CN101443336B

CN101443336B - Cyclopropyl fused indolobenzazepine HVC ns5b inhibitors

Info

Publication number: CN101443336B
Application number: CN2007800177584A
Authority: CN
Inventors: 约翰·A·本德; 丁敏; 罗伯特·G·金特尔斯; 皮亚塞纳·赫瓦瓦萨姆
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2006-05-17
Filing date: 2007-05-04
Publication date: 2012-07-04
Anticipated expiration: 2027-05-04
Also published as: CN101443336A

Abstract

The invention encompasses compounds of formula (I) as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.

Description

Cyclopropyl-anellated [indoles] simultaneously [benzo-aza *] HCV NS5B inhibitor

Cross-reference to related applications

The U.S. Provisional Application sequence number 60/801 filed an application this application claims on May 17th, 2006,125th, 60/802 filed an application on May 19th, 2006,005th, 60/894,757 priority that 14,60/852,084 and 2007 on the March that on October 16th, 2006 files an application files an application.

Background technology

HCV (HCV) is a kind of primary human's cause of disease, infection estimated 100,000,000 7 million people in the whole world-this rough is five times in the number infected by human immunodeficiency virus type 1.These most of systems through HCV infection develop serious progressive hepatopathy, including hepatic sclerosis and hepatocellular carcinoma (Lauer, G.M.；Walker, B.D.N.Engl.J.Med.2001,345,41-52).

HCV is positive chain RNA virus.Based on extensive similarity by the comparison of institute's deduced amino acid sequences and in 5 '-untranslated region, HCV has been classified as indivedual kinds in flaviviridae.All members of flaviviridae have the virion of encapsulating, and it contains the positive chain RNA genome translated and encoded to all known viruse specific proteinses via single continual open read frame.

Considerable heterologous is found in the nucleotides in whole HCV genomes and encoded amino acid sequence.At least six kinds main genotypes have been characterized, and more than 50 kinds hypotypes have been described.HCV main genotypes are variant in its global distribution, and the clinical importance still unpredictable of HCV gene heterologous, although made many researchs to the possibility of pathology and therapy for genotype.

Sub-thread HCV rna gene groups are about 9500 length of nucleotides, and the single open read frame (ORF) encoded with the single big polyprotein to about 3000 amino acid.In infected cell, this polyprotein in multiple positions by leukoprotease and virus protease cracking, to produce structural protein matter and unstructuredness (NS) protein.In the case of HCV, the generation of ripe nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is reached by two kinds of virus proteases.It is metalloproteinases to believe the first virus protease, and is cracked in NS2-NS3 joints；Second of virus protease is the serine protease (also referred to as NS3 protease) being comprised in NS3 N- stub areas, and all follow-up cracking in mediation NS3 downstreams, cracked, and cracked in remaining NS4A-NS4B, NS4B-NS5A and NS5A-NS5B position with trans with cis in NS3-NS4A positions.NS4A protein seems to play multi-functional, uses the co-factor of NS3 protease as, thereby increases and it is possible to help the cell membrane localization of NS3 and other rdrp virus compositions.NS3 protein and NS4A compound formation are seemingly necessary for processing event, and this improves the breaks down proteins efficiency on all positions.NS3 protein also shows nuclear nucleoside triphosphatase and RNA helicase activities.NS5B (also referred to as HCV polymerases) is RNA RNA-dependent polymerases, and it is related to HCV duplication.HCV NS5B protein is described in " Structural Analysis of the HepatitisC Virus RNA Polymerase in Complex with Ribonucleotides " (Bressanelli；S.etal., Journal of Virology 2002,3482-3492 and Defrancesco and Rice, Clinics inLiver Disease 2003,7,211-242) in.

At present, maximally effective HCV therapy system causes lasting effect (Poynard, T.et al.Lancet 1998,352,1426-1432) using the combination of alpha-interferon and Ribavirin in 40% patient.Nearest clinical effectiveness is confirmed, as monotherapy, and the alpha-interferon system through PEGylation is better than unmodified alpha-interferon (Zeuzem, S.et al.N.Engl.J.Med.2000,343,1666-1672).But, even if for relating to the experimental treatment dosage regimen of the combination of alpha-interferon and Ribavirin through PEGylation, there is not lasting reduction in terms of viral load in most of patient.Therefore, there is clear and important demand for the effective therapeutic agent of exploitation to treat HCV infection.

The content of the invention

One aspect of the invention is compound of formula I：

Wherein

R¹For CO₂R⁵Or CONR⁶R⁷；

R²For

Or

R³For hydrogen, halogen, alkyl, alkenyl, hydroxyl, benzyl epoxide, alkoxy or halogenated alkoxy；

R⁴For cycloalkyl；

R⁵For hydrogen or alkyl；

R⁶For hydrogen, alkyl, alkyl SO₂, cycloalkyl SO₂, haloalkyl SO₂、(R⁹)₂NSO₂Or (R¹⁰)SO₂；

R⁷For hydrogen or alkyl；

R⁸For hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, alkyl-carbonyl, naphthene base carbonyl, halogenated alkyl carbonyl, alkoxy carbonyl, alkyl SO₂, cycloalkyl SO₂, haloalkyl SO₂, amino carbonyl, (alkyl amino) carbonyl, (dialkyl amido) carbonyl, benzyl, benzyloxycarbonyl or pyridine radicals；

R⁹For hydrogen, alkyl or cycloalkyl；And

R¹⁰For azelidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperidinyl or high morpholinyl, and replaced by 0-3 alkyl substituent；

Or its officinal salt.

Another aspect of the present invention is compound of formula I, wherein

R¹For CO₂R⁵Or CONR⁶R⁷；

R²For

Or

R³For hydrogen, halogen, alkyl, alkenyl, hydroxyl, benzyl epoxide or alkoxy；

R⁴For cycloalkyl；

R⁵For hydrogen or alkyl；

R⁷For hydrogen or alkyl；

R⁸For hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, alkyl-carbonyl, alkoxy carbonyl, benzyl, benzyloxycarbonyl or pyridine radicals；

R⁹For hydrogen or alkyl；And

R¹⁰For azelidinyl, pyrrolidinyl, piperidyl, piperazinyl, N- (alkyl) piperazinyl, morpholinyl, thio-morpholinyl, homopiperidinyl or high morpholinyl；

Or its officinal salt.

Another aspect of the present invention is compound of formula I, wherein R¹For CONR⁶R⁷；R⁶For alkyl SO₂, cycloalkyl SO₂, haloalkyl SO₂、(R⁹)₂NSO₂Or (R¹⁰)SO₂；And R⁷For hydrogen.

Another aspect of the present invention is compound of formula I, wherein R³For hydrogen.

Another aspect of the present invention is compound of formula I, wherein R³For methoxyl group.

Another aspect of the present invention is compound of formula I, wherein R⁴For cyclohexyl.

Another aspect of the present invention is compound of formula I, wherein R⁶For (R⁹)₂NSO₂Or (R¹⁰)SO₂。

Another aspect of the present invention is compound of formula I, wherein R⁶For (dimethylamino) SO₂。

Another aspect of the present invention is compound of formula I, wherein R⁶For alkyl SO₂。

Another aspect of the present invention is compound of formula I, wherein R⁶For isopropyl SO₂。

Another aspect of the present invention is according to following stereochemical compound of formula I.

Any variable (including R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹Or R¹⁰) any scope independently can be used together with the scope of any other situation of variable.

Unless otherwise stated, these terms have following meanings." alkyl " means the straight or branched alkyl being made up of 1 to 6 carbon." alkenyl " means the straight or branched alkyl being made up of 2 to 6 carbon and with least one double bond." cycloalkyl " means the single cyclic rings system being made up of 3 to 7 carbon." hydroxy alkyl ", " alkoxy " and other terms with substituted alkyl part include the straight chain and branched chain isomer being made up of 1 to 6 carbon atom of the alkyl segment." haloalkyl " includes all halogenation isomers with " halogenated alkoxy ", the alkyl replaced from the alkyl that single halogen replaces to perhalogeno element." aryl " includes carbocyclic aromatic substituent and heterocyclic aromatic substituent.Bracket is intended to illustrate marriage relation to those skilled in the art with multiple bracket term.For example, for example ((R) alkyl) word means the alkyl substituent for being further substituted base R substitutions.

The present invention includes all pharmaceutical acceptable salts of the compound.Officinal salt will not significantly encourage the physiologically active or toxicity of compound and itself use the officinal salt of pharmacology equivalent as wherein counter ion counterionsl gegenions.These salt can be made according to general organic technology of Commercial reagents.Some anionic salt forms include acetate, acistrate (acistrate), benzene sulfonate, bromide, camsilate, chloride, citrate, fumarate, glucuronate salt, hydrobromate, hydrochloride, hydriodate, iodide, lactate, maleate, mesylate, nitrate, embonate, phosphate, succinate, sulfate, tartrate, toluene fulfonate and xinafoate (xinofoate).Some cation salts include ammonium salt, aluminium salt, benzyl star (benzathine) salt, bismuth salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, lithium salts, magnesium salts, meglumine salt, 4- phenyl cyclohexylamine salt, piperazine salt, sylvite, sodium salt, butantriol amine salt and zinc salt.

Some the compounds of this invention have asymmetric carbon atom (see, for example, hereafter structure).The present invention includes the mixture of all stereoisomeric forms in any ratio, including enantiomter and diastereoisomer, and stereoisomer, for example racemic modification.Method as known in the art can be used to be made for some stereoisomers.The compound can be separated into individual isomer to the three-dimensional heterogeneous mixture of related intermediate according to known method generally in the art.In following scheme and form, the asterisk used in the description of molecular structure is meant only to indicate relative stereochemistry, and is not construed as implying that absolute stereochemical is specified.

Synthetic method

The compound can be made up of method as known in the art (including described below).Some reagents are known in the art with intermediate.Other reagents can be made up with intermediate of method as known in the art using handy material.How to be manufactured for illustrating that the variable (such as numbered " R " substituent) of compound synthesis is only intended to illustrate, without should be with the confounding of variable in claims or used in other paragraphs of patent specification.Abbreviation used in scheme is in general manner according to Conventional abbreviations used in the art.

The bromo- 3- cyclohexyl -1H- indole -6-carboxylic methyl esters of 2- can be hydrolyzed into the bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2- (referring to scheme 1).In anhydrous THF, using such as 1,1 '-N,N'-carbonyldiimidazole and the carbon -7- alkene of 1,8- diazabicylo [5.4.0] 11, above-claimed cpd can be condensed with a variety of sulfonylureas.Such as Su Chuji (Suzuki) coupling condition can be used, resulting acyl sulfonamides is carried out known coupling reaction, the cyclic hemiacetal amine intermediate of description type to provide with a variety of 2- formyls ylboronic acids or ester.These compounds can be converted to [indoles] simultaneously [benzo-aza

] derivative, its mode is in DMF, under the influence of cesium carbonate, to react, handled with 2- (dimethoxyphosphoryl) methyl acrylate via continuous Michael and Horner Emmons.

Related fused rings propylester derivative can be produced by method as known in the art, including [indoles] simultaneously [benzo-aza

Figure 2007800177584100002G2007800177584D0005150400QIETU

] ester in DMSO under strongly alkaline conditions with iodate trimethyl sulfoxonium (trimethylsulfoxonium iodide) handle.The aliphatic (acid) ester residue remained in resulting fusion cyclopropane can be hydrolyzed, and the piperazine condensation that product acid can be bridged with a variety of alkyl.For example, tetrafluoro boric acid O- (1H- BTA -1- bases)-N, N, N ' in DMSO, N '-tetramethyl

The piperazine carboxylic acid amides of alkyl bridge joint can be obtained with diisopropylethylamine.

Scheme 1

The shielded piperazines of N can also be coupled to intermediate [indoles] simultaneously [benzo-aza

] acid, and method as known in the art can be used to be deprotected for resulting piperazine carboxylic acid amides, and carry out derivatization using various synthetic schemes, some of illustrative embodiment is shown hereinafter (referring to scheme 2).

Scheme 2

It is related to the simultaneously [benzo-aza of the tert-butyl ester [indoles] shown in scheme 3 available for the intermediate for synthesizing some the compounds of this invention

Figure 2007800177584100002G2007800177584D0006150533QIETU

] preparation.

Scheme 3

This maneuver is related to the alkali catalyzed hydrolysis of shown indoles methyl esters, and then it reacts with thionyl chloride and potassium tert-butoxide, or is alkylated reaction with silver carbonate and tert-butyl bromide.The similar chemical method previously summarized can be used to convert for resulting compound, to provide mixed ester [indoles] illustrated above simultaneously [benzo-aza

]。

These intermediates can be used in interchangeable program, and it may be utilized in preparing the piperazine that acyl sulfonamides are bridged with acyl sulfonamides alkyl, as shown in scheme 4.The intermediate tert-butyl ester [indoles] simultaneously [benzo-aza

] the cracking of Cyclopropanated and subsequent tert-butyl ester base can produce acid, it can be coupled to a variety of sulfonamide and sulfonylureas.Sequential hydrolysis effect obtains related aliphatic acid, and its piperazine that can be bridged with a variety of alkyl is coupled.For example, tetrafluoro boric acid O- (1H- BTA -1- bases)-N, N, N ' in DMSO, N '-tetramethyl

Scheme 4

Some embodiments exist with three-dimensional heterogeneous mixture.The present invention covers all stereoisomers of the compound.The method for separating three-dimensional heterogeneous mixture is well known in the art, and the including but not limited to chiral supercritical fluid chromatography (SFC) of preparative and chiral high performance liquid chromatography (HPLC).It is shown in using the embodiment of this processing mode in scheme 5.

Scheme 5

Another method for reaching such a separation is related to the mixture for preparing diastereoisomer, and a variety of methods as known in the art can be used to separate for it.One embodiment of this processing mode is shown hereinafter (scheme 6).

Scheme 6

Diastereoisomer is separated by reversed-phase HPLC

Some diastereomeric amides can be used reversed-phase HPLC to separate.After hydrolysis, resulting optically active acid can be coupled (scheme 6) with the bridged piperazine derivatives of bridge joint.For example, tetrafluoro boric acid O- (1H- BTA -1- bases)-N, N, N ' in DMSO, N '-tetramethyl

Figure 2007800177584100002G2007800177584D0008150601QIETU

It can be used for obtaining the piperazine carboxylic acid amides that alkyl is bridged with diisopropylethylamine.Also other standard amide coupling methods can be used, to obtain optical activity carboxylic acid amides.

Scheme 6

Scheme 7-9 illustrates to manufacture other methods of intermediate and compound.

Scheme 7

Scheme 8

Scheme 9

Biological method

When being determined in HCV RdRp detections below, the compound presents resistance HCV NS5B activity.

HCV NS5B RdRp clone, expression and purifying

The cDNA that HCV genotype 1b NS5B protein is encoded is cloned into pET21a expression vectors.This protein is expressed as 18 amino acid C-terminal butts (truncation), to improve solubility.Escherichia coli vigor cell system BL21 (DE3) is used for protein expression.Culture grows about 4 hours at 37 DEG C, until culture is untill 600 nanometers reach optical density 2.0.Culture is cooled to 20 DEG C, and induced with 1mM IPTG.The new ampicillin of addition to ultimate density is 50 mcg/mls, and cell is stayed overnight in 20 DEG C of growths.

Make (3 liters) dissolvings of cell precipitation for purifying, obtain 15-24 milligrams of purified NS5B.Lysis buffer solution includes 20mM Tris-HCl (pH 7.4), 500mM NaCl, 0.5%triton X-100,1mMDTT, 1mM EDTA, 20% glycerine, 0.5 mg/ml lysozyme, 10mM MgCl₂, 15 mcg/ml deoxyribonuclease Is and complete TM protease inhibitors tablet (Roche).After addition lysis buffer solution, using tissue homogenizer, make chilled cell precipitation settling flux.To reduce the viscosity of sample, using micro- tip through being connected to Branson ultrasonic processors, make the decile liquid of lysate ultrasonically treated on ice.Make sonicated lysate at 4 DEG C 100,000 × g is centrifuged 1 hour, and by the filtering of 0.2 micron membrane filter unit (Corning).

Carry out protein purification using three continuous chromatography steps：Heparin-agarose CL-6B, polyU sepharose 4B and HiTrap SP agaroses (Pharmacia).Chromatographic buffers are identical with lysis buffer solution, but do not contain lysozyme, deoxyribonuclease I, MgCl₂Or protease inhibitors, and the NaCl concentration of buffer solution adjusts according to the need for protein is filled in chromatographic column.Each chromatographic column is eluted with NaCl gradients liquid, it changes between 5 to 50 chromatogram column volumes, depending on chromatographic column type.After final chromatographic step, resulting enzyme purity>90%, based on SDS-PAGE is analyzed.Enzyme is divided into decile liquid, and is stored in -80 DEG C.

Standard HCV NS5B RdRp enzymes are detected

It is 60 microlitres in final volume and HCV RdRp genotype 1b detections is carried out in 96 orifice plates (Costar 3912).Detect buffer solution by 20mM Hepes (pH 7.5), 2.5mM KCl, 2.5mM MgCl₂, 1mM DTT, 1.6 unit RNase inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961) and 2% glycerine constituted.By all compounds in DMSO serial dilution (3- times), and further in water dilute so that the ultimate densities of DMSO in the detection be 2%.HCVRdRp genotype 1b enzymes are used when ultimate density is 28nM.PolyA templates are used in 6nM, and are used through biotinylated widow-dT12 primers when ultimate density is 180nM.Template is purchased in market and obtained (Amersham 27-4110).Biotinylated primer is prepared by Sigma Genosys.3H-UTP is used at 0.6 μ Ci (0.29 μM of total UTP).Reaction is triggered by adding enzyme, is cultivated 60 minutes at 30 DEG C, and is stopped by adding 25 microlitres of 50mM EDTA (4 mg/mls, AmershamRPNQ 0007) containing SPA beads.In incubated at room temperature>After 1 hour, plate is read on Packard Top Count NXT.

Modified HCV NS5B RdRp enzymes detection

The detection of modified enzyme is substantially carried out by standard enzyme detection is described, unlike, make through biotinylated few dT12 primers pre-capture on the SPA beads that streptavidin (streptavidin) is coated, its mode is to mix primer and bead in detection buffer solution, and in incubated at room temperature one hour.After centrifugation, uncombined primer is removed.The bead for combining primer is resuspended in 20mMHepes buffer solutions (pH 7.5), and when ultimate density is 20nM primers and 0.67 microgram/microlitre bead for detecting.Order of addition in the detection：Enzyme (14nM) is added in diluted compound, the mixture for the bead that template (0.2nM), 3H-UTP (0.6 μ Ci, 0.29 μM) and primer are combined then is added, with initiation reaction, institute is ultimate density to concentration.Reaction is allowed to be carried out 4 hours at 30 DEG C.

The IC of compound₅₀Value is measured using seven kinds of differences [I].IC₅₀Value calculates self-inhibiting effect, and it uses formula y=A+ ((B-A)/(1+ ((C/x) ^D))).

FRET detects preparation

In order to carry out HCV FRET selective mechanisms, 96 porocyte culture plates are used.FRET peptides (Anaspec companies) (Taliani et al., Anal.Biochem.1996,240,60-67) contain the fluorogenic donor EDANS close to the peptide one end and the acceptor DABCYL close to the other end.(RET) can be shifted by the intermolecular resonant between donor and acceptor, make the fluorescent quenching of the peptide, but when NS3 protease cracks the peptide, product no longer occurs RET and is quenched, and the fluorescence of donor becomes apparent.Detection reagent is made as following：Promega (#E153A) the plain enzyme cell culture lysis reagent of 5X cell fluorescences will be derived from H₂O is diluted to 1X, and FRET peptides are diluted to final 20 μM by addition NaCl to being finally 150mM from 2mM storing solutions.

In order to prepare plate, make extra large Matthiola incana luciferase (Renilla luciferase) the report subbase of with or without because HCV replicon cells through trypsinized, it is placed in each hole of 96- orifice plates, wherein the addition of the testing compound through titration is in the 3rd to 12 arranges；Row 1 and 2 contain control compound (HCV protease inhibitor), and bottom line contains the cell without compound.Then, plate is placed in 37 DEG C of CO₂In incubator.

Detection

After above-mentioned testing compound (FRET detects preparation) is added, plate is taken out in different time, and the addition Alamar blue solutions (Trek Diagnostics, #00-100) per hole, it is used as a kind of metering system of cytotoxicity.After being read in the instruments of Cytoflour 4000 (PE Biosystems), plate is rinsed with PBS, 30 microlitres of above-mentioned FRET peptides detection reagents (FRET detects preparation) are then added by every hole and are used for FRET detections.Then, plate is placed in the instruments of Cytoflour 4000, it has been configured to 340 and has excited/490 transmittings, and automatic mode is read after 20 circulations, and plate in dynamic mode.Typically, the signal of use end point analysis is at least three times to noise after reading.Or, after Alamar bluenesss are read, plate is rinsed with PBS, addition does not have 50 microlitres of phenol red DMEM (high glucose), then using Promega Dual-Glo Luciferase Assay System, plate is detected for luciferase.

Compound analysis to being quantified with respect to HCV replicons inhibitory action and relative cytotoxicity value by being determined.In order to calculate cytotoxicity values, the average Alamar blue-fluorescences signal derived from control wells is set as that 100% is non-toxic.Then, by each signal divided by average control group signal in each compound test hole and 100% is multiplied by, to determine percentage cytotoxicity.In order to calculate HCV replicon inhibiting values, average background is derived from two holes containing maximum amount HCV protease inhibitor at the end of during detecting.These values are similar to the value derived from natural Huh-7 cells.

Then, background value is deducted from the average signal derived from control wells, and this value is used as 100% activity.Then, by the mean control value after each signal divided by background deduction in each compound test hole and 100% is multiplied by, to determine Percent Active.The EC that protease inhibitors is titrated₅₀Value is calculated as that the concentration of 50% reduction can be caused in FRET or uciferase activity.It is that percentage cytotoxicity is used for the important compound that determination is treated further to analyze with Percent Active for two values obtained by compound plate.

The representative data of compound is reported in table 1.

Table 1

A>0.5μM；B is 0.001 μM -0.5 μM；C<0.02 μM, but explicit value do not determine；D>0.04 μM, but explicit value do not determine；IC₅₀Value is determined using preculture scheme.EC₅₀Value detects to determine using FRET.

Pharmaceutical composition and treatment method

The compound presents resistance HCV NS5B activity, and available for treatment HCV and HCV infection.Therefore, another aspect of the present invention is a kind of composition, it includes the compound or pharmaceutically acceptable salt thereof and pharmaceutical acceptable carrier of the present invention.

Another aspect of the present invention is a kind of composition, it further includes the compound with anti-HCV activity.

Another aspect of the present invention is a kind of composition, wherein the compound with anti-HCV activity is interferon.In another aspect of the present invention, the interferon is selected from interferon-' alpha ' 2B, the interferon-' alpha ' through PEGylation, interferon concensus (consensus interferon), interferon-' alpha ' 2A and lymphoblastoid interferon τ.

Another aspect of the present invention is a kind of composition, wherein the compound with anti-HCV activity is cyclosporin.In another aspect of the present invention, the cyclosporin is cyclosporin A.

Another aspect of the present invention is a kind of composition, wherein the compound with anti-HCV activity be selected from interleukin 2, interleukin-6, interleukin 12, can improve 1 type helper cell response development compound, RNA interfering, antisense RNA, Imiqimod, Ribavirin, 5'-IMP dehydrogenase inhibitor, amantadine and Rimantadine.

Another aspect of the present invention is a kind of composition, wherein the compound with anti-HCV activity can effectively suppression target function, the target is selected from HCV metalloproteinases (HCVmetalloprotease), HCV serine proteases (HCV serine protease), HCV polymerases (HCVpolymerase), HCV helicases (HCV helicase), HCV NS4B protein (HCV NS4Bprotein), HCV enters (HCV entry), HCV assembles (HCV assembly), HCV disengages (HCVegress), HCV NS5A protein (HCV NS5A protein), IMPDH and nucleoside analog (nucleoside analog), to treat HCV infection.

Another aspect of the present invention is a kind of composition, it includes compound or pharmaceutically acceptable salt thereof, pharmaceutical acceptable carrier, interferon and the Ribavirin of the present invention.

Another aspect of the present invention is a kind of method for suppressing HCV replicons (HCV replicon) function, it includes contacting HCV replicons and the compound or pharmaceutically acceptable salt thereof of the present invention.

Another aspect of the present invention is a kind of method of suppression HCV NS5B protein functions, it includes contacting HCV NS5B protein and the compound or pharmaceutically acceptable salt thereof of the present invention.

Another aspect of the present invention is a kind of method for treating HCV infection in patients, it includes the compounds of this invention or its officinal salt that therapeutically effective amount is given to the patient.In another embodiment, compound of the invention can effectively suppress the function of HCV replicons.In another embodiment, compound of the invention can effectively suppress the function of HCV NS5B protein.

Another aspect of the present invention is a kind of method for treating HCV infection in patients, it includes the compounds of this invention or its officinal salt that therapeutically effective amount is given to the patient, and gives (before, afterwards or simultaneously) other compounds with anti-HCV activity.

Another aspect of the present invention is the method that wherein other compounds with anti-HCV activity are interferon.

Another aspect of the present invention is the method that wherein described interferon is selected from interferon-' alpha ' 2B, the interferon-' alpha ' through PEGylation, interferon concensus, interferon-' alpha ' 2A and lymphoblastoid interferon τ.

Another aspect of the present invention is the method that wherein other compounds with anti-HCV activity are cyclosporin.

Another aspect of the present invention is the method that wherein described cyclosporin is cyclosporin A.

Another aspect of the present invention is the method that wherein other compounds with anti-HCV activity are selected from interleukin 2, interleukin-6, interleukin 12, the compound that can improve 1 type helper cell response development, RNA interfering, antisense RNA, Imiqimod, Ribavirin, 5'-IMP dehydrogenase inhibitor, amantadine and Rimantadine.

Another aspect of the present invention is wherein other compounds with anti-HCV activity can effectively suppression target function method, the target is selected from that HCV metalloproteinases, HCV serine proteases, HCV polymerases, HCV helicases, HCV NS4B protein, HCV enter, HCV assemblings, HCV disengage, HCV NS5A protein, IMPDH and nucleoside analog, to treat HCV infection.

The method of the function of target rather than HCV NS5B protein in HCV Life Cycles can effectively be suppressed another aspect of the present invention is wherein other compounds with anti-HCV activity.

" treatment effective " means the amount for providing the medicine required for significant patients ' interest, as the medical practitioner in hepatitis and HCV infection field understands.

" patient ", which means, to be infected by HCV virus and is adapted to the people for the treatment of, as the medical practitioner in hepatitis and HCV infection field understands.

" treatment ", " therapy ", " dosage regimen ", " HCV infection " and relational language are used as the medical practitioner in hepatitis and HCV infection field understands.

The compounds of this invention is given typically in the form of pharmaceutical composition, and the composition includes the compounds of this invention or its officinal salt and pharmaceutical acceptable carrier of therapeutically effective amount, and can contain conventional excipients.Therapeutically effective amount is the amount required for the significant patients ' interest of offer.Pharmaceutical acceptable carrier is the conventionally known carrier with acceptable security.Composition covers all conventional solids and liquid form, including capsule, tablet, lozenge and powder agent and liquid suspension, syrup, elixir and solution.Composition is made using general formula technique, and conventional excipients (for example adhesive and wetting agent) are generally used for composition with medium (for example water and alcohol).

Solid composite is typically formulated into dosage unit, and the composition of about 1 to 1000 milligram of active ingredient of offer is preferable per dosage.Some embodiments of dosage are 1 milligram, 10 milligrams, 100 milligrams, 250 milligrams, 500 milligrams and 1000 milligrams.In general, the unit range of other medicines is similar to the classical unit range clinically used.Typically, this is 0.25-1000 milligrams/unit.

Fluid composition is generally in dosage unit ranges.In general, the unit dosage ranges of fluid composition are 1-100 mg/mls.Some embodiments of dosage are 1 mg/ml, 10 mg/mls, 25 mg/mls, 50 mg/mls and 100 mg/mls.In general, the unit range of other medicines is similar to the classical unit range clinically used.Typically, this is 1-100 mg/mls.

The present invention covers all conventional administration patterns；It is orally preferable with parenteral method.In general, dosage regimen is similar to the other medicines clinically used.Typically, dosage is taken day for daily 1-100 mg kg of body weight.In general, oral way needs more compound, and parenteral mode needs less compound.But, specific dosage regimen is determined by the safe and reliable medical judgment of doctor.

The present invention also covers the method that wherein the compounds of this invention is used in combination treatment.I.e. described compound can and with available for treatment hepatitis and HCV infection other medicines, but the compound be different from the other medicines.In these combined methods, the compound is generally arranged in pairs or groups other medicines, is given using taking dosage day as daily 1-100 mg kg of body weight.Other medicines are general to be given with treating upper used amount.But, specific dosage regimen is determined by the safe and reliable medical judgment of doctor.

The compound of suitable composition and some embodiments of method are listed in Table 2.

Table 2

Brand name	Inhibitor type or target type	Source company
			Omega IFN	IFN-ω	Intarcia Therapeutics
BILN-2061	Serpin	Boehringer Ingelheim Pharma KG, Ingelheim, Germany
			Summetrel	It is antiviral	Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA
Roferon A	IFN-α2A	F.Hoffmann-La Roche LTD, Basel, Switzerland
			Pegasys	IFN-α 2A through PEGylation	F.Hoffmann-La Roche LTD, Basel, Switzerland

Brand name	Inhibitor type or target type	Source company
			Pegasys and Ribavirin	IFN-α 2A/ Ribavirins through PEGylation	F.Hoffmann-La Roche LTD, Basel, Switzerland
CellCept	HCV IgG immunodepressant	F.Hoffmann-La Roche LTD, Basel, Switzerland
			Wellferon	Lymphocyte sample IFN-α N1	GlaxoSmithKline plc, Uxbridge, UK
Albuferon-α	Albumin IFN-α 2B	Human Genome Sciences Inc., Rockville, MD
			Levovirin	Ribavirin	ICN Pharmaceuticals, Costa Mesa, CA
IDN-6556	Caspase (caspase) inhibitor	Idun Pharmaceuticals Inc., San Diego, CA
			IP-501	Fibrosis	Indevus Pharmaceuticals Inc., Lexington, MA
Actimmune	INF-γ	InterMune Inc., Brisbane, CA
			Infergen A	IFN α-1	InterMune Pharmaceuticals Inc., Brisbane, CA
ISIS 14803	Antisense thing	ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NY
			JTK-003	RdRp inhibitor	Japan Tobacco Inc., Tokyo, Japan
Pegasys and Ceplene	IFN-α 2A/ immunomodulators through PEGylation	Maxim Pharmaceuticals Inc., San Diego, CA
			Ceplene	Immunomodulator	Maxim Pharmaceuticals Inc., San Diego, CA
Civacir	HCV IgG immunodepressant	Nabi Biopharmaceuticals Inc., Boca Raton, FL
			Intron A and Zadaxin	IFN-α 2B/ α 1- thymosin extrasins	RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc, San Mateo, CA
Levovirin	IMPDH inhibitor	Ribapharm Inc., Costa Mesa, CA
			Viramidine	Ribavirin pro-drug	Ribapharm Inc., Costa Mesa, CA
Heptazyme	Ribozyme	Ribozyme Pharmaceuticals Inc., Boulder, CO
			Intron A	IFN-α2B	Schering-Plough Corporation, Kenilworth, NJ
PEG-Intron	IFN-α 2B through PEGylation	Schering-Plough Corporation, Kenilworth, NJ
			Rebetron	IFN-α 2B/ Ribavirins	Schering-Plough Corporation, Kenilworth, NJ
Ribavirin	Ribavirin	Schering-Plough Corporation, Kenilworth, NJ
			PEG-Intron/Ribavirin	IFN-α 2B/ Ribavirins through PEGylation	Schering-Plough Corporation, Kenilworth, NJ
Zadazim	Immunomodulator	SciClone Pharmaceuticals Inc., San Mateo, CA
			Rebif	IFN-β1A	Serono, Geneva, Switzerland
IFN-β and EMZ701	IFN-β and EMZ701	Transition Therapeutics Inc., Ontario, Canada
			Batabulin(T67)	'beta '-tubulin inhibitor	Tularik Inc., South San Francisco, CA
Merimepodib(VX-497)	IMPDH inhibitor	Vertex Pharmaceuticals Inc., Cambridge, MA
			Telaprevir (VX-950, LY-570310)	NS3 serpins	Vertex Pharmaceuticals Inc., Cambridge, MA/Eli Lilly and Co. Inc., Indianapolis, IN
Omniferon	Natural IFN-α	Viragen Inc., Plantation, FL

Brand name	Inhibitor type or target type	Source company
			XTL-6865(XTL-002)	Monoclonal antibody	XTL Biopharmaceuticals Ltd., Rehovot, Isreal
HCV-796	NS5B replicates enzyme inhibitor	Wyeth/Viropharma
			NM-283	NS5B replicates enzyme inhibitor	Idenix/Novartis
GL-59728	NS5B replicates enzyme inhibitor	Gene Labs/Novartis
			GL-60667	NS5B replicates enzyme inhibitor	Gene Labs/Novartis
2’C MeA	NS5B replicates enzyme inhibitor	Gilead
			PSI 6130	NS5B replicates enzyme inhibitor	Roche
R1626	NS5B replicates enzyme inhibitor	Roche
			SCH 503034	Serpin	Schering Plough
NIM811	The ring film (cyclophilin) inhibitor	Novartis
			Suvus	Methylene blue	Bioenvision
Multiferon	Long-acting IFN	Viragen/Valentis
			Actilon(CPG10101)	TLR9 activators	Coley
Interferon-β	Interferon-beta -1A	Serono
			Zadaxin	Immunomodulator	Sciclone
Pyrazolopyrimidine compounds and salts From WO-2005047288 26 May 2005	HCV inhibitor	Arrow Therapeutics Ltd.
			2’C Methyl adenosine	NS5B replicates enzyme inhibitor	Merck
GS-9132(ACH-806)	HCV inhibitor	Achillion/Gilead

Embodiment

Unless otherwise stated, obtaining the analytical LCMS data on following intermediates and embodiment using following chromatographic column and condition.Dwell time：+ 1 minute liquid time of gradient；Start concentration：0%B, unless otherwise indicated；Eluant, eluent A：Contain 10mM NH₄OAc 5%CH₃CN/95%H₂O (being used for chromatographic column A, D and E) or the 10%MeOH/90%H containing 0.1%TFA₂O (is used for chromatographic column B and C)；Eluant, eluent B：Contain 10mM NH₄OAc 95%CH₃CN/5%H₂O (being used for chromatographic column A, D and E) or the 90%MeOH/10%H containing 0.1%TFA₂O (is used for chromatographic column B and C)；Chromatographic column A：10 μ of Phenomenex, 4.6 × 50 millimeters of C18；Chromatographic column B：3.0 × 50 millimeters of 10 μ of Phenomenex C18；Chromatographic column C：4.6 × 50 millimeters of μ of C18 10 of Phenomenex；Chromatographic column D：3.0 × 50 millimeters of Phenomenex Lina C185 μ；Chromatographic column E：5 μ of Phenomenex, 4.6 × 50 millimeters of C18.

Intermediate 1

The bromo- 3- cyclohexyl -1H- indole -6-carboxylic methyl esters of 2-

At 2 DEG C, by the tribromide pyrrole ingot (pyridinium tribromide) just recrystallized, ((every 1 gram 5 milliliters) of self-heating AcOH is recrystallized, rinsed with cold AcOH, and dried under a high vacuum with KOH) add by several times (after 10 minutes) to 3- cyclohexyl -1H- indole -6-carboxylic methyl esters (60 grams, 233 mMs) (being made using program described in WO2004/065367) in CHCl₃/THF(1:1,1.25 liter) in just in agitating solution.Reaction solution is stirred 2.5 hours at 0-5 DEG C, and with saturation NaHSO₃The aqueous solution (1 liter), (1 liter) washing of 1N HCl (1 liter) and salt solution.Organic layer is set to dry (MgSO₄), and concentrate.By resulting reddish oil with Et₂O dilutes, and concentration.Resulting pink solid is set to be dissolved in Et₂In O (200 milliliters), with (300 milliliters) processing of hexane, and partly concentrate.Solid is collected by filtering, and is rinsed with hexane.Make mother liquor concentrations to dry, and repeat this program.Solid is merged, the bromo- 3- cyclohexyl -1H- indole -6-carboxylic methyl esters of 2- (64 grams, 190 mMs, 82%) is obtained, is fluffy pink solid, using it without being further purified.¹H NMR (300MHz, CDCl3) δ 8.47 (br s, 1H), 8.03 (d, J=1.4Hz, 1H), 7.74 (dd, J=1.4,8.8Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7,11.7Hz, 1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H).¹³C NMR (75MHz, CDCl3) δ 168.2,135.6,130.2,123.1,120.8,120.3,118.7,112.8,110.7,52.1,37.0,32.2 (2), 27.0 (2), 26.1.LCMS：m/e 334(M-H)^-, retention time 3.34 minutes, chromatographic column A, 4 minutes gradients.

Intermediate 2

The bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2-

By the bromo- 3- cyclohexyl -1H- indole -6-carboxylic methyl esters of 2- (20 grams, 60 mMs) and LiOH (3.8 grams, 160 mMs) in MeOH/THF/H₂O(1:1:1,300 milliliter) in solution 90 DEG C heat 2 hours.Make reactant mixture in ice/H₂Cooled down in O baths, with (about 160 milliliters) neutralizations of 1M HCl, with H₂(250 milliliters) dilutions of O, and be stirred at room temperature 1 hour.Sediment is collected by filtering, with H₂O is rinsed, and is dried, and the bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids (quantitative) of 2- is obtained, using it without being further purified.

It is described below available for the alternative program for providing the bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2-：

By the bromo- 3- cyclohexyl -1H- indole -6-carboxylic methyl esters of 2- (117 grams, 349 mMs) and LiOHH₂O (26.4 grams, 629 mMs) is in MeOH/THF/H₂O(1:1:1,1.8 liter) in solution be heated at reflux 3 hours.Make reactant mixture in ice/H₂About 2 DEG C are cooled in O baths, is neutralized with 1M HCl (about 650 milliliters) (being added in the case where making speed of the temperature no more than 5 DEG C), with H₂(1 liter) dilution of O, and stir, while being warmed to environment temperature.Sediment is collected by filtering, with H₂O is rinsed, and is dried, and is obtained single THF solvates (135.5 grams, 345 mMs, 99%) of the bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2-, is yellow solid, using it without being further purified.¹H NMR (300MHz, CDCl3) δ 11.01 (br s, 1H), 8.77 (s, 1H), 8.07 (d, J=1.5Hz, 1H), 7.82 (dd, J=1.5,8.8Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 3.84-3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m, 3H).¹³C NMR (75 MHz, CDCl3) δ 172.7,135.5,130.7,122.3,120.9 (2), 118.8,113.3,111.1,67.9 (2), 37.0,32.2 (2), 27.0 (2), 26.1,25.5 (2).LCMS：m/e 320(M-H)^-, retention time 2.21 minutes, chromatographic column A, 4 minutes gradients.

Intermediate 3

The bromo- 3- cyclohexyl-N- of 2- [(dimethylamino) sulfonyl] -1H- indoles -6- carboxylic acid amides

22 DEG C by (1.17 grams, 7.2 mMs) of 1,1 '-N,N'-carbonyldiimidazole added to the bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2- (2.03 grams, 6.3 mMs) in the agitated solution in THF (6 milliliters).Disengage CO in real time₂, and when it slows down, solution is heated 1 hour at 50 DEG C, 22 DEG C are subsequently cooled to.Add N, N- dimethyl sulfonamides (0.94 gram, 7.56 mMs), are then added dropwise DBU (1, carbon -7- the alkene of 8- diazabicylos [5.4.0] 11) solution of (1.34 grams, 8.8 mMs) in THF (4 milliliters).Persistently stir 24 hours.Mixture is set to make distribution processing between ethyl acetate and dilute HCl.By ethyl acetate layer with water washing, then with salt water washing, and with Na₂SO₄Dry.Extract is concentrated to dryness, title product is left, is faint yellow frangible foam thing (2.0 grams, 74%, the purity estimated from NMR>90%).¹HNMR (300MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, the 7H) (dd of 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57, J=8.42,1.46Hz, 1H) 7.74 (d, J=8.78Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).

On preparing during the alternative of the bromo- 3- cyclohexyl-N- of 2- [(dimethylamino) sulfonyl] -1H- indoles -6- carboxylic acid amides is described below.

In N₂Under equipped with mechanical agitator, temperature controller, N₂The bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2- (102.0 grams, 0.259 mole) and anhydrous THF (300 milliliters) are added in 1 liter of four neck round-bottom flask of inlet tube and condenser.After stirring 10 minutes, CDI (1,1 '-N,N'-carbonyldiimidazole) (50.3 grams, 0.31 mole) is added by several times.Then, reactant mixture is heated to 50 DEG C, kept for 2 hours.After being cooled to 30 DEG C, N is disposably added, DBU (54.1 milliliters, 0.362 mole) was then added dropwise, after 1 hour in N- dimethylaminos sulfonamide (41.7 grams, 0.336 mole).Then, reactant mixture is stirred at room temperature 20 hours.Solvent is removed in a vacuum, and makes residue in EtOAc and 1N HCl (1:1,2 liter) between make distribution processing.Organic layer is separated, and with EtOAc (500 milliliters) aqueous layer extracted.By the organic layer of merging with (1.5 liters) washings of salt solution, and with MgSO₄Dry, filtering solution, and concentrate in a vacuum, obtain crude product (111.0 grams).Crude product is set to be suspended in EtOAc (400 milliliters) at 60 DEG C.Heptane (2 liters) is slowly added in this suspension.Resulting suspension is stirred, and is cooled to 0 DEG C.Then filtered.Filter cake is rinsed with a small amount of heptane, and air-dried 2 days in a vacuum.Product is collected, is white solid (92.0 grams, 83%).¹H NMR (MeOD, 300MHz) δ 7.89 (s, H), 7.77 (d, J=8.4Hz, 1H), 7.55 (dd, J=8.4 and 1.8Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H)；m/z 429(M+H)+.

Intermediate 4

3- cyclohexyl-N- [(dimethylamino) sulfonyl] -2- (2- formoxyl -4- methoxyphenyls) -1H- indoles -6- carboxylic acid amides

By (4.28 grams of the bromo- 3- cyclohexyl-N- of 2- [(dimethylamino) sulfonyl] -1H- indoles -6- carboxylic acid amides; 0.01 mole), (2.7 grams of 4- methoxyl group -2- formyl phenylboronic acids; 0.015 mole), 2- dicyclohexyls phosphino- -2 '; (41 milligrams of 6 '-dimethoxy-biphenyl; 0.0001 mole), palladium (11.2 milligrams) and (4.24 grams of the potassium carbonate through fine ground; 0.02 mole) mixture in toluene (30 milliliters) is in backflow and stirred under nitrogen 30 minutes, and now LC/MS analyses display reaction has been completed.Then, reactant mixture is diluted with ethyl acetate and water, be then acidified with excessive dilute HCl.Then ethyl acetate layer is collected, and with dilute HCl, water and salt water washing.Then, organic solution is made to dry (magnesium sulfate), filtering, and concentration, obtain jelly.By jelly with (25 milliliters) dilutions of hexane (250 milliliters) and ethyl acetate, and stir mixture 20 hours at 22 DEG C, within this time, product changes into distinct yellow granular solid (4.8 grams), and it is directly employed without to be further purified.

Alternative program on preparing 3- cyclohexyl-N- [(dimethylamino) sulfonyl] -2- (2- formoxyl -4- methoxyphenyls) -1H- indoles -6- carboxylic acid amides is provided below.

In the bromo- 3- cyclohexyl-N- of 2- [(dimethylamino) sulfonyl]-(54.0 grams of indoles -6- carboxylic acid amides; 126 mMs), (29.5 grams of 4- methoxyl group -2- formyl phenylboronic acids; 164 mMs) and LiCl (13.3 grams, 315 mMs) in EtOH/ toluene (1:1,1 liter) in pulp solution in addition Na₂CO₃The solution of (40.1 grams, 379 mMs) in water (380 milliliters).Reactant mixture is stirred 10 minutes, Pd (PPh are then added₃)₄(11.3 grams, 10.0 mMs).Reaction solution is rinsed with nitrogen, and is heated overnight at 70 DEG C (internal monitorings), room temperature is subsequently cooled to.With EtOAc (1 liter) and EtOH (100 milliliters) diluting reaction thing, carefully washed with salt solution (500 milliliters) with 1N HCl/waters solution (1 liter), dry (MgSO₄), filtering, and concentration.By residual solids and Et₂O (600 milliliters) is stirred 1 hour together; and collected by filtering; obtain 3- cyclohexyl-N- [(dimethylamino) sulfonyl] -2- (2- formoxyl -4- methoxyphenyls) (52.8 grams of -1H- indoles -6- carboxylic acid amides; 109 mMs; 87%); for yellow powder, using it without being further purified.¹H NMR (300MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.59 (dd, J=1.4,8.4Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6,8.4Hz, 1H), 6.54 (d, J=8.8Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H).¹³C NMR (75MHz, CDCl3) δ 165.7,158.8,147.2,139.1,134.3,132.0,123.4,122.0,119.2,118.2,114.8,112.3,110.4,109.8,79.6,45.9,37.2 (2), 34.7,32.0 (2), 25.9 (2), 24.9.LCMS：m/e 482(M-H)^-, retention time 2.56 minutes, chromatographic column A, 4 minutes gradients.

Intermediate 5

11- cyclohexyl-N- [(dimethylamino) sulfonyl] -6- ethyoxyl -8- methoxyl group -6H- iso-indoles simultaneously [2,1-a] indoles -3- carboxylic acid amides

Equipped with temperature controller, condenser, N₂Toluene (900 milliliters), EtOH (900 milliliters), the bromo- 3- cyclohexyl-N- (N of 2- are added in 5 liter of four neck round-bottom flask of inlet tube and mechanical agitator; N- DimethylsuIfamoyls) (90 grams of -1H- indoles -6- carboxylic acid amides; 0.21 mole), (49.2 grams of 2- formoxyl -4- methoxyphenyl-boronic acids; 0.273 mole) and LiCl (22.1 grams, 0.525 mole).Resulting solution is set to be bubbled 15 minutes with N2.Add Na₂CO₃(66.8 grams, 0.63 mole) are in H₂Solution in O (675 milliliters), and make reactant mixture with N₂Recurrence bubble 10 minutes.Add Pd (PPh₃)₄(7.0 grams, 6.3 mMs), and reactant mixture is heated to 70 DEG C, kept for 20 hours.After being cooled to 35 DEG C, 1N HCl solution (1.5 liters) is slowly added.Resulting mixture is transferred in 6 liters of separatory funnels, and with (2 × 1.5 liters) extractions of EtOAc.By the organic extract liquid of merging with (2 liters) washings of salt solution, with MgSO₄Dry; filtering; and concentrate in a vacuum; obtain yellow solid; it is developed together with the 20%EtOAc (450 milliliters, 50 DEG C to 0 DEG C) in hexane, 11- cyclohexyl-N- [(dimethylamino) sulfonyl] -6- ethyoxyl -8- methoxyl group -6H- iso-indoles simultaneously [2 is obtained; 1-a] indoles -3- carboxylic acid amides (65.9 grams) is yellow solid.HPLC purity is 98%.

So that being concentrated in a vacuum from the mother liquor developed.Residue is set to be flowed back 3 hours together with EtOH (50 milliliters).Then, solution is made to be cooled to 0 DEG C.Filtering precipitate, and with (20 milliliters) washings of TBME (t-butyl methyl ether) (5 DEG C) through cooling.Filter cake is air-dried in a vacuum, obtain the title compound of additional amount, be white solid (16.0 grams).HPLC purity is 99%.¹H NMR (CDCl3,300MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.45 (dd, J=8.4 and 1.4Hz, 1H), 7.09 (d, J=2.2Hz, 1H), 6.98 (dd, J=8.4 and 2.2Hz, 1H), 6.50 (s, 1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7H), 1.40-1.42 (m, 3H), 1.05 (t, J=7.1Hz, 3H).m/z 512(M+H)+.

Intermediate 6

Making 11- cyclohexyl-N- (N, N- DimethylsuIfamoyl) -6- ethyoxyl -8- methoxyl group -6H- iso-indoles, simultaneously [2,1-a] indoles -3- carboxylic acid amides is dissolved in THF (75 milliliters).2N HCl solution (300 milliliters) is added in this solution.By mixture in room temperature and N₂Under be stirred vigorously 16 hours.Suspension obtained by filtering, and with (2 × 30 milliliters) washings of TBME through cooling.Make filter cake vacuum air dried overnight, obtain title compound, be yellow solid.HPLC purity is 99%.¹H NMR (DMSO-d6,300MHz) δ 11.65 (s, 1H), 8.16 (s, 1H), 7.76 (d, J=5.9Hz, 1H), 7.73 (d, J=5.9Hz, 1H), 7.58 (dd, J=8.5 and 1.5Hz, 1H), 7.17-7.20 (m, 2H), 7.08 (dd, J=8.5 and 1.4Hz, 1H), 6.55 (d, J=8.6Hz, 1H), 3.86 (s, 3H), 3.14-3.18 (m, 1H), 2.91 (s, 6H), 1.75-1.99 (m, 7H), 1.48-1.60 (m, 3H)；m/z 484(M+H)+.

Intermediate 7

13- cyclohexyl -10- [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- methoxyl group -7H- indoles simultaneously [2,1-a] [2] benzo-aza

- 6- carboxylate methyl esters

By 3- cyclohexyl-N- (N; N- DimethylsuIfamoyls) -2- (2- formoxyl -4- methoxyphenyls) (4.8 grams of -1H- indoles -6- carboxylic acid amides; 0.01 mole), (9.7 grams of 2- (dimethoxyphosphoryl) methyl acrylate; 0.02 mole) and mixture of the cesium carbonate (7.1 grams, 0.02 mole) in DMF (28 milliliters) stirred 20 hours in 55 DEG C of oil bath temperature.Pour the mixture into frozen water, and be acidified with dilute HCl, precipitate crude product.Solid is collected, is dried, and in SiO₂Flash chromatography is carried out on (110 grams), the ethyl acetate containing 2% acetic acid and dichloromethane (1 is used:10) solution.Merge the eluting fraction of homogeneous, and evaporate, obtain title compound, be faint yellow solid (3.9 grams, 71% yield).MS：552 (M=H+).

On preparing 13- cyclohexyl -10- [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- methoxyl group -7H- indoles simultaneously [2,1-a] [2] benzo-aza

The alternative program of -6- carboxylate methyl esters is provided below.

By 11- cyclohexyl-N- [(dimethylamino) sulfonyl] -6- hydroxyl -8- methoxyl group -6H- iso-indoles simultaneously [2; 1-a] (63.0 grams of indoles -3- carboxylic acid amides (cyclic hemiacetal amine); 130 mMs), (60 grams of 2- (dimethoxyphosphoryl) methyl acrylate; 261 mMs) and solution of the cesium carbonate (106 grams, 326 mMs) in DMF (400 milliliters) heated 4.5 hours under 60 DEG C (bath temperature).Other 2- (dimethoxyphosphoryl) methyl acrylate (15 grams, 65 mMs) of addition and cesium carbonate (21.2 grams, 65 mMs), and reactant is heated overnight at 60 DEG C, it is subsequently cooled to room temperature.By the reactant mixture in stirring with H₂(1 liter) dilution of O, is neutralized, stirs 3 hours, then collect sediment by filtering at leisure with 1N HCl/waters solution (800 milliliters).By solid and Et₂O (800 milliliters) is developed together, and is dried, and obtains 13- cyclohexyl -10- [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- methoxyl group -7H- indoles simultaneously [2,1-a] [2] benzo-aza

Figure 2007800177584100002G2007800177584D0034154101QIETU

- 6- carboxylate methyl esters (70.2 grams, 127 mMs, 98%), are yellow solid, using it without being further purified.¹H NMR (300MHz, CDCl3 the) (s of δ 8.67, 1H), 8.09 (s, 1H), 7.86 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=8.4Hz, 1H), 7.42 (d, J=8.8Hz, 1H), 7.08 (dd, J=2.6, 8.8Hz, 1H), 6.98 (d, J=2.6Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H).LCMS：M/e550 (M-H)-, retention time 3.21 minutes, chromatographic column A, 4 minutes gradients.

Intermediate 8

(+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester

By (5 milliliters) of DMSO added in iodate trimethyl sulfoxonium (199 milligrams, 0.906 mM) and NaH (38 milligrams, in 60% oil dispersion liquid, 0.953 mM) mixture in round-bottomed flask.Reactant mixture is stirred at room temperature 0.5 hour.Then 13- cyclohexyl -10- [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- (methoxyl group) -7H- indoles simultaneously [2,1-a] [2] benzo-aza is added

- 6- carboxylate methyl esters (125 milligrams, 0.227 mM), and reactant mixture is stirred at room temperature 3 hours, and be then stirred for 3 hours at 50 DEG C.Reaction is quenched with water, and is acidified with 1N HCl solutions.Then, crude product is precipitated in the form of faint yellow solid, and it is collected by filtering, and air-dries (106 milligrams, 83% yield).Then, 6 milligrams of this materials is purified by preparative HPLC, obtain title compound, be faint yellow solid (1.8 milligrams).MS m/z 566(MH⁺), retention time is 3.850 minutes.¹HNMR (500MHz, MeOD the) (m of δ ppm 0.28, 0.36H) 1.19-2.20 (m, 11.64H) 2.70-3.02 (m, 2H) 3.03 (s, 2.16H) 3.05 (s, 3.84H) 3.49 (d, J=15.26Hz, 0.64H) 3.54 (s, 1.92H) 3.83 (s, 1.08H) 3.91 (s, 3H) 4.08 (d, J=15.26Hz, 0.36H) 5.29 (d, J=15.26Hz, 0.36H) 5.50 (d, J=14.95Hz, 0.64H) 6.98-7.06 (m, 1H) 7.16 (d, J=2.44Hz, 0.36H) 7.23 (d, J=2.44Hz, 0.64H) 7.30 (d, J=8.55Hz, 0.64H) 7.34 (d, J=8.55Hz, 0.36H) 7.56 (dd, J=8.55, 1.53Hz, 0.64H) 7.63 (dd, J=8.55, 1.53Hz, 0.36H) 7.88 (d, J=8.55Hz, 0.64H) 7.91 (d, J=8.55Hz, 0.36H) 8.12 (s, 0.36H) 8.33 (d, J=1.53Hz, 0.64H).

Alternative program on preparing title compound is provided below.

In N₂Under equipped with mechanical agitator, N₂Sodium hydride (95%) (3.09 grams, 129.2 mMs) and dry DMF (200 milliliters) are added in four necks, 1 liter of round-bottomed flask dried through flame of inlet tube and thermometer.Along with being stirred vigorously, iodate trimethyl sulfoxonium (32.5 grams, 147.3 mMs) is added by several times, within this time, temperature rises to 30 DEG C.After stirring for 30 minutes, it is rapid to add 13- cyclohexyl -10- [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- (methoxyl group) -7H- indoles simultaneously [2,1-a] [2] benzo-aza

Solution of -6- the carboxylate methyl esters (33.8 grams, 61.3 mMs) in dry DMF (70 milliliters).Reactant mixture is stirred below 30 minutes at 30 DEG C, 1N HCl (130 milliliters) are then poured into by several times in the ice cold solution in H2O (2 liters).After resulting suspension is mechanically stirred into 1 hour, filtering precipitate, and with H₂(100 milliliters) washing filter cakes of O.Make filter cake in EtOAc and 0.5N HCl (1:Isosorbide-5-Nitrae liter) between make distribution processing.Organic phase is separated, with H₂(1 liter) washing of O (1 liter) and salt solution, with MgSO₄Dry, filtering, and concentrate in a vacuum.Residue is dissolved in EtOAc (150 milliliters), and make solution by (300 grams, in hexane) filterings of silicagel pad, and with (5 liters) flushings of 50%EtOAc in hexane.Filtrate is set to concentrate in a vacuum; obtain slightly yellow solid; it is developed together with the 10%EtOAc (220 milliliters) in 50 DEG C to 0 DEG C of TBME; obtain (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester, is white solid (26.1 grams, 75% yield).HPLC purity is 100%.¹H NMR(DMSO-d₆, the 300MHz) (s of δ 11.61, 1H), 8.47 (s, 0.5H), 8.25 (s, 0.5H), 7.81-7.88 (m, 1H), 7.57-7.63 (m, 1H), 7.23-7.29 (m, 2H), 7.01-7.07 (m, 1H), 5.43 (d, J=15.0Hz, 0.5H), 5.22 (d, J=15Hz, 0.5H), 4.04 (dd, J=15.4 and 6.6Hz, 0.5H), 3.83 (s, 3H), 3.75 (s, 1H), 3.08-3.47 (m, 0.5H), 3.29 (s, 3H), 2.73-2.92 (m, 8H), 1.11-1.99 (m, 10.5H), 0.20 (m, 0.5H)；m/z 566(M+H)+.

Intermediate 9

(-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester

Make (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

The sample of -1a (2H)-carboxylate methyl ester is dissolved in EtOH/CH with the concentration of 50 mg/mls₃In CN1/1+0.5%DEA (DEA addition ensures that the compound is still remained in solution during injection process).Then this solution is injected on Thar SFC-350 preparatives SFC under conditions of discussed below.

Preparation condition on Thar SFC-350：Chromatographic column is 5 × 25 centimetres of Chiralcel OJ-H；Mobile phase is in CO₂In 25%MeOH/CH3CN (1/1)；Pressure (bar) is 100；Flow velocity (ml/min) is 240；Solution concentration (mg/ml) is 50；Injection volume (milliliter) is 4.5-5；Circulation time (minute/injection) is 6.5-7；Temperature (DEG C) is 45；Throughput (Grams Per Hour) is about 2；Detector wavelength (nanometer) is 254.

Obtain amounting to 177.3 grams of (-) isomers for wanting the second elution from 371.4 grams of racemic initiation materials, contain about 1 molar equivalent diethylamine.This substance migration following programs are purified.The mixture (24.7 grams) that will be had been dissolved in dichloromethane (800 milliliters) is with 0.5N HCl (1 × 400 milliliter, 1 × 240 milliliter), H₂O (2 × 240 milliliters) and salt solution (2 × 240 milliliters) successive wash.Then, organic layer is made to dry (anhydrous Na₂SO₄); filtering, and evaporate, obtain 22.33 grams of (-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester, it is yellow solid (92% reclaims).HPLC¹>99% (retention time 2.38 minutes)；LC/MS(ES⁺) 566.51 (M+H, 100)；[α]_D ^25C- 194.64 ° (c 1.03, MeOH).To C₃₀H₃₅N₃O₆S·0.33H₂O analytically calculated value：C, 63.04, H, 6.29, N, 7.35, S, 5.61, H₂O, 1.04；Measured value：C, 63.07, H, 6.01, N, 7.24, S, 5.58, H₂O, 1.03.NMR is shown in the absence of Et₂NH.The EE of this material determined using following analysis HPLC programs (>99%).

EE analysis condition is determined on the analytical SFC of Thar：Analytical chromatographic column is ChiralcelOJ (0.46 × 25 centimetre, 10 microlitres)；BPR pressure is 100 bars；Temperature is 35 DEG C；Flow velocity is 3.0 ml/mins；Mobile phase is in CO₂In 15%MeOH/CH₃CN(1/1)；Detector wavelength is 254 nanometers；Retention time (minute) is 4 and 6.5.

Intermediate 10

- 1a (2H)-carboxylic acid

In (-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester (22.33 grams, 39.5 mMs) was slowly added 1N NaOH (120 milliliters) in the solution in MeOH (300 milliliters), after 20 minutes, while keeping reaction temperature<30℃.By mixture in room temperature and N₂Lower stirring 18 hours.HPLC display reactions have been completed.1N HCl (130 milliliters) are added in reaction solution.After the addition was complete, the pH value of reactant mixture is about 2.Evaporate the methanol in reactant mixture.By water, (300 milliliters) are added in mixture, then by it with CH₂Cl₂(1 × 600 milliliter, 1 × 200 milliliter) extraction.With H₂The extract that (2 × 300 milliliters) washings of O (2 × 300 milliliters) and salt solution merge, dries (Na₂SO₄), and evaporate, 20.82 grams of (96% yield) title compounds are obtained, are yellow solid.HPLC conditions：Chromatographic column is PhenomenoexSynergi Polar-RP 4 microns 4.6 × 50 millimeters；UV is 220 nanometers；Gradient timetable is 4 minutes；Flow velocity is 4 ml/mins, 75-100%B；Solvent orange 2 A is to contain 0.2%H₃PO₄10%MeOH/90%H₂O, solvent B are to contain 0.2%H₃PO₄90%MeOH/10%H₂O.HPLC>99% (retention time 1.80 minutes).LC/MS(ES⁺) 552.25 (M+H, 100)；[α]_D ^25C- 166.99 ° (c 1.00, MeOH).GC is analyzed：CH₂Cl₂4.94%；To C₂₉H₃₃N₃O₆S·0.16H₂O·0.35CH₂Cl₂Analytically calculated value：C, 60.37, H, 5.87, N, 7.20, S, 5.49, H₂O, 0.49, CH₂Cl₂, 5.02；Measured value：C, 59.95, H, 5.89, N, 7.03, S, 5.38, H₂O, 0.47, CH₂Cl₂, 4.94.

Intermediate 11

- 1a (2H)-carboxylic acid

In (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

Addition 2N NaOH solutions (1.0 milliliters) in the solution of -1a (2H)-carboxylate methyl ester (100 milligrams, 0.177 mM) in THF/ carbinol mixtures (2.0 milliliters/2.0 milliliters).Reactant mixture is heated 5 minutes at 90 DEG C under microwave condition.Then concentrate it, be acidified with 1N HCl solutions, and with (2 × 20 milliliters) extractions of ethyl acetate.Merge organic layer, dry (MgSO₄), filtering, and concentration.Make residue pass through preparative HPLC to purify, obtain desired product, be faint yellow solid (59 milligrams, 60% yield).MS m/z552(MH⁺), retention time is 3.850 minutes.¹H NMR (300MHz, MeOD the) (m of δ ppm 0.25, 0.38H) 1.14-2.22 (m, 11.62H) 2.69-2.98 (m, 2H) 3.02 (s, 2.28H) 3.02 (s, 3.72H) 3.41 (d, J=15.00Hz, 0.62H) 3.88 (s, 3H) 4.01 (d, J=15.00Hz, 0.38H) 5.26 (d, J=15.00Hz, 0.38H) 5.45 (d, J=14.64Hz, 0.62H) 6.94-7.02 (m, 1H) 7.13 (d, J=2.56Hz, 0.38H) 7.21 (d, J=2.20Hz, 0.62H) 7.26 (d, J=8.42Hz, 0.62H) 7.30 (d, J=8.78Hz, 0.38H) 7.53 (dd, J=8.42, 1.46Hz, 0.62H) 7.61 (dd, J=8.60, 1.65Hz, 0.38H) 7.85 (d, J=8.42Hz, 0.62H) 7.89 (d, J=8.42Hz, 0.38H) 8.10 (s, 0.38H) 8.28 (d, J=1.46Hz, 0.62H).

Intermediate 12

(1aR)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides

By (437 milligrams of TBTU; 1.36 mMs) and (0.95 milliliter of DIPEA (diisopropylethylamine); 5.436 mMs) it is added to (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid (500 milligrams, 0.906 mM) is in the solution in DMSO (20.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then (2S, 3R) -3- amino -1,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- alcohol (280 milligrams, 1.36 mMs), and reactant mixture is stirred at room temperature overnight are added.Reactant mixture is quenched with water, and is acidified with 1N HCl solutions.Brown solid is separated, it is collected by filtering.Then, this material is separated by preparative HPLC under the following conditions：Chromatographic column is Sunfire19 millimeters × 100 millimeters of Waters；Solvent orange 2 A is 10%CH₃CN-90%H₂O-0.1%TFA；Solvent B is 90%CH₃CN-10%H₂O-0.1%TFA；Program is initially held time as 5 minutes to be started with 65% solvent B, and 90% solvent B was then gradually increased in 30 minutes, and flow velocity is 25 ml/mins.Loading capacity is 50-60 milligrams/operation.

(1aR)-[part] -8- cyclohexyl-N is eluted under the conditions of above-mentioned HPLC⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides then elute (1aS)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides.Products therefrom is faint yellow solid (230 milligrams, 36% yield).MS m/703(MH⁺), retention time is 3.936 minutes.¹H NMR (500MHz, MeOD) δ ppm 0.14-0.24 (m, 2.64H) 0.51 (s, 2.46H) 0.72-2.21 (m, 20.9H) 2.49 (m, 0.18H) 2.62 (m, 0.82H) 2.85 (m, 0.18H) 2.96 (m, 0.82H) 3.03 (s, 6H) 3.39 (m, 0.82H) 3.49-3.58 (m, 1.64H) 3.71-3.80 (m, 0.36H) 3.90 (s, 3H) 4.17 (d, J=14.65Hz, 0.18H) 5.06 (d, J=14.65Hz, 0.18H) 5.37 (d, J=14.95Hz, 0.82H) 6.73 (d, J=5.49Hz, 0.82H) 6.98-7.05 (m, 1H) 7.08 (d, J=4.58Hz, 0.18H) 7.10 (d, J=2.44Hz, 0.18H) 7.21 (d, J=2.44Hz, 0.82H) 7.31 (d, J=8.55Hz, 0.82H) 7.34 (d, J=8.55Hz, 0.18H) 7.59-7.64 (m, 1H) 7.87-7.93 (m, 1H) 7.99 (s, 0.18H) 8.09 (d, J=1.22Hz, 0.82H).

Intermediate 13

(1aS)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides

By (437 milligrams of TBTU; 1.36 mMs) and (0.95 milliliter of DIPEA; 5.436 mMs) it is added to (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid (500 milligrams, 0.906 mM) is in the solution in DMSO (20.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then (2S, 3R) -3- amino -1,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- alcohol (280 milligrams, 1.36 mMs), and reactant mixture is stirred at room temperature overnight are added.Reactant mixture is quenched with water, is then acidified with 1N HCl solutions.Solid of the separation with brown, it is collected by filtering.Then, this material is separated by preparative HPLC under the following conditions：Chromatographic column is 19 millimeters × 100 millimeters of Waters Sunfire；Solvent orange 2 A is 10%CH₃CN-90%H₂O-0.1%TFA；Solvent B is 90%CH₃CN-10%H₂O-0.1%TFA；Program is initially held time as 5 minutes to be started with 65% solvent B, and 90% solvent B was then gradually increased in 30 minutes, and flow velocity is 25 ml/mins；Loading capacity is 50-60 milligrams/operation.

Under the conditions of above-mentioned HPLC, in (1aR)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

(1aS)-[part] -8- cyclohexyl-N is eluted after -1a, 5 (2H)-dicarboxamides⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides.Products therefrom is faint yellow solid (215 milligrams, 34% yield).MS m/703(MH⁺), retention time is 4.038 minutes.¹H NMR(500MHz,MeOD)δppm 0.20(m,0.38H)0.75(s,1.86H)0.76(s,1.86H)0.84(s,1.86H)0.85(s,1.14H)0.89-2.18(m,18.9H)2.52(m,0.38H)2.70(m,0.62H)2.85(m,0.38H)2.97(m,0.62H)3.03(s,2.28H)3.04(s,3.72H)3.33-3.39(m,0.62H)3.43-3.51(m,1.24H)3.73-3.77(m,0.38H)3.78-3.84(m,0.38H)3.90(s,1.86H)3.90(s,1.14H)4.14(d,J=14.65Hz,0.38H)5.11(d,J=14.65Hz,0.38H)5.44(d,J=15.26Hz,0.62H)6.68(d,J=4.88Hz,0.62H)6.96-7.03(m,1H)7.07(d,J=5.19Hz,0.38H)7.12(d,J=2.44Hz,0.38H)7.23(d,J=2.14Hz,0.62H)7.27(d,J=8.54Hz,0.62H)7.33(d,J=8.54Hz,0.38H)7.55(dd,J=8.39,1.68Hz,0.62H)7.62(dd,J=8.55,1.53Hz,0.38H)7.87(d,J=8.54Hz,0.62H)7.91(d,J=8.55Hz,0.38H)8.08(d,J=1.22Hz,0.38H)8.10(d,J=1.22Hz,0.62H).

Intermediate 14

(-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza- 1a (2H)-carboxylic acid

10N NaOH (2.0 milliliters, 20 mMs) solution and 4 milliliters of water are added to (1aR)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides (160 milligrams, 0.228 mM) are in the solution in THF/MeOH (7 milliliters/7 milliliters).Reactant mixture is heated 1 hour at 120 DEG C under microwave condition.Then concentrate it, be acidified with dense HCl solution, and be extracted twice with ethyl acetate (2 × 30 milliliters).Merge organic layer, dry (MgSO₄), filtering, and orange oil is condensed into a vacuum.Then, make crude product pass through preparative HPLC chromatogram post to purify, obtain product, be faint yellow solid (80 milligrams, 64% yield).- 130.85 ° of (solvent MeOH of average specific rotatory power (average specific rotation)；589 nanometers of wavelength；50 centimeter of sample ponds).MS m/552(MH⁺), retention time is 3.760 minutes.¹H NMR (500MHz, MeOD) δ ppm0.27 (m, 0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09 (m, 6.62H) 3.45 (d, J=14.95Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H) 4.04 (d, J=15.26Hz, 0.38H) 5.28 (d, J=15.26Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55Hz, 0.62H) 7.33 (d, J=8.54Hz, 0.38H) 7.54 (dd, J=8.39, 1.68Hz, 0.62H) 7.63 (dd, J=8.55, 1.53Hz, 0.38H) 7.86 (d, J=8.55Hz, 0.62H) 7.91 (d, J=8.55Hz, 0.38H) 8.11 (d, J=1.22Hz, 0.62H) 8.29 (d, J=1.22Hz, 0.38H).

Intermediate 15

(+) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid

10N NaOH (1.8 milliliters, 18 mMs) solution and 4 milliliters of water are added to (1aS)-[part] -8- cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b- dihydros-N^1a- [(2R, 3S) -3- hydroxyls -4,7, the ring of 7- trimethyls two simultaneously [2.2.1] hept- 2- yls] -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxamides (130 milligrams, 0.185 mM) are in the solution in THF/MeOH (7 milliliters/7 milliliters).Reactant mixture is heated 1 hour at 120 DEG C under microwave condition.It is concentrated, is acidified with dense HCl solution, and be extracted twice with ethyl acetate (2 × 30 milliliters).Merge organic layer, dry (MgSO₄), filtering, and concentrate in a vacuum, obtain orange oil.Then, make crude product pass through preparative HPLC chromatogram post to purify, obtain product, be faint yellow solid (68 milligrams, 67% yield).Average+174.73 ° of specific rotatory power (solvent MeOH；589 nanometers of wavelength；50 centimeter of sample ponds).MSm/552(MH⁺), retention time is 3.773 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.27, 0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09 (m, 6.62H) 3.45 (d, J=14.95Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H) 4.04 (d, J=15.26Hz, 0.38H) 5.28 (d, J=15.26Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55Hz, 0.62H) 7.33 (d, J=8.54Hz, 0.38H) 7.54 (dd, J=8.39, 1.68Hz, 0.62H) 7.63 (dd, J=8.55, 1.53Hz, 0.38H) 7.86 (d, J=8.55Hz, 0.62H) 7.91 (d, J=8.55Hz, 0.38H) 8.11 (d, J=1.22Hz, 0.62H) 8.29 (d, J=1.22Hz, 0.38H).

Intermediate 16

The bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids 1 of 2-, 1- dimethylethyl esters

In (80 grams of bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids of 2-, 0.24 mole) molecular sieve (4A of activation is added in the solution stirred through mechanical system in anhydrous methylene chloride (1.2 liters) and THF (100 milliliters), 80 grams) and silver carbonate (275 grams, 0.99 mole).Reactant mixture is cooled to 0 DEG C, and tert-butyl bromide (142 grams, 1.04 moles) is added dropwise.Mixture is stirred at room temperature overnight, and passes through TLC (hexane-ethyl acetates 80:20, R_f(product)=0.7) monitor.If there is any bromic acid unconverted, further 10% silver carbonate of addition, and persistently stirring 2-4 hours again.When completing, make reactant mixture by the thin bed filtering of diatomite.By filtrate with (500 milliliters) washings of dichloromethane.The filtrate of merging is concentrated in a vacuum, and makes so obtained crude product pass through silica gel chromatograph to purify (230-400 mesh, with 0-2% gradient elution of the ethyl acetate in petroleum ether).Merge the eluting fraction of homogeneous, and evaporate under reduced pressure, obtain 80 grams of (85%) title compounds.HPLC：90.1% (RT=6.56 minutes), chromatographic column is C18 BDS (50 × 4.6 millimeters), and mobile phase is 0.1%TFA (trifluoroacetic acid) in water:Gradient in ACN (acetonitrile) (30 → 100 → 30), flow velocity is 0.8 ml/min.LCMS：99.8% (RT=4.44 minutes), chromatographic column is Geneis C1850 × 4.6 millimeter, and mobile phase is 0.1% formic acid in water：Gradient in ACN (70 → 95 → 70), flow velocity is 0.8 ml/min；M-1=376.5；¹H NMR(CDCl₃) (400MHz) δ 1.37-1.40 (m, 3H, cyclohexyl), 1.62 (s, 9H, the tert-butyl groups), 1.80-1.94 (two groups of multiplets, respectively 3H and 4H, cyclohexal moiety), 2.81 (m, 1H, the CH of cyclohexyl-benzyl), 7.70-7.75 (m, 2H, indoles-H_{4 and 5}), 8.04 (s, 1H, indoles-H₇), 8.52 (s, 1H, indoles-NH).

Intermediate 17

3- cyclohexyl -2- (2- formoxyl -4- methoxyphenyls) -1H- Indole-6-carboxylic acids 1,1- dimethylethyl esters

The bromo- 3- cyclohexyl -1H- Indole-6-carboxylic acids tert-butyl esters of 2- (72 grams, 0.19 mole) are made to be dissolved in the 1 of toluene and ethanol:In 1 mixture (720 milliliters), and deaerate.Then addition LiCl (23.9 grams, 0.51 mole), then adds sodium carbonate (720 milliliters, 1.0M solution is degassed in addition) and Pd- four (Pd-tetrakis) (13.1 grams, 0.011 mole).After stirring 0.25 hour, 2- formoxyl -4- methoxyphenyl-boronic acids (41.1 grams, 0.22 mole) are added, and reactant mixture is heated to 85 DEG C, are kept for 4 hours.Then, reaction passes through TLC (hexane-ethyl acetates 80:20, R_f(product)=0.55) monitor.When completing, reactant mixture is cooled to room temperature, and add water (1.0 liters), then add ethyl acetate (1.0 liters).By organic layer with salt water washing, and dry, and be concentrated under vacuum, obtain title compound, be yellow solid.75 grams of yield (74%).HPLC：99.7% (RT=6.30 minutes), chromatographic column is C18 BDS (4.6 × 50 millimeters), and SC-307, mobile phase is 0.1%TFA in water:Gradient in ACN (30 → 100 → 30), the ml/min of flow velocity 0.8.LCMS：98.0% (RT=5.28 minutes), chromatographic column is Geneis C18 (50 × 4.6 millimeters), and mobile phase is 0.1% formic acid in water:Gradient in ACN (70 → 95 → 70), flow velocity is 0.8 ml/min；M-1=432.2；¹H NMR(DMSO-d₆) (400MHz) δ 1.40-1.48 (m, 3H, cyclohexyl), 1.57 (s, 9H, the tert-butyl group), 1.84-1.90 (m, 7H, cyclohexal moiety), 3.09 (m, 1H, the CH of cyclohexyl-benzyl), 3.84 (s, 3H, OCH₃), 6.55 (d, J=4Hz, 1H, aryl H_2’), 7.06 (d, 1H, aryl H_3’), 7.08 (s, 1H, aryl H_6’), 7.23 (d, 1H, indoles-H₅), 7.53 (d, J=8Hz, 1H, indoles-H₄), 7.70-7.75 (m, 2H, NH+ indoles-H₇), 8.06 (s, 1H, CHO).

Intermediate 18

13- cyclohexyl -7H- indoles simultaneously [2,1-a] [2] benzo-aza

- 6,10- dicarboxylic acids 10- (1,1- dimethylethyl esters) 6- methyl esters

3- cyclohexyl -2- (2- formoxyl -4- the methoxyphenyls) -1H- Indole-6-carboxylic acids tert-butyl esters (62.5 grams, 0.144 mole) is dissolved in dry DMF (1.2 liters), and mechanically stir.Then (84 grams of cesium carbonate is added; 0.17 mole) (65-70%GC is pure for methyl acrylate with 2- (dimethoxy phosphono); 56.2 grams; 0.18 mole); and reactant mixture is heated to 65 DEG C; kept for 4 hours, and reaction passes through TLC (hexane-ethyl acetates 80:20, R_f(product)=0.7) monitor.When completing, mixture is cooled to room temperature, reaction then is quenched with water (1.0 liters).Yellow solid precipitate, it is collected by filtering, and is air-dried.Then, this material is made into slurries in methyl alcohol, filtered, and be dried under vacuum, obtained product, be yellow powder (70 grams, 90%).HPLC：99.1% (RT=6.45 minutes), chromatographic column is C18BDS (4.6 × 50 millimeters), and mobile phase is 0.1%TFA in water:Gradient in ACN (30 → 100 → 30), the ml/min of flow velocity 0.8.LCMS：100% (RT=7.00 minutes), chromatographic column is Geneis C18 (50 × 4.6 millimeters), and mobile phase is 0.1% formic acid in water:Gradient in ACN (70 → 95 → 70), flow velocity is 0.8 ml/min；M+1=502.2.¹H NMR(CDCl₃) (400MHz) δ 1.10-1.30 (m, 3H, cyclohexyl), 1.64 (s, 9H, the tert-butyl group), 1.77-2.07 (m, 7H, cyclohexal moiety), 2.80 (m, 1H, the CH of cyclohexyl-benzyl), 3.84 (s, 3H, OCH₃), 3.93 (s, 3H, COOCH₃), 4.15 and 5.65 (two broad peaks, each 1H, pi-allyl CH₂), 6.95 (s, 1H, aryl H_6’), 7.01 (d, 1H, aryl H_2’), 7.53 (d, J=8Hz, 1H, aryl H_3’), 7.70 (d, J=4Hz, 1H, indoles-H₅), 7.84 (s+d, 2H, alkene H+ indoles-H₄), 8.24 (s, 1H, indoles-H₇)；¹³C NMR(CDCl₃) (100.0MHz) δ 166.92,165.71,158.96,142.28,136.47,13.50,134.61,132.43,132.01,129.73,124.78,124.68,120.33,119.39,119.04,115.62,115.05,111.27,80.27,55.49,52.50,39.09,36.81,33.40,28.38,27.15,26.28.

Intermediate 19

2- (dimethoxy phosphono) -2- methyl acrylates

Equipped with mechanical agitator, condenser, temperature controller and N₂Paraformaldehyde (paraformaldehyde) (40.5 grams, 1.35 moles), MeOH (2 liters) and piperidines (2 milliliters) are added in 5 liter of four neck round-bottom flask of inlet tube.By reactant mixture in N₂Under be heated to backflow, keep 3 hours.After being cooled to 50 DEG C, disposable addition acetic acid 2- (dimethoxy phosphono) ester (150 grams, 0.824 mole).Reactant mixture is set to continue backflow 18 hours.After cooling to room temperature, concentrated reaction solution in a vacuum, obtains clear, colorless oil.Equipped with temperature controller, N₂In 3 liter of four neck round-bottom flask of inlet tube, magnetic stirrer and Dean-Stark trap (Dean-Stark apparatus), make to be dissolved in oil in dry toluene (1 liter).TsOHH is added in this solution₂O (5.2 grams).Then, reactant mixture is flowed back 18 hours in azeotropic mode, remove methanol.After cooling to room temperature, solution is concentrated in a vacuum, obtain yellow oil, it is evaporated in vacuo under 150-155 DEG C/0.2 millimetres of mercury, obtain product, be colorless oil (135.0 grams).Purity 90%, is based on¹H NMR。¹H NMR (CDCl3,300MHz) δ 7.0 (dd, J=42.4 and 1.5Hz, 1H), 6.73 (dd, J=20.5 and 1.8Hz, 1H), 3.80 (s, 6H), 3.76 (s, 3H).

Intermediate 20

(+/-) -8- cyclohexyl -1,12b- dihydro -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, 5 (2H)-dicarboxylic acids 5- (1,1- dimethylethyl esters) 1a- methyl esters

Under a nitrogen by (96 milligrams, 4 mMs) of sodium hydride added to chlorination trimethyl sulfoxonium (567 milligrams, 4.4 mMs) in the agitated suspension in anhydrous DMSO (10 milliliters).Resulting mixture is stirred at room temperature 30-45 minutes, then pure 13- cyclohexyl -3- methoxyl group -7H- indoles simultaneously [2,1-a] [2] benzo-aza is added with small portions

- 6,10- dicarboxylic acids 10- (1,1- dimethylethyl esters) 6- methyl esters (1.0 grams, 2 mMs).By this suspension with (5 milliliters) dilutions of DMSO, and heated 3-4 hours at 50 DEG C.Reactant mixture is cooled to room temperature, and add water.Solid is separated, it is collected by filtering, and with water washing, then air dried overnight, obtains 1.15 grams of crude products.Make this material pass through flash column chromatography to purify (silica gel, the 3%MeOH in DCM), obtain pure title compound (0.96 gram).LC/MS：Retention time 3.816 minutes；m/e 516(MH⁺)。¹H NMR (400MHz, CDCl₃)：NMR spectra based on compound, it is found that product exists in the form of the rotational isomer (rotamer) mutually converted.

Following programs is reach parsing racemic (+/-) -8- cyclohexyl -1,12b- dihydro -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, the embodiment of the method for 5 (2H)-dicarboxylic acids 5- (1,1- dimethylethyl esters) 1a- methyl esters.Make (+/-) -8- cyclohexyl -1,12b- dihydro -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a, the sample of 5 (2H)-dicarboxylic acids 5- (1,1- dimethylethyl esters) 1a- methyl esters is dissolved in the mixture (8 of isopropanol and acetonitrile:2) in, ultimate density is obtained for 20 mg/mls.This mixture is injected on preparative chirality SFC chromatographic systems, following conditions are used：Chiralcel OJ-H chromatographic columns, 4.6 × 250 millimeters, 5 microns；Mobile phase is in CO₂In 8%MeOH；Temperature is 35 DEG C；Flow velocity was 2 ml/mins, after 16 minutes；UV is monitored at 260 nanometers；Inject 5 microlitres of IPA:ACN(8:2), about 20.0 mg/ml.

Intermediate 21

- 1a, 5 (2H)-dicarboxylic acids 1a- methyl esters

(5 milliliters) of TFA is added to (+/-) -8- cyclohexyl -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (methoxycarbonyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid tert-butyl esters (515 milligrams, 1 mM) are in the solution in anhydrous DCM (dichloromethane) (10 milliliters).Resulting solution is stirred at room temperature about 8 to 12 hours.Then, reactant is evaporated to dryness, obtains title compound (0.47 gram, 100%).LC/MS：Retention time 2.245 minutes；m/e 460(MH⁺).¹H NMR (400MHz, CDCl₃)：Based on compound N MR spectrum, the mixture for finding product mutually to convert rotational isomer is present.

Intermediate 22

8- cyclohexyl -1,12b- dihydro -11- methoxyl groups -5- [[[(methylamino) sulfonyl] amino] carbonyl]-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester

By 8- cyclohexyl -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (methoxycarbonyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acids (140 milligrams, 0.31 mM) are stirred 1 hour with solution of the CDI (64 milligrams, 0.40 mM) in THF (3 milliliters) at 60 DEG C.N- methylsulfonamides (68 milligrams, 0.62 mM) and DBU (71.6 milligrams, 0.47 mM) are added, and mixture is stirred overnight at 60 DEG C.Then, reactant is poured into cold water, be acidified with watery hydrochloric acid, and extracted in ethyl acetate.By extract with watery hydrochloric acid (0.1N) and salt solution successive wash, (anhydrous sodium sulfate) then is dried, filtering, and evaporation, title compound is obtained, is brown solid.ESI-MS m/e 552(MH⁺).Using this material without being further purified.

Intermediate 23

8- cyclohexyl -1,12b- dihydro -11- methoxyl groups -5- [[[(methylamino) sulfonyl] amino] carbonyl]-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza- 1a (2H)-carboxylic acid

Make 8- cyclohexyl -5- [[[(methylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester is dissolved in THF and MeOH mixture (2 milliliters, 2 milliliters).Then addition 2.5M NaOH (aqueous solution) (1.2 milliliters, 3 mMs), and make reactant be vibrated 2 hours at 22 DEG C.Then neutralize solution with 1M HCl (aqueous solution) (3 milliliters), and concentration, to remove organic solvent.By residue with H₂O is made into slurries, and collects solid by filtering, with H₂O is washed, and is dried, and obtains title compound (160 milligrams, 0.30 mM).ESI-MSm/e 538(MH⁺).Using this material without being further purified.

Intermediate 24

(+/-) -8- cyclohexyl -5- [[[(benzylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- (methoxyl group) -12- (methoxyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester

By (+/-) -8- cyclohexyl -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (methoxycarbonyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acids (200 milligrams, 0.44 mM) are stirred 1 hour with solution of the CDI (92 milligrams, 0.57 mM) in THF (5 milliliters) at 60 DEG C.Then addition N- benzyls sulfonamide (164 milligrams, 0.88 mM) and DBU (100 milligrams, 0.66 mM), and resulting mixture is stirred overnight at 60 DEG C.Then, reactant is poured into cold water, be acidified with watery hydrochloric acid, and extracted in ethyl acetate.By organic phase with hydrochloric acid (0.1N) and salt water washing, and (sodium sulphate) is dried, and be evaporated in vacuo, obtained title compound, be brown solid.ESI-MS m/e 628(MH⁺)。

Intermediate 25

(+/-) -8- cyclohexyl -1,12b- dihydro -11- methoxyl groups -5- [[[[(phenyl methyl) amino] sulfonyl] amino] carbonyl]-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid

Title compound, which is used, to be similar on 8- cyclohexyl -5- [[[(methylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid described program, from (+/-) -8- cyclohexyl -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (methoxycarbonyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acids start and are made.ESI-MS m/e613(MH+).¹H NMR (500MHz, MeOD) δ ppm 1.22-2.20 (m, 13H) 3.27-3.31 (m, 1H) 3.47 (d, J=14.95Hz, 0.6H) 3.92 (d, J=2.44Hz, 3H) 4.04 (d, 0.4H) 4.31 (d, J=2.75Hz, 2H) 5.24 (d, 0.4H) 5.48 (d, 0.6H) 7.02 (d, 1H) 7.17 (d, J=2.75Hz, 1H) 7.19-7.35 (m, 5H) 7.39 (t, J=7.48Hz, 2H) 7.45-7.52 (m, 1H) 7.80 (d, J=1.53Hz, 0.4H) 7.85 (dd, J=8.39, 6.87Hz, 1H) 8.22 (d, J=1.53Hz, 0.6H).

Intermediate 26

(+/-) -8- cyclohexyl -5- [[(Cyclopropylsulfonyl) amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid

- 5- carboxylic acids (1 equivalent) are heated 30 minutes with mixture of the N,N'-carbonyldiimidazole (1.5 equivalent) in anhydrous THF at 50 DEG C, then allow to cool to room temperature.Then it is continuous to add 1 equivalent cyclopropyl-sulfonylamide and the carbon -7- alkene (2 equivalent) of 1,8- diazabicylo [5.4.0] 11.Resulting mixture is stirred at room temperature overnight.After acidic aqueous solution processing, make separated crude product pass through preparative HPLC to purify.Then, intermediate ester is hydrolyzed using the 1N NaOH in THF-MeOH, obtains title compound.LC/MS：Retention time is 2.030 minutes；m/e 549(MH⁺)。¹H NMR (400MHz, CDCl₃)：NMR spectra based on compound, finds product mutually to convert rotational isomer presence.

Intermediate 27

3- methyl -8- (phenyl methyl) -3,8- diazabicylos [3.2.1] octane

Make cis -1- benzyls -2 in 3 neck, 5 liters of round-bottomed flasks equipped with mechanical agitator, reflux condensing tube and thermometer, 5- bis- (chloromethyl) pyrrolidine hydrochloride (37.5 grams, 0.13 mole) (being made by described in the PCT Patent Application WO200232902 announced) is suspended in CH₃In CN (900 milliliters).Agitated suspension is warmed to 50 DEG C, add NaHCO₃(97 grams, 1.1 moles), and this suspension is warmed to 70 DEG C.NaI (50 grams, 0.33 mole) is added, and is stirred 5 minutes at 70 DEG C, will now add liquid funnel and be attached on condenser top.850 milliliters of CH are added in liquid funnel is added₃48 milliliters of 40%MeNH in CN₂The aqueous solution (0.55 mole), and this solution is added dropwise (speed of addition is maintained between 10-15 ml/mins).Addition is completed after 75 minutes, reactant is cooled to room temperature, is filtered out solid, and make solvent concentration into about 800 milliliters.Reactant is poured into EtOAc (800 milliliters), and with (2 × 100 milliliters) washings of 1N NaOH.With EtOAc (2 × 100 milliliters) aqueous phase extracteds again, make the organic phase of merging with Na₂SO₄Dry, and concentration.Resulting residue is loaded onto on silica gel (620 grams), and with CHCl₃In the dense NH of 2.8%MeOH/0.4%₄OH (amounting to 6 liters) elution.4 liters, which are risen to, from 2 collects pure eluting fraction.8.76 grams of (32% yield) title compounds are concentrated to give, are brown oil.¹H NMR (400MHz, CDCl3) δ ppm 1.79-1.87 (m, 2H) 1.92-1.99 (m, 2H) 2.23 (s, 3H) 2.27-2.37 (m, 2H) 2.54-2.63 (m, 2H) 3.10 (s, 2H) 3.52 (s, 2H) 7.20-7.26 (m, 1H) 7.30 (t, J=7.30Hz, 2H) 7.36-7.42 (m, 2H).LC methods：Solvent orange 2 A=10%MeOH/90%H₂O/0.1%TFA, solvent B=90%MeOH/10%H₂O/0.1%TFA, starts %B=0%, final %B=100%, the ml/min of flow velocity=4, gradient timetable=2 minute, and operating time=3 minute, chromatographic column is 10 microns C1850 millimeters × 3.0 millimeters, Rt=0.23 minutes of Phenomenex-Luna；MS：(ES+) m/z (M+H) +=217.3.Another 6.1 grams mixing eluting fraction (purity are obtained from chromatographic column>80%, it is based on¹H NMR are integrated).

Intermediate 28

3- methyl -3,8- diazabicylo [3.2.1] dihydrochloride salt

The ring diamines of N- methyl-N-benzyls two (14.22 grams, 65.7 mMs) is dissolved in 650 ml methanols, and add 17 milliliters of 12M aqueous hydrochloric acid solutions.Solution is placed in 2 liters of Parr bottles (Parr bottle) under a nitrogen, and 3.66 grams of 20% palladium dydroxide/carbon are added in reactant.Mixture is placed on Parr shaker under 60psi hydrogen, kept for 17 hours.Analyzed by TLC, judge that reaction has been completed (silica gel plate is eluted with the solution of the 2M ammonia of 10 volume parts through being dissolved in the chloroform of 90 volume parts in methyl alcohol).Reactant is filtered by diatomite packed column, then rinse it with water and methanol in succession.The filtrate of merging is concentrated in a vacuum, and adds methanol and benzene, untill obtaining homogeneous solution.Then the 2.0M hydrochloric acid in 75 milliliters of ether is added.Volatile materials is removed in a vacuum from reaction mixture, water is repeated azeotropic from reaction mixture using methanol/benzol mixture, thus finally give faint yellow solid.Solid product 3- methyl -3,8- diazabicylo [3.2.1] octane is dried in a vacuum overnight, obtain 11.98 grams of (91%) hygroscopic solids.Product is taken out from flask, and bottled under a nitrogen in bag glove, this is due to its hygroscopic nature.¹(s, 3H contain H to H NMR (500MHz, DMSO-D6) δ ppm 1.96-2.14 (m, 2H) 2.34 (d, J=8.24Hz, 2H) 2.66 (s, 3H) 3.46 (d, J=11.90Hz, 2H) 3.58₂O) 4.17 (s, 2H) 9.92 (s, 1H) 10.21 (s, 1H) 11.39 (s, 1H)；¹³C NMR (126MHz, DMSO-D6) δ ppm24.04 (s, 1C) 43.49 (s, 1C) 52.50 (s, 1C) 54.47 (s, 1C).

Intermediate 29 and 30

3,8- diazabicylos [3.2.1] octyl- 3- carboxylic acid phenyls methyl esters and 3- (phenyl methyl) -3,8- diazabicylos [3.2.1] octane

By triethylamine, (1.44 milliliters, 10.363 mMs) are added to 8- tertbutyloxycarbonyls -3,8- diazabicylo [3.2.1] octane (2.0 grams, 9.421 mMs) in CH₂Cl₂In solution in (20 milliliters), benzyl chloroformate (1.46 milliliters, 10.363 mMs) is added dropwise at 0 DEG C, and reactant mixture is stirred 0.5 hour at 0 DEG C, then warms to room temperature it, and persistently stir 3 days.Then reactant mixture is quenched with water, and is acidified with 1N HCl solutions.Organic layer is separated, with salt water washing, (MgSO is dried₄), and concentration, colourless thick oil is obtained, is crude product.Then, 70 milligrams of this materials is dissolved in 1,2- dichloroethanes (2 milliliters), and add TFA (0.5 milliliter).Reactant mixture is stirred at room temperature 2 hours.Then, solvent is evaporated with TFA, obtain the mixture of two kinds of title compounds, be colourless thick oil.

Intermediate 31

General procedure on manufacturing sulfonamide

Sour (1 equivalent) is heated 30 minutes with mixture of the N,N'-carbonyldiimidazole (1.5 equivalent) in anhydrous THF at 50 DEG C, room temperature is then allowed to cool to.Then it is continuous to add 1 equivalent sulphamide (R=NR₂) or sulfonamide (R=alkyl or aryls) and DBU (2 equivalent).Resulting mixture is stirred at room temperature overnight.After acidic aqueous solution processing, make separated crude product pass through preparative HPLC to purify, obtain title intermediate.

Intermediate 32

General procedure on manufacture acid

Methyl esters is hydrolyzed using the 1N NaOH in THF-MeOH.

Intermediate 33

By (0.049 gram pure of CDI, 0.302 mM) it is added to (0.092 gram of acid, 0.200 mM) in agitated solution in THF (1 milliliter), and mixture is heated 30 minutes at 50 DEG C, then allow to cool to room temperature.Then it is continuous to add N- cyclopropyl-N- methylsulfonamides (0.0451 gram, 0.300 mM) and DBU (0.060 milliliter, 0.400 mM).Make mixture ultrasonically treated 1-2 hours, be then stirred at room temperature overnight.Reaction is quenched with MeOH (0.5 milliliter), is then acidified with 1N HCl, and with (2 × 25 milliliters) extractions of EtOAc, Yi Shui and salt water washing, and dry (Na₂SO₄).Crude product (0.123 gram) is purified (5%MeOH in DCM) by flash chromatography on silica gel, obtain desired product.Product is pale solid (0.101 gram, 85%).

Intermediate 34

Under a nitrogen by (2 milliliters, 2.000 mMs) of 1N NaOH added to methyl esters (0.098 gram, 0.166 mM) in the agitated solution in THF-MeOH.Mixture is stirred at room temperature 2 hours, then with (3 milliliters) acidifyings of 1N HCl, with (2 × 25 milliliters) extractions of EtOAc, Yi Shui and salt water washing, and dry (MgSO₄).Evaporation solvent, obtains acid, is pale solid (0.0942 gram, 98%).LC/MS：m/e 578(MH+).LC/MS methods：It is 0 to start %B, and final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.

Intermediate 35

The tert-butyl alcohol (1.35 milliliters, 14 mMs) is added dropwise to CSI (1.24 milliliters, 14 mMs) in CH at 0 DEG C₂Cl₂In solution in (10 milliliters).Produced solution is stirred 2 hours at 0 DEG C.N- methyl propyl- 2- amine (1.57 milliliters, 14.13 mMs) is added dropwise with TEA (2.167 milliliters, 15.54 mMs) in CH₂Cl₂Solution in (3 milliliters).Produced reactant mixture is stirred at room temperature 2 hours, with EtOAc diluted reaction mixtures, and with cold 1N HCl and salt water washing, (MgSO is dried₄), solvent is removed, and make residue pass through Biotage 40M chromatographic columns to purify (EtOAc-MeOH (90-10)/hexane 5% to 100%), product is obtained, is colorless gum (2.3 grams, 65%).¹H NMR (400MHz, chloroform-d) δ ppm 1.19 (d, J=6.55Hz, 6H) 1.49 (s, 9H) 2.90 (s, 3H) 4.05-4.26 (m, 1H) 7.02 (width unimodal, 1H).

Intermediate 36

The cold HCl (6 milliliters, 24.00 mMs) of addition in N- isopropyl-N- meth vlsulfonamides carbamate (2.3 grams, 9.12 mMs); and be stirred at room temperature 2 hours, solvent is removed, product is obtained; for fawn-coloured solid (1.38 grams, 99%).¹H NMR (400MHz, chloroform-d) δ ppm 1.16 (d, J=6.80Hz, 5H) 2.72 (s, 3H) 4.16 (dt, J=13.53,6.70Hz, 1H) 4.43 (width unimodal, 1H).

Intermediate 37

Using CDI and DBU, product (0.261 gram, 81%) system certainly sour (0.25 gram, 0.54 mM) and amine.LC-MS retention times are 3.635 minutes；MS m/z(M+H)594.¹H NMR show that compound exists with rotational isomer (about 4/3).LC/MS methods：It is 0 to start %B, and final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.

Intermediate 38

Using the NaOH in THF/MeOH, this sour (0.22 gram, 87%) is made from ester (0.258 gram, 0.435 mM).Acid is separated into faint yellow solid.LC-MS retention times are 3.608 minutes；MSm/z(M+H)580.LC/MS methods：It is 0 to start %B, and final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.¹H NMR, which are shown, has rotational isomer (about 1/2).Main isomer¹H NMR (400MHz, chloroform-d) 0.41 (t of δ ppm, J=6.30Hz, 1H) 1.08-2.15 (m, 17H) 2.63-2.80 (m, 1H) 2.84-2.96 (m, 1H) 3.04 (s, 3H) 3.84 (s, 3H) 4.03 (d, J=14.86Hz, 1H) 4.22-4.41 (m, 1H) 5.35 (d, J=15.11Hz, 1H) 6.86 (dd, J=8.44, 2.39Hz, 1H) 6.98 (d, J=2.27Hz, 1H) 7.20 (d, J=8.56Hz, 1H) 7.67 (d, J=8.31Hz, 1H) 7.81-7.89 (m, 1H) 8.10 (s, 1H).

General procedure on manufacturing some embodiment acid amides

Acid derivative (1 equivalent) is merged in dry DMF with corresponding amine (1.2 equivalent), triethylamine (2-3 equivalents) and TBTU (1.3 equivalent), and be stirred at room temperature 1-2 hours, untill completing acid amides coupling.Make separated crude product pass through preparative HPLC to purify, obtain wanted acid amides.

Embodiment 1

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

By (43.7 milligrams of TBTU; 0.136 mM) and (0.095 milliliter of DIPEA; 0.544 mM) it is added to (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid (50 milligrams, 0.0906 mM) is in the solution in DMSO (2.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then 3- methyl -3 is added, (27.1 milligrams of 8- diazabicylos [3.2.1] dihydrochloride salt { J ＆ W PharmLab, LLCMorrisville, PA 19067-3620 }, 0.136 mM), and reactant mixture is stirred at room temperature 3 hours.Then concentrate it, and make residue pass through preparative reversed-phase HPLC to purify, obtain final product, be yellow solid (32 milligrams, 46% yield).MS m/z 660(MH⁺), retention time is 2.445 minutes,¹H NMR (300MHz, MeOD the) (m of δ ppm 0.20, 0.23H) 1.11-2.25 (m, 15.77H) 2.58 (m, 0.23H) 2.69 (m, 0.77H) 2.75-3.11 (m, 10H) 3.28-3.75 (m, 5H) 3.91 (s, 2.31H) 3.92 (s, 0.69H) 4.15-4.37 (m, 1H) 4.68 (m, br, 1H) 4.94-5.00 (m, 0.23H) 5.16 (d, J=15.00Hz, 0.77H) 7.00-7.09 (m, 1H) 7.18 (d, J=2.56Hz, 0.23H) 7.21 (d, J=2.56Hz, 0.77H) 7.33 (d, J=8.41Hz, 0.77H) 7.35 (d, J=8.42Hz, 0.23H) 7.57 (dd, J=8.42, 1.46Hz, 0.77H) 7.62 (dd, J=8.78, 1.46Hz, 0.23H) 7.91 (d, J=8.42Hz, 0.77H) 7.93 (d, J=8.42Hz, 0.23H) 8.00 (s, 0.77H) 8.07 (s, 0.23H).

Embodiment 2

(+/-) -3- [[8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydro -11- methoxies basic ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-azasBase -1a (2H)-yl] carbonyl] -3,8- diazabicylos [3.2.1] octyl- 8- carboxylic acids 1,1- dimethylethyl esters

By (131 milligrams of TBTU; 0.408 mM) and (0.237 milliliter of DIPEA; 1.36 mMs) it is added to (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylic acid (150 milligrams, 0.272 mM) is in the solution in DMSO (4.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then addition 8- tertbutyloxycarbonyls -3,8- diazabicylo [3.2.1] octane (86.7 milligrams, 0.408 mM), and reactant mixture is stirred at room temperature overnight.Then concentrate it, and make residue pass through preparative reversed-phase HPLC to purify, obtain title product, be faint yellow solid (110 milligrams, 54% yield).MS m/z746(MH⁺), retention time is 3.040 minutes.¹H NMR (300MHz, MeOD the) (m of δ ppm 0.17,0.25H) 1.08 (m, 0.25H) 1.17-2.28 (m, 24.5H) 2.38-3.12 (m, 8H) 3.43-4.43 (m, 10H) 4.76-4.85 (m, 0.25H) 4.96-5.19 (m, 0.75H) 7.02 (dd, J=8.60,2.38Hz, 1H) 7.17 (d, J=2.19Hz, 0.25H) 7.20 (d, J=2.20Hz, 0.75H) 7.26-7.39 (m, 1H) 7.49-7.70 (m, 1H) 7.80-8.00 (m, 1.75H) 8.12 (s, 0.25H).

Embodiment 3

(+/-) -8- cyclohexyl -1a- (3; 8- diazabicylos [3.2.1] oct-3-yl carbonyl)-N- [(dimethylamino) sulfonyl] -1,1a, 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza- 5- carboxylic acid amides

By TFA, (2 milliliters) are added to (+/-) -3- [[8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of 12b- dihydro -11- methoxies basic ring third

Base -1a (2H)-yl] carbonyl] -3,8- diazabicylos [3.2.1] octyl- 8- carboxylic acids 1,1- dimethylethyl esters (98 milligrams, 0.131 mM) are in the solution in 1,2- dichloroethanes (3 milliliters).Reactant mixture is stirred at room temperature 2 hours.Then concentrate it, obtain desired product, for the solid (100 milligrams, 100% yield) with brown.MSm/646(MH⁺), retention time is 2.478 minutes.¹H NMR (500MHz, MeOD) δ ppm0.24 (m, 0.28H) 1.14 (m, 0.28H) 1.19-2.23 (m, 15.22H) 2.57 (m, 0.28H) 2.69 (m, 0.72H) 2.81-3.09 (m, 8H) 3.30-3.40 (m, 1H) 3.67 (d, J=15.87Hz, 0.72H) 3.91 (s, 2.16H) 3.93 (s, 0.84H) 3.90-4.27 (m, 4.28H) 4.88-4.91 (m, 0.28H) 5.11 (d, J=15.56Hz, 0.72H) 7.00-7.09 (m, 1H) 7.19 (d, J=2.75Hz, 0.28H) 7.21 (d, J=2.14Hz, 0.72H) 7.34 (d, J=8.54Hz, 0.72H) 7.37 (d, J=8.55Hz, 0.28H) 7.59 (dd, J=8.55, 1.53Hz, 0.72H) 7.63 (dd, J=8.39, 1.37Hz, 0.28H) 7.92 (d, J=8.55Hz, 0.72H) 7.94-7.99 (m, 1H) 8.10 (s, 0.281H).

Embodiment 4

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(8- methyl -3; 8- diazabicylos [3.2.1] oct-3-yl) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

In (+/-) -8- cyclohexyl -1a- (3; 8- diazabicylos [3.2.1] oct-3-yl carbonyl)-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

Addition paraformaldehyde (6.4 milligrams, 0.213 mM), ZnCl in the solution of -5- carboxylic acid amides (54 milligrams, 0.071 mM) in methanol (3 milliliters)₂(29 milligrams, 0.213 mM) and Na (CN) BH₃(13.4 milligrams, 0.213 mM).Resulting mixture is heated 2 hours at 60 DEG C, room temperature is subsequently cooled to.The solid of presence is removed by filtering, and filtrate is concentrated under vacuum, and makes residue pass through preparative reversed-phase HPLC to purify, title compound is obtained, for flaxen solid (37 milligrams, 67% yield).MS m/660(MH⁺), retention time is 2.495 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.21, 0.3H) 1.13 (m, 0.3H) 1.18-2.22 (m, 15.4H) 2.58 (m, 0.3H) 2.68 (m, 0.7H) 2.76-3.11 (m, 11H) 3.32-3.37 (m, 1H) 3.63 (d, J=15.56Hz, 0.7H) 3.82-4.32 (m, 7.3H) 4.88-4.92 (m, 0.3H) 5.08 (d, J=15.56Hz, 0.7H) 7.00-7.08 (m, 1H) 7.18 (d, J=2.14Hz, 0.3H) 7.21 (d, J=2.14Hz, 0.7H) 7.32 (d, J=8.55Hz, 0.7H) 7.35 (d, J=8.55Hz, 0.3H) 7.57 (d, J=7.93Hz, 0.7H) 7.62 (dd, J=8.39, 1.37Hz, 0.3H) 7.91 (d, J=8.55Hz, 0.7H) 7.93-7.99 (m, 1H) 8.09 (s, 0.3H).

Embodiment 5

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [[8- (1- Methylethyls) -3; 8- diazabicylos [3.2.1] oct-3-yl] carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Addition acetone (1 milliliter), ZnCl in the solution of -5- carboxylic acid amides (40 milligrams, 0.071 mM) in methanol (3 milliliters)₂(29 milligrams, 0.213 mM) and Na (CN) BH₃(13.4 milligrams, 0.213 mM).Reactant mixture is heated overnight at 60 DEG C, room temperature is subsequently cooled to.The solid of presence is removed by filtering, and filtrate is concentrated under vacuum, and makes residue pass through preparative reversed-phase HPLC to purify, title compound is obtained, for flaxen solid (29 milligrams, 69% yield).MS m/688(MH⁺), retention time is 2.477 minutes.¹H NMR (300MHz, MeOD the) (m of δ ppm 0.20, 0.23H) 1.12 (m, 0.23H) 1.18-2.41 (m, 21.54H) 2.51-3.18 (m, 10H) 3.64 (d, J=15.37Hz, 0.77H) 3.79-4.51 (m, 8.23H) 4.81-4.88 (m, 0.23H) 5.07 (d, J=14.27Hz, 0.77H) 6.99-7.08 (m, 1H) 7.17-7.23 (m, 1H) 7.28-7.36 (m, 1H) 7.57 (dd, J=8.42, 1.10Hz, 0.77H) 7.61 (dd, J=8.42, 1.47Hz, 0.23H) 7.83-8.00 (m, 1.77H) 8.09 (s, 0.23H).

Embodiment 6

(1aR; 12bS) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Addition TBTU (178 milligrams, 0.555 mM) and DIPEA (0.39 milliliter, 2.22 mMs) in solution of-the 1a (2H)-carboxylic acid (204 milligrams, 0.37 mM) in DMSO (8.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then addition 3- methyl -3,8- diazabicylo [3.2.1] dihydrochloride salt (111 milligrams, 0.555 mM), and reactant mixture is stirred at room temperature 2 hours.Then concentrate it, and make residue pass through preparative reversed-phase HPLC to purify, obtain yellow solid, be final tfa salt (265 milligrams, 92% yield).Average specific rotatory power is -53.56 ° of (solvent MeOH；589 nanometers of wavelength；50 centimeter of sample ponds).MS m/z 660(MH⁺), retention time is 3.035 minutes.¹H NMR (300MHz, MeOD the) (m of δ ppm 0.20, 0.23H) 1.11-2.25 (m, 15.77H) 2.58 (m, 0.23H) 2.69 (m, 0.77H) 2.75-3.11 (m, 10H) 3.28-3.75 (m, 5H) 3.91 (s, 2.31H) 3.92 (s, 0.69H) 4.15-4.37 (m, 1H) 4.68 (m, br, 1H) 4.94-5.00 (m, 0.23H) 5.16 (d, J=15.00Hz, 0.77H) 7.00-7.09 (m, 1H) 7.18 (d, J=2.56Hz, 0.23H) 7.21 (d, J=2.56Hz, 0.77H) 7.33 (d, J=8.41Hz, 0.77H) 7.35 (d, J=8.42Hz, 0.23H) 7.57 (dd, J=8.42, 1.46Hz, 0.77H) 7.62 (dd, J=8.78, 1.46Hz, 0.23H) 7.91 (d, J=8.42Hz, 0.77H) 7.93 (d, J=8.42Hz, 0.23H) 8.00 (s, 0.77H) 8.07 (s, 0.23H).

On synthesis (1aR; 12bS)-relative-(-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

The alternative program of -5- carboxylic acid amides is provided below.In N₂Under in (-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-(25.2 grams of carboxylic acid, 45.68 mMs) and 3- methyl -3,8- diazabicylos-(10.0 grams of [3.2.1] dihydrochloride salt, 50.22 mMs) addition DIPEA (23.62 grams, 182.72 mMs) in mixture in anhydrous MeCN (acetonitrile) (300 milliliters).After 15 minutes, TBTU (16.12 grams, 50.22 mMs) is added.By reaction solution in N₂Lower stirring 30 minutes.HPLC shows disappearance of starting material.The solvent in solution is evaporated, foam thing is obtained.It is set to be dissolved in EtOAc (2.5 liters), with H₂O (1.5 liters), H₂O/ salt solution (8:2) (1.5 liters) and (1.5 liters) washings of salt solution, with Na₂SO₄Dry, and evaporate, obtain 28.8 grams of crude products.By this solid with derived from 45.4 grams of materials that five times are reacted in addition collecting, obtain amounting to 74.2 grams of crude products.Silicagel pad (E.Merck 230-400 mesh, 1 kilogram) is passed to, with MeOH/CH₂Cl₂(2.5:97.5) elute.After evaporation, foam thing is obtained, it is handled with EtOAc and hexane and changes into solid.After being dried 7 hours under 50 DEG C and vacuum, GC analyses show that it has each 1.4% EtOAc and hexane.After 61-64 DEG C is further dried, GC analyses show that it still has 1.0% hexane and 1.4%EtOAc.Product is set to be dissolved in Et₂In O, and slowly evaporate three times in a vacuum, dried 3 hours under 60 DEG C and vacuum, obtain 68.3 grams.By it with H₂(900 milliliters) washings of O, and re-dry 7 hours under 68 DEG C and vacuum, obtain the compound of 67.1 grams of (77% yield) embodiments 6.GC analyses show that it has 0.97%Et₂O.HPLC conditions：Chromatographic column is 3 × 250 millimeters of Cadenza CD-C18；UV is 257 and 220 nanometers；25℃；Flow velocity is 0.5 ml/min；Gradient timetable is 38 minutes, 0-80%B (0-35 minutes) and 80%B (35-38 minutes)；Solvent orange 2 A is the 25nM CH in water that pH is 4.7₃COONH₄, solvent B is MeCN；HPLC purity 99.7% (retention time 26.54 minutes).Chiral HPLC conditions：Chromatographic column is Regis (S, S) Whelk-O1250 × 4.6 millimeter；258 nanometers of UV；35℃；The ml/min of flow velocity 2.0；Mobile phase CO₂/MeOH；Gradient timetable 20 minutes, 30%MeOH (0-1 minutes), 30-48%MeOH (1-19 minutes), 48%MeOH (19-20 minutes)；Chiral HPLC purity>99.8% (retention time 16.60 minutes)；LC/MS(ES⁺) 660.36 (M+H, 100)；HRMS：Calculated value 660.3220, measured value 660.3197；[α]_D ^25C- 79.66 ° (c1.06, MeOH)；To C₃₆H₄₅N₅O₅S·0.6H₂O·0.09Et₂O analytically calculated value：C, 64.53, H, 7.00, N, 10.35, S, 4.74, H₂O, 1.51, Et₂O, 0.97；Measured value：C, 64.50, H, 7.12, N, 10.41, S, 5.14, H₂O, 1.52, Et₂O, 0.97.(1aR; 12bS)-relative-(-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

The absolute stereochemical of -5- carboxylic acid amides goes out as drawn by above, and by being determined based on the x- ray crystal structures obtained by (R)-camsilate.

In addition, preparing following salt：Hydrochloride, phosphate, acetate, sulfate, camsilate, sodium salt, calcium salt and magnesium salts.Its hydrochloride has following characteristics：There is possible fusing/degraded heat absorption of the small wide heat absorption and peak from 25 DEG C to 75 DEG C between 253 DEG C and 258 DEG C in DSC；Weightless and about 200 DEG C degraded is weightless early stage in TGA with since 25 DEG C to 75 DEG C between 0.003% and 1.5%.

Embodiment 7

(+/-) -8- cyclohexyl-N- (Cyclopropylsulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

By the tetrahydrochysene -11- methoxyl groups of (+/-) -8- cyclohexyl -5- (Cyclopropylsulfonyl carbamyl) -1,1a, 2,12b--ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a- carboxylic acids (1 equivalent) and 3- methyl -3,8- diazabicylos [3.2.1] octane (1.2 equivalent), triethylamine (3 equivalent) and TBTU (1.3 equivalent) merge in dry DMF, and be stirred at room temperature about 2 hours, until finding that reaction is carried out untill completing by lcms analysis.Then, product is separated by preparative reversed-phase HPLC, is obtained single tfa salt of wanted title compound, is buff white solid.LC/MS：Retention time is 2.986 minutes；m/e 657(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (400MHz, chloroform-D)：δ ppm 0.22-0.36 (m, 1H), 1.09-1.20 (m, J=8.06Hz, 3H), 1.18-1.30 (m, 2H) 1.29-1.48 (m, 5H), 1.48-1.67 (m, 1H), 1.68-1.86 (m, 3H), 1.87-2.09 (m, 5H), 2.11-2.40 (m, 1H), 2.42-2.67 (m, 1H), 2.67-2.88 (m, J=4.78Hz, 1H), 2.86-3.02 (m, 2H), 3.02-3.28 (m, 2H), 3.42-3.55 (m, 1H), 3.55-3.77 (m, 2H), 3.83-3.92 (m, 3H), 3.93-4.15 (m, 1H), 4.28-4.58 (m, 1H), 4.61-4.99 (m, J=106.26Hz, 1H), 5.04-5.26 (m, 1H), 6.90-7.03 (m, 1H), 7.07-7.15 (m, J=2.52Hz, 1H), 7.27-7.36 (m, 1H), 7.42-7.68 (m, 1H), 7.82-7.96 (m, J=8.56Hz, 1H), 8.01-8.18 (m, 1H).

Embodiment 8

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [[3- (phenyl methyl) -3; 8- diazabicylos [3.2.1] octyl- 8- yls] carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

In 8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

Addition TBTU (35 milligrams, 0.109 mM) and DIPEA (0.076 milliliter, 0.435 mM) in solution of-the 1a (2H)-carboxylic acid (40 milligrams, 0.0725 mM) in DMSO (1.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then, the mixture of preparation of the addition derived from above-mentioned 3,8- diazabicylos [3.2.1] octyl- 3- benzyl carboxylates, and reactant is stirred at room temperature overnight.Then concentrate it, and make residue pass through preparative reversed-phase HPLC to purify, obtain product, be faint yellow solid (12.5 milligrams, 20% yield).MS m/z 736(MH⁺), retention time is 2.631 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.20, 0.16H) 1.11-2.25 (m, 15.84H) 2.57 (m, 0.16H) 2.70 (m, 0.84H) 2.85 (m, 0.16H) 2.80-3.60 (m, 11.84H) 3.65 (d, J=15.26Hz, 0.84H) 3.92 (s, 3H) 4.22 (d, J=14.95Hz, 0.16H) 4.33-4.76 (m, 3H) 4.96 (m, 0.16H) 5.08-5.33 (m, 0.84H) 6.97-7.10 (m, 1H) 7.17 (d, J=2.44Hz, 0.16H) 7.22 (d, J=2.44Hz, 0.84H) 7.28-7.42 (m, 1H) 7.43-7.74 (m, 6H) 7.87-7.96 (m, 1H) 7.99-8.19 (m, 1H).

Embodiment 9

(+/-) -8- [[8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydro -11- methoxies basic ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-azas

Base -1a (2H)-yl] carbonyl] -3,8- diazabicylos [3.2.1] octyl- 3- carboxylic acid phenyl methyl esters

Addition TBTU (35 milligrams, 0.109 mM) and DIPEA (0.076 milliliter, 0.435 mM) in solution of-the 1a (2H)-carboxylic acid (40 milligrams, 0.0725 mM) in DMSO (1.0 milliliters).Reactant mixture is stirred at room temperature 15 minutes.Then the mixture of preparation of the addition derived from 3,8- diazabicylos [3.2.1] octyl- 3- benzyl carboxylates, and reactant is stirred at room temperature overnight.Then, resulting mixture is concentrated in a vacuum, and make residue pass through preparative reversed-phase HPLC to purify, obtain product, be faint yellow solid (42 milligrams, 74% yield).MS m/z 780(MH⁺), retention time is 3.070 minutes.¹H NMR (500MHz, MeOD) δ ppm0.14 (m, 0.22H) 1.06-2.20 (m, 15.78H) 2.51 (m, 0.22H) 2.58-3.23 (m, 9.78H) 3.54-4.07 (m, 6.78H) 4.16 (d, J=14.65Hz, 0.22H) 4.31-4.59 (m, br, 1H) 4.96 (m, 0.22H) 5.02-5.23 (m, 2.78H) 6.94-7.07 (m, 1H) 7.16 (d, J=2.44Hz, 0.22H) 7.21 (s, 0.78H) 7.26-7.45 (m, 6H) 7.50-7.65 (m, 1H) 7.82-8.04 (m, 1.78H) 8.10 (s, 0.22H).

Embodiment 10

(+/-) -8- cyclohexyl -1a- (3; 8- diazabicylos [3.2.1] octyl- 8- bases carbonyl)-N- [(dimethylamino) sulfonyl] -1,1a, 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

In 8- [[8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b- dihydro -11- methoxies basic ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-azas

Base -1a (2H)-yl] carbonyl] -3, addition 10%Pd/ carbon (40 milligrams) in solution of 8- diazabicylos [3.2.1] the octyl- 3- carboxylic acid phenyls methyl esters (360 milligrams, 0.462 mM) in methanol/ethyl acetate (20 milliliters/20 milliliters).Reactant mixture is stirred overnight under hydrogen (1 atmospheric pressure).Then, mixture is filtered by diatomite, and filtrate is washed with methanol and ethyl acetate.The filtrate merged is concentrated, product is obtained, is yellow solid (275 milligrams, 92% yield).MS m/z 646(MH⁺), retention time is 2.983 minutes.¹H NMR (500MHz, MeOD) δ ppm0.20 (m, 0.2H) 1.12-2.29 (m, 15.8H) 2.52-2.86 (m, 1.2H) 2.99 (m, 0.8H) 3.02 (s, 4.8H) 3.03 (s, 1.2H) 3.09-3.49 (m, 5H) 3.68 (d, J=15.26Hz, 0.8H) 3.91 (s, 2.4H) 3.92 (s, 0.6H) 4.03-4.26 (m, 0.4H) 4.62-4.85 (m, 1H) 5.17 (d, J=13.71Hz, 0.8H) 6.99-7.11 (m, 1H) 7.19 (s, 0.2H) 7.23 (s, 0.8H) 7.32-7.40 (m, 1H) 7.59 (d, J=8.24Hz, 0.8H) 7.63 (d, J=8.24Hz, 0.2H) 7.89-7.96 (m, 1H) 7.98 (s, 0.8H) 8.09 (s, 0.2H).

Embodiment 11

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1a- [(3- ethyls -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] -1; 1a; 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

In (+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

Addition acetaldehyde (0.013 milligram, 0.232 mM), ZnCl in the solution of -5- carboxylic acid amides (30 milligrams, 0.0465 mM) in methanol (2 milliliters)₂(19 milligrams, 0.14 mM) and Na (CN) BH₃(8.8 milligrams, 0.14 mM).Resulting mixture is stirred at room temperature overnight, within this time, sediment is formed.This solid by filtration is removed, and filtrate is concentrated under vacuum.Then, make residue pass through preparative reversed-phase HPLC to purify, obtain the tfa salt of title compound, be faint yellow solid (35 milligrams, 96% yield).MS m/z 674(MH⁺), retention time is 3.013 minutes.¹HNMR (500MHz, MeOD the) (m of δ ppm 0.22, 0.16H) 1.09-2.29 (m, 18.84H) 2.59 (m, 0.16H) 2.70 (m, 0.84H) 2.86 (m, 0.16H) 2.97-3.03 (m, 5.88H) 3.03 (s, 0.96H) 3.11-3.81 (m, 7H) 3.92 (s, 2.52H) 3.93 (s, 0.48H) 4.22 (d, J=14.95Hz, 0.16H) 4.39 (s, br, 0.84H) 4.60-4.85 (m, 1.16H) 5.20 (d, J=14.64Hz, 0.84H) 7.01-7.09 (m, 1H) 7.20 (d, J=2.75Hz, 0.16H) 7.22 (d, J=2.44Hz, 0.84H) 7.33-7.38 (m, 1H) 7.59 (dd, J=8.39, 1.37Hz, 0.84H) 7.63 (dd, J=8.55, 1.53Hz, 0.16H) 7.90-7.96 (m, 1H) 8.02 (s, 0.84H) 8.09 (s, 0.16H).

Embodiment 12

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [[3- (1- Methylethyls) -3; 8- diazabicylos [3.2.1] octyl- 8- yls] carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Addition acetone (0.010 milligram, 0.14 mM) and ZnCl in solution of-the 5- carboxylic acid amides (30 milligrams, 0.0465 mM) in methanol (2 milliliters)₂(19 milligrams, 0.14 mM).Reactant mixture is heated 1 hour at 50 DEG C.Then Na (CN) BH is added₃(8.8 milligrams, 0.14 mM), and reactant is stayed overnight in 50 DEG C of holdings, within this time, form sediment.This material is removed by filtering, filtrate is then concentrated in a vacuum.Then, make resulting residue pass through preparative HPLC chromatogram post to purify, obtain the tfa salt of title compound, be faint yellow solid (35 milligrams, 94% yield).MS m/z688(MH⁺), retention time is 3.011 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.21, 0.19H) 1.11-2.24 (m, 21.81H) 2.58 (m, 0.19H) 2.72 (m, 0.81H) 2.85 (m, 0.19H) 2.93-3.03 (m, 5.67H) 3.03 (s, 1.14H) 3.14-3.73 (m, 6H) 3.91 (s, 2.43H) 3.93 (s, 0.57H) 4.22 (d, J=14.95Hz, 0.19H) 4.39 (s, br, 0.81H) 4.58-4.80 (m, br, 1H) 4.84 (m, 0.19H) 5.19 (d, J=15.26Hz, 0.81H) 6.99-7.09 (m, 1H) 7.20 (d, J=2.44Hz, 0.19H) 7.23 (d, J=2.44Hz, 0.81H) 7.31-7.39 (m, 1H) 7.58 (d, J=8.55Hz, 0.81H) 7.63 (d, J=8.55Hz, 0.19H) 7.93 (d, J=8.24Hz, 1H) 8.01 (s, 0.81H) 8.11 (s, 0.19H).

Embodiment 13

(+/-) -8- cyclohexyl -1a- [[3- (Cvclopropvlmethvl) -3; 8- diazabicylos [3.2.1] octyl- 8- yls] carbonyl]-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

The addition formaldehyde of ring third (cycloporpanecarboxaldehyde) (0.007 milligram, 0.093 mM), ZnCl in the solution of -5- carboxylic acid amides (20 milligrams, 0.031 mM) in methanol (2 milliliters)₂(12.7 milligrams, 0.093 mM) and Na (CN) BH₃(5.8 milligrams, 0.093 mM).Mixture is stirred at room temperature 2 hours, then insoluble solid is removed by filtering.Filtrate is concentrated in a vacuum, and make resulting residue pass through preparative reversed-phase HPLC to purify, obtain the tfa salt of title compound, be faint yellow solid (10 milligrams, 40% yield).MS m/z 700(MH⁺), retention time is 3.033 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.21, 0.18H) 0.47 (s, br, 2H) 0.69-0.85 (m, 2H) 0.93-2.29 (m, 16.82H) 2.58 (m, 0.18H) 2.71 (m, 0.82H) 2.86 (m, 0.18H) 2.94-3.80 (m, 13.82H) 3.91 (s, 2.46H) 3.93 (s, 0.54H) 4.23 (d, J=14.95Hz, 0.18H) 4.41 (s, br, 0.82H) 4.61-4.79 (m, 1H) 4.98 (m, 0.18H) 5.19 (d, J=14.35Hz, 0.82H) 7.01-7.09 (m, 1H) 7.19 (d, J=2.75Hz, 0.18H) 7.22 (d, J=2.44Hz, 0.82H) 7.32-7.39 (m, 1H) 7.58 (d, J=8.24Hz, 0.82H) 7.63 (d, J=8.24Hz, 0.18H) 7.90-7.96 (m, 1H) 8.02 (s, 0.82H) 8.09 (s, 0.18H).

Embodiment 14

(+/-) -1a- [(3- acetyl group -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysenes -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

By (15 milligrams of TBTU, 0.0465 mM) and (0.027 milliliter of DIPEA, 0.155 mM) acetic acid (3 milligrams, 0.0465 mM) is added in the solution in DMSO (1.0 milliliters), and mixture is stirred at room temperature 15 minutes.Then (+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1 is added; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides (20 milligrams, 0.031 mM), and reactant is stirred at room temperature overnight.Then concentrate it, and make residue pass through preparative HPLC chromatogram post to purify, obtain title compound, be faint yellow solid (7 milligrams, 33% yield).MS m/z 688(MH⁺), retention time is 3.278 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.18, 0.2H) 1.07-2.27 (m, 18.8H) 2.55 (m, 0.2H) 2.72 (m, 0.8H) 2.86 (m, 0.2H) 2.95-3.08 (m, 6.8H) 3.15-3.78 (m, 5H) 3.91 (s, 2.4H) 3.93 (s, 0.6H) 4.05-4.29 (m, 1H) 4.40-4.59 (m, 1H) 4.93 (m, 0.2H) 5.16 (m, 0.8H) 6.99-7.10 (m, 1H) 7.19 (m, 0.2H) 7.23 (d, J=2.14Hz, 0.8H) 7.30-7.41 (m, 1H) 7.59 (d, J=8.85Hz, 0.8H) 7.64 (d, J=8.24Hz, 0.2H) 7.86-8.06 (m, 1.8H) 8.13 (s, 0.2H).

Embodiment 15

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [[3- (2- pyridine radicals) -3; 8- diazabicylos [3.2.1] octyl- 8- yls] carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

In microwave reaction pipe fitting; (+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1 is added under a nitrogen; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides (20 milligrams, 0.031 mM), Pd₂(dba)₃(0.6 milligram, 2 moles of %), 1,3- bis- (diphenylphosphino) propane (0.5 milligram, 4 moles of %), (8.9 milligrams of sodium tert-butoxide, 0.093 mM) and 2- bromopyridines (0.006 milliliter, 0.062 mM).Then, by reaction pipe fitting sealing, and dioxane (1 milliliter) is added, then reactant mixture is heated overnight in oil bath at 70 DEG C.Then reactant, and concentration are filtered, and makes residue pass through preparative HPLC chromatogram post to purify, the tfa salt of title compound is obtained, is pale solid (2.2 milligrams, 7.5% yield).MS m/z 723(MH⁺), retention time is 3.048 minutes.¹H NMR (500MHz, MeOD the) (m of δ ppm 0.25, 0.2H) 1.11-2.23 (m, 15.8H) 2.60 (m, 0.2H) 2.76 (m, 0.8H) 2.79-3.10 (m, 7H) 3.13-4.00 (m, 8H) 4.27 (d, J=15.26Hz, 0.2H) 4.46 (s, br, 0.8H) 4.63-4.81 (m, 1H) 4.99 (m, 0.2H) 5.26 (d, J=15.26Hz, 0.8H) 7.02-7.16 (m, 2H) 7.20-7.27 (m, 1H) 7.32-7.68 (m, 3H) 7.77 (d, J=7.93Hz, 0.2H) 7.85-8.18 (m, 3.8H).

Embodiment 16

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysenes -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] -11- (Phenylmethoxy)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

Make (+/-) -8- cyclohexyl -5- [[[(dimethylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- (Phenylmethoxy)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-(496 milligrams of carboxylic acid, 0.79 mM) it is dissolved in 7 milliliters of DMF, and add (392 milligrams of TBTU, 1.22 mMs), and then reactant is added into (525 milligrams of DMAP in room temperature and stirred under nitrogen 1 hour, 4.29 mMs), then 3- methyl -3,8- diazabicylo [3.2.1] dihydrochloride salt (196 milligrams, 0.98 mM) is added.By reactant in room temperature and stirred under nitrogen 17 hours, it is subsequently poured into 100 milliliters of water.By aqueous mixture with ethyl acetate extraction.By organic extract liquid with water washing twice, then washed twice with salt solution, and dried with magnesium sulfate.Volatile materials is removed in a vacuum, 615 milligrams of crude products are obtained, it is adsorbed on 1.5 grams of silica gel, and carries out chromatographic isolation on 18 grams of silica gel, is eluted with 3% methanol in dichloromethane.Merge pure products eluting fraction, and remove volatile materials in a vacuum, obtain 216 milligrams (37%) and connect subdiaphanous amorphous solid.¹H NMR (500MHz, chloroform-D) 0.27 (t of δ ppm, J=5.80Hz, 0.4H) 1.14-1.30 (m, 2.9H) 1.30-1.48 (m, 3.7H) 1.57 (d, J=15.26Hz, 2.3H) 1.63-1.87 (m, 11.2H) 1.85-2.20 (m, 8.4H) 2.30 (s, 1.3H) 2.39 (s, 0.9H) 2.69 (s, 1.2H) 2.79 (s, 1.2H) 2.85-3.01 (m, 1.9H) 3.01-3.11 (m, 6.0H) 3.25-3.51 (m, 1.8H) 3.59 (d, J=15.26Hz, 1.2H) 4.14 (d, J=14.95Hz, 0.4H) 4.40 (s, 0.9H) 4.75 (d, J=13.73Hz, 0.4H) 5.07-5.21 (m, 2.8H) 6.92-7.11 (m, 1.5H) 7.21 (d, J=2.75Hz, 1.0H) 7.27-7.49 (m, 7.0H) 7.53 (d, J=7.93Hz, 0.6H) 7.87 (dd, J=8.55, 4.88Hz, 1.0H) 7.91-8.03 (m, 0.9H) 8.83 (s, 0.2H) 9.67 (s, 0.3H).

Embodiment 17

(+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysene -11- hydroxyls -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Utilize heating; by (+/-) -8- cyclohexyl-N- [(dimethylamino) sulfonyl] -1; 1a; 2; 12b- tetrahydrochysenes -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] -11- (Phenylmethoxy)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides (189 milligrams, 0.26 mM) is dissolved in the mixture for the THF that 5 ml methanols are free of inhibitor with 2 milliliters.In cooling, some species precipitates are separated out.1N aqueous hydrochloric acid solutions (0.3 milliliter, 0.3 mM) are added to help to dissolve.Before addition 20% palladium dydroxide/carbon (46 milligrams), reactant is placed under nitrogen.Reaction is set to be carried out 6.75 hours under room temperature and hydrogen (atmospheric pressure) (gas cylinder).Reactant is set to be filtered by diatomite packed column.The volatile materials in filtrate is removed in a vacuum, is obtained 161 milligrams of (92%) products, is faint yellow solid.¹H NMR (500MHz, DMSO-D6) δ ppm 0.01 (t, J=5.34Hz, 0.3H) 0.39 (s, 0.3H) 1.08-1.60 (m, 6.6H) 1.62-1.83 (m, 2.9H) 1.82-2.20 (m, 6.3H) 2.58-2.84 (m, 4.9H) 2.84-2.96 (m, 6.9H) 3.07-3.19 (m, 1.0H) 3.20-3.29 (m, 1.6H) 3.34 (s, 10.0H, H₂O) 3.42 (s, 0.9H) 3.58 (d, J=14.65Hz, 0.8H) 4.13 (d, J=14.95Hz, 0.4H) 4.31-4.62 (m, 0.8H) 4.91 (d, J=14.95Hz, 0.3H) 4.98-5.21 (m, 0.7H) 6.85 (t, J=8.55Hz, 1.1H) 6.99 (s, 1.0H) 7.09-7.25 (m, 1.0H) 7.62 (d, J=20.14Hz, 1.0H) 7.72-7.91 (m, 1.0H) 7.92-8.29 (m, 0.9H) 9.92 (s, 1.0H) 10.16 (d, J=56.15Hz, 0.8H) 11.63 (d, J=10.68Hz, 0.9H).

Embodiment 18

(-) -8- cyclohexyl -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups-N- [(methylamino) sulfonyl] -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

By 8- cyclohexyl -5- [[[(methylamino) sulfonyl] amino] carbonyl] -1,12b- dihydros -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-(158 milligrams of carboxylic acid, 0.29 mM), 3- methyl -3, (59 milligrams of 8- diazabicylos [3.2.1] dihydrochloride salt, 0.29 mM), (112 milligrams of diisopropylethylamine (0.15 milliliter) and TBTU, 0.35 mM) solution in DMF (1.5 milliliters) stirs 1 hour at 22 DEG C, and purified by preparative HPLC, obtain title compound, for faint yellow solid (150 milligrams, 80.1%).ESI-MS m/e 646(MH⁺)。¹H NMR (500MHz, MeOD) δ ppm 0.93-2.08 (m, 16H) 2.49-2.53 (m, 1H) 2.55 (s, 3H) 2.60-2.93 (m, the 4H) (s of 3.15 (s, 3H) 3.24 (m, 2H) 3.73,3H) 3.88-4.18 (m, 1H) 4.41-4.56 (m, 1H) 4.86-5.03 (m, 1H) 6.86 (d, J=8.24Hz, 1H) 6.97-7.06 (m, 1H) 7.09-7.20 (m, 1H) 7.37-7.49 (m, 1H) 7.73 (d, J=8.24Hz, 1H) 7.77-7.94 (m, 1H).

Embodiment 19

(+/-) -8- cyclohexyl -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl]-N- [[(phenyl methyl) amino] sulfonyl]-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

(+/-) -8- cyclohexyl-N- ((benzylamino) sulfonyl) -1a- ((3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl) -11- (methoxyl group) -1; 1a; 2; simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of 12b- tetrahydrochysenes ring third

- 5- carboxylic acid amides is with similar on synthesis (-) -8- cyclohexyl-N- ((methylamino) sulfonyl) -1a- ((3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl) -11- (methoxyl group) -1; 1a; 2; simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of 12b- tetrahydrochysenes ring third

Mode described in -5- carboxylic acid amides is from (+/-) -8- cyclohexyl -5- [[[(benzylamino) sulfonyl] amino] carbonyl] -1; 12b- dihydros -11- (methoxyl group) -12- (methoxyl group)-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a (2H)-carboxylate methyl ester starts and is made.ESI-MSm/e722(MH+).¹H NMR (500MHz, MeOD) δ ppm 1.14-2.20 (m, 16H) 2.56-3.08 (m, 7H) 3.39-3.72 (m, 3H) 3.89-3.96 (m, 3H) 4.21-4.37 (m, 3H) 4.60-4.74 (m, 1H) 5.11-5.22 (m, 1H) 7.06 (dd, J=8.55,2.44Hz, 1H) 7.17-7.24 (m, 2H) 7.28 (t, J=7.63Hz, 2H) 7.33-7.43 (m, 3H) 7.45-7.56 (m, 1H) 7.86-8.00 (m, 2H).

Embodiment 20

(+/-)-N- (amino-sulfonyl) -8- cyclohexyl -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- [(3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl] simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

By (40 milligrams of 10% palladium/carbon; 0.038 mM) it is added to (+/-) -8- cyclohexyl-N- ((benzylamino) sulfonyl) -1a- ((3- methyl -3; 8- diazabicylos [3.2.1] octyl- 8- yls) carbonyl) -11- (methoxyl group) -1; 1a; 2; simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of 12b- tetrahydrochysenes ring third

- 5- carboxylic acid amides (20 milligrams, 0.028 mM) makes reactant mixture receive vacuum and nitrogen flushing in succession in the solution in EtOH (10 milliliters), such three times, is then placed under hydrogen (1 atmospheric pressure).Reactant mixture is stirred at room temperature two days, it is filtered by Celite pad, and concentration.Make residue pass through preparative HPLC to purify (acetonitrile/H containing TFA buffer solutions₂O), title compound is obtained, is white film.ESI-MS m/e 632(MH⁺)。¹H NMR (500MHz, MeOD) δ ppm 1.13-2.23 (m, 16H) 2.48-3.11 (m, 9H) 3.54-3.75 (m, 1H) 3.86-3.97 (m, 3H) 4.15-4.37 (m, the 1H) (s of 4.62 (s, 1H) 5.19 (s, 1H) 7.05,1H) 7.16-7.24 (m, 1H) 7.31-7.39 (m, 1H) 7.55-7.67 (m, 1H) 7.88-7.97 (m, 1H) 7.99-8.12 (m, 1H).

Embodiment 20-31 is analyzed by following LC/MS methods.Analysis condition：Chromatographic column is 3.0 × 50 millimeters of S10 of PHENOMENNEX-LUNA；Mobile phase is (A) 10:90 methanol-waters and (B) 90:10 methanol-waters；Buffer solution is 0.1%TFA；Gradient scope is 0-100%B；Gradient timetable is 2 minutes；Flow velocity is 4 ml/mins；Analysis time is 3 minutes.Testing conditions：Detector 1 is UV, at 220 nanometers；Detector 2 is MS (ESI+).

Embodiment 21

(+/-) -8- cyclohexyl -5- (morpholinosulfonyl carbamyl) -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a- carboxylic acids

Make product pass through preparative HPLC to purify, and be separated into buff white solid.LC/MS：Retention time is 1.968 minutes；m/e 460(MH⁺)。¹H NMR (400MHz, CDCl₃)：It was found that compound exists mutually to convert rotational isomer.

Embodiment 22

(+/-) -8- cyclohexyl -5- (4- methylpiperazine-1-yl Herbicidal sulphonylaminos formoxyl) -1,1a, 2,12b- tetrahydrochysene -11- methoxyl groups-ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 1a- carboxylic acids

Make product pass through preparative HPLC to purify, and separated in single tfa salt form, be buff white solid.LC/MS：Retention time is 1.687 minutes；m/e 607(MH⁺)。¹H NMR (400MHz, CDCl₃)：It was found that compound exists mutually to convert rotational isomer.

Embodiment 23

(+/-) -8- cyclohexyl-N- (morpholinosulfonyl) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third- 5- carboxylic acid amides

Product is passed through preparative HPLC to purify, and separated with tfa salt.LC/MS：Retention time is 1.770 minutes；m/e 702(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm1.14-1.59 (m, 7H), 1.69-1.88 (m, 3H), 1.87-2.15 (m, 6H), 2.49-2.66 (m, 1H), 2.80-3.02 (m, 3H), 3.05-3.32 (m, 1H), 3.41-3.55 (m, 5H), 3.58-3.68 (m, J=15.56Hz, 1H), 3.70-3.81 (m, 4H), 3.83-3.93 (m, 3H), 3.94-4.14 (m, 1H), 4.43-4.71 (m, 3H), 4.75-4.87 (m, 1H), 5.18 (s, 1H), 6.90-7.02 (m, 1H), 7.07-7.15 (m, J=2.75Hz, 1H), 7.27-7.36 (m, J=9.16, 9.16Hz, 1H), 7.37-7.60 (m, 1H), 7.83-7.95 (m, J=8.39, 8.39Hz, 1H), 8.03 (s, 1H), 9.47 (s, 1H).

Embodiment 24

(+/-) -8- cyclohexyl-N- (pyrrolidin-1-yl sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Product is passed through preparative HPLC to purify, and separated with tfa salt.LC/MS：Retention time is 2.873 minutes；m/e 686(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm 1.12-1.30 (m, 3H), 1.29-1.45 (m, 3H), 1.45-1.60 (m, 2H), 1.71-1.86 (m, 3H), 1.86-1.98 (m, J=6.17, 6.17Hz, 6H), 1.97-2.12 (m, J=23.42Hz, 3H), 2.12-2.32 (m, 1H), 2.56-2.72 (m, 1H), 2.80-2.88 (m, J=4.78Hz, 1H), 2.88-3.02 (m, 2H), 3.07-3.23 (m, 1H), 3.45-3.52 (m, 1H), 3.51-3.60 (m, 4H), 3.60-3.74 (m, 2H), 3.85-3.93 (m, 3H), 4.02-4.18 (m, 1H), 4.50-4.64 (m, 1H), 4.78-4.92 (m, 1H), 5.10-5.26 (m, 1H), 6.90-7.02 (m, 1H), 7.07-7.16 (m, J=2.52Hz, 1H), 7.26-7.34 (m, J=9.19, 9.19Hz, 1H), 7.48-7.64 (m, 1H), 7.82-7.97 (m, J=9.19, 9.19Hz, 1H), 8.08-8.27 (m, 1H), 9.52 (s, 1H).

Embodiment 25

(+/-) -8- cyclohexyl-N- (piperidin-1-yl sulfonyl) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- 5- carboxylic acid amides

Product is passed through preparative HPLC to purify, and separated with tfa salt.LC/MS：Retention time is 1.882 minutes；m/e 700(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm 1.17-1.30 (m, 2H), 1.30-1.46 (m, J=14.23, 6.92Hz, 4H), 1.47-1.61 (m, J=11.33Hz, 4H), 1.61-1.72 (m, J=4.03Hz, 4H), 1.71-1.86 (m, 3H), 1.86-2.11 (m, J=10.32Hz, 6H), 2.21-2.38 (m, 1H), 2.51-2.68 (m, 1H), 2.77-3.02 (m, 3H), 3.33-3.47 (m, 4H), 3.47-3.52 (m, 1H), 3.58-3.73 (m, 2H), 3.86-3.93 (m, 3H), 3.93-4.13 (m, 1H), 4.57-4.77 (m, 2H), 5.06-5.23 (m, 1H), 6.91-7.02 (m, 1H), 7.06-7.16 (m, J=2.52Hz, 1H), 7.26-7.33 (m, 1H), 7.37-7.56 (m, 1H), 7.82-7.94 (m, 1H), 7.98-8.12 (m, 1H), 9.03 (s, 1H).

Embodiment 26

(+/-) -8- cyclohexyl-N- ((2S; 6R) -2; 6- thebaines are for sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3,8- diazabicylo [3.2.1] octane -8- carbonyls) ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

- 5- carboxylic acid amides

Product is passed through preparative HPLC to purify, and separated with tfa salt.LC/MS：Retention time is 2.911 minutes；m/e 730(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm 1.13-1.23 (m, 5H), 1.22-1.31 (m, J=5.29Hz, 1H), 1.31-1.47 (m, J=7.30, 7.30Hz, 3H), 1.47-1.62 (m, 1H), 1.74-1.91 (m, J=20.90Hz, 1H), 1.91-2.10 (m, 2H), 2.70-2.92 (m, 4H), 3.02-3.12 (m, 1H), 3.18-3.39 (m, 6H), 3.44-3.52 (m, 3H), 3.58-3.79 (m, 8H), 3.90 (s, 3H), 3.92-4.01 (m, 1H), 4.00-4.11 (m, 1H), 4.30-4.47 (m, 1H), 4.80-4.93 (m, 1H), 5.09-5.23 (m, 1H), 6.92-7.02 (m, 2H), 7.08-7.14 (m, J=2.52Hz, 1H), 7.29 (d, J=8.31Hz, 1H), 7.85-7.93 (m, 1H), 7.94-8.02 (m, 1H), 8.85 (s, 1H).

Embodiment 27

(+/-) -8- cyclohexyl-N-4- (4- methylpiperazine-1-yls sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- 5- carboxylic acid amides

Make product pass through preparative HPLC to purify, and separated with two tfa salts.LC/MS：Retention time is 1.563 minutes；m/e 715(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm 0.23-0.33 (m, 1H), 1.14-1.30 (m, 2H), 1.28-1.46 (m, 3H), 1.45-1.61 (m, 1H), 1.63-1.86 (m, 3H), 1.85-2.09 (m, 5H), 2.50-2.66 (m, 1H), 2.77-2.90 (m, 4H), 2.88-3.17 (m, 4H), 3.44-3.54 (m, 2H), 3.52-3.75 (m, 5H), 3.84-3.94 (m, 3H), 3.95-4.19 (m, 4H), 4.31-4.52 (m, 1H), 4.55-4.70 (m, 1H), 4.73-4.87 (m, 1H), 5.00-5.23 (m, 1H), 6.89-7.05 (m, 2H), 7.05-7.15 (m, 1H), 7.25-7.32 (m, 1H), 7.45-7.64 (m, 1H), 7.78-7.91 (m, 1H), 7.95-8.13 (m, 1H).

Embodiment 28

(+/-) -8- cyclohexyl-N- (isopropelsulfonyl) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- 5- carboxylic acid amides

Make product pass through preparative HPLC to purify, and separated in single tfa salt form, be buff white solid.LC/MS：Retention time is 1.818 minutes；m/e 659(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm1.11-1.29 (m, 2H), 1.28-1.66 (m, 8H), 1.67-1.87 (m, 3H), 1.86-2.11 (m, 5H), 2.12-2.42 (m, 2H), 2.43-2.72 (m, 2H), 2.72-3.04 (m, 4H), 3.05-3.30 (m, J=7.55, 4.28Hz, 2H), 3.31-3.57 (m, 2H), 3.57-3.78 (m, J=18.63Hz, 2H), 3.85-3.93 (m, 3H), 3.96-4.15 (m, 2H), 4.37-4.76 (m, J=71.51Hz, 1H), 5.04-5.25 (m, 1H), 6.86-7.02 (m, 1H), 7.07-7.16 (m, J=2.52Hz, 1H), 7.26-7.36 (m, J=8.31, 8.31Hz, 1H), 7.44-7.69 (m, 1H), 7.90 (d, J=8.56Hz, 1H), 8.00-8.29 (m, J=48.09Hz, 1H), 9.33 (s, 1H).

Embodiment 29

(+/-) -8- cyclohexyl-N- (N; N- DimethylsuIfamoyls) -1; 1a; 2; 12b- tetrahydrochysene -11- difluoro-methoxies -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Product acts on (difluoromethylation) (ClCHF by the difluoromethylization of corresponding phenol derivative (phenolic derivative)₂, 1N NaOH, acetone-isopropanol, room temperature) and be made, and purified by preparative HPLC, and separated in single tfa salt form, it is buff white solid.LC/MS：Retention time is 1.798 minutes；m/e 696(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (500MHz, chloroform-D)：δ ppm 0.25-0.81 (m, 3H), 0.81-1.33 (m, 6H), 1.29-1.64 (m, 4H), 1.78 (s, 2H), 1.85-2.17 (m, J=4.58Hz, 4H), 2.36-2.59 (m, 2H), 2.79 (t, J=11.90Hz, 2H), 2.84-2.93 (m, 1H), 2.97-3.10 (m, 5H), 3.08-3.23 (m, 1H), 3.45 (s, 1H), 4.40 (s, 1H), 5.07 (s, 1H), 6.44-6.66 (m, 1H), 6.73-6.86 (m, J=14.34Hz, 1H), 7.17 (d, J=1.83Hz, 1H), 7.28 (dd, J=8.55, 2.44Hz, 1H), 7.42-7.60 (m, 2H), 7.92 (d, J=8.55Hz, 1H), 8.09 (s, 1H), 8.91 (s, 1H).

Embodiment 30

(+/-) -8- cyclohexyl-N- (N; N- DimethylsuIfamoyls) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- N- methyl -5- carboxylic acid amides

Product is in Mitsonobu conditions (Ph₃P (triphenylphosphine); DEAD; MeOH-THF; 0-23 DEG C) under pass through (+/-) -8- cyclohexyl-N- (N, N- DimethylsuIfamoyl) -1,1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3,8- diazabicylo [3.2.1] octane -8- carbonyls) ring third simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza

The N- methylations of -5- carboxylic acid amides and be made, and purified by preparative HPLC, and separated in single tfa salt form, be buff white solid.LC/MS：Retention time is 1.828 minutes；m/e674(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：1HNMR (400MHz, chloroform-D)：δ ppm 1.12-1.62 (m, 6H), 1.65-2.32 (m, 8H), 2.46 (d, J=5.29Hz, 2H), 2.69-2.91 (m, 3H), 2.90-2.99 (m, 7H), 2.96-3.19 (m, 2H), 3.25-3.34 (m, 3H), 3.33-3.43 (m, 1H), 3.49 (s, 1H), 3.63 (d, J=15.36Hz, 1H), 3.67-3.84 (m, J=1.51Hz, 1H), 3.89 (s, 3H), 3.93-4.20 (m, 1H), 4.44-4.67 (m, 1H), 5.09-5.27 (m, 1H), 6.92-7.02 (m, J=8.69, 2.64Hz, 1H), 7.06-7.14 (m, J=2.52Hz, 1H), 7.26-7.33 (m, 2H), 7.64 (s, 1H), 7.89 (d, J=8.31Hz, 1H).

Embodiment 31

(+/-) -8- cyclohexyl-N- (N- Cyclopropylsulfamoyls base) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- N- methyl -5- carboxylic acid amides

Make product pass through preparative HPLC to purify, and separated in single tfa salt form, be buff white solid.LC/MS：Retention time is 2.751 minutes；m/e 672(MH⁺).By following¹H NMR have found compound mutually to convert rotational isomer presence：¹H NMR (400MHz, chloroform-D)：δ ppm0.55-0.96 (m, 3H), 1.05-1.59 (m, 6H), 1.60-2.19 (m, 8H), 2.22-2.45 (m, 2H), 2.44-2.81 (m, 6H), 2.81-3.09 (m, 4H), 3.36-3.52 (m, J=25.68Hz, 1H), 3.59-3.80 (m, 2H), 3.82-3.94 (m, 3H), 3.97-4.19 (m, 1H), 5.14-5.29 (m, 1H), 5.99 (s, 1H), 6.90-7.02 (m, J=8.44, 2.90Hz, 1H), 7.06-7.14 (m, J=2.52Hz, 1H), 7.26-7.35 (m, 1H), 7.53-7.71 (m, 1H), 7.93 (d, J=8.56Hz, 1H), 8.23 (s, 1H), 9.95 (s, 1H).

Embodiment 32-36 is analyzed by following LC/MS methods：It is 0 to start %B；Final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.

Embodiment 32

(+/-) -8- cyclohexyl-N- (methyl sulphonyl) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third- 5- carboxylic acid amides

By indole-carboxylic acid-(1.3 grams of cyclopropyl ester, 2.83 mMs) and (0.64 gram of CDI, 3.97 mMs) mixture in THF (20 milliliters) heats 0.5 hour at 50 DEG C, cool down, and add (0.4 gram of methylsulfonamides, 4.2 mMs) and DBU (0.264 milliliter, 1.77 mMs).Stir the mixture for 20 hours, and diluted with EtOAc, with cold 1N HCl (2 ×) and salt water washing, dry (MgSO₄), solvent is removed, and purified by flash chromatography (Biotage 40M), compound 1-2 (1.28 grams, 85%) is obtained, is faint yellow solid.LC-MS retention times are 3.51；MS m/z 537(M+H).It was found that sulfonamide exists mutually to convert rotational isomer.Main isomer：¹H NMR (400MHz, chloroform-D) δ ppm1.11-2.17 (m, 12H), 2.84-2.98 (m, 2H), 3.43 (d, J=14.86Hz, 1H), 3.49 (s, 3H), 3.55 (s, 3H), 3.89 (s, 3H), 5.40 (d, J=15.11Hz, 1H), 6.91-6.96 (m, 1H), 7.13 (d, J=2.52Hz, 1H), 7.22-7.27 (m, 1H), 7.39 (dd, J=8.31, 1.51Hz, 1H), 7.85 (d, J=8.81Hz, 1H), 8.23 (d, J=1.26Hz, 1H), 8.75 (s, 1H).

In sulfonamide -ester (1.28 grams, 2.4 mMs) NaOH (1N, 12 milliliters, 12 mMs) is added in the solution in THF (5 milliliters) and MeOH (5 milliliters).It is stirred at room temperature after 3 hours, mixture is diluted with EtOAc, with cold 1N HCl and salt water washing, dries (MgSO₄), and solvent is removed in a vacuum, acid is obtained, is buff white solid (1.20 grams, 96%).LC-MS retention times are 3.46；MS m/z 523(M+H).Pass through¹H NMR (400MHz, chloroform-D) have found that compound 1-2 exists mutually to convert rotational isomer (about 1/1).

The addition Et in sour (0.060 gram, 0.11 mM) with mixture of 3- methyl -3,8- diazabicylo [3.2.1] dihydrochloride salt (0.034 gram, 0.17 mM) in DMC (1.5 milliliters)₃N (triethylamine) (0.096 milliliter, 0.69 mM) and HBTU (0.065 gram, 0.17 mM).Mixture is stirred at room temperature 0.5 hour, diluted with MeOH, solvent is removed.Residue is dissolved in methanol, filter, and purified by preparative HPLC, obtain the tfa salt (0.0378 gram, 82%) of product.LC-MS retention times are 2.96；MS m/z 631(M+H).It was found that product exists mutually to convert rotational isomer.¹H NMR (400MHz, chloroform-D) δ ppm 1.04-1.61 (m, 8H), 1.68-2.38 (m, 10H), 2.48-3.03 (m, 6H), 3.09-3.20 (m, 1H) 3.30-3.78 (m, 2H), 3.41 (s, 3H), 3.88 (s, 3H), 4.05 (d, J=14.10Hz, 1H), 5.06-5.28 (m, 1H), 6.97 (dd, J=8.81, 2.27Hz, 1H), 7.11 (d, J=2.27Hz, 1H), 7.24-7.34 (m, 1H), 7.54-7.73 (m, 1H), 7.82-7.94 (m, J=7.18, 5.41Hz, 1H), 8.17 (s, 1H).

Embodiment 33

(+/-) -8- cyclohexyl-N- (ethylsulfonyl) -1; 1a, 2,12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of ring third

- 5- carboxylic acid amides

Product is prepared with similar manner as above：Sulfonamide (0.47 gram, 44%)；LC-MS retention times are 3.54 minutes；MS m/z 551(M+H)；Sour (0.43 gram, 94%)；LC-MS retention times are 3.49 minutes；MS m/z 537(M+H).Prepare the tfa salt (0.0378 gram, 71%) of product.LC-MS retention times are 3.028 minutes；MS m/z 645(M+H).It was found that product exists mutually to convert rotational isomer, main isomer：¹H NMR (500MHz) ppm 1.12-2.37 (m, 19H), 2.51-2.66 (m, 1H), 2.69-3.03 (m, 4H), 3.08-3.22 (m, 1H), 3.21-3.83 (m, 8H), 3.90 (s, 3H), 5.11-5.28 (m, 1H), 6.87-6.95 (m, 1H), 6.97-7.00 (m, 1H), 7.12 (d, J=2.14Hz, 1H), 7.30 (d, J=8.85Hz, 1H), 7.88-7.96 (m, 1H), 8.08 (s, 1H).

Embodiment 34

(+/-) -8- cyclohexyl-N- (azetidine -1- bases sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

Product is prepared in a manner analogous to that described above：Sulfonamide (0.96 gram, 59%)；LC-MS retention times are 3.58 minutes；MS m/z 578(M+H).It was found that compound exists mutually to convert rotational isomer (3/4).Main isomer：¹H NMR (400MHz, chloroform-D) δ ppm 1.16-1.59 (m, 4H), 1.72 (dd, J=9.44, 4.15Hz, 3H), 1.88-2.12 (m, 4H), 2.24-2.36 (m, 2H), 2.75-2.97 (m, 2H), 3.44 (d, J=14.86Hz, 1H), 3.56 (s, 3H), 3.89 (s, 3H), 4.09 (d, 1H), 4.24-4.37 (m, 4H), 5.41 (d, J=14.86Hz, 1H), 6.92-6.96 (m, 1H), 7.13 (d, J=2.01Hz, 1H), 7.24-7.30 (m, 1H), 7.39 (dd, J=8.31, 1.51Hz, 1H), 7.84-7.88 (m, 1H), 8.24 (d, J=1.51Hz, 1H)；Sour (0.93 gram, 100%)；LC-MS retention times are 3.51 minutes；MS m/z564(M+H).It was found that compound exists mutually to convert rotational isomer (about 3/4).Main isomer：¹H NMR (400MHz) ppm 0.34-0.42 (m, 1H), 1.15-2.10 (m, 11H), 2.22-2.38 (m, 2H), 2.65-2.78 (m, 1H), 2.84-2.94 (m, J=3.02Hz, 1H), 3.84 (s, 3H), 4.03 (d, J=15.11Hz, 1H), 4.21-4.43 (m, 4H), 5.34 (d, J=14.86Hz, 1H), 6.87 (dd, J=8.56, 2.77Hz, 1H), 6.98 (d, J=2.52Hz, 1H), 7.21 (d, J=8.31Hz, 1H), 7.69-7.75 (m, 1H), 7.86-7.90 (m, 1H), 8.13 (s, 1H).Prepare the tfa salt of product：LC-MS retention times are 3.51 minutes；MS m/z672(M+H).It is based on¹H NMR (400MHz, chloroform-D) have found title compound mutually to convert rotational isomer presence：¹H NMR (400MHz) ppm 1.02-1.63 (m, 8H), 1.72-2.36 (m, 10H), 2.47-3.23 (m, 6H), 3.45 (d, J=29.46Hz, 2H), 3.59-3.75 (m, 2H), 3.89 (s, 3H), 4.12-4.38 (m, 4H), 4.38-4.98 (m, 2H), 5.12-5.30 (m, 1H), 6.90-7.03 (m, 2H), 7.12 (d, J=2.52Hz, 1H), 7.27-7.35 (m, J=9.06, 9.06Hz, 1H), 7.59-7.75 (m, 1H), 7.84-7.96 (m, 1H).

Embodiment 35

(+/-) -8- cyclohexyl-N- (N- ethyl-N-methylaminos sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third

- 5- carboxylic acid amides

With certainly sour similar to method as described above system.Sulfonamide (0.109 gram, 67%).LC-MS retention times are 3.60 minutes；MS m/z 580(M+H).It was found that compound exists mutually to convert rotational isomer (about 5/4).Main isomer：¹H NMR (400MHz) ppm 1.16-2.09 (m, 14H), 2.73-2.93 (m, 2H), 3.07 (s, 3H), 3.31-3.52 (m, 3H), 3.76 (s, 3H), 3.88 (s, 3H), 4.05-4.10 (m, 1H), 5.40 (d, J=15.11Hz, 1H), 6.88-6.93 (m, 1H), 7.13 (d, J=2.27Hz, 1H), 7.22-7.29 (m, 1H), 7.33-7.42 (m, 1H), 7.82-7.86 (m, 1H), 8.19 (d, J=1.51Hz, 1H).Sour (0.108 gram, 100%).LC-MS retention times are 3.55 minutes；MS m/z 566(M+H).Prepare the tfa salt (0.0437 gram, 54%) of product.LC-MS retention times are 3.10 minutes；MS m/z674(M+H).¹H NMR (500MHz) ppm 1.14-1.62 (m, 6H), 1.22 (t, J=7.17Hz, 3H), 1.69-2.21 (m, 10H), 2.25-3.31 (m, 11H), 3.02 (s, 3H), 3.43 (q, J=7.02Hz, 2H), 3.55-3.80 (m, 1H), 3.89 (s, 3H), 5.08-5.29 (m, 1H), 6.93-7.00 (m, 1H), 7.11 (d, J=2.44Hz, 1H), 7.28-7.31 (m, 1H), 7.39-7.56 (m, 1H), 7.85-7.91 (m, 1H), 8.04 (s, 1H).

Embodiment 36

(+/-) -8- cyclohexyl-N- (N; N- diethylaminos sulfonyl) -1; 1a; 2; 12b- tetrahydrochysene -11- methoxyl groups -1a- (3- methyl -3; 8- diazabicylos [3.2.1] octane -8- carbonyls) simultaneously [d] indoles simultaneously [2,1-a] [2] benzo-aza of-ring third- 5- carboxylic acid amides

So that similar to method as described above, system is certainly sour.Sulfonamide (0.127 gram, 67%)；LC-MS retention times are 3.64 minutes；MS m/z 594(M+H).It was found that compound exists mutually to convert rotational isomer：¹H NMR (400MHz) ppm 1.11-2.13 (m, 18H), 2.64 (dd, J=10.07, 6.80Hz, 1H), 2.84-2.96 (m, 1H), 3.34-3.67 (m, 4H), 3.75 (s, 3H), 3.88 (s, 3H), 4.03-4.10 (m, 1H), 5.40 (d, J=15.36Hz, 1H), 6.90-6.95 (m, 1H), 7.13 (d, J=2.01Hz, 1H), 7.21-7.29 (m, 1H), 7.33-7.39 (m, 1H), 7.83 (d, J=8.06Hz, 1H), 8.20 (d, J=1.26Hz, 1H).Acid：(0.126 gram, 100%).LC-MS retention times are 3.57 minutes；MS m/z 580(M+H).Prepare the tfa salt (0.431 gram, 52%) of product.LC-MS retention times are 3.18 minutes；MS m/z688(M+H).¹H NMR (400MHz, chloroform-D) ppm 1.13-1.55 (m, 6H), 1.21 (t, J=7.18Hz, 6H), 2.31-3.55 (m, 11H), 2.41-3.29 (m, 10H), 3.49 (q, J=7.05Hz, 4H), 3.59-3.67 (m, 1H), 3.89 (s, 3H), 5.02-5.29 (m, 1H), 6.97 (dd, J=8.81, 2.27Hz, 1H), 7.10 (d, J=2.52Hz, 1H), 7.28 (d, J=8.56Hz, 1H), 7.36-7.49 (m, 1H), 7.83-7.91 (m, 1H), 7.95-8.06 (m, 1H).

Embodiment 37

Under a nitrogen by pure tetrafluoro boric acid 2- (1H- BTA -1- bases) -1,1,3,3- tetramethyl

(0.0535 gram, 0.167 mM) it is added to (0.0774 gram of compound 1-4,0.128 mM), 3- methyl -3, (0.026.4 grams of 8- diazabicylos [3.2.1] octane 2HCl, 0.128 mM) and TEA (0.071 milliliter, 0.512 mM) in agitated mixture in DCM (2 milliliters).Mixture is stirred at room temperature 1 hour, and reaction is quenched with MeOH (0.5 milliliter), is then evaporated to dryness, and is purified by reversed-phase HPLC, single tfa salt form (0.0613 gram, 60%) of separation product is obtained, is buff white solid.LC/MS：m/e 686(MH+).LC/MS methods：It is 0 to start %B, and final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.

Embodiment 38

Use the HBTU and TEA in dichloromethane, tfa salt (0.0465 gram, the 56%) system certainly sour (0.060 gram, 0.104 mM) and amine of acid amides.LC-MS retention times are 3.146 minutes；MSm/z(M+H)688.LC/MS methods：It is 0 to start %B, and final %B is 100；Gradient timetable is 3 minutes；Dwell time is 4 minutes；Flow velocity is 4 ml/mins；Wavelength is 220；Solvent orange 2 A is 10%MeOH/90%H₂O/0.1% trifluoracetic acids；Solvent B is 10%H₂O/90%MeOH/0.1% trifluoracetic acids；Chromatographic column is 4.6 × 50 millimeters of S5 of XBridge.¹H NMR show there is rotational isomer, principal mode：¹H NMR (400MHz, chloroform-d) δ ppm 1.14-1.18 (m, 6H) 1.19-2.12 (m, 16H) 2.19-3.77 (m, 9H) 2.95 (s, 3H) 3.89 (s, 3H) 3.95-5.02 (m, 4H) 5.03-5.24 (m, 1H) 6.97 (dd, J=8.81,2.77Hz, 1H) 7.11 (d, J=2.52Hz, 1H) 7.28 (d, J=8.56Hz, 1H) 7.40-7.64 (m, 1H) 7.88 (d, J=8.31Hz, 1H) 8.07 (width unimodal, 1H).

Claims

1. compound of formula I or its officinal salt：

Wherein

R¹For CO₂R⁵Or CONR⁶R⁷；

R²For

R³For hydrogen, hydroxyl, benzyl epoxide, alkoxy or halogenated alkoxy；

R⁴For cycloalkyl；

R⁵For hydrogen or alkyl；

R⁶For alkyl SO₂, cycloalkyl SO₂、(R⁹)₂NSO₂Or (R¹⁰)SO₂；

R⁷For hydrogen or alkyl；

R⁸For hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, alkyl-carbonyl, alkoxy carbonyl, alkyl SO₂, (alkyl amino) carbonyl, (dialkyl amido) carbonyl, benzyl, benzyloxycarbonyl or pyridine radicals；

R⁹For hydrogen, alkyl or cycloalkyl；And

R¹⁰For azelidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, and replaced by 0-3 alkyl substituent,

Alkyl wherein in alkyl, alkoxy and halogenated alkoxy has 1 to 6 carbon atom, and alkenyl has 2 to 6 carbon atoms, and cycloalkyl has 3 to 7 carbon atoms.

2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein

R³For hydroxyl, benzyl epoxide or alkoxy；

R⁹For hydrogen or alkyl；And

R¹⁰For azelidinyl, pyrrolidinyl, piperidyl, piperazinyl, N- (alkyl) piperazinyls or morpholinyl.

3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R¹For CONR⁶R⁷；R⁶For alkyl SO₂, cycloalkyl SO₂、(R⁹)₂NSO₂Or (R¹⁰)SO₂；And R⁷For hydrogen.

4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R³For hydrogen.

5. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R³For methoxyl group.

6. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R⁴For cyclohexyl.

7. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R⁶For alkyl SO₂、(R⁹)₂NSO₂Or (R¹⁰)SO₂。

8. the compound or pharmaceutically acceptable salt thereof of claim 1, the compound has following spatial chemistry

Wherein R¹、R²、R³And R⁴As defined in claim 1.

9. the compound or pharmaceutically acceptable salt thereof of claim 1, the compound has following spatial chemistry

Wherein R¹、R²、R³And R⁴As defined in claim 1.

10. the compound or pharmaceutically acceptable salt thereof of claim 1, the compound is selected from

11. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is

12. the compound or pharmaceutically acceptable salt thereof of claim 11, wherein the salt is hydrochloride.

13. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is

14. a kind of composition, it includes the compound or pharmaceutically acceptable salt thereof and pharmaceutical acceptable carrier of claim 1.

15. the compound of the composition of claim 14, wherein claim 1 is

16. the compound or pharmaceutically acceptable salt thereof of claim 1 is preparing the purposes in being used to treat the medicine of hepatitis C infection.

17. the compound of the purposes of claim 16, wherein claim 1 is

Or its officinal salt.