 1N KOH solution. After drying over sodium sulfate and removal of the solvent, 90mg (24%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide are obtained.
NMR(300MHz，DMSO-d6)：δ 1.25(s，9H)，2.00(s，6H)，2.25(t，2H)，3.24(q，2H)，7.00-7.10(m，3H)，7.21-7.60(m，10H)，9.80(s，1H)，11.71(s，1H)。
Example 75- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with propylamine (89mg, 1.5mmol) according to the operating manual 1, 450mg (93%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid propionamide was obtained, which was used in the following reaction without further purification.
281mg (77%) of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide product was obtained after reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid propionamide (400mg, 1.24mmol) with ammonium formate (390mg, 6.18mmol) in the presence of palladium on carbon (40mg) according to guide 2.
NMR(300MHz，DMSO-d6)：δ 0.76(t，3H)，1.33-1.40(m，2H)，3.11(q，2H)，4.64(br，2H)，6.62-66(m，2H)，7.00(t，1H)，7.17(d，1H)，7.33-7.36(m，1H)，7.43-7.46(m，4H)，11.19(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide (146mg, 0.5mmol) with 4-cyanophenylsulfonyl chloride (121mg, 0.60mmol) and chromatography (silica gel, hexane/ethyl acetate)) according to guide 3, 41mg (18%) of the 5- (4-cyanophenylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.76(t，3H)，1.31-1.43(m，2H)，3.11(q，2H)，6.96(dd，1H)，7.00(s，1H)，7.27-7.49(m，7H)，7.77(d，2H)，8.03(d，2H)，10.08(s，1H)，11.75(s，1H)。
Example 85- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide (146mg, 0.5mmol) with 4-bromophenylsulfonyl chloride (153mg, 0.60mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 91mg (35%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.76(t，3H)，1.31-1.43(m，2H)，3.11(q，2H)，6.96-7.03(m，2H)，7.26-7.49(m，7H)，7.53(d，2H)，7.77(d，2H)，9.86(s，1H)，11.73(s，1H)。
Example 95- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide (146mg, 0.5mmol) with 4-tert-butylbenzenesulfonyl chloride (139mg, 0.60mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 52mg (21%) of the product was obtained.
NMR(300MHz，CDCl3)：δ 0.73(t，3H)，1.29-1.41(m，11H)，3.22(q，2H)，5.92(t，1H)，6.47(s，1H)，7.04(s，1H)，7.07(dd，1H)，7.34-7.61(m，10H)，9.55(s，1H)。
Example 105- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide (146mg, 0.5mmol) with 4- (trifluoromethoxy) phenyl-sulfonyl chloride (156mg, 0.60mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 106mg (41%) of the product was obtained.
NMR(300MHz，CDCl3)：δ 0.73(t，3H)，1.28-1.38(m，2H)，3.22(q，2H)，5.95(t，1H)，6.76(s，1H)，7.02(s，1H)，7.06(dd，1H)，7.20(d，2H)，7.37-7.51(m，6H)，7.71(d，2H)，9.81(s，1H)。
Example 115- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid propionamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid propionamide (146mg.0.50mmol) with 4-methylsulfonylbenzene-sulfonyl chloride (153mg, 0.60mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 87mg (39%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ 0.76(t，3H)，1.31-1.43(m，2H)，3.11(q，2H)，3.25(s，3H)，7.00(dd，1H)，7.05(s，1H)，7.27(d，2H)，7.34-7.38(m，3H)，7.43-7.49(m，2H)，7.87(d，2H)，8.10(d，2H)，10.10(s，1H)，11.75(s，1H)。
Example 125- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
The 5-nitro-3-phenyl-1H-indole-2-carboxylic acid phenylamide product was obtained in quantitative yield after reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (1.27g mg, 4.5mmol) with aniline (419mg, 1.5mmol) according to the operating manual 1 and was used in the following reaction without further purification.
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid phenylamide (1.61g, 4.5mmol) with ammonium formate (1.42g, 22.5mmol) in the presence of palladium on carbon (160mg) according to the operating manual 2, 1.19mg (81%) of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide product was obtained.
NMR(300MHz，DMSO-d6)：δ4.90(br，2H)，6.68-6.72(m，2H)，7.15(t，1H)，7.20-7.40(m，4H)，7.44-7.60(m，6H)，9.38(s，1H)，11.5(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide (164mg, 0.5mmol) with 4-tert-butylbenzenesulfonyl chloride (116mg, 0.50mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 117mg (44%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide product was obtained.
NMR(300MHz，DMSO-d6)：δ1.26(s，9H)，7.08(m，2H)，7.17(d，1H)，7.28-7.51(m，10H)，7.55(d，2H)，7.59(d，2H)，9.65(s，1H)，9.85(s，1H)，11.94(s，1H)。
Example 135- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide (164mg, 0.50mmol) with 4-cyanobenzenesulfonyl chloride (100mg, 0.50mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 35mg (14%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ 7.04-7.11(m，3H)，7.46-7.51(m，10H)，7.80(d，2H)，8.05(d，2H)，9.66(s，1H)，10.12(s，1H)，11.99(s，1H)。
Example 145- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide (164mg, 0.50mmol) with 4-bromobenzenesulfonyl chloride (127mg, 0.50mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 76mg (27%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ 7.02-7.10(m，3H)，7.28-7.51(m，10H)，7.57(d，2H)，7.78(d，2H)，9.67(s，1H)，9.92(s，1H)，11.98(s，1H)。
Example 155- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide (164mg, 0.50mmol) with 4- (trifluoromethoxy) benzenesulfonyl chloride (130mg, 0.50mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 161mg (58%) of product was obtained.
NMR(300 MHz，DMSO-d6)：δ 7.02-7.09(m，2H)，7.14(d，1H)，7.28-7.57(m，12H)，7.77(d，2H)，7.78(d，2H)，9.67(s，1H)，9.98(s，1H)，11.98(s，1H)。
Example 165- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid phenylamide (164mg, 0.5mmol) with 4-methylsulfonylbenzenesulfonyl chloride (127mg, 0.50mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 140mg (51%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ 3.27(s，3H)，7.03-7.09(m，2H)，7.16(d，1H)，7.28-7.51(m，10H)，7.91(d，2H)，8.12(d，2H)，9.66(s，1H)，10.15(s，1H)，11.99(s，1H)。
Example 175- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (1.27g, 4.5mmol) with 2-aminopyridine (423mg, 4.5mmol) according to operating manual 1, 1.46g (90%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid-pyridin-2-ylamide product was obtained, which was used in the following reaction without further purification.
After reacting the obtained pyridine-2-ylamide-5-nitro-3-phenyl-1H-indole-2-carboxylate (1.45g, 4.05mmol) with ammonium formate (1.27g, 20.23mmol) in the presence of palladium on carbon (145mg) according to the operating manual 2, 490mg (37%) of pyridine-2-ylamide-5-amino-3-phenyl-1H-indole-2-carboxylate product are obtained.
NMR(300MHz，DMSO-d6)：δ 5.40(br，2H)，6.57(s，1H)，6.73(dd，1H)，7.06-7.10(m，1H)，7.23(d，1H)，7.43-7.53(m，5H)，7.79(td，1H)，8.15-8.23(m，2H)，9.00(s，1H)，11.60(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide (98mg, 0.3mmol) with 4-tert-butylbenzenesulfonyl chloride (70mg, 0.3mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 72mg (45%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide are obtained.
NMR(300 MHz，DMSO-d6)：δ1.26(s，9H)，7.06-7.12(m，3H)，7.36-7.60(m，10H)，7.80(td，1H)，8.14(d，1H)，8.23(d，1H)，9.31(s，1H)，9.86(s，1H)，12.1(s，1H)。
Example 185- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-pyridin-2-ylamide
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide (98mg, 0.3mmol) with 4-cyanobenzenesulfonyl chloride (60mg, 0.3mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 3, 49mg (33%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ6.99(s，1H)，7.04(dd，1H)，7.11(dd，1H)，7.36-7.54(m，6H)，7.77-7.84(m，3H)，8.05(d，2H)，8.14(d，1H)，8.25(d，1H)，9.34(s，1H)，10.12(s，1H)，12.09(s，1H)。
Example 195- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with 4- (2-aminoethyl) morpholine (0.197mg, 1.5mmol) according to operating manual 1, 528mg (89%) of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide product was obtained and used in the following reaction without further purification.
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide (521mg, 1.32mmol) with ammonium formate (416mg, 6.60mmol) in the presence of palladium on carbon (52mg) according to the operating manual 2, 337mg (70%) of 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ 2.16-2.22(m，4H)，2.25(t，2H)，3.26(q，2H)，3.40-3.48(m，4H)，4.75(br，2H)，6.55(d，1H)，6.64(dd，1H)，6.80(t，1H)，7.20(d，1H)，7.32-7.56(m，5H)，11.28(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide (330mg, 0.91mmol) with 4-tert-butylbenzenesulfonyl chloride (212mg, 0.91mmol) and chromatography purification (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 130mg (25%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，2.25-2.36(m，6H)，3.27(q，2H)，3.40-3.41(m，4H)，6.98(t，1H)，7.02-7.05(m，2H)，7.29-7.51(m，6H)，7.53(d，2H)，7.57(d，2H)，9.79(s，1H)，11.73(s，1H)。
Example 205- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (423mg, 1.5mmol) with 1-amino-4-methylpiperazine (0.282ml, 1.5mmol) according to the operating manual 1, 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide product was obtained in quantitative yield after chromatographic purification (silica gel, dichloromethane/methanol (0-30% methanol)).
NMR(300MHz，DMSO-d6)：δ2.60(s，3H)，2.85-3.10(m，8H)，7.40-7.60(m，5H)，7.64(d，1H)，8.23(dd，1H)，8.48(d，1H)，9.20(s，1H)，12.60(s，1H)。
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide (830mg, 2.19mmol) with ammonium formate (688mg, 10.91mmol) in the presence of palladium on carbon (83mg) and purification by chromatography (silica gel, dichloromethane/methanol (0-40% methanol)) according to the operating manual 2, 720mg (94%) of 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ2.35(s，3H)，2.60-2.80(m，8H)，6.60-6.70(m，2H)，7.14(d，1H)，7.25-7.35(m，1H)，7.38-7.50(m，4H)，8.42(s，1H)，11.25(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide (720mg, 2.06mmol) with 4-tert-butylbenzenesulfonyl chloride (476mg, 2.06mmol) and chromatography purification (silica gel, dichloromethane/methanol (0-30% methanol)) according to operating manual 3, 170mg (15%) of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methyl-piperazin-1-yl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，2.65(s，3H)，3.03-3.16(m，8H)，7.03(d，1H)，7.16(s，1H)，7.29-7.35(m，4H)，7.43-7.46(m，2H)，7.50-7.60(m，4H)，9.08(s，1H)，9.85(s，1H)，11.80(s，1H)。
Example 215- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridine (pyrindin) -4-ylamide
After reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid (1.0g, 3.54mmol) with 4-aminopyridine (382mg, 3.54mmol) according to guide 1, 1.16g (91%) of the pyridine-4-ylamide product of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid was obtained and used in the following step without further purification.
Following reaction of 5-nitro-3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide (280mg, 0.75mmol) with ammonium formate (237mg, 3.76mmol) in the presence of palladium on carbon (28mg), 110mg (43%) of the pyridine-4-ylamide 5-amino-3-phenyl-1H-indole-2-carboxylate product was obtained according to operating manual 2.
NMR(300MHz，DMSO-d6)：δ5.05(br，2H)，6.70-6.74(m，2H)，7.24(d，1H)，7.33(t，1H)，7.41-7.50(m，6H)，8.41(d，2H)，9.95(s，1H)，11.16(s，1H)。
After reaction of 5-amino-3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide (33mg, 0.10mmol) with 4-tert-butylbenzenesulfonyl chloride (28mg, 0.12mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 17mg (32%) of pyridine-4-ylamide 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid product was obtained.
NMR(300MHz，DMSO-d6)：δ1.26(s，9H)，7.11(dd，1H)，7.18(s，1H)，7.31-7.61(m，12H)，8.43(d，2H)，9.87(s，1H)，10.14(s，1H)，12.00(1H)。
Example 225- (4-tert-Butylbenzylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide
Pyridine-4-ylamide 5-amino-3-phenyl-1-indole-2-carboxylate (270mg, 0.82mmol) and 4-tert-butylbenzaldehyde (146mg, 0.90mmol) were introduced into 34ml of xylene, mixed with titanium tetraethoxide (0.34ml, 1.64mmol) and refluxed for 9 hours. After removal of the solvent and purification of the residue by chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)), 130mg (33%) of pyridin-4-ylamide-5- { [1- (4-tert-butylphenyl) -methylene (methylidene) ] -amino } -3-phenyl-1H-indole-2-carboxylate were obtained.
NMR(300MHz，DMSO-d6)：δ1.30(s，9H)，7.38-7.63(m，12H)，7.88(d，2H)，8.44(d，2H)，8.69(s，1H)，10.17(s，1H)，12.10(s，1H)。
5- { [1- (4-tert-butylphenyl) -methine ] -amino } -3-phenyl-1H-indole-2-carboxylic acid-pyridin-4-ylamide (70mg, 0.15mmol) was dissolved in 5ml of methanol and combined with sodium borohydride (44mg, 1.14mmol) at 0 ℃. Water was added to stop the reaction. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent and chromatography of the residue (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)), 50mg (71%) of pyridin-4-ylamide 5- (4-tert-butylbenzylamino) -3-phenyl-1H-indole-2-carboxylate product was prepared.
NMR(300MHz，DMSO-d6)：δ1.27(s，9H)，4.18(d，2H)，5.91(t，1H)，6.56(d，1H)，6.84(dd，1H)，7.20-7.45(m，10H)，7.48(d，2H)，8.43(d，2H)，9.90(s，1H)，11.56(s，1H)。
Example 235- (4-tert-butylbenzoylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
4-tert-butylbenzoic acid (185mg, 1.04mmol) was introduced into 5ml of DME and combined with thionyl chloride (0.09ml, 1.24mmol) at 0 ℃. After 30 minutes, 5-amino-3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide (500mg, 1.55mmol) was added and then stirred at room temperature for 20 hours. The reaction was stopped by adding 5ml of 10% aqueous citric acid solution and then bringing the solution to the alkaline range with saturated sodium bicarbonate solution. After extraction with ethyl acetate, the combined organic phases are dried over sodium sulfate. After removal of the solvent under reduced pressure and purification by chromatography (silica gel, dichloromethane/methanol (0-10% methanol)), 22mg (3%) of the product were obtained.
NMR(300MHz，DMSO-d6)：δ1.31(s，9H)，2.00(s，6H)，2.22(t，2H)，3.38(q，2H)，7.00(t，1H)，7.38-7.56(m，8H)，7.61(dd，1H)，7.88(d，2H)，7.93(s，1H)，10.08(s，1H)，11.70(s，1H)。
Example 245- (4-tert-Butylsulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 5-nitro-1H-indole-2-carboxylate (500mg, 2.13mmol) with ammonium formate (671mg, 10.65mmol) in the presence of palladium on carbon (50mg) according to the guidelines 2, 330mg (76%) of ethyl 5-amino-1H-indole-2-carboxylate was prepared.
NMR(300MHz，DMSO-d6)：δ1.32(t，3H)，4.30(q，2H)，4.70(br，2H)，6.64-6.72(m，2H)，6.83(d，1H)，7.25(d，1H)，11.40(s，1H)。
After reaction of ethyl 5-amino-1H-indole-2-carboxylate (160mg, 0.78mmol) with 4-tert-butylbenzenesulfonyl chloride (181mg, 0.78mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 3, 270mg (86%) of the product ethyl 5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate were obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.32(t，3H)，4.32(q，2H)，7.02-7.08(m，2H)，7.30(d，1H)，7.35(d，1H)，7.52(d，2H)，7.62(d，2H)，9.97(s，1H)，11.35(s，1H)。
After reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (270mg, 0.67mmol) with N-bromosuccinimide (120mg, 0.67mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 4, 240mg (75%) of the product ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate was obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.32(t，3H)，4.34(q，2H)，7.12-7.18(m，2H)，7.35(d，1H)，7.52(d，2H)，7.65(d，2H)，10.10(s，1H)，12.1(s，1H)。
After reaction of ethyl 3-bromo-5- (4-tert-butylphenylsulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) with 2-chlorophenylboronic acid (186mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 320mg (70%) of the ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.02(t，3H)，1.25(s，9H)，4.10-4.20(m，2H)，6.82(s，1H)，7.14(d，1H)，7.22(dd，1H)，7.32-7.44(m，3H)，7.46-7.58(m，5H)，9.80(s，1H)，12.08(s，1H)。
After reaction (320mg, 0.63mmol) with 11.5ml of a 1M NaOH solution in ethanol/water (1/1), 290mg (95%) of the product 5- (4-tert-butylbenzenesulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid was obtained according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，6.77(d，1H)，7.12(d，1H)，7.25(dd，1H)，7.32-7.44(m，3H)，7.48-7.56(m，5H)，9.80(s，1H)，11.90(s，1H)，12.75(br，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid (290mg, 0.6mmol) with N, N-dimethylethylenediamine (0.066ml, 0.6mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 180mg (54%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.96(s，6H)，2.19(t，2H)，3.18-3.23(m，2H)，6.73-6.74(m，2H)，7.05(dd，1H)，7.28(dd，1H)，7.35(d，1H)，7.40-7.53(m，6H)，7.59(dd，1H)，9.75(s，1H)，11.80(s，1H)。
Example 255- (4-tert-Butylsulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) with 3-chlorophenylboronic acid (186mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 300mg (66%) of the ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.15(t，3H)，1.25(s，9H)，4.22(q，2H)，7.08(s，1H)，7.13(dd，1H)，7.20-7.28(m，1H)，7.34-7.45(m，4H)，7.52(d，2H)，7.60(d，2H)，9.92(s，1H)，12.05(s，1H)。
After reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylate (300mg, 0.58mmol) with 10.9ml of a 1M NaOH solution in ethanol/water (1/1), 240mg (85%) of the product 5- (4-tert-butylbenzenesulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid was obtained according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.23(s，9H)，7.06(s，1H)，7.11(dd，1H)，7.25(d，1H)，7.34-7.45(m，4H)，7.51(d，2H)，7.10(d，2H)，9.89(s，1H)，11.92(s，1H)，12.20(br，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid (240mg, 0.5mmol) with N, N-dimethylethylenediamine (0.054ml, 0.5mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 90mg (33%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product were obtained.
NMR(300MHz，DMSO-d6)：δ1.23(s，9H)，2.06(s，6H)，2.25(t，2H)，3.24(q，2H)，7.04-7.07(m，2H)，7.24(d，1H)，7.32-7.35(m，3H)，7.45-7.59(m，6H)，9.86(s，1H)，11.82(s，1H)。
Example 265- (4-tert-Butylsulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (500mg, 1.05mmol) with 4-chlorophenylboronic acid (236mg, 1.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 396mg (74%) of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.15(t，3H)，1.25(s，9H)，4.22(q，2H)，7.07(s，1H)，7.14(dd，1H)，7.34(d，2H)，7.39(d，1H)，7.44-7.60(m，6H)，9.90(s，1H)，11.98(s，1H)。
After reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylate Azb SV 148(396mg, 0.77mmol) with 14.5ml of a 1M NaOH solution in ethanol/water (1/1), 302mg (81%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid product was obtained according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.23(s，9H)，7.14(s，1H)，7.19(dd，1H)，7.38-7.48(m，3H)，7.47(d，2H)，7.53(d，2H)，7.60(d，2H)，9.89(s，1H)，11.90(s，1H)，12.90(br，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid (335mg, 0.69mmol) with N, N-dimethylethylenediamine (0.08ml, 0.69mmol) and purification by chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 112mg (29%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.03(s，6H)，2.23(t，2H)，3.23(q，2H)，7.01-7.04(m，2H)，7.17(t，1H)，7.29-7.35(m，3H)，7.51-7.60(m，6H)，9.83(s，1H)，11.78(s，1H)。
Example 275- (4-tert-Butylsulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
Following reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) with 2, 4-dichlorophenylboronic acid (227mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 370mg (81%) of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.15(t，3H)，1.23(s，9H)，4.22(q，2H)，6.80(d，1H)，7.14(dd，1H)，7.30(d，1H)，7.40(d，1H)，7.42-7.56(m，5H)，7.70(d，1H)，9.89(s，1H)，12.12(s，1H)。
After reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylate (370mg, 0.68mmol) with 12.6ml of a 1M NaOH solution in ethanol/water (1/1), 330mg (94%) of the product 5- (4-tert-butylbenzenesulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid was obtained according to operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.23(s，9H)，6.78(d，1H)，7.12(dd，1H)，7.30(d，1H)，7.38(d，1H)，7.42-7.58(m，5H)，7.70(d，1H)，9.85(s，1H)，12.02(s，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid (330mg, 0.64mmol) with N, N-dimethylethylenediamine (0.07ml, 0.64mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 170mg (45%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.00(s，6H)，2.21(t，2H)，3.21-3.24(m，2H)，6.73(d，1H)，6.85(t，1H)，7.06(dd，1H)，7.31-7.39(m，2H)，7.47-7.56(m，5H)，7.77(d，1H)，9.79(s，1H)，11.87(s，1H)。
Example 285- (4-tert-Butylsulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) with o-toluoylboronic acid (161mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 250mg (55%) of the ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.02(s，3H)，1.25(s，9H)，1.88(s，3H)，4.11(q，2H)，6.70(d，1H)，7.02(d，1H)，7.12-7.24(m，2H)，7.28-7.32(m，2H)，7.38(d，1H)，7.45-7.53(m，4H)，9.80(s，1H)，11.90(s，1H)。
The product 5- (4-tert-butylbenzenesulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid was obtained in quantitative yield after reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylate (250mg, 0.51mmol) with 9.4ml of a 1M NaOH solution in ethanol/water (1/1) according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.23(s，9H)，1.88(s，3H)，6.68(s，1H)，7.00(d，1H)，7.12(dd，1H)，7.14-7.20(m，1H)，7.24-7.28(m，2H)，7.35(d，1H)，7.50(m，4H)，9.73(s，1H)，11.78(s，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid (320mg, 0.69mmol) with N, N-dimethylethylenediamine (0.076ml, 0.69mmol) and purification by chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 140mg (38%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product were obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.88(s，3H)，1.89(s，6H)，2.08-2.12(m，2H)，3.13-3.18(m，2H)，6.42(t，1H)，6.62(d，1H)，7.04-7.10(m，2H)，7.24-7.30(m，1H)，7.34-7.37(m，3H)，7.49(2d，4H)，9.70(s，1H)，11.71(s，1H)。
Example 295- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (500mg, 1.05mmol) with p-toluoylboronic acid (204mg, 1.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 420mg (82%) of the ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.14(t，3H)，1.24(s，9H)，2.38(s，3H)，4.22(q，2H)，7.05(d，1H)，7.10(dd，1H)，7.18(d，2H)，7.22(d，2H)，7.36(d，1H)，7.52-7.60(m，4H)，9.84(s，1H)，11.82(s，1H)。
After reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3- (4-methylphenyl) -1H-indole-2-carboxylate (420mg, 0.86mmol) with 16 ml of a 1M NaOH solution in ethanol/water (1/1), 340mg (85%) of the product 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid was obtained according to operating manual 5.
NMR(300MHz，DMSO-d6)：δ.1.23(s，9H)，2.34(s，3H)，6.98-7.04(m，2H)，7.12(d，2H)，7.21(d，2H)，7.30(d，1H)，7.50-7.60(m，4H)，9.75(s，1H)，11.48(s，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid (340mg, 0.74mmol) with N, N-dimethylethylenediamine (0.082ml, 0.74mmol) and chromatographic purification (silica gel, amine phase, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 260mg (66%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product were obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.99(s，6H)，2.19(t，2H)，2.38(s，3H)，3.21(q，2H)，6.94-7.03(m，3H)，7.1 7(d，2H)，7.26-7.33(m，3H)，7.51(d，2H)，7.56(d，2H)，9.76(s，1H)，11.67(s，1H)。
Example 305- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid pyridin-4-ylamide
Following the manual 1, after reaction of 5- (4-tert-butylbenzenesulfonyl-amino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid (170mg, 0.37mmol) with 4-aminopyridine (35mg, 0.37mmol), 130mg (65%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，2.36(s，3H)，7.09(dd，1H)，7.16-7.25(m，5H)，7.38(d，1H)，7.49(d，2H)，7.53(d，2H)，7.59(d，2H)，8.43(d，2H)，9.85(s，1H)，10.09(s，1H)，11.94(s，1H)。
Example 315- (4-tert-Butylsulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (500mg, 1.05mmol) with 4-methoxyphenylboronic acid (228mg, 1.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 400mg (75%) of the ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.14(t，3H)，1.24(s，9H)，3.82(s，3H)，4.22(q，2H)，6.96(d，2H)，7.08-7.12(m，2H)，7.24(d，2H)，7.35(d，1H)，7.53(d，2H)，7.64(d，2H)，9.85(s，1H)，11.80(s，1H)。
The product 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid was obtained in quantitative yield after reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylate (420mg, 0.86mmol) with 15ml of a 1M NaOH solution in ethanol/water (1/1) according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，3.82(s，3H)，6.96(d，2H)，7.08-7.12(m，2H)，7.22(d，2H)，7.34(d，1H)，7.52(d，2H)，7.60(d，2H)，9.80(s，1H)，11.70(s，1H)，12.25(br，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid (390mg, 0.82mmol) with N, N-dimethylethylenediamine (0.091ml, 0.82mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) according to the operating manual 1, 200mg (44%) of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product were obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，2.01(s，6H)，2.22(t，2H)，3.22(q，2H)，3.83(s，3H)，6.93(t，1H)，6.98-6.99(m，2H)，7.03(d，2H)，7.21(d，2H)，7.31(d，1H)，7.52(d，2H)，7.56(d，2H)，9.77(s，1H)，11.63(s，1H)。
Example 325- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
After reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (500mg, 1.05mmol) with pyridine-3-boronic acid (184mg, 1.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 280mg (56%) of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylate product was obtained.
NMR(300MHz，DMSO-d6)：δ1.14(t，3H)，1.24(s，9H)，4.21(q，2H)，7.05(d，1H)，7.12(dd，1H)，7.40-7.60(m，6H)，7.72(m，1H)，8.50(d，1H)，8.58(dd，1H)，9.90(s，1H)，12.10(s，1H)。
Following the instructions 5, after reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3-pyridin-3-yl-1H-indole-2-carboxylate (280mg, 0.59mmol) with 11ml of a 1M NaOH solution in ethanol/water (1/1), 260mg (98%) of the 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid product was obtained.
NMR(300MHz，DMSO-d6)：δ1.22(s，9H)，7.08-7.12(m，2H)，7.40(d，1H)，7.52(d，2H)，7.58(d，2H)，7.70-7.76(m，1H)，8.05(d，1H)，8.68(dd，1H)，8.72(d，1H)，9.95(s，1H)，12.12(s，1H)。
After reaction of 5- (4-tert-butylbenzenesulfonyl-amino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid (260mg, 0.58mmol) with N, N-dimethylethylenediamine (0.064ml, 0.58mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) and subsequent recrystallization from dichloromethane, 130mg (43%) of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide product was obtained according to operating manual 1.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，2.06(s，6H)，2.25(t，2H)，3.24(q，2H)，7.04-7.08(m，2H)，7.36(d，1H)，7.44-7.58(m，6H)，7.68-7.71(m，1H)，8.46(d，1H)，8.56(dd，1H)，9.82(s，1H)，11.85(s，1H)。
Example 33: 5- (4-tert-Butylsulfonylamino) -3- (4-hydroxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
5- (4-tert-Butylsulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide (180mg, 0.33mmol) was mixed with 9.70ml of a 1M boron tribromide solution in dichloromethane (9.70mmol) and stirred at room temperature for 20H. The reaction was stopped by adding saturated sodium bicarbonate solution. After extraction with ethyl acetate, the combined organic phases are washed with a 2N sodium hydroxide solution and a saturated sodium chloride solution. After drying over sodium sulfate, removal of the solvent and chromatography (silica gel, dichloromethane/methanol (0-50% methanol)), 60mg (34% of th.) of the product are obtained.
NMR(300MHz，DMSO-d6)：δ1.26(s，9H)，2.00(s，6H)，2.19(t，2H)，3.23(q，2H)，6.81-6.87(m，3H)，6.94(s，1H)，6.99-7.08(m，3H)，7.31(d，1H)，7.50-7.56(AA`BB`，4H)，9.58(s，1H)，9.75(s，1H)，11.58(s，1H)。
Example 34: 5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
Ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylate: after reaction of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) with 3-fluorophenylboronic acid (167mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 290mg (71%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.17(t，3H)，1.24(s，9H)，4.23(q，2H)，7.05-7.65(m，11H)，9.88(s，1H)，12.01(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid:
the product obtained in quantitative yield was obtained after reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3- (3-fluorophenyl) -1H-indole-2-carboxylate (280mg, 0.59mmol) with 9.1ml of a 1M NaOH solution in ethanol/water (1/1) according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，6.98-7.21(m，5H)，7.34-7.46(m，6H)，9.86(s，1H)，11.89(s，1H)，12.90(br，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid (240mg, 0.51mmol) with N, N-dimethylethylenediamine (0.056ml, 0.51mmol) and chromatography (silica gel, dichloromethane/methanol (0-30% methanol)) according to operating manual 1, 160mg (59%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.06(s，6H)，2.26(t，2H)，3.25(q，2H)，7.04-7.13(m，4H)，7.19-7.30(m，2H)，7.35(d，1H)，7.36-7.59(m，5H)，9.81(s，1H)，11.79(s，1H)。
Example 35: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxypropyl) amide
5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid ethyl ester:
after reaction of ethyl 3-bromo-5- (4-tert-butylphenyl-sulfonylamino) -1H-indole-2-carboxylate (2.0g, 4.15mmol) with phenylboronic acid (725mg, 5.9mmol) and chromatography (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)) according to the operating manual 6, 1.35g (68%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.17(t，3H)，1.25(s，9H)，4.19(q，2H)，7.07(d，1H)，7.12(dd，1H)，7.23-7.44(m，6H)，7.50-7.59(m，4H)，9.85(s，1H)，11.90(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid:
after reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3-phenyl-1H-indole-2-carboxylate (1.35g, 2.83mmol) with 55ml of a 1m naoh solution in ethanol/water (1/1), 1.17g (92%) of the product was obtained according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，7.05(d，1H)，7.09(dd，1H)，7.27-7.43(m，6H)，7.55(d，2H)，7.60(d，2H)，9.82(s，1H)，11.80(s，1H)，12.5(br，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxy-propyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with 1-amino-2-propanol (0.035ml, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to the operating manual 1, 33mg (15%) of the product (AP 3795) were obtained.
NMR(300MHz，DMSO-d6)：δ0.94(d，3H)，1.25(s，9H)，2.99-3.23(m，2H)，3.54-3.66(m，1H)，4.60(d，1H)，7.02-7.04(m，2H)，7.16(t，1H)，7.28-7.51(m，6H)，7.52(d，2H)，7.57(d，2H)，9.79(s，1H)，11.71(s，1H)。
Example 36: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxyethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with 2-methoxyethylamine (0.039ml, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to the operating manual 1, 20mg (9%) of the product are obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，3.16(s，3H)，3.31(m，4H)，7.02-7.05(m，2H)，7.20(br，1 H)，7.30-7.48(m，6H)，7.52(d，2H)，7.57(d，2H)，9.79(s，1H)，11.71(s，1H)。
Example 37: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
23mg (11%) of product were obtained after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with ethanolamine (0.027ml, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to operating manual 1.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，3.22(q，2H)，3.35-3.41(m，2H)，4.61(t，1H)，7.02-7.07(m，2H)，7.30-7.47(m，7H)，7.52(d，2H)，7.57(d，2H)，9.79(s，1H)，11.69(s，1H)。
Example 38: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxy-1-methylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with 2-amino-propanol (0.035ml, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to the operating manual 1, 32mg (14%) of the product were obtained.
NMR(300MHz，DMSO-d6)：δ0.96(d，3H)，1.25(s，9H)，3.16-3.33(m，2H)，3.87-3.96(m，1H)，4.63(t，1H)，6.95-7.06(m，3H)，7.28-7.47(m，6H)，7.52(d，2H)，7.57(d，2H)，9.79(s，1H)，11.71(s，1H)。
Example 39: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with N-acetylethylenediamine ((0.047ml, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to the operating manual 1, 42mg (18%) of product are obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.76(s，3H)，3.07-3.10(m，2H)，3.17-3.26(m，2H)，7.03(dd，1H)，7.08(s，1H)，7.27-7.49(m，7H)，7.52(d，2H)，7.57(d，2H)，7.80(t，1H)，9.79(s，1H)，11.66(s，1H)。
Example 40: 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with 4-aminotetrahydropyran (45mg, 0.44mmol) and preparative thin-layer chromatography (silica gel, dichloromethane/methanol 95: 5) according to the operating manual 1, 45mg (19%) of the product are obtained.
NMR(300MHz，DMSO-d6)：δ 1.13-1.44(m，11H)，1.66-1.70(m，2H)，3.30-3.37(m，2H)，3.69-3.73(m，2H)，3.84-3.89(m，1H)，7.03(dd，1H)，7.09(d，1H)，7.29-7.47(m，7H)，7.52(d，2H)，7.58(d，2H)，9.80(s，1H)，11.73(s，1H)。
Example 41: 5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (1-methylpiperidin-4-yl) amide
After reaction of 5- (4-tert-butylphenyl-sulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid (199mg, 0.44mmol) with 4-amino-1-methylpiperidine (51mg, 0.44mmol) and purification by chromatography according to the operating manual 1, 154mg (64%) of product are obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.37-1.53(br，2H)，1.85-1.91(m，2H)，2.60(s，3H)，2.69-2.89(br，2H)，3.07-3.10(br，2H)，3.87-3.89(br，1H)，7.03(dd，1H)，7.12(s，1H)，7.29-7.47(m，7H)，7.52(d，2H)，7.57(d，2H)，9.82(s，1H)，11.71(s，1H)。
Example 42: 5- (4-tert-Butylsulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
Ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylate: after purification of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) and 4-N, N-dimethylaminophenylboronic acid (196mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 90mg (21%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.23(t，3H)，1.25(s，9H)，2.96(s，6H)，4.20(q，2H)，6.74(d，2H)，7.06-7.17(m，4H)，7.34(d，1H)，7.53(d，2H)，7.58(d，2H)，9.81(s，1H)，11.69(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylic acid: the product was obtained in quantitative yield after reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylate (90mg, 0.59mmol) with 3.2ml of a 1M NaOH solution in ethanol/water (1/1) according to the manual 5.
5- (4-tert-butylbenzenesulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (4-N, N-dimethylaminophenyl) -1H-indole-2-carboxylic acid (220mg, 0.45mmol) with N, N-dimethylethylenediamine (0.049ml, 0.45mmol) and purification by chromatography (silica gel, dichloromethane/methanol (0-30% methanol)) according to the operating manual 1, 22mg (9%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.05(s，6H)，2.27(t，2H)，2.97(s，6H)，3.24(q，2H)，6.81(d，2H)，6.89(t，1H)，6.98-7.01(m，2H)，7.11(d，2H)，7.29(d，1H)，7.50-7.57(AA′BB′，4H)，9.74(s，1H)，11.54(s，1H)。
Example 43: 5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid ethyl ester: after purification of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) and 3-methoxyphenylboronic acid (181mg, 1.19mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 250mg (60%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.16(t，3H)，1.24(s，9H)，3.79(s，3H)，4.20(q，2H)，6.84(d，1H)，6.92-6.96(m，2H)，7.11-7.14(m，2H)，7.30-7.42(m，2H)，7.51(d，2H)，7.58(d，2H)，9.88(s，1H)，11.90(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid: 190mg (81%) of product were obtained after reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylate (250mg, 0.49mmol) with 9.1ml of a 1M NaOH solution in ethanol/water (1/1) according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，3.78(s，3H)，6.84(d，1H)，6.90-6.92(m，2H)，7.07-7.12(m，2H)，7.28-7.36(m，2H)，7.51(d，2H)，7.57(d，2H)，9.85(s，1H)，11.79(s，1H)，12.90(br，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (190mg, 0.40mmol) with N, N-dimethylethylenediamine (0.044ml, 0.40mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) according to the operating manual 1, 120mg (55%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.02(s，6H)，2.23(t，2H)，3.23(q，2H)，3.79(s，3H)，6.83-6.97(m，2H)，6.96-7.09(m，4H)，7.31-7.40(m，2H)，7.50(d，2H)，7.56(d，2H)，9.80(br，1H)，11.71(s，1H)。
Example 44: 5- (4-tert-Butylsulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
5- (4-tert-Butylsulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid ethyl ester: after purification of ethyl 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylate (400mg, 0.83mmol) and 3-trifluoromethylphenylboronic acid (226mg, 1.19mmol) by chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to the operating manual 6, 300mg (66%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.16(t，3H)，1.22(s，9H)，4.21(q，2H)，7.09(s，1H)，7.15(dd，1H)，7.41(d，1H)，7.49(d，2H)，7.56-7.59(m，3H)，7.65-7.75(m，3H)，9.95(s，1H)，12.08(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid: 270mg (95%) of product were obtained after reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylate (300mg, 0.55mmol) with 10.2ml of a 1M NaOH solution in ethanol/water (1/1) according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，7.08-7.18(m，2H)，7.40(d，1H)，7.52(d，2H)，7.58-7.75(m，6H)，9.91(s，1H)，11.99(s，1H)，12.40(br，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid (270mg, 0.52mmol) with N, N-dimethylethylenediamine (0.057ml, 0.52mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) according to the operating manual 1, 180mg (59%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.22(s，9H)，2.05(s，6H)，2.25(t，2H)，3.24(q，2H)，7.05-7.09(m，2H)，7.35(d，1H)，7.44-7.51(m，3H)，7.57-7.61(m，4H)，7.66-7.75(m，2H)，9.89(s，1H)，11.86(s，1H)。
Example 45: 5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with ethanolamine (0.019ml, 0.32mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 27mg (16%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，3.24(q，2H)，3.40(q，2H)，4.64(t，1H)，7.05-7.21(m，5H)，7.34(d，1H)，7.42-7.61(m，6H)，9.83(s，1H)，11.79(s，1H)。
Example 46: 5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with 4-aminotetrahydropyran (33mg, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 57mg (33%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.32-1.36(m，2H)，1.67-1.71(m，2H)，3.33-3.38(m，2H+H2O)，3.74-3.78(m，2H)，3.87-3.94(m，1H)，7.04-7.20(m，5H)，7.34(d，1H)，7.43-7.73(m，6H)，9.84(s，1H)，11.81(s，1H)。
Example 47: 5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with N-acetylethylenediamine (0.03ml, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 45mg (26%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.77(s，3H)，3.10(q，2H)，3.20(q，2H)，7.08-7.20(m，5H)，7.35(d，1H)，7.43-7.59(m，5H)，7.76(t，1H)，7.84(t，1H)，9.83(s，1H)，11.76(s，1H)。
Example 48: 5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with 4- (2-aminoethyl) morpholine (0.042ml, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 58mg (32%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.26-2.33(m，6H)，3.27-3.33(m，2H+H2O)，3.44-3.46(m，4H)，7.05-7.15(m，4H)，7.19-7.26(m，2H)，7.34(d，1H)，7.47-7.62(m，5H)，9.82(s，1H)，11.82(s，1H)。
Example 49: 5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (200mg, 0.42mmol) with ethanolamine (0.025ml, 0.42mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 48mg (22%) of product was obtained.
NMR(300 MHz，DMSO-d6)：δ1.24(s，9H)，3.21-3.31(m，2H)，3.36-3.42(m，2H)，3.79(s，3H)，4.62(t，1H)，6.85-6.95(m，3H)，7.04(dd，1H)，7.14(d，1H)，7.29-7.38(m，3H)，7.50(d，2H)，7.57(d，2H)，9.82(s，1H)，11.70(s，1H)。
Example 50: 5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (200mg, 0.42mmol) with N-acetylethylenediamine (0.04ml, 0.42mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 110mg (47%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.76(s，3H)，3.07-3.11(m，2H)，3.18-3.24(m，2H)，3.79(s，3H)，6.85-6.95(m，3H)，7.04(dd，1H)，7.17(s，1H)，7.31-7.37(m，2H)，7.50-7.62(m，5H)，7.81(t，1H)，9.83(s，1H)，11.68(s，1H)。
Example 51: 5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid (210mg, 0.47mmol) with N-acetylethylenediamine (0.045ml, 0.47mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 66mg (26%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.25(s，9H)，1.78(s，3H)，3.09-3.14(m，2H)，3.16-3.24(m，2H)，7.06-7.09(m，2H)，7.37(d，1H)，7.44(dd，1H)，7.52(d，2H)，7.57(d，2H)，7.67-7.69(m，1H)，7.86(t，1H)，7.93(t，1H)，8.47(d，1H)，8.53(dd，1H)，9.83(s，1H)，11.85(s，1H)。
Example 52: 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid (140mg, 0.31mmol) with 4-aminotetrahydropyran (32mg, 0.31mmol) and chromatography (silica gel, dichloromethane/methanol (0-50% methanol)) according to operating manual 1, 30mg (18%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.34-1.39(m，2H)，1.67-1.71(m，2H)，3.32-3038(m，2H+H2O)，3.76-3.80(m，2H)，3.87-3.97(m，1H)，7.07(dd，1H)，7.11(s，1H)，7.37(d，1H)，7.45(dd，1H)，7.52(d，2H)，7.58(d，2H)，7.66-7.69(m，1H)，7.82(d，1H)，8.46(d，1H)，8.51(d，1H)，9.83(s，1H)，11.87(s，1H)。
Example 53: 5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid ethyl ester:
after purification of 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylic acid ethyl ester (500mg, 1.05mmol) with pyridine-4-boronic acid (184mg, 1.5mmol 1) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to operating manual 6, 310mg (62%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.18(t，3H)，1.24(s，9H)，4.23(q，2H)，7.11-7.16(m，2H)，7.32(d，2H)，7.42(d，1H)，7.53(d，2H)，7.59(d，2H)，8.62(d，2H)，9.95(s，1H)，12.17(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid:
after reaction of ethyl 5- (4-tert-butylbenzenesulfonyl-amino) -3-pyridin-4-yl-1H-indole-2-carboxylate (310mg, 0.65mmol) with 12ml of a 1M NaOH solution in ethanol/water (1/1), 290mg (99%) of the product was obtained according to the operating manual 5.
NMR (300MHz, DMSO-d 6): δ 1.24(s, 9H), 7.10(dd, 1H), 7.20(d, 1H), 7.41(d, 1H), 7.52-7.63(m, 6H), 8.73(d, 2H), 9.99(s, 1H), 12.24(s, 1H). 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-acetyl-aminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid (180mg, 0.4mmol) with N-acetylethylenediamine (0.038ml, 0.4mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 22mg (10%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.77(s，3H)，3.12-3.16(m，2H)，3.20-3.27(m，2H)，7.04(dd，1H)，7.19(d，1H)，7.27(d，2H)，7.36(d，1H)，7.54(d，2H)，7.59(d，2H)，7.89(t，1H)，8.09(t，1H)，8.58(d，2H)，9.95(br，1H)，11.97(br，1H)。
Example 54: 5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid (145mg, 0.32mmol) with 4- (2-aminoethyl) morpholine (0.042ml, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 58mg (32%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.30-2.38(m，6H)，3.30-3.34(m，2H+H2O)，3.45-3.47(m，4H)，7.05(dd，1H)，7.16(d，1H)，7.30(d，2H)，7.35(d，1H)，7.49-7.65(m，5H)，8.61(d，2H)，9.89(br，1H)，11.97(br，1H)。
Example 55: 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid (145mg, 0.32mmol) with 4-aminotetrahydropyran (33mg, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 90mg (53%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.31-1.49(m，2H)，1.69-1.74(m，2H)，3.39-3.50(m，2H)，3.79-3.82(m，2H)，3.89-4.00(m，1H)，7.06(dd，1H)，7.24(d，1H)，7.27(d，2H)，7.37(d，1H)，7.54(d，2H)，7.60(d，2H)，8.03(d，1H)，8.57(d，2H)，9.87(s，1H)，11.96(s，1H)。
Example 56: 5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
Ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylate: after 3-bromo-5- (4-tert-butylbenzenesulfonylamino) -1H-indole-2-carboxylic acid ethyl ester (500mg, 1.05mmol) and m-toluoylboronic acid (204mg, 1.5mmol) and chromatography (silica gel, hexane/ethyl acetate (0-100% ethyl acetate)) according to guide 6, 330mg (67%) of the product was obtained.
NMR(300MHz，DMSO-d6)：δ1.18(t，3H)，1.24(s，9H)，2.55(s，3H)，4.19(q，2H)，7.06-7.21(m，5H)，7.30(t，1H)，7.37(d，1H)，7.52(d，2H)，7.58(d，2H)，9.88(s，1H)，11.88(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid: after reaction of ethyl 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylate (330mg, 0.67mmol) with 12ml of a 1M NaOH solution in ethanol/water (1/1), 300mg (97%) of the product was obtained according to the operating manual 5.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.35(s，3H)，7.05-7.15(m，5H)，7.29(t，1H)，7.34(d，1H)，7.5 1(d，2H)，7.57(d，2H)，9.85(s，1H)，11.77(s，1H)。
5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide: after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid (210mg, 0.45mmol) with N-acetylethylenediamine (0.043ml, 0.45mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 120mg (49%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，1.75(s，3H)，2.36(s，3H)，3.06-3.10(m，2H)，3.19-3.23(m，2H)，7.02-7.09(m，2H)，7.13-7.23(m，3H)，7.33-7.35(m，2H)，7.41(t，1H)，7.52(d，2H)，7.57(d，2H)，7.81(t，1H)，9.82(s，1H)，11.65(s，1H)。
Example 57: 5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
22mg (10%) of product were obtained after reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid (210mg, 0.45mmol) with ethanolamine (0.027ml, 0.45mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to guide 1.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.36(s，3H)，3.16-3.26(m，2H)，3.35-3.39(m，2H)，4.62(t，1H)，7.02-7.09(m，3H)，7.17-7.25(m，3H)，7.31-7.36(m，2H)，7.52(d，2H)，7.58(d，2H)，9.81(s，1H)，11.68(s，1H)。
Example 58: 5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with 4- (2-aminoethyl) morpholine (0.042ml, 0.32mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 90mg (49%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.13-2.19(m，4H)，2.27(t，2H)，2.37(s，3H)，3.27-3.39(m，2H)，3.39(br，4H)，6.92(t，1H)，7.02-7.10(m，3H)，7.15(s，1H)，7.22(d，1H)，7.34-7.40(m，2H)，7.52(d，2H)，7.57(d，2H)，9.80(s，1H)，11.70(s，1H)。
Example 59: 5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid (150mg, 0.32mmol) with 4-aminotetrahydropyran (33mg, 0.32mmol) and purification by HPLC, according to the operating manual 1, 50mg (29%) of the product are obtained.
NMR(300MHz，DMSO-d6)：δ1.20-1.35(m，11H)，1.63-1.71(m，2H)，2.36(s，3H)，3.33-3.38(m，2H+H2O)，3.68-3.72(m，2H)，3.87-3.99(m，1H)，7.02(dd，1H)，7.08-7.11(m，2H)，7.17-7.20(m，3H)，7.30-7.37(m，2H)，7.51(d，2H)，7.57(d，2H)，9.83(s，1H)，11.70(s，1H)。
Example 60: 5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid (140mg, 0.31mmol) with 4- (2-aminoethyl) morpholine (0.04ml, 0.31mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-50% methanol)) according to operating manual 1, 30mg (17%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.31-2.40(m，6H)，3.48(br，4H)，3.59-3.60(m，2H)，7.05-7.11(m，2H)，7.37(d，1H)，7.46-7.59(m，6H)，7.70(d，1H)，8.50(d，1H)，8.55(dd，1H)，9.83(s，1H)，11.86(s，1H)。
Example 61: 5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (125mg, 0.26mmol) with 4-aminotetrahydropyran (29mg, 0.29mmol) and chromatography (silica gel, dichloromethane/methanol (0-20% methanol)) according to operating manual 1, 110mg (75%) of product was obtained.
NMR(300MHz，DMSO-d6)：δ1.24-1036(m，11H)，1.67-1.70(m，2H)，3.31-3.38(m，2H+H2O)，3.69-3.79(m，2H)，3.79(s，3H)，3.86-3.98(m，1H)，6.86-6.96(m，3H)，7.04(dd，1H)，7.16(d，1H)，7.31-7.38(m，3H)，7.51(d，2H)，7.57(d，2H)，9.83(s，1H)，11.73(s，1H)。
Example 62: 5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
After reaction of 5- (4-tert-butylbenzenesulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid (125mg, 0.26mmol) with 4- (2-aminoethyl) morpholine (0.034ml, 0.26mmol) and chromatographic purification (silica gel, dichloromethane/methanol (0-20% methanol)) according to the operating manual 1, 60mg (39%) of product were obtained.
NMR(300MHz，DMSO-d6)：δ1.24(s，9H)，2.21(br，4H)，2.28(t，2H)，3.26-3.30(m，2H+H2O)，3.40(br，4H)，3.79(s，3H)，6.86-6.90(m，2H)，6.97-7.08(m，4H)，7.31-7.42(m，2H)，7.51(d，2H)，7.56(d，2H)，9.81(d，1H)，11.72(s，1H)。
The following compounds were prepared in analogy to the above examples:
biological examples:
example 1: sAC-assay
Soluble, sperm-specific adenylate cyclase catalyzes the reaction of Adenosine Triphosphate (ATP) to cyclic adenosine triphosphate (cAMP) and pyrophosphate, in a suitable buffer system. The free cAMP produced in this manner is then used in a competitive assay procedure, in which the binding of europium krypton (Eu K) -labeled anti-cAMP antibodies (anti-cAMP-Eu K-AK) to cAMP-molecule labeled, modified allophycocyanine-1 molecules (cAMP-XL 665) is prevented. In the absence of exogenous cAMP, it results in Fluorescence Resonance Energy Transfer (FRET) between anti-cAMP-Eu [ K ] -AK (FRET-donor) and cAMP-XL665 (FRET-acceptor) molecules upon excitation at 335 nm. The process was quantified at different times (time-resolved) based on the emission of the FRET-acceptor XL665(665nm and 620 nm). The decrease in signal (measured as the wave ratio (waveratio); calculated formula: [ (E665nm/E620 nm). times.10000 ]) can be attributed to the presence of cAMP and thus to the activity of sAC.
First, 1.5. mu.l of test substance (in 30% DMSO) (only 30% DMSO in a solvent control) was introduced into each well of a 384-well test plate (polystyrene; 384, NV). Then, 10. mu.l of diluted sAC enzyme solution (zymogen solution in 300mmol NaCl, 10% glycerol, pH 7.6; in 1.0mmol MnCl) was supplemented (recover)20.2% BSA; intermediate and final enzyme dilutions were made in 50mmol of tris at pH 7.5 in water at a) 1: 10 and b) 1: 2000, respectively). Add 5. mu.l ATP substrate solution (200. mu. mol in H)2ATP in O) to start the enzyme reaction and to complete the reaction after incubation (25 min at room temperature) by adding 5 μ l of stop solution (200 μmol EDTA in PBS). Finally, the total volume of the whole reaction was adjusted to 91.5. mu.l by adding 70. mu.l of PBS.
Then, 8. mu.l of test solution 1 was introduced into the well of a 384-well measurement plate (measurement plate: polystyrene; 384, SV-black; test solution 1: 50. mu.l of cAMP-XL 665; 950. mu.l of regeneration buffer; 2200. mu.l of PBS; cAMP-XL 665: according to Cis Bio Kit:#62AMPPEC Specification 5ml H2Adding O into the freeze-dried product to prepare; and (3) storage: aliquoted at-80 ℃). Then, 3. mu.l of the sample was taken out of 91.5. mu.l and added to the corresponding well of the test plate. Finally, 8. mu.l of detection solution 2 (detection solution 2: 50. mu.l of anti-cAMP-Eu [ K ]]-AK; 950. mu.l of regeneration buffer; 2200 μ l of PBS; anti-cAMP-Eu [ K ]]-AK: according to the CisBio Kit: preparation as specified in #62AMPPEC specification; and (3) storage: aliquoted at-80 ℃).
After an additional 90 minutes of incubation at room temperature, the HTRF results were measured with a Packard Discovery or a RubiStarHTRF measuring device (delay: 50. mu.s; integration time: 400. mu.s). Example 2 isolation of human sperm from semen and sperm capacitation
2.1. Separation of sperm
Human sperm derived from seminal fluid were purified by a two-layer gradient system (two-layer gradient system) based on colloidal silica particles (trade name: Percoll or ISolate).
For each semen, 2.5ml of each preheated lower layer ("90% isocyanate lower layer," Irvine corporation) was introduced into a 15ml centrifuge tube (conical, plastic), carefully covered with 2.5ml of preheated upper layer (50% isocyanate upper layer, "Irvine corporation), and held in a 37 ℃ water bath (hold back) < 1 hour. Care was taken to coat up to 3ml of normal (in terms of sperm count, motility and liquefaction) semen on the gradient. Sperm were settled at 1000 Xg for 25 minutes at room temperature. Two layers were drawn with a glass capillary to just above the sperm particles (sperm pellets). To wash off the Isolate gradient, the sperm particles resuspended at about 200. mu.l were transferred to a column containing 12ml of mHTF medium (4mmol of NaHCO)3(ii) a 0.01% BSA; 37 ℃) in plastic tubes and the sperm were settled at 1000 Xg for 20 minutes. The medium was pumped out just above the particles and with a mHTF medium (4mmol of NaHCO)3(ii) a 0.01% BSA; 37 ℃ C.) was adjusted to 1000. mu.l. The number of spermatozoa is determined in a Neubauer counting chamber and optionally in a mHTF medium (4mmol of NaHCO)3(ii) a 0.01% BSA; 37 ℃ C.) adjusted to 4X 106 sperm/150. mu.l for subsequent sperm capacitation.
2.2. Capacitation of sperm
If the effect of the test substance in the acrosome reaction is to be examined, the sperm must be pre-incubated with the test substance. Pre-incubation (incubation for 15 minutes in an incubator at 37 ℃) is necessary to allow the test substance to penetrate into the sperm before the sperm starts to capacitate, i.e. to achieve pre-saturation of the binding sites in the sperm, particularly in the case of substances that do not cross the cell membrane well. In addition, pre-incubation is necessary because an increase in BSA concentration may result in a decrease in the concentration of effective test substance in the formulation when capacitated by high lipid binding of BSA.
The test substances were dissolved in DMSO and used in mHTF medium (4mmol of NaHCO)3(ii) a 0.01% BSA; 37 ℃) so that the DMSO concentration is 0.5% in the final sperm-energized 400. mu.l preparation. Each 150. mu.l of the above-mentioned conditioned test substance solution was pipetted into 150. mu.l of the sperm suspension and preincubated for 15 minutes at 37 ℃. By adding 100. mu.l of mHTF medium (88mmol of NaHCO)3(ii) a 4% BSA; sperm capacitation was initiated at 37 ℃. In the final 400. mu.l sperm capacitation formulation, the sperm concentration was 10X 106/ml, the bicarbonate concentration was 4mmol, and the BSA concentration was 1%. Sperm capacitation was performed in an incubator at 37 ℃ for 3 hours.
To complete sperm capacitation, each formulation (400. mu.l each) was completely transferred to a container with 1.5mlmHTF (4mmol of NaHCO)3(ii) a 37 ℃) in a 15ml sample tube, centrifugation at 1000 Xg for 5 minutes and removal of the supernatant. With this step, a large amount of protein as well as the test substance is removed.
Example 3 Flow cytometry assay of acrosome reaction
3.1. Introduction to acrosome reaction by ionophore treatment with CD46-FITC staining
Acrosomal Reaction (AR) of the sperm is triggered by the binding of the sperm to the Zona Pellucida (ZP). In this case, the release of the enzyme from the acrosome makes it possible for the sperm to penetrate the oocyte via the ZP. In the case of AR, in sperm, it results in incomplete fusion of the plasma membrane with the acrosomal outer membrane (OAM). The head of the last sperm cell is limited to the Inner Acrosomal Membrane (IAM). The CD 46-antigen was detectable only on IAM.
Acrosomal responses can be induced in vitro on capacitated sperm with the appropriate concentration of calcium-ionophore A23187, but not on non-capacitated sperm or sperm inhibited by the test substance. Acrosomally-reacted sperm were distinguished in a flow cytometer from IAM unexposed intact acrosome (acrosome-intact) sperm by means of an FITC-labeled anti-CD 46 antibody (Pharmingen) against IAM. Dead cells, dead sperm, can be distinguished from live sperm by simultaneous staining with the DNA dye ethidium bromide dimer (EhD), which only stains DNA membrane defects.
Since the ionophore dilution appeared to be very unstable in trigger AR and had to be mixed with the CD46-FITC solution for simultaneous staining, the solution could not be prepared before the start of the test but had to be prepared during the preparation of the (working-up) capacitative formulation.
The sperm particles were resuspended in the residual supernatant and washed with 450. mu.l of mHTF (4mmol of NaHCO) in a water bath (37 ℃)3(ii) a 0.01% BSA; diluted at 37 ℃). A100. mu.l aliquot of the sperm suspension was transferred into a prepared FACS-flow tube sample (in a water bath). Mu.l of a solution containing ionophore and FITC-labeled anti-CD 46 antibody was pipetted into the sperm. The final concentration was in mHTF (4mmol of NaHCO)3(ii) a 0.01% BSA; 37 ℃) with 800nmol of ionophore and 1: 125 dilution of anti-CD 46 antibody. The sperm were incubated therein in a water bath at 37 ℃ for 30 minutes in the absence of light.
The incubation was stopped by adding 3.5ml PBS [ 0.1% BSA ]/formulation, followed by centrifugation at 700 Xg (room temperature) for 5 minutes and subsequent aspiration of the supernatant. After centrifugation, the samples were incubated on a hot plate until the measurement was completed.
EhD staining (for differentiation of dead/live acrosome-reacted sperm).
After aspiration, the sperm particles were mixed with 500. mu.l portions of freshly prepared EhD solution (150nmol EhD in PBS [ w/o BSA ]; 37 ℃). The sample can then be measured in a flow cytometer (BD Facs Calibur). The measurement was carried out at the laser excitation wavelength 488 nm; 10,000 sperm were detected for each measurement. Acrosome-reacted sperm were measured at 530nm with CD46-FITC in FL-1 filters. Dead sperm were measured by EhD-DNA-staining at 634nm in FL-2 filters. The measurement channels are first appropriately calibrated with respect to each other.
3.3 evaluation:
a very uniform population of sperm cells was selected in the FSC-H (Forward Scattering) of SSC-H (side scatter) dot blot (Dotblot). Since two-color fluorescent staining was applied, evaluation was performed by means of quadrant analysis (quadrantanalysis) of FL-2(FITC-CD46, Y-axis) dot blot (Dotblot) with FL-1(EhD, X-axis) of the sperm population selected by FSC versus SSC Dotblot.
| Quadrant of FL-1 vs FL-2 dot blot | Dyeing process | Analysis of | |
| Q1＝UL | Upper left of | EhD only | Dead, acrosome-free sperm |
| Q2＝UR | Upper right part | EhD and FITC-CD46 | Dead, acrosomally reacted sperm |
| Q3＝LL | Left lower part | Undyed | Viable, acrosome-free sperm |
| Q4＝LR | Lower right | FITC-CD46 alone | Viable, acrosomally reacted sperm |
Only live sperm of Q3 and Q4 were used and their total number was set equal to 100% to calculate the% acrosomal-reacted sperm induced (═ IAR [% ]). The IAR is then calculated as follows:
img id="idf0086" file="A20058003226501481.GIF" wi="136" he="37" img-content="drawing" img-format="GIF"/
some sperm had spontaneously undergone acrosome reaction without addition of ionophore ("SAR%"). Thus, control measurements were always also performed with identically treated sperm cells without ionophore added. SAR is calculated similarly to IAR. The acrosome reaction actually triggered by the ionophore (═ ARIC% ]) was calculated as the difference: ARIC ═ IAR-SAR.
Positive capacitation control (═ with NaHCO containing 25mmol without test substance)3mHTF medium incubation of 1% BSA) was set at 100% for analysis of the effect of our inhibitors on sAC-mediated sperm capacitation as follows (measuring the ability of sperm to undergo ionophore-induced acrosome reaction). The ability of sperm mixed with the test substance to undergo acrosome reaction is characterized relative to the maximum acrosome reaction.
The materials used were:
human tubule fluid (Irvine Scientific), Dulbecco phosphate-buffered salt (Gibco) with Ca2+、Mg2+, 1g/l D-glucose, 36mg/l sodium pyruvate, w/o phenolsulfonphthalein, w/o NaHCO3) (ii) a Bovine serum albumin, Fraction V (Fluka corporation); dimethyl sulfoxide (DMSO), anhydrous (Merck corporation); sodium bicarbonate 7.5% solution (893mmol) (Irvine Scientific Co.); separation gradient (Irvine Scientific); ionophore-A23187 free acid (Calbiochem Corp.); ethidium bromide dimer (EhD) (Molecular Probe), murine anti-human CD 46: FITC (Pharmingen).
Reference documents:
J.W.Carver-Ward，Human Reproduction Vol.11，No.9，pp：1923 ff，1996 High Fertilization Prediction by FlowCytometric Analysis of the CD46Antigen on the Inner Acrosomal Membrane of Spermatozoa
O.J.D`Cruz，G.G.Haas，Fertility and Sterility Vol.65，No.4，pp：843ff，1996 Fluorescence-Labeled Fucolectins are Superior Markers for FlowCytometric Quantitation of the Sperm Acrosome Reaction
E.Nieschlag，H.M.Behre，Andrologie[Andrology]，Springer Verlag1996
biological data
| # | IC50[M] | Solubility (g/l) |
| 1 | 3.4E-6 | 0.001 |
| 2 | 4.9E-6 | 0.001 |
| 3 | 2.0E-6 | 0.001 |
| 6 | 3.7E-7 | 0.0001 |
| 9 | 5.3E-6 | 0.0015 |
| 10 | 2.2E-6 | 0.0021 |
| 19 | 1.5E-7 | 0.004 |
| 20 | 2.6E-6 | |
| 21 | 3.4E-6 | 0.0001 |
| 24 | 1.6E-6 | 0.008 |
| 25 | 6.3E-7 | 0.005 |
| 26 | 9.9E-6 | 0.003 |
| 28 | 2.7E-6 | 0.005 |
| 29 | 2E-6 | 0.007 |
| 31 | 1.2E-6 | 0.007 |
| 32 | 1.3E-6 | 0.055 |
| 37 | 7E-8 | 0.013 |
| 40 | 8.6E-8 | 0.005 |
Comparison with known Compounds
The compounds of the invention were compared to known compounds in an enzymatic assay. The results are as follows.
From the table, it can be seen that50Expression of values for inhibition of soluble adenylate cyclase, the compounds of the invention sometimes have 150 × higher activity than known catechol estrogens (OH-estradiol). Catecholic estrogens are toxic and therefore the compounds of the present invention are far superior to the known compounds. The compounds of the invention are also about 100 x more effective than those produced by Zippin.
Claims (19)
1. A compound of formula I:
wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl radicalhalo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-alkyl radical、C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents C which is optionally substituted in one or more positions in the same or different manner by halogen, optionally substituted in one or more positions1-C6-alkyl or C1-C6Acyl or by C1-C6Alkoxy, hydroxy, cyano, CO2-(C1-C6Alkyl), N- (C)1-C6-alkyl groups)2、CO-NR4R5Or by CF3Substituted C6-C12-aryl, representing optionally halogen, optionally in one or more positions, in the same or different manner, by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, hydroxy, cyano, CO2-(C1-C6Alkyl), N- (C)1-C6-alkyl groups)2、CO-NR4R5Or by CF3Substituted C5-C12-heteroaryl or represents halogen, CF, optionally in one or more positions, in the same or different manner3Hydroxy, cyano, CO2-(C1-C6Alkyl), C1-C6Alkyl radical, C1-C6-acyl, N- (C)1-C6-alkyl groups)2、CO-NR4R5Or C1-C6-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, optionally substituted in one or more positions in the same or different manner by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, optionally substituted in one or more positions in the same or different manner by C1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5-to 8-membered ring which together may contain further heteroatoms, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents a nitrogen atom or a nitrogen atom,
n represents 0 to 4.
2. The compound of claim 1, wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12-heteroaryl, representing optionally in one or more positions, in the same or different manner, by chlorine and/or fluorine,CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12-aryl or represents optionally atOne or more positions being halogen, C, in the same or different ways1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5-to 8-membered ring which together may contain further heteroatoms, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
3. A compound according to claim 1 or 2, wherein
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo or-O-CF3、-SO2-CH3And in the para-position,
R3represents the following group
R4Represents hydrogen or- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x representsSulfonyl, carbonyl or represents CH2，
Y represents a carbonyl group or represents (CH)2)n，
Z represents nitrogen or represents
n is 1 to 2.
4. The compound of claim 1, wherein
R1Represents hydrogen, tert-butyl, cyano, bromine or represents-O-CF3or-SO2-CH3，
R2Represents tert-butyl, cyano, bromo, or represents-O-CF3or-SO2-CH3And are and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or cyano radicals takeSubstituted C5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
5. The compound of claim 1, wherein
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo, or-O-CF3or-SO2-CH3And in the para position, and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
6. The compound of claim 1, wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy radicalRadical, cyano radical, hydroxy radical, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different waysHalogen, C1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C6-acyl group, C1-C6Alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3Or C substituted by cyano5-C12Heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5 to 8 membered ring which may contain other hetero atoms in common, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents a nitrogen atom or a nitrogen atom,
n represents 0 to 4.
7. The compound of claim 1, wherein
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo, or represents-O-CF3or-SO2-CH3And in the para position, and
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen or represents- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x represents sulfonyl, carbonyl or CH2，
Y represents a carbonyl group, or represents (CH)2)n，
Z represents nitrogen or represents
n represents 1 to 2.
8. The compound of claim 1, wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl-yl, or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents the following groups:
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl radical、C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5A 5 to 8 membered ring which may contain other hetero atoms in common, and
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
9. The compound of claim 1, wherein
R1Represents hydrogen, and is selected from the group consisting of,
R2represents tert-butyl, cyano, bromo or represents-O-CF3or-SO2-CH3And in the para position, and
R3represents the following groups:
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
x represents sulfonyl, carbonyl or CH2，
Y represents a carbonyl group or represents (CH)2)n，
Z represents nitrogen or represents
n represents 1 to 2.
10. The compound of claim 1, wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted byC5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen or- (CH)2)n-N-(CH3)2、-(CH2)2-CH3、-(CH2)2-NH-COCH3、-(CH2)-CHCH3-OH、-(CH2)2-O-CH3、-(CH2)2-OH、-CHCH3-CH2-OH、
R5Represents hydrogen, and is selected from the group consisting of,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen, and
n represents 0 to 2.
11. The compound of claim 1, wherein
R1Represents hydrogen, halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl radical-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6Alkyl optionally interrupted in the same or different manner by oxygen, sulfur or nitrogen in one or more positions, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R2represents halogen, CF3C which is optionally polysaturated and optionally polysubstituted3-C6-cycloalkyl or represents C1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3In which C is1-C6Alkyl radical, C1-C6-aryl, C1-C6-acyl, halo-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6Alkyl radical, C1-C6-alkyl-C1-C6-acyl group, C1-C6-acyl-C1-C6-acyl group, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6The alkyl group may be optionallyInterrupted by oxygen, sulfur or nitrogen in one or more positions in the same or different manner, or represents sulfonyl-C1-C6-an alkyl, sulfonamide or cyano group,
R3represents optionally halogen, C in one or more positions, in the same or different manner1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C6-C12-aryl, representing C, optionally substituted in one or more positions, in the same or different manner, by chlorine and/or fluorine1-C6Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, cyano, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or CF3Substituted C5-C12Heteroaryl, representing a residue which may optionally be substituted in one or more positions in the same or different manner by chlorine and/or fluorine, CF3Cyano, C1-C3Alkyl radical, C1-C3-acyl, hydroxy, N- (CH)3)2、CO2-(C1-C3Alkyl), CO-NR4R5Or C1-C3-alkoxy-substituted C3-C6-a cycloalkyl group,
R4represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12-aryl or representsOptionally halogen, C in the same or different manner at one or more positions1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R5represents hydrogen, represents optionally substituted in one or more positions by C in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3-alkoxy or CF3Substituted C3-C6-cycloalkyl, representing optionally in one or more positions, in the same or different manner, by halogen, C1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano6-C12Aryl or represents halogen, C, optionally in one or more positions, in the same or different manner1-C3Alkyl radical, C1-C3-acyl group, C1-C3Alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3Or C substituted by cyano5-C12-heteroaryl or represents C which may be substituted in any desired manner1-C6-an alkyl group,
R4and R5The common constituent may comprise 5 to 8 membered rings which may contain further heteroatoms,
x represents sulfonyl, (CH)2)nOr a carbonyl group, or a mixture of two or more thereof,
y represents a carbonyl group or (CH)2)n，
Z represents nitrogen or represents
n represents 0 to 2.
12. A compound according to claims 1-11 selected from the group comprising:
1.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclopropylamide
2.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-3-ylamide
3.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid cyclohexanamide
4.4-tert-butyl-N- [ 3-phenyl-2- (pyrrolidine-1-carbonyl) -1H-indol-5-yl ] -benzenesulfonamide
4-tert-butyl-N- [2- (morpholine-4-carbonyl) -3-phenyl-1H-indol-5-yl ] -benzene-sulfonamide
6.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
7.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
8.5- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
9.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
10.5- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
11.5- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-propionamide
12.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
13.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
14.5- (4-Bromobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
15.5- (4- (trifluoromethoxy) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid-phenylamide
16.5- (4- (methylsulfonyl) benzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid phenylamide
17.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide
18.5- (4-Cyanobenzenesulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-2-ylamide
19.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
20.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methylpiperazin-1-yl) amide
21.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide
22.5- (4-tert-butylbenzylamino) -3-phenyl-1H-indole-2-carboxylic acid pyridin-4-ylamide
5- (4-tert-Butylcarbonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
24.5- (4-tert-Butylsulfonylamino) -3- (2-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
25.5- (4-tert-Butylsulfonylamino) -3- (3-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
26.5- (4-tert-Butylsulfonylamino) -3- (4-chlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
27.5- (4-tert-Butylsulfonylamino) -3- (2, 4-dichlorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
28.5- (4-tert-Butylsulfonylamino) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
29.5- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
30.5- (4-tert-Butylsulfonylamino) -3- (4-methylphenyl) -1H-indole-2-carboxylic acid pyridin-4-ylamide
31.5- (4-tert-Butylsulfonylamino) -3- (4-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
32.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
33.5- (4-tert-Butylsulfonylamino) -3- (4-hydroxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
34.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
35.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxypropyl) amide
36.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxyethyl) amide
37.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
38.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-hydroxy-1-methylethyl) amide
39.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
40.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
41.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid- (1-methylpiperidin-4-yl) amide
5- (4-tert-Butylsulfonylamino) -3- (4-N, N-dimethylamino-phenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
43.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
44.5- (4-tert-Butylsulfonylamino) -3- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid- (2-dimethylaminoethyl) amide
45.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
46.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
47.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-acetylamino) amide
48.5- (4-tert-Butylsulfonylamino) -3- (3-fluorophenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
49.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
50.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
51.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
52.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
53.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
54.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
55.5- (4-tert-Butylsulfonylamino) -3-pyridin-4-yl-1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
56.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-acetylaminoethyl) amide
57.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-hydroxyethyl) amide
58.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
59.5- (4-tert-Butylsulfonylamino) -3- (3-methylphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
60.5- (4-tert-Butylsulfonylamino) -3-pyridin-3-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
61.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (tetrahydropyran-4-yl) amide
62.5- (4-tert-Butylsulfonylamino) -3- (3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-ylethyl) amide
63.5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carboxylic acid piperidin-4-ylamide
64.4- { [5- (4-tert-Butylsulfonylamino) -3-phenyl-1H-indole-2-carbonyl ] -amino } piperidine-1-carboxylic acid tert-butyl ester
65.5- (4-tert-butyl-phenylsulfonyl-amino) -3-naphthalen-1-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
66.5- (4-tert-butyl-phenylsulfonyl-amino) -3-m-tolyl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
67.5- (4-tert-butyl-phenylsulfonyl-amino) -3-thiophen-2-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
68.5- (4-tert-butyl-phenylsulfonyl-amino) -3-thiophen-3-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
69.3-benzofuran-2-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
70.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (5-chloro-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
71.5- (4-tert-butyl-phenylsulfonyl-amino) -3-furan-2-yl-1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
72.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-fluoro-4-methoxy-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
73.3-benzo [1, 3] dioxol-5-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
74.3- (4-acetyl-phenyl) -5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
3- (3-acetyl-phenyl) -5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
76.3-benzo [ b ] thiophen-2-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
77.3-benzo [ b ] thiophen-3-yl-5- (4-tert-butyl-benzenesulfonylamino) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
78.5- (4-tert-butyl-benzenesulfonylamino) -3- (5-methyl-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
79.3- [5- (4-tert-butyl-phenylsulfonyl-amino) -2- (2-morpholin-4-yl-ethylcarbamoyl) -1H-indol-3-yl ] -benzoic acid methyl ester
80.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2-fluoro-3-methoxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
81.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-chloro-4-methyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
82.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 4-dimethoxy-pyrimidin-5-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
83.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 5-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
84.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 4-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
85.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 3-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
86.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2, 6-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
87.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-hydroxy-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
88.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-hydroxyphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
89.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-fluoro-4-methylphenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
90.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-trifluoromethyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
91.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-cyanomethyl-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
5- (4-tert-butyl-phenylsulfonyl-amino) -1H, 1 'H- [3, 4' ] biindole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
93.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-cyano-4-fluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
94.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (2-fluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
95.5- (4-tert-butyl-benzenesulfonylamino) -3- (3, 4-difluoro-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
96.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (3-cyano-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
97.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-cyano-phenyl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
98.5- (4-tert-butyl-phenylsulfonyl-amino) -3- (4-methyl-thiophen-2-yl) -1H-indole-2-carboxylic acid- (2-morpholin-4-yl-ethyl) -amide
99.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-chloro-phenyl) -amide
100.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-isoxazol-5-yl) -amide
101.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-fluoro-phenyl) -amide
102.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-fluoro-phenyl) -amide
103.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (6-methyl-pyridin-2-yl) -amide
104.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-carbamoyl-pyridin-2-yl) -amide
105.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-hydroxy-phenyl) -amide
106.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxy-phenyl) -amide
107.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methoxy-phenyl) -amide
108.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methoxy-phenyl) -amide
109.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-chloro-phenyl) -amide
110.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-dimethylamino-phenyl) -amide
111.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-chloro-pyridin-2-yl) -amide
112.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid p-tolylamide
113.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid pyrazin-2-ylamide
114.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-cyano-phenyl) -amide
115.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-isothiazol-5-yl) -amide
116.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-bromo-phenyl) -amide
117.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-carbamoyl-phenyl) -amide
118.5- (4-tert-butyl-benzenesulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-pyridin-2-yl) -amide
119.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-chlorophenyl) -amide
120.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-methyl-2H-pyrazol-3-yl) -amide
121.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid quinolin-5-ylamide
122.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid quinolin-6-ylamide
123.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 6-dichloro-pyridin-4-yl) -amide
124.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-fluoro-phenyl) -amide
125.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methyl-pyridin-4-yl) -amide
126.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-fluoro-pyridin-4-yl) -amide
127.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-pyridin-4-yl) -amide
128.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-bromo-pyridin-4-yl) -amide
129.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 3-dihydroxy-propyl) -amide
130.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-oxo-tetrahydro-thiophen-3-yl) -amide
131.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (2-oxo-imidazolidin-1-yl) -ethyl ] -amide
132.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 2-diethoxy-ethyl) -amide
133.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-ethoxy-propyl) -amide
134.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-isopropoxy-propyl) -amide
135.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-morpholin-4-yl-propyl) -amide
136.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-diethylamino-propyl) -amide
137.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-dimethylamino-propyl) -amide
138.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (furan-2-ylmethyl) -amide
139.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methylsulfanyl-ethyl) -amide
140.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-diethylamino-ethyl) -amide
141.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -amide
142.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-piperidin-1-yl-ethyl) -amide
143.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-pyrrolidin-1-yl-propyl) -amide
144.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-phenethyl-amide
145.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-methoxy-1-methyl-ethyl) -amide
146.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-2-ylmethyl) -amide
147.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-3-ylmethyl) -amide
148.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (pyridin-4-ylmethyl) -amide
149.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-diethylamino-1-methyl-butyl) -amide
150.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-imidazol-1-yl-ethyl) -amide
151.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-benzylamide
152.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2, 2, 2-trifluoro-ethyl) -amide
153.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-methoxy-benzylamide
154.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclopentamide
155.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-methyl-butyl) -amide
156.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (4-methyl-piperazin-1-yl) -propyl ] -amide
157.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (4-hydroxy-phenyl) -ethyl ] -amide
158.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (4-chloro-phenyl) -ethyl ] -amide
159.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-cyclopropylamide
160.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclohexylmethyl-amide
161.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (tetrahydro-furan-2-ylmethyl) -amide
162.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (thien-2-ylmethyl) -amide
163.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-fluoro-benzylamide
164.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-thiophen-2-yl-ethyl) -amide
165.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyrrolidin-1-yl-ethyl) -amide
166.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 4-methyl-benzylamide
167.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (1-ethyl-pyrrolidin-2-ylmethyl) -amide
168.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyridin-3-yl-ethyl) -amide
169.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 3-chloro-benzylamide
170.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (3-chlorophenyl) -ethyl ] -amide
171.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((R) -2-hydroxy-1-phenyl-ethyl) -amide
172.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (2-methyl-piperidin-1-yl) -propyl ] -amide
173.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-phenyl-propyl) -amide
174.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-carbamoyl-ethyl) -amide
175.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (5-methyl-1H-pyrazol-4-yl) -propyl ] -amide
176.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (4-methyl-cyclohexyl) -amide
177.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((S) -2-methoxy-1-methyl-ethyl) -amide
178.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cyclopropylmethyl-amide
179.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid-carbamoylmethyl-amide
180.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid cycloheptylamide
181.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- ((R) -2-methoxy-1-methyl-ethyl) -amide
182.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (furan-3-ylmethyl) -amide
183.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid 3-fluoro-benzamide
184.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (5-methyl-pyrazin-2-ylmethyl) -amide
185.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-pyridin-2-yl-ethyl) -amide
186.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-phenoxy-ethyl) -amide
187.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (2-benzimidazol-1-yl-ethyl) -amide
188.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (3-imidazol-1-yl-propyl) -amide
189.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- (1-benzyl-piperidin-4-yl) -amide
190.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -amide
191.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amide
192.5- (4-tert-butyl-phenylsulfonyl-amino) -3-phenyl-1H-indole-2-carboxylic acid methyl- (2-morpholin-4-yl-ethyl) -amide
13. A medicament comprising at least one compound according to claims 1 to 12.
14. A medicament according to claim 13, which comprises an effective amount of a compound of formula I.
15. Use of a compound of general formula I according to claims 1-12 for the preparation of a medicament for the treatment of diseases caused by disorders of cAMP metabolism.
16. Use of a compound of general formula I according to claims 1-12 for the preparation of a non-hormonal contraceptive.
17. Use of a compound of general formula I according to claims 1-12 for the preparation of a medicament for the inhibition of soluble adenylyl cyclase.
18. A compound according to claims 1-12, together with suitable dosage form materials and excipients, as a medicament according to claims 13 and 14.
19. The use of compounds of general formula I according to claims 1 to 12 in the form of pharmaceutical preparations for enteral, parenteral and oral administration.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004047272.6 | 2004-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1110597A true HK1110597A (en) | 2008-07-18 |
Family
ID=
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