CN100522161C - (Indol-3-yl)-heterocycle derivatives as agonists of the cannabinoid CB1 receptor - Google Patents

(Indol-3-yl)-heterocycle derivatives as agonists of the cannabinoid CB1 receptor Download PDF

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CN100522161C
CN100522161C CNB2005800071203A CN200580007120A CN100522161C CN 100522161 C CN100522161 C CN 100522161C CN B2005800071203 A CNB2005800071203 A CN B2005800071203A CN 200580007120 A CN200580007120 A CN 200580007120A CN 100522161 C CN100522161 C CN 100522161C
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indole
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cyclohexyl
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CN1929836A (en
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J·亚当-沃勒尔
A·J·莫里森
G·维斯哈特
清位孝夫
D·R·麦克阿瑟
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Merck Sharp and Dohme BV
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Abstract

The invention relates to (indol-3-yl)-heterocycle derivatives having general Formula (I) wherein A represents a 5-membered aromatic heterocyclic ring, wherein X1, X2 and X3 are independently selected from N, O, S and CR; R is H or (C1-4)alkyl; or R, when present in X2 or X3, may form together with R3 a 5-8 membered ring; R1 is a 5-8 membered saturated carbocyclic ring, optionally containing a heteroatom selected from O and S; R2 is H, CH3 or CH2-CH3; or R2 is joined together with R7 to form a 6-membered ring, optionally containing a heteroatom selected from O and S, and which heteroatom is bonded to the 7-position of the indole ring; R3 and R4 are independently H, (C1-6)alkyl or (C3-7)cycloalkyl, the alkyl groups being optionally substituted with OH, (C1-4)alkyloxy, (C1-4)alkylthio, (C1-4)alkylsulfonyl, CN or halogen; or R3 together with R4 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen; or R3 together with R5 forms a 4-8 membered ring optionally containing a further heteroatom selected from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy- (C1-4)alkyl, or halogen; or R3 together with R, when present in X2 or X3, forms a 5-8 membered ring; R5 is H or (C1-4)alkyl; or R5 together with R3 forms a 4-8 membered ring optionally containing a further heteroatom selected from O and S, and which is optionally substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4) alkyloxy- (C1-4)alkyl, or halogen; R5' is H or (C1-4)alkyl; or a pharmaceutically acceptable salt thereof, as agonists of the cannabinoid CB1 receptor, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

Description

(indol-3-yl)-Hete rocyclic derivatives as the agonist of cannabinoid CB 1 receptor
The present invention relates to (indol-3-yl)-Hete rocyclic derivatives, relate to the pharmaceutical composition that contains (indol-3-yl)-Hete rocyclic derivatives and relate to these (indol-3-yl)-Hete rocyclic derivatives in treatment, particularly the purposes in treatment pain.
Pain therapy is subject to current available side effects of pharmaceutical drugs usually.For the pain of moderate, be extensive use of opioid drug (opioid) to severe.These medicaments are cheap and effectively but be subjected to influence serious and side effect potential threat life, described side effect is respiration inhibition and muscle rigidity the most significantly.And that the dosage of the opioid drug that can use is subject to is nauseating, vomiting, constipation, pruritus and urine retention, causes the patient to select to accept the pain control of inferior appropriateness and be reluctant to be subjected to these poignant side effect usually.And these side effect cause the long-term hospitalization of needs of patients usually.Opioid drug is very habit-forming and is restricted medicine (scheduled drugs) in a lot of fields.Therefore exist comparing, under the AD that equates, have the needs of new analgesic of the side effect character of improvement with the medicine of current use.
The evidence of accumulation shows that cannabinoid (cannabinoid) agonist has the potential as analgesic and anti-inflammatory agent.Relate to two types Cannabined receptor, be cannabinoid CB 1 receptor (its mainly be arranged in the central nervous system but its also express by peripheral neurons and more low degree ground be positioned at other peripheral tissues) and cannabinoid CB2 receptor (its major part is positioned at immunocyte (Howlett, A.C. etc.: International Union of Pharmacology.XXVII.Classification of Cannabinoid Receptors.Pharmacol.Rev.54,161-202,2002).When CB2 receptor and immunity of adjusting cannabinoid and anti-inflammatory response are interrelated, cannabinoid receptor agonists, those agonist that particularly act on the CB1 receptor have been suggested and have can be used for treating pain and (see Iversen, L. and Chapman, V.CurrentOpinion in Pharmacology, 2,50-55,2002 reach list of references wherein).
WIN 55,212-2, i.e. (R)-(+)-[2,3-dihydro-5-methyl-[(morpholinyl) methyl] pyrrolo-[1,2,3-de]-1, the 4-benzoxazinyl]-mesylate of (1-naphthyl) ketone is disclosed in United States Patent (USP) 4,939 as analgesic, among 138 (the Sterling Drug Inc.).This chemical compound is prototype (Eissenstat, M.A. etc., the J.Med.Chem. of amino alkyl indole 38, 3094-3105,1995), it is the effective cannabinoid CB 1 receptor agonist that can produce in the animal model of acute pain, persistence inflammatory pain and neuropathic pain with the antagonism nociperception of morphine equal authenticity.
Have the amino alkyl indole of intending Fructus Cannabis character the key structure feature (Adam, J. and Cowley, P.Expert Opin.Ther.Patents, 121475-1489; 2002) be aminoalkyl substituent group in indole part position 1; and other big substituent group in indole ring position 3; for example United States Patent (USP) 4; aroyl among 939,138 (Sterling Drug companies) and the more recent WO02060447 (University of Connecticut) in the disclosed amino alkyl indole, or the acylamino-that is substituted in the disclosed chemical compound among the WO0158869 (Bristol-Myers Squibb).Recently, 1-(aminoalkyl) indole derivatives that has the oxadiazole-5-basic ring that is substituted in position 3 is disclosed among the WO0236590 (Amrad Operations PTY Ltd.) as Cannibinoid receptor modulators with as analgesic.
Still there are the needs that the cannabinoid agonists with improved characteristics (for example enhanced water solublity) are used as therapeutic agent.
For this purpose, the invention provides (the indol-3-yl)-Hete rocyclic derivatives as the cannabinoid CB 1 receptor agonist, it has following general formula (I),
Figure C200580007120D00071
Wherein
A represents 5-membered aromatic heterocycle, wherein X 1, X 2And X 3Be independently selected from N, O, S and CR;
R is H or (C 1-4) alkyl; Perhaps
R is being present in X 2Or X 3Among the time can with R 3Form 5-8 unit ring together;
R 1Be 5-8 unit saturated carbon ring, the optional hetero atom that is selected from O and S that contains;
R 2Be H, CH 3Or CH 2-CH 3Perhaps
R 2Connect R 7Form 6 yuan of rings together, choose wantonly and contain the hetero atom that is selected from O and S, and this hetero atom is connected to the position 7 of indole ring;
R 3And R 4Be H, (C independently 1-6) alkyl or (C 3-7) cycloalkyl, this alkyl is by OH, (C 1-4) alkoxyl, (C 1-4) alkylthio group, (C 1-4) alkyl-sulfonyl, CN or halogen is optional replaces; Perhaps
R 3With R 4And their N of connecting form the optional heteroatomic 4-8 unit ring that is selected from O and S that also contains together, and should ring by OH, (C 1-4) alkyl, (C 1-4) alkoxyl, (C 1-4) alkoxyl-(C 1-4) alkyl or the optional replacement of halogen; Perhaps
R 3And R 5Form together to choose wantonly and contain the first ring of other heteroatomic 4-8 that is selected from O and S, and be somebody's turn to do ring by OH, (C 1-4) alkyl, (C 1-4) alkoxyl, (C 1-4) alkoxyl-(C 1-4) alkyl or the optional replacement of halogen; Perhaps
Be present in X 2Or X 3Among the time, R and R 3Form 5-8 unit ring together;
R 5Be H or (C 1-4) alkyl; Perhaps
R 5With R 3Form together to choose wantonly and contain the first ring of other heteroatomic 4-8 that is selected from O and S, and be somebody's turn to do ring by OH, (C 1-4) alkyl, (C 1-4) alkoxyl, (C 1-4) alkoxyl-(C 1-4) alkyl or the optional replacement of halogen;
R 5' be H or (C 1-4) alkyl;
R 6Expression is independently selected from H, (C 1-4) alkyl, (C 1-4) 1-3 substituent group of alkoxyl, CN and halogen;
R 7Be H, (C 1-4) alkyl, (C 1-4) alkoxyl, CN and halogen; Perhaps
R 7With R 2Be connected to form together to choose wantonly and contain other heteroatomic 6 yuan of rings that are selected from O and S, and this hetero atom is connected to the position 7 of indole ring; Or its pharmaceutically acceptable salt, it can be used for treating for example perioperative pain of pain, chronic pain, neuropathic pain, cancerous pain and pain and the spasticity relevant with multiple sclerosis.
As what use in the definition of formula I, heterocycle A represents 5 membered aromatic heterocycles, and it contains 1-3 hetero atom that is selected from N, O and S.This expression is used to define the X at least of heterocycle A 1, X 2And X 3One of can not be CR.Representational heterocycle A comes from thiophene, furan, triazole, thiazole, thiadiazoles, oxazole, oxadiazole and their isomer, comprises isothiazole, different thiadiazoles, isoxazole He those heterocycles of Yi oxadiazole.Preferred heterocycle A is 1,2,4-oxadiazole (X 1Be N, X 2Be O, X 3Be N), 1,2,4-thiadiazoles (X 1Be N, X 2Be S, X 3Be N) and thiazole (X 1Be S, X 2Be CR, X 3Be N).
In the definition of formula I, R is being present in X 2Or X 3The time can with R 3Form 5-8 unit ring together, contain two member ring systems that the ring of N is contained in the 5-8 unit that is fused to 5-membered aromatic heterocycle A so that form with ring A.The example of this condensed ring system is to come from 5, and 6-dihydro-4H-pyrrolo-[3,4-d] isoxazole, 4,5,6,7-tetrahydrochysene-oxazoles [5,4-c] pyridine, 4,5,6,7-tetrahydrochysene-thiazole [5,4-c] pyridine, 5,6,7,8-tetrahydrochysene-4H-isoxazole [5,4-c] azatropylidene, 5,6-dihydro-4H-pyrrolo-[3,4-d] thiazole and 5, those systems of 6-dihydro-4H-pyrrolo-[3,4-d] isothiazole.
Term (the C that in the definition of formula I, uses 1-4) alkyl refer to have 1-4 carbon atom side chain or unbranched alkyl arranged, as butyl, isobutyl group, the tert-butyl group, propyl group, isopropyl, ethyl and methyl.
At term (C 1-4) in the alkoxyl, (C 1-4) alkyl has meaning as defined above.
Term halogen refers to F, C1, Br or I.
As R at formula I 1Definition in saturated carbocyclic ring representative ring penta ring, hexamethylene ring, the ring ring in heptan of the term 5-8 unit that uses or ring is hot encircles.These rings can contain be selected from O and S hetero atom to form saturated heterocycle, as THP trtrahydropyranyl, tetrahydrofuran base, tetrahydro thiapyran base or tetrahydro-thienyl.Preferred carbocyclic ring is cyclohexyl and THP trtrahydropyranyl.
In the definition of formula I, R 2Can with R 7Connect to form to choose wantonly and contain the heteroatomic 6 yuan of rings that are selected from O and S, this atom is connected on the position 7 of indole ring.In 5 yuan of heterocycles of these (indol-3-yls) of the present invention-replace, indol-3-yl is trinucleated fused rings system, promptly 2, and 3-dihydro-pyrrolo-[3,2,1-ij] quinoline system (R 7And R 2Expression-CH together 2-CH 2-), 2,3-dihydro-pyrrolo--[1,2,3-de]-1,4-benzoxazinyl system (R 7And R 2Expression-O-CH together 2-) or 2,3-dihydro-pyrrolo-[1,2,3-de]-1,4-benzothiazine system (R 7And R 2Expression-S-CH together 2-) a part.
In the definition of formula I, R 3With R 4The N that is connected with them can form the optional first ring of other heteroatomic 4-8 that is selected from O and S that contains together.The example of these rings is pyrrolidine-1-base, piperidines-1-base, azepine
Figure C200580007120D0009092149QIETU
-1-base, morpholine-4-base and thiomorpholine-4-base.Be preferably pyrrolidine-1-base, piperidines-1-base and morpholine-4-base.
In the definition of formula I, R 3And R 5Can form the optional first ring of other heteroatomic 4-8 that is selected from O and S that contains together.Be appreciated that R 3The N and the R that connect 5The carbon atom that connects is the part of 4-8 unit ring.The example of these rings is pyrrolidine-2-base, piperidines-2-base, azepine
Figure C200580007120D0010092202QIETU
-2-base, morpholine-3-base and thiomorpholine-3-base.
Be preferably (indol-3-yl)-Hete rocyclic derivatives, wherein R according to formula I 2Be H or R wherein 2And R 7Connect to form to choose wantonly and contain the heteroatomic 6 yuan of rings that are selected from O and S, and this atom is connected on the position 7 of indole ring.
More preferably wherein R, R 5, R 5' and R 6It is the present invention's (indol-3-yl)-Hete rocyclic derivatives of H.
Also be preferably wherein R 1It is (the indol-3-yl)-Hete rocyclic derivatives of formula I according to the present invention of cyclohexyl or THP trtrahydropyranyl.
Especially preferably wherein heterocycle A is 1,2,4-oxadiazole (X 1Be N, X 2Be O, X 3Be N), 1,2,4-thiadiazoles (X 1Be N, X 2Be S, X 3Be N) or thiazole (X 1Be S, X 2Be CR, X 3Be N) (the indol-3-yl)-Hete rocyclic derivatives according to formula I.
Particularly preferred (the indol-3-yl)-Hete rocyclic derivatives of the present invention is:
-7-chloro-3-(5-{[N-ethyl-N-(2-methoxy ethyl) amino] methyl }-[1,2,4]-thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-{ (5-[(pyrrolidine-1-yl) methyl]-[1,2,4]-thiadiazoles-3-yl }-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-(5-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,2,4]-thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-(4-{[N-(2-ethoxy)-N-isopropylamino] methyl }-[1,3]-thiazole 2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-(4-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,3]-thiazol-2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-(4-{[N-(2-methoxy ethyl)-N-methylamino] methyl }-[1,3]-thiazol-2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
-7-chloro-3-{5-[(2,2-dimethyl-pyrrolidine-1-yl) methyl]-[1,2,4]-oxadiazoles-3-yl }-1-(tetrahydropyran-4-base) Methyl-1H-indole;
Or its pharmaceutically acceptable salt.
(indol-3-yl)-Hete rocyclic derivatives of the present invention generally can be by known method preparation in the organic chemistry filed.
(indol-3-yl)-Hete rocyclic derivatives of formula I can be for example from formula II chemical compound, and wherein Y is a leaving group, and for example halogen or alkyl sulfonic acid ester group are by using formula NHR 3R 4This leaving group of amine nucleophilic displacement and preparing.Wherein Y is that the formula II chemical compound of alkyl sulfonic acid ester group can be the formula II chemical compound of hydroxyl from Y wherein, when having alkali such as triethylamine, by preparing with the heteroaryl-alkylsulfonyl halides reaction.
R wherein 5' be that formula I (the indol-3-yl)-heterocycle of hydrogen can be used formula NHR when having Reducing agent such as sodium triacetoxy borohydride 3R 4Amine by reduction amination and from the formula III compound.
This is well known, and promptly Y is hydroxyl and R 5' be that the formula II chemical compound of hydrogen can be by using suitable Oxidizing and Reducing Agents, as Burke D.S., Danheiser, R.L.Handbookof Reagents for Organic Synthesis:Oxidising and Reducingagents (Wiley:New York, 1999) describe in, carry out oxidation and reduction and change mutually with the formula III chemical compound.Equally, wherein Y is hydroxyl and R 5And R 5' both is the formula II chemical compound of hydrogen and R wherein 5Be the formula III chemical compound of hydrogen can be by using suitable Reducing agent reduction from R wherein 8Be hydrogen or (C 1-4) the formula IV compound of alkyl.Wherein Y is hydroxyl and R 5' be (C 1-4) the formula II chemical compound of alkyl can use (C 1-4) alkylmetal reagent such as alkyl Grignard reagent or lithium alkylide, by nucleophilic addition from the formula III compound.
Formula I, formula II, formula III or formula IV chemical compound can adopt the compound of heterocyclic method from formula V-formula XII that be used to construct well known in the art.These methods are described in general handbook Katritzky, (front page among the A.R.:Comprehensive heterocyclic chemistry, Pergamon Press, 1984, especially referring to the 4th volume, the 3rd part, Five-membered rings with one oxygen, the 4B part of sulfur or nitrogen atom and the 6th volume, Five-membered rings with two or moreoxygen, sulfur or nitrogen atoms).
Figure C200580007120D00121
Formula V is to the chemical compound of formula XII, wherein R 1, R 2, R 6And R 7Have implication and R as previous definition 8Be H or (C 1-4) alkyl, can be by the amending method preparation of known literature method of those skilled in the art or literature method.
For example, formula VI chemical compound can be from formula V chemical compound or its activatory derivant by preparing with ammonia react The suitable solvent.
Formula VII chemical compound can use vulcanizing agent, prepares from compound VI as phosphorus pentasulfide or Lawesson ' s reagent.Alternatively, formula VII chemical compound can be from formula VIII chemical compound by preparing with the thioacetamide reaction solvent such as dimethyl formamide.
Formula VIII chemical compound can be from formula VI chemical compound by when existing alkali such as triethylamine, for example uses the trifluoroacetic anhydride dehydration and prepare.
Formula X chemical compound can be from formula IX chemical compound by preparing with azanol reaction The suitable solvent.
Wherein Y is NH 2Formula XI chemical compound can be from formula V chemical compound or its activated derivatives, by forming the oxo acetonitrile, use Reducing agent such as hydrogen that nitrile is reduced into primary amine during the palladium on having catalyst such as active carbon subsequently and prepare with cyanogen root anionic reactive.
Formula XII chemical compound can be from formula VIII chemical compound by preparing with azanol reaction The suitable solvent.
Formula V chemical compound and formula XI chemical compound can prepare by acidylate formula XIII chemical compound.For example, R wherein 8The formula V chemical compound that is hydrogen can at high temperature prepare with the aqueous NaOH hydrolysis subsequently by use trifluoroacetic acid anhydride acylation formula XIII chemical compound in solvent such as dimethyl formamide.Wherein Y is that the formula XI chemical compound of chlorine can prepare with chloracetyl chloride acidylate formula XIII chemical compound when having alkali such as pyridine.
Formula IX chemical compound can be from formula XIII chemical compound by formylated, for example uses Vilsmeier reaction (relevant summary is seen Jutz, Ady.Org.Chem.9, pt.1,225-342,1976) and prepares.
Alternatively, formula V chemical compound can use by (J.Med.Chem. such as Wijngaarden from formula XIV chemical compound 36, 3693-3699,1993) or the method described of Hwu etc. (J.Org.Chem.59,1577-1582,1994) or the amending method preparation of these methods.
Figure C200580007120D00131
Formula XIII chemical compound can be by the amending method preparation of known literature method of those skilled in the art or literature method.For example, formula XIII chemical compound can be by alkanisation formula XV chemical compound, by handling with alkali such as sodium hydride, is for example alkylating agent R of halogen or alkyl sulfonic acid ester group of leaving group with Y wherein subsequently 1R 2CHY reacts and prepares.Formula XV chemical compound can obtain from commercial source, can be by the amending method preparation of known literature method of those skilled in the art or literature method.
Alternatively, formula XIII chemical compound can adopt Fischer indole synthesis or its amending method preparation (Chem.Rev. from formula XIV chemical compound 69, 227-250,1969).
Formula XIV chemical compound can be by the amending method preparation of known literature method of those skilled in the art or literature method.For example, R wherein 2With R 7Being connected to form 6 yuan of heterocyclic formula XIV chemical compounds together can be from formula XVI chemical compound, by when having catalyst such as Nickel dichloride. (II), with Reducing agent such as sodium borohydride reduction and prepare.Can be for example when there be nickel (II) catalyst in formula XVI chemical compound, by coupling reaction such as the sharp refined reagent reacting preparation of 2-chloroquinoline dative.
R wherein 2With R 7Connecting the formula XIV chemical compound that forms 6 yuan of rings containing aerobic or sulfur can be the formula XVII chemical compound of OH or SH and Y wherein is that the formula XVIII chemical compound reaction of leaving group forms ether or thioether by Z wherein, subsequently by being amine with nitroreduction and preparing by reductive cyclization.This reduction and cyclisation can be carried out with hydrogen when the palladium on having catalyst such as active carbon.
Figure C200580007120D00141
Formula XVII chemical compound and formula XVIII chemical compound can obtain from commercial source, can be by the amending method preparation of known literature method of those skilled in the art or literature method.For example wherein Y is that the formula XVIII chemical compound of bromine can use for example bromine and preparing of bromating agent from formula XIX chemical compound solvent such as methanol.
Formula I, formula II, formula III or formula IV chemical compound can alternatively use transition metal-catalyzed coupling reaction preparation from formula XX chemical compound, as at general handbook Hegedus, describe among the L.S.Transition Metals in the Synthesis of Complex Organic Molecules (second edition, University Science:Sausalito 1999).
For example, the formula III chemical compound can adopt Suzuki reaction (Chem.Rev. 95, 2457-2483,1995) or its amending method, wherein Y 1Be the formula XX chemical compound of halogen and Y wherein 2It is the formula XXI chemical compound reaction of boric acid or borate and preparing.
Figure C200580007120D00142
Formula XX chemical compound and formula XXI chemical compound can obtain from commercial source, can be by the amending method preparation of known literature method of those skilled in the art or literature method.Y wherein for example 1Be that the formula XX chemical compound of bromine can use bromine to come bromination formula XIII chemical compound in solvent such as dimethyl formamide and prepares.
Those skilled in the art should be appreciated that, can use blocking group (as aryl sulfonyl) temporary protection between the transition phase that indole nitrogen is described in the above, and go protection and alkylation in synthetic last stages.Should be further appreciated that these protecting groups can be used for modifying the stability of intermediate and the indole ring reactivity to electrophilic reagent.Suitable protecting group is described in Kocienski, P.J.:Protecting Groups, Thieme, Stuttgart; New York, 1994.
Equally, the technical staff will appreciate that multiple (indol-3-yl) Hete rocyclic derivatives of formula I can be by corresponding some substituent R 3-R 7Functional group suitable conversion reaction and obtain.For example, R wherein 3Or R 4Be by hydroxyl, (C 1-4) alkoxyl, (C 1-4) alkylthio group, (C 1-4) formula I chemical compound optional C1 to the C6 linearity that replaces of alkyl sulphonyl or cyano group, side chain or cyclic alkyl, can be by when having alkali such as potassium carbonate, R wherein 3Or R 4Be the formula I chemical compound of hydrogen and C1 to C6 alkyl halide or functionalized C1 to C6 alkyl halide reaction and prepare.
The salt of (indol-3-yl)-Hete rocyclic derivatives of formula I and they can comprise at least one chiral centre, and therefore as stereoisomer, comprises enantiomer and diastereomer and exists.The present invention includes the above-mentioned stereoisomer of formula I chemical compound and every kind independently R and S enantiomer and their salt, described every kind independently R and S enantiomer and their salt are not have other enantiomer substantially, promptly with being lower than 5%, preferably be lower than 2%, be lower than other enantiomer of 1% especially, and the mixture that comprises any ratio of these enantiomer, comprise the racemic mixture of two kinds of enantiomer that comprise basic equivalent.
The method that is used for asymmetric synthesis or chiral separation and obtains pure stereoisomers is well known in the art, for example synthetic or initial synthetic from the obtainable chiral substrates of commerce with chiral induction, or separation stereoisomerism, for example on Chiral Media, use chromatograph or pass through to use chirality equilibrium ion Crystallization Separation.
Pharmaceutically acceptable salt can pass through with for example hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid or for example free alkali acquisition of ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic, succinic acid, propanoic acid, acetic acid and methanesulfonic acid processing formula I chemical compound of organic acid of mineral acid.
The compounds of this invention can be present in the non-solvent form also can be present in solvation form with pharmacy acceptable solvent such as water, ethanol etc.Usually, think that for the object of the invention the solvation form is equal to the non-solvent form.
The present invention further provides contain can accept auxiliary agent with pharmacy and optional other therapeutic agent is blended, according to (the indol-3-yl)-Hete rocyclic derivatives of general formula I or the pharmaceutical composition of its pharmaceutically acceptable salt.Term " can be accepted " to refer to compatible with other composition of compositions and harmless to its receiver.That compositions comprises is oral as being suitable for, in the Sublingual, subcutaneous, intravenous, epidural, sheath, intramuscular, through skin, lung, part or rectal administration etc., all those compositionss of using with the form of unit dose.Preferred route of administration is an intravenous route.
For Orally administered, active component can show as isolating unit, for example tablet, capsule, powder, granule, solution, suspensoid etc.
For parenteral administration, pharmaceutical composition of the present invention may reside in the container of unit dose or multiple dose, the injection of scheduled volume for example, for example be present in the bottle and ampoule of sealing, and can store in cryodesiccated (freeze dried) condition, it only needs to add sterile liquid carrier before use, as water.
Can accept auxiliary agent with these pharmacy mixes, as at canonical reference book Gennaro, A.R. wait Remington:The Science and Practice of Pharmacy (the 20th edition, Lippincott Williams and Wilkins, 2000, especially referring to the 5th part: describe Pharmaceutical Manufacturing), activating agent can be pressed into solid dosage unit for example pill, tablet, or be processed into capsule, suppository or patch.By the pharmacy acceptable liquid, activating agent can be used as the fluid composition of solution, suspensoid, Emulsion form, for example as ejection preparation, or uses as spray such as nasal mist.
For the preparation solid dosage unit, consider to use conventional additive such as filler, coloring agent, polymeric adhesive etc.Generally speaking, can use not any pharmacy of interferon activity compound functions can accept additive.Make activator of the present invention can be used as suitable carriers that solid composite uses and comprise the lactose that uses with appropriate amount, starch, cellulose derivative etc., or its mixture.For parenteral administration, can use aqueous suspension, normal isotonic saline solution and aseptic injectable solution, it contains pharmacy can accept dispersant and/or wetting agent, for example propylene glycol or butanediol.
The present invention comprises in addition and the pharmaceutical composition described above of the packaging material combination that is suitable for described compositions that described packaging material comprise the description that is used for above-described purposes about this compositions.
(indol-3-yl)-Hete rocyclic derivatives of the present invention it is found that it is the agonist of CB1 receptor, measures in people CB1 receptor detects as using Chinese hamster ovary celI.The active method of external biological that is used to measure receptors bind and Cannibinoid receptor modulators is known in this area.Usually, receptor of expressing and the chemical compound that is used to test contacts and measure stimulation or the inhibition that combination or function respond.
Be the measurement function response, the CB1 acceptor gene of will encoding, the separated DNA of optimized encoding people CB1 acceptor gene is expressed in suitable host cells.This cell can be a Chinese hamster ovary cell, but other cell also is fit to.Preferably, this cell is a mammal.
The method that is used for the cell line of construction expression recombinant C B1 is (Sambrook etc. well known in the art, Molecular Cloning:a Laboratory Manual, ColdSpring Harbor Laboratory Press, Cold Spring Harbor, latest edition).Receptor expression realizes by the expression of the DNA of coding desirable protein matter.Nowadays the technology that is used to connect extra sequence and make up suitable expression system all is well known in the art.The part or all of DNA of coding desirable protein matter can adopt synthetic structure of solid phase technique of standard, preferably includes the restriction site that makes ease of connection.The suitable control element of transcribing and translating of the coded sequence that can comprise being used for offers the dna encoding sequence.As everyone knows, can obtain now and multiple host, comprise compatible expression systems such as prokaryotic hosts such as antibacterial and eucaryon host such as yeast, plant cell, insect cell, mammalian cell, birds cell.
The cell that to express this receptor then contacts with test compounds to observe the stimulation or the inhibition of the response of combination or function.
Alternatively, contain the combination that the isolated cell film of CB1 (or CB2) receptor of expression can be used for measuring chemical compound.
For measuring combination, can use radioactivity or fluorescently-labeled chemical compound.The most widely used radiolabeled cannabinoid probe be [ 3H] CP55940, it has approximately identical affinity to CB1 with the CB2 binding site.
Another kind of algoscopy relates to by measuring second message,second messenger's reaction, and the cannabinoid CB 1 agonist compound is screened in the variation of for example measuring in receptor-mediated cAMP or the map kinase approach.Thereby this method relates at the cell surface expression CB1 of host cell receptor and this cell is contacted with test compounds.Measure second message,second messenger's response subsequently.Second message,second messenger's level will reduce or raise, and this depends on that test compounds is to being bonded to the influence of receptor.
CAMP level in the cell that for example exposes except direct measurement, also can use a kind of like this cell, promptly this cell is except the DNA transfection with the coding receptor, and also with the DNA transfection of another kind of coding reporter gene, the expression of the DNA of described coding reporter gene is relevant with receptor activation.Usually, the expression of reporter gene any response element that can react by the change to second message,second messenger's level is controlled.Suitable reporter gene is for example LacZ, alkali phosphatase, firefly luciferase and green fluorescence protein gene.This trans-activation is measured ratio juris and is well known in the art and is described in for example Stratowa, Ch, Himmler, A. and Czernilofsky, A.P., Curr.Opin.Biotechnol. 6, in 574 (1995).For selecting the active agonist compound of CB1 receptor, EC 50Be worth necessary＜10 -5M, preferred＜10 -7M.
This chemical compound can be used as analgesic in the treatment for example perioperative pain of pain (peri-operativepain), chronic pain, neuropathic pain, cancerous pain and pain relevant with multiple sclerosis and spasticity.
Cannabinoid agonists of the present invention also can be used for the treatment of other disease potentially, comprises multiple sclerosis, spasticity, inflammation, glaucoma, nausea and vomiting, inappetence, sleep disordered (sleep disturbances), respiratory disorder, allergy, epilepsy, migraine, cardiovascular disorder, neurodegenerative disorders (neurodegenerative disorders), anxiety neurosis, traumatic brain injury and apoplexy.
Chemical compound can also and other medicines, for example analgesic drug product such as opioid drug and nonsteroidal anti-inflammatory agent (NSAIDs) comprise that the COX-2 selective depressant unites use.
Chemical compound of the present invention can and be administered to the people with sufficient dosage and come mitigation symptoms in the sufficiently long time.For instance, the dosage level that is used for the people can be at every kg body weight 0.001-50
The scope of mg is preferably at the dosage range of every kg body weight 0.01-20mg.
The present invention sets forth by the following examples.
Conventional method:
Unless otherwise indicated, microwave reaction Emrys Optimizer TM(PersonalChemistry) carry out.Flash column chromatography carries out on silica gel.Half prepares type high pressure liquid chromatography (partly preparing HPLC) adopts the method for listing below to carry out:
Method (i):Agilent CombiHT (SB-C18,5 μ m) 12mm ID x 100mm; The acetonitrile-water gradient of 5-95% in 9 minutes; 25ml/ minute; 0.1% trifluoroacetic acid buffer; UV by 254nm measures.
Method is (ii):Waters Xterra (RP18,5 μ m) 30mm x 100mm; The acetonitrile-water gradient of 10-100% in 25 minutes; 30ml/ minute; 0.1% trifluoroacetic acid buffer; UV by 254nm measures.
1H NMR coupling constant provides with Hz.
Embodiment 1
1-(cyclohexyl) methyl-3-{5-[(dimethylamino) methyl]-[1,2,4] Evil two Azoles-3-yl }-7-methoxyl group-1H-indole, hydrochlorate
(45.0g, 306mmol) solution is cooled to and adds trifluoroacetic anhydride (TFAA) in 5 ℃ and 20 minutes (60.5ml 433mmol), maintains the temperature under 10 ℃ with the 7-methoxyl group indole in the dimethyl formamide (360ml) under nitrogen.Mixture was stirred 2 hours down at 5-10 ℃, be injected into subsequently (1600ml) in the water.The suspension that obtains stirred 15 minutes and leach 7-methoxyl group-3-[(trifluoromethyl) carbonyl]-1H-indole precipitate, water with its washing to neutral.
The solid suspension of humidity (1700ml) and agitating heating in the 4M aqueous NaOH were refluxed 2 hours.Cooling mixture is also used diethyl ether (2 * 400ml) washings.Subsequently with 5M hydrochloric acid with aqueous phase as acidified to pH1 and leach the thin precipitate that obtains, water with its washing to neutral and dry 7-methoxyl group-1H-indole-3-carboxylic acid (42.7g) pink solid.
Under nitrogen, under 10 ℃ in 20 minutes with sodium hydride (60% is scattered in the mineral oil, 23.0g, 575mmol) portioning is added to the 7-methoxyl group-1H-indole-3-carboxylic acid solution (42.7g in the dimethyl formamide (1250ml), 224mmol), maintain the temperature at below 15 ℃.Remove cooling bath and stirred suspension 90 minutes.Adding cyclohexyl methyl bromine (64.7ml, 464mmol).With mixture 60 ℃ of following agitating heating 3 hours.Cooling mixture to 10 ℃ also injects water (3600ml).Wash emulsion (3 * 500ml) with diethyl ether.Use 5M hydrochloric acid with aqueous phase as acidified to pH1 and leach precipitate, water with its washing to neutral and dry 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid (55g) white solid.
Under ice-water cooling, with oxalyl chloride (12.4g, 97.4mmol) (7.0g 24.4mmol) and in the mixture of dichloromethane (150ml) and with the mixture that obtains at room temperature stirred 18 hours to drop to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid.Remove dichloromethane and excessive oxalyl chloride and the residue that obtains is mixed with dichloromethane (150ml) by evaporation.Under ice-water-bath cooling, ammonia bubbled entered the mixture that obtains 30 minutes.Concentrated reaction mixture in a vacuum, the solid that obtains with 0.5M hydrochloric acid, 5% aqueous carbonic acid sodium and water development successively subsequently, and its drying under reduced pressure obtained 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide (5.1g) brown solid.
Under ice-water cooling, with trifluoroacetic anhydride (TFAA) (12.0g, 57.1mmol) drop to 1-(cyclohexyl) methyl-7-methoxyl group-1H-draw diindyl-3-carboxylic acid amide (4.1g, 14.3mmol), triethylamine (11.6g, 115mmol) with 1, in the mixture of 4-diox (250ml).At room temperature the mixture that obtains was stirred 12 hours.Add entry (30ml) and concentrate the mixture that obtains in a vacuum.Add entry (300ml) to the residue that obtains, and (4 * 300ml) extract this mixture with dichloromethane.Merge organic layer, aqueous carbonic acid hydrogen sodium with 5% and salt water washing, dry and concentrated in a vacuum on magnesium sulfate.By obtaining 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-nitrile (2.48g) crystalline solid with the residue that the column chromatography purification obtains with 10% in the normal heptane (v/v) eluent ethyl acetate.
With oxammonium hydrochloride. (966mg, 13.9mmol) be added to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-nitrile (2.48g, 9.24mmol), (1.41g, 13.9mmol) and in the mixture of ethanol (50ml), the mixture that will obtain refluxes and stirred 20 hours down triethylamine subsequently.After being cooled to room temperature, concentrated reaction mixture in a vacuum.The residue that obtains is mixed with water (150ml), and aqueous NaOH is adjusted to pH 10 with it and (4 * 100ml) extract with dichloromethane by adding.Merge organic layer, use the salt water washing, dry and concentrated in a vacuum on magnesium sulfate.With the residue that obtains by with the acetone eluting of 10% (v/v) in the dichloromethane with the column chromatography purification, obtain 1-(cyclohexyl) methyl-N-hydroxyl-7-methoxyl group-1H-indole-3-Methanamide (940mg).
Under nitrogen with molecular sieve (
Figure C200580007120D0020092843QIETU
, powder, (250mg 0.829mmol) in the suspension, and at room temperature stirred this mixture 30 minutes 200mg) to be added to 1-(cyclohexyl) methyl-N-hydroxyl-7-methoxyl group-1H-indole-3-Methanamide in the oxolane (6ml).The adding sodium hydride (60% is suspended in the oil, 36mg, and 0.900mmol), the mixture that stirring obtains under 60 ℃ is 20 minutes subsequently.Reactant mixture is cooled to room temperature and adds N, and (194mg is 1.66mmol) to this mixture for N-dimethylglycine methyl ester.Under reflux temperature, the mixture that obtains was stirred 2 hours and concentrated in a vacuum subsequently.The residue that obtains is mixed with dichloromethane (200ml), its aqueous carbonic acid sodium with 5% is washed, dry and concentrated in a vacuum on magnesium sulfate.With the oil that obtains by with the flash column chromatography purification of 0.6% in the dichloromethane (v/v) methanol-eluted fractions to obtain the oily product.This oil is dissolved in the isopropyl alcohol (3ml), adds hydrogen chloride (the 1M solution in the diethyl ether subsequently; 3ml) to this solution.The concentrated in a vacuum mixture that obtains is to obtain title compound (1:1 hydrochlorate) (66mg).
1H?NMR(400MHz，CD 3OD)δ?0.96-1.30(5H，m)，1.52-1.94(6H，m)，3.13(6H，s)，3.97(3H，s)，4.30(2H，d，.J?6.8)，4.83(2H，s)，6.81(1H，d，J?8.0)，7.13(1H，dd，.J?8.0，8.0)，7.71(1H，d，.J?8.0)，7.85(1H，s)。Es?IMS：m/z?369.2[M+H] +。
Embodiment 2
Replace N with the amino-acid ester of alternative synthetic or commercial acquisition, N-dimethylglycine methyl ester is used to prepare following chemical compound in addition with the method for embodiment 1.
The method that is used for synthesizing amino acid esters intermediate
Method A:
With the benzyl bromide a-bromotoluene acetas (500mg, 2.18mmol) be added to pyrrolidine in the oxolane (7ml) (171mg, 2.40mmol) and sodium carbonate (254mg is in mixture 2.40mmol).At room temperature stirred the mixture 18 hours, and concentrated in a vacuum subsequently.Residue is mixed with water (200ml) and extract with dichloromethane (3 x 100ml).Merge organic layer, dry and concentrated in a vacuum on sodium sulfate.By the flash column chromatography purification with the methanol-eluted fractions of the 0-10% in the dichloromethane (v/v) obtain pyrrolidine-1-guanidine-acetic acid benzyl ester (230mg, 1.05mmol).
Method B:
With methyl bromoacetate (199 μ l, 2.10mmol) be added to (S)-2-methoxy pyrrolidine in the acetonitrile (3ml) (268 μ l, 2.17mmol), potassium carbonate (319mg, 2.31mmol) and sodium iodide (315mg is in mixture 2.10mmol).Allow mixture under 160 ℃, accept microwave irradiation 5 minutes, between dichloromethane and water, distribute subsequently.With the dichloromethane extraction water layer and with the organic layer salt water washing that merges, dry and concentrated in a vacuum on sodium sulfate.By the flash column chromatography purification with the 0-10% in the dichloromethane (v/v) methanol-eluted fractions obtain (S)-(2-methoxy-pyrrolidine-1-yl) methyl acetate (133mg, 0.71mmol).
Method C:
With the D-proline (10.0g, 86.9mmol) be added to sulfuric acid solution in the methanol (45ml) (3.5ml, 65.3mmol) in.This mixture of stirring and refluxing 18 hours.With this solution to 0 of postcooling ℃ and by adding wet chemical (2.5M; 10ml) neutralization.Add formaldehyde (37% solution in the water; 11ml, 136mmol) and under 0 ℃, stirred the mixture 15 minutes.(1.6g 42.3mmol) also at room temperature stirred the mixture 3 hours to add sodium borohydride down at 0 ℃.Leach precipitate and filter liquor is distributed between dichloromethane and water.Use solid sodium carbonate that isolating water layer is adjusted to pH 10 and uses dichloromethane extraction.With organic layer dry and thick (the R)-1-methylpyrrolidin-2-carboxylate methyl ester (13.13g) of concentrated in a vacuum generation on sodium sulfate that merges.
A this crude product (5.0g) is obtained (R)-1-methylpyrrolidin-2-carboxylate methyl ester (1.30g) by the flash column chromatography purification with the 0-2% in the dichloromethane (v/v) methanol-eluted fractions.
2A:1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(pyrrolidine-1-yl) methyl]-[1, 2,4] oxadiazole-3-yl }-the 1H--indole, hydrochlorate
Use is according to the pyrrolidine-1-guanidine-acetic acid benzyl ester of method A preparation, prepares title compound according to the method for embodiment 1. 1H?NMR(400MHz，CD 3OD)δ?0.98-1.31(5H，m)，1.54-1.94(6H，m)，2.10-2.24(4H，m)，3.46-3.74(4H，m)，3.97(3H，s)，4.30(2H，d，J?7.2)，4.86(2H，s)，6.81(1H，d，J?8.0)，7.14(1H，dd，J?8.0，8.0)，7.70(1H，d，J?8.0)，7.84(1H，s)。Es?IMS：m/z?395.2[M+H] +。
2B:1-(cyclohexyl) methyl-3-{5-[(N-ethyl-N-isopropylamino) methyl]-[1, 2,4] oxadiazole-3-yl }-7-methoxyl group-1H-indole, hydrochlorate
Title compound should (N-ethyl-N-isopropylamino) methyl acetate be according to method A with the preparation of (N-ethyl-N-isopropylamino) methyl acetate, prepared with methyl bromoacetate and N-ethyl 2-aminopropane..Es?IMS：m/z?411.1[M+H] +。
2C: 1-(cyclohexyl) methyl-7-methoxyl group-3-(5-{[two-(2-methoxy ethyl) Amino] methyl }-[1,2,4] oxadiazole-3-yls)-the 1H-indole, hydrochlorate
Title compound should [two-(2-methoxy ethyl) amino] methyl acetate be according to method A with the preparation of [two-(2-methoxy ethyl) amino] methyl acetate, with methyl bromoacetate and two-(2-methoxy ethyl) amine preparation.Es?IMS：m/z?457.5[M+H] +。
2D:1-(cyclohexyl) methyl-3-{5-[1-(diformazan ammonia) ethyl]-[1,2,4] oxadiazole-3- Base }-7-methoxyl group-1H-indole, hydrochlorate
Title compound prepares with 2-diformazan ammonia methyl propionate, and this 2-diformazan ammonia methyl propionate is according to method A, with methyl-2 bromopropionic acid ester and dimethylamine preparation.Eg?IMS：m/z?383.0[M+H] +。
2E:(S)-1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(2-methoxy pyrroles Alkane-1-yl) methyl]-[1,2,4] oxadiazole-3-yls }-the 1H-indole, hydrochlorate
(S)-(2-methoxy-pyrrolidine-1-yl) the methyl acetate preparation of title compound according to method B preparation.
Es?IMS：m/z?439.3[M+H] +。
2F:(R)-1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(2-methoxy pyrrolidine -1-yl) methyl]-[1,2,4] oxadiazole-3-yls }-the 1H-indole, hydrochlorate
Title compound should (R)-(2-methoxy-pyrrolidine-1-yl) methyl acetate be according to method B with the preparation of (R)-(2-methoxy-pyrrolidine-1-yl) methyl acetate, with the preparation of (R)-2-methoxy pyrrolidine.
Es IMS:m/z 439.1[M+H] +[α] D 22+ 21.6 ° (c=0.8mg/ml in the chloroform).
2G:(R)-1-(cyclohexyl) methyl-7-methoxyl group-3-[5-(1-methylpyrrolidin-2-yl) -[1,2,4] oxadiazole-3-yls }-the 1H-indole, hydrochlorate
(the R)-1-methylpyrrolidin-2-methyl acetate preparation of title compound according to method C preparation.
Es IMS:m/z 395.0[M+H] +[α] D 22+ 50.1 ° (c=1.70mg/ml in the chloroform).
2H:(S)-1-(cyclohexyl) methyl-7-methoxyl group-3-[5-(1-methylpyrrolidin-2-yl) -[1,2,4] oxadiazole-3-yls }-the 1H-indole, hydrochlorate
Title compound should (S)-1-methylpyrrolidin-2-methyl acetate be according to method C with the preparation of (S)-1-methylpyrrolidin-2-methyl acetate, replaced the D-proline and prepared with the L-proline.Es IMS:m/z 395.0[M+H] +.[α] D 22-51.7 ° (c=1.35mg/ml in the chloroform).
2I:1-(cyclohexyl) methyl-7-methoxyl group-3-[5-(1-methyl piperidine-2-yl)-[1,2, 4] oxadiazole-3-yl }-the 1H-indole, hydrochlorate
Title compound is the method according to embodiment 1, replaces N with ethyl 1-methyl piperidine ester (pipecolinate), the preparation of N-dimethylglycine methyl ester.
Es?IMS：m/z?409.3[M+H] +。
Embodiment 3
1-(cyclohexyl) methyl-3-[(5-aminomethyl)-[1,2,4] oxadiazole-3-yl]-7- Methoxyl group-1N-indole, hydrochlorate
With molecular sieve (
Figure C200580007120D00241
Powder, (500mg 1.66mmol) in the suspension, and at room temperature stirred the mixture that obtains 30 minutes 300mg) to be added to 1-(cyclohexyl) methyl-N-hydroxyl-7-methoxyl group-1H-indole-3-Methanamide in the oxolane (10ml).(60% is suspended in the grease, and 100mg 2.55mmol) and at 65 ℃ stirred the mixture that obtains down 20 minutes to add sodium hydride.Reaction mixture is to room temperature and add N-Boc-glycine N-hydroxy-succinamide ester (871mg is 3.32mmol) to this mixture.The mixture heated that obtains is extremely refluxed, stirred simultaneously 2 hours, subsequently it is cooled to room temperature.Add aqueous NaOH (4M; 5ml) and with the mixture that obtains stirred 14 hours.Reactant mixture is concentrated in a vacuum, subsequently the residue that obtains is mixed with water (200ml).With the dichloromethane (mixture that 4 * 200ml) extractions obtain.Merge organic layer, use the salt water washing, dry and concentrated in a vacuum on magnesium sulfate.The grease that obtains by with the column chromatography purification of 0.4% in the dichloromethane (v/v) methanol-eluted fractions to obtain ({ 3-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] [1,2,4] oxadiazole-5-yls } methyl) t-butyl carbamate (125mg).
Will ({ 3-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] [1,2,4] oxadiazole-5-yl } methyl) t-butyl carbamate (110mg, 0.25mmol) and the mixture of trifluoroacetic acid (4ml) at room temperature stirred 1.5 hours.Reactant mixture is injected 5% aqueous carbonic acid sodium (200ml) carefully and (4 * 200ml) extract the mixture that obtains with dichloromethane.Merge organic layer, subsequently it is used the salt water washing, dry and concentrated in a vacuum on magnesium sulfate.The oil that obtains obtains the free alkali yellow oil of title compound by the column chromatography purification with 1.5% in the dichloromethane (v/v) methanol-eluted fractions.This oil is dissolved in the diethyl ether, and (the 1M solution in the diethyl ether that adds hydrogen chloride subsequently; 3ml) to this solution.The mixture that obtains is concentrated the 1:1 hydrochlorate (71mg) that obtains title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)δ?0.98-1.29(5H，m)，1.52-1.78(5H，m)，1.79-1.94(1H，m)，3.98(3H，s)，4.31(2H，d，J?7.2)，4.55(2H，s)，6.81(1H，d，J?7.6)，7.14(1H，dd，J?7.6，8.0)，7.72(1H，d，J?8.0)，7.83(1H，s)。Es?IMS：m/z?341.1[M+H] +。
Embodiment 4
1-(cyclohexyl) methyl-3-{5-[(diformazan ammonia) methyl]-[1,2,4] oxadiazole-3- Base }-7-fluoro-1H-indole, hydrochlorate
Title compound can replace the preparation of 7-methoxyl group indole with the 7-fluoro indole according to the method for embodiment 1.Es?IMS：m/z?357.3[M+H] +，247.4。
Embodiment 5
7-chloro-1-(cyclohexyl) methyl-3-{5-[(diformazan ammonia) methyl]-[1,2,4] Evil two Azoles-3-yl }-the 1H-indole, hydrochlorate
Title compound can replace the preparation of 7-methoxyl group indole with the 7-chloro-indole according to the method for embodiment 1.Es?IMS：m/z?375.1，373.1[M+H] +。
Embodiment 6
1-(cyclohexyl) methyl-3-(5-{[N-isopropyl-N-(2-methoxy ethyl) amino] Methyl }-[1,2,4] triazole-3-yl)-7-methoxyl group-1H-indole, hydrochlorate
Hydrogen chloride gas is bubbled by 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-nitrile in the methanol (200ml) (as the preparation of describing among the embodiment 1; 3.15g 11.0mmol) solution of cold (0 ℃) is 30 minutes.
Allow the mixture that obtains place 72 hours, concentrate 2/3rds in the vacuum then.Add this product of diethyl ether crystallization, and collect the hydrochlorate (3.82g) that the solid that produces obtains 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-azomethine acid methyl ester by filtering.
With 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-azomethine acid methyl ester hydrochloride salt (0.10g, 0.297mmol), hydrazine hydrate (0.289ml, 5.94mmol), aluminum chloride (39.6mg, 0.297mmol) and toluene (18ml) mixes and allow this mixture accept 120 ℃ microwave irradiation 60 minutes.The mixture that obtains is concentrated in a vacuum, be dissolved in the toluene once more and twice of reconcentration in a vacuum.With the residue that obtains toluene/acetonitrile mixture (12/1) suspend in (19.5ml) and add chloracetyl chloride (0.118ml, 1.49mmol), with the microwave irradiation of 120 ℃ of this mixture acceptance of relief 12 minutes.The concentrated in a vacuum mixture that obtains also dissolves it in acetonitrile (3ml) again.Add N-(2-methoxy ethyl) 2-aminopropane. (0.068ml, 0.446mmol), potassium carbonate (45.2mg, 0.327mmol) and sodium iodide (44mg, 0.297mmol) and allow this mixture accept 160 ℃ microwave irradiation 5 minutes, it was placed 72 hours with relief, and concentrated in a vacuum then.The residue that obtains is obtained the 1:1 hydrochlorate (46mg) of title compound by the column chromatography purification with the 2.5%-5% in the dichloromethane (v/v) methanol-eluted fractions. 1H?NMR(400MHz，CD 3OD)：0.95-1.12(2H，m)，1.13-1.24(3H，m)，1.50(6H，s(br))，1.55-1.73(5H，m)，1.79-1.93(1H，m)，3.34-3.50(5H，m)，3.70-3.99(6H，m)，4.24(2H，d，J?6.4)，4.67(2H，s(br))，6.70(1H，d，J?7.7)，7.16(1H，t，J?7.7)，7.95(1H，d，J?7.7)，8.02(1H，s(br))；Es?IMS：m/z?440.3[M+H] +。
Embodiment 7
1-(cyclohexyl) methyl-3-{5-[(diethylamino) methyl]-[1,2,4] thiadiazoles-3- Base }-7-methoxyl group-1H-indole, hydrochlorate
With chloroformyl sulphinyl chlorine (2.4ml; 28.4mmol) be added to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide in the oxolane (120ml) and (press to describe among the embodiment 1 and prepare from 7-methoxyl group indole; 4.0g, in suspension 14mmol) and will be under the reaction mixture refluxed heating 15 minutes with postcooling.Remove in a vacuum subsequently and desolvate and excessive reagent, obtain 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indole)-[1,3,4]-oxygen thiazole-2-ketone (5.2g, 14.4mmol) pink solid.
(2.74ml, (1.0g is in suspension 2.77mmol) and use Emrys 27.7mmol) to be added to 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indole) [1,3,4]-oxygen thiazole-2-ketone in the meta-xylene (15ml) with the ethyl cyanide carbamate TMOptimizer EXP allows reactant accept 160 ℃ microwave irradiation 10 minutes.Repeat this reaction three times with identical scale, obtain 3-(1-(cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1 with the reactant mixing and by flash column chromatography purification with the 0-50% in the heptane (v/v) dichloromethane eluting, 2,4] thiadiazoles-5-carboxylic acid, ethyl ester (4.38g, 11mmol) white solid.
Sodium borohydride is added to 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1,2,4] thiadiazoles-5-carboxylic acid, ethyl ester in oxolane (80ml) and the methanol (80ml) in batches, and (4.0g is in the cold solution (ice/methanol bath) 10mmol).Further reaction stirred was also used hydrochloric acid (20ml) the cancellation reaction of 1M in 20 minutes subsequently.Remove methanol and oxolane in a vacuum and add the hydrochloric acid (50ml) of dichloromethane (200ml) and 2M.The separation organic layer is also used saline (50ml) washing, and dry also removing in a vacuum desolvated on magnesium sulfate.The residue that obtains is obtained [3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1 by the flash column chromatography purification with 50% in the heptane (v/v) diethyl ether eluting, 2,4] thiadiazoles-5-yl] methanol (3.15g, 8.8mmol) baby pink solid.
With methylsufonyl chloride (0.595ml, 7.68mmol) be added to [3-(1-cyclohexyl methyl-7-methoxyl group-1H-diindyl-3-yl)-[1 in the dichloromethane (150ml), 2,4] thiadiazoles-5-yl]-methanol (2.3g, 6.4mmol) in the cold solution (ice/methanol bath) and add subsequently triethylamine (1.16ml, 8.32mmol).Reactant was stirred 10 minutes and was injected in the separatory funnel subsequently.With 5% aqueous carbonic acid sodium (2 * 100ml), saline (100ml) washing organic layer, its drying on magnesium sulfate is also obtained methanesulfonic acid 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl) two [1 except that desolvating in a vacuum, 2,4] thiadiazoles-5-base methyl ester (2.9g, 6.7mmol), it need not to be further purified and can use.
With diethylamine (0.22ml, 2.13mmol) be added to the methanesulfonic acid 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1 in the oxolane (1ml), 2,4] (93mg is 0.2mmol) in the solution and allow reactant accept 150 ℃ microwave irradiation 15 minutes for thiadiazoles-5-base methyl ester.Reactant is injected separatory funnel and uses dichloromethane (40ml) eluting.With 5% aqueous carbonic acid sodium (2 * 20ml), saline (organic layer that 2 * 20ml) washings merge, it is dry and remove in a vacuum and desolvate on magnesium sulfate.The residue that obtains is obtained title compound (54mg, free alkali 0.13mmol) by the flash column chromatography purification.Be dissolved in this free alkali in the dichloromethane and add hydrogen chloride (the 2M solution in the diethyl ether; 1.0ml, 2.0mmol).Concentrate this mixture in a vacuum to obtain the 1:1 hydrochlorate of title compound. 1H?NMR(400MHz，CD 3OD)：0.95-1.12(2H，m)，1.16-1.27(3H，m)，1.45(6H，t，J?7)，1.55-1.63(2H，m)，1.63-1.8(3H，m)，1.8-1.95(1H，m)，3.28-3.32(4H，m)，3.97(3H，s)，4.3(2H，d，J?7)，4.96(2H，s)，6.79(1H，d，J?8)，7.13(1H，t，J?8)，7.95(1H，s)，8.04(1H，d，J?8)；Es?IMS：m/z?413.1[M+H] +。
Embodiment 8
The method of embodiment 7 is further used for preparing following chemical compound:
8A:1-(cyclohexyl) methyl-7-methoxyl group-3-(5-{[two-(2-methoxy ethyl) Amino] methyl }-[1,2,4] thiadiazoles-3-yl)-the 1H-indole, hydrochlorate
Title compound replaces the diethylamine preparation with two-(2-methoxyl group) amine.Es?IMS：m/z473.1[M+H] +。
8B:1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(pyrrolidine-1-yl) methyl]-[1, 2,4] thiadiazoles-3-yl }-the 1H-indole, hydrochlorate
Title compound can replace the diethylamine preparation with pyrrolidine.Es?IMS：m/z?411.1[M+H] +，342.0。
8C: 1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(2-methyl piperidine-1-yl) first Base]-[1,2,4] thiadiazoles-3-yl }-the 1H-indole, trifluoroacetate
Title compound can replace the diethylamine preparation with pipecoline.By partly preparing HPLC[method (i)] the purification free alkali obtains the 1:1 trifluoroacetate of title compound.Es?IMS：m/z?439.3[M+H] +。
8D: 1-(cyclohexyl) methyl-3-(5-{[N-(2-ethoxy) N-methylamino] methyl }-[1, 2,4] thiadiazoles-3-yl)-and 7-methoxyl group-1H-indole, hydrochlorate
Title compound can replace the diethylamine preparation with (2-ethoxy) methylamine.By partly preparing HPLC[method (i)] the purification free alkali obtains the 1:1 trifluoroacetate of title compound.Es?IMS：m/z?415.3[M+H] +，328.3。
8E: 1-(cyclohexyl) methyl-7-methoxyl group-3-(5-{[N-(2-methoxy ethyl)-N- Methylamino] methyl }-1,2,4] thiadiazoles-3-yl)-the 1H-indole, hydrochlorate
Title compound can use N-(2-methoxy ethyl)-N-methylamine to replace the diethylamine preparation.Es?IMS：m/z?429.4[M+H] +。
Embodiment 9
1-(cyclohexyl) methyl-3-{5-[1-(diethylamino) ethyl]-[1,2,4] thiadiazoles -3-yl }-7-methoxyl group-1H-indole, hydrochlorate
With methyl-magnesium-bromide solution (0.52ml, 3M in the diethyl ether, 1.56mmol) be added to the 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1 in the diethyl ether (50ml), 2,4] (500mg 1.3mmol) in the cold solution (dry ice acetone bath) and reaction stirred 15 minutes, adds another part methyl-magnesium-bromide solution (0.25ml to thiadiazoles-5-carboxylic acid, ethyl ester subsequently, 3M in the diethyl ether, 0.75mmol) and stirred reaction mixture 5 minutes.Use saturated aqueous ammonium chloride (5ml) cancellation reaction subsequently and allow reactant be warming up to room temperature.Reactant mixture is injected separatory funnel and water (20ml) washing organic layer.Use diethyl ether (20ml) back scrubbing water layer subsequently.The organic layer that merges is dry on magnesium sulfate, filter and remove in a vacuum and desolvate.The residue that obtains is obtained 1-[3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1,2,4] thiadiazoles-5-yl by the flash column chromatography purification] ethyl ketone (170mg, 0.46mmol) yellow solid.
With diethylamine (0.248ml, 2.4mmol) and acetic acid (0.137ml, 2.4mmol) be added to the 1-[3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-[1 in the acetonitrile (3ml), 2,4] thiadiazoles-5-yl] (90mg is 0.24mmol) in the solution and stirred reaction mixture 30 minutes for ethyl ketone.Add cyano group boron hydride (204mg, last sample 2.35mmolg that polymer is supported -1, 0.48mmol) to reactant and allow reactant mixture accept 150 ℃ microwave irradiation 10 minutes.Reactant mixture is passed through 5g Strata TMSCX giga manages filtration.With this pipe of methanol wash and use 2M ammonia eluting in the methanol subsequently.Evaporation methanol ammonia solution and the residue that obtains by the flash column chromatography purification are to obtain title compound (62mg, free alkali 0.145mmol).Be dissolved in free alkali in the dichloromethane (1ml) and add diethyl ether (1ml, 2mmol) the 2M HCl in removes the 1:1 hydrochlorate that excessive reagent and solvent obtain title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)：1.0-1.2(2H，m)，1.16-1.26(3H，m)，1.38-1.5(6H，m)，1.55-1.78(5H，m)，1.82-1.94(4H，m)，3.32-3.68(4H，m)，3.97(3H，s)，4.3(2H，d，J?7.5)，5.36-5.48(1H，m)，6.8(1H，d，J?8)，7.14(1H，t，J?7.5)，7.94(1H，s)，8.02(1H，d，J?8)；Es?IMS：m/z?427.4[M+H] +，328.4。
Embodiment 10
1-(cyclohexyl) methyl-3-{5-[(diethylamino) methyl]-[1,2,4] thiadiazoles-3- Base }-7-fluoro-1H-indole, trifluoroacetate
According to the method for embodiment 7, with 1-(cyclohexyl) methyl-7-fluoro-1H-indole-3-carboxylic acid amide (from 7-fluoro indole preparation) and use diethylamine, the preparation title compound.By partly preparing HPLC[method (i)] the purification free alkali obtains 1: 1 trifluoroacetate of title compound.Es?IMS：m/z?401.3[M+H] +。
Embodiment 11
7-chloro-1-(cyclohexyl) methyl-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2, 4] thiadiazoles-3-yl }-the 1H-indole, trifluoroacetate
According to the method for embodiment 7, replace diethylamine to prepare title compound with 7-chloro-1-(cyclohexyl) Methyl-1H-indole-3-carboxylic acid amide (from the preparation of 7-chloro-indole) and with pyrrolidine.By partly preparing HPLC[method (i)] the purification free alkali obtains the trifluoroacetate of the 1:1 of title compound.Es?IMS：m/z?417.3，415.3[M+H] +。
Embodiment 12
1-(cyclohexyl) methyl-7-ethyl-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2, 4] thiadiazoles-3-yl }-the 1H-indole, trifluoroacetate
According to the method for embodiment 7, replace diethylamine to prepare title compound with 1-(cyclohexyl) methyl-7-ethyl-1H-indole-3-carboxylic acid amide (from the preparation of 7-ethylindole) and with pyrrolidine.By partly preparing HPLC[method (i)] the purification free alkali obtains the trifluoroacetate of the 1:1 of title compound.Es?IMS：m/z?409.3[M+H] +。
Embodiment 13
(R)-and 3-cyclohexyl-6-{5-[(diethylamino) methyl]-[1,2,4]-thiadiazoles-3-yl }-2, 3-dihydro-pyrrolo-[1,2,3-de]-1,4-benzoxazinyl, hydrochlorate
With diisopropyl azodiformate (19.5ml, 99.2mmol) (method that prepare (S) enantiomer by being used for of describing prepares to be added to (R)-N-Boc-2-cyclohexyl ethyl alcohol amine in the toluene (150ml) under 0 ℃, people J.Org.Chem.52 such as Luly, 1487-1492,1987; 29.4g, 94.5mmol) and triphenylphosphine (37.2g is in mixture 141.8mmol).Stir after 1 hour, (12.1ml 104.0mmol) is added to this mixture with the 2-bromophenol under 0 ℃.Also at room temperature stirred 20 hours in 2 hours at 0 ℃ of following stirred reaction mixture.The mixture that obtains is distributed in dichloromethane and water.With the dichloromethane extraction water layer and with the organic layer 2N sodium hydroxide solution and the salt water washing that merge, dry and concentrated on sodium sulfate.With residue by the flash column chromatography purification with the 0-10% in the heptane (v/v) eluent ethyl acetate obtain (R)-2-(2-tert-butoxy formamido group-2-cyclohexyl ethyoxyl) bromobenzene (12.80g, 32.1mmol).
With (R)-2-in the toluene (4.0ml) (2-tert-butoxycarbonyl amino-2-cyclohexyl ethyoxyl) bromobenzene (500mg, 1.26mmol), tetrakis triphenylphosphine palladium (0) (146mg, 0.126mmol) and sodium tert-butoxide (181mg, 120 ℃ of microwave irradiations of mixture acceptance 1.88mmol) 10 minutes.The mixture that obtains is distributed between dichloromethane and water.With the dichloromethane extraction water layer and with the organic layer salt water washing that merges, dry and concentrated on sodium sulfate.Residue is obtained (R)-4-tert-butoxycarbonyl-3-cyclohexyl-3 by the flash column chromatography purification with the 0-17% in the heptane (v/v) eluent ethyl acetate, 4-dihydro-2H-1, the 4-benzoxazinyl (270mg, 0.85mmol).This reaction is obtained identical intermediate 13 times with identical scale repetition, and (total amount is 3.98g, 12.5mmol).
With (R)-4-tert-butoxycarbonyl-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazinyl (3.98g, 12.5mmol), the mixture of 5N hydrochloric acid (10ml) and ethanol (10ml) stirred 50 minutes down at 70 ℃.Remove ethanol in a vacuum and residue is distributed between dichloromethane and 2N sodium hydroxide solution.With the dichloromethane extraction water layer and with the organic layer salt water washing that merges, dry also concentrating obtains (R)-3-cyclohexyl-3 on sodium sulfate, 4-dihydro-2H-1, the 4-benzoxazinyl (2.72g, 12.5mmol).
With (R)-3-cyclohexyl-3,4-dihydro-2H-1, the 4-benzoxazinyl (2.72g 12.5mmol) is dissolved in N, add in the dinethylformamide (20ml) and under 0 ℃ sodium nitrite solution in the entry (949mg, 13.8mmol).Subsequently, add 5N hydrochloric acid (6.0ml) down at 0 ℃.Reactant mixture was stirred 1 hour down at 0 ℃, subsequently it is distributed between ethyl acetate and water.With the ethyl acetate extraction water layer and with the organic layer salt water washing that merges, dry and concentrated on sodium sulfate.The residue that obtains is dissolved in the diethyl ether (50ml), and at 0 ℃ of lithium aluminium hydride (1.0M that adds down in the oxolane; 9.51ml, 9.51mmol).Reactant mixture was stirred 1 hour down at 0 ℃, use the frozen water cancellation subsequently.Add ethyl acetate to this mixture and by Celite plug filtering mixt, and use the ethyl acetate washing leaching cake.Distribute filter liquor and use the ethyl acetate extraction water layer.With the organic layer salt water washing that merges, dry and concentrated on sodium sulfate.Residue is obtained (R)-4-amino-3-cyclohexyl-3 by the flash column chromatography purification with the 0-17% in the heptane (v/v) eluent ethyl acetate, 4-dihydro-2H-1, the 4-benzoxazinyl (1.47g, 6.33mmol).
With ethyl pyruvate (882mg 7.59mmol) is added to (R)-4-amino-3-cyclohexyl-3 in the ethanol (40ml), 4-dihydro-2H-1, (1.47g is 6.33mmol) in the solution for the 4-benzoxazinyl.At room temperature reactant mixture was stirred 15 minutes, (10%v/v is in ethanol to add sulphuric acid in reactant mixture; 8.0ml).With reaction mixture refluxed 2 hours.Cooling off this mixture distributes between ethyl acetate and sodium carbonate liquor to room temperature and with it.With the ethyl acetate extraction water layer and with the organic layer salt water washing that merges, dry and concentrated on sodium sulfate.Residue is obtained ethyl (R)-3-cyclohexyl-2 by the flash column chromatography purification with the eluent ethyl acetate of the 0-10% in the heptane (v/v), and the 3-pyrrolin is [1,2,3-de]-1 also, and 4-benzoxazinyl-5-carboxylate (1.49g, 4.76mmol).
(5.94ml 23.8mmol) is added to ethyl (R)-3-cyclohexyl-2 in the ethanol (50ml), and the 3-pyrrolin is [1,2,3-de]-1 also, and (1.49g is 4.76mmol) in the solution for 4-benzoxazinyl-5-carboxylate with the 4N sodium hydroxide.Under 70 ℃, stirred the mixture 40 minutes.Remove ethanol in a vacuum, and with in the 2N hydrochloric acid and residue, and it is distributed between dichloromethane and water.With the dichloromethane extraction water layer and with the organic layer salt water washing that merges, dry and concentrated on sodium sulfate.Residue is dissolved in the quinoline (20ml), add subsequently copper powder (453mg, 7.13mmol).Under 210 ℃, stirred the mixture 1 hour.Ethyl acetate and water at room temperature are added to this mixture,, and use the ethyl acetate washing leaching cake by Celite plug filtering mixt.With 5N hcl acidifying filter liquor and with its distribution.With the ethyl acetate extraction water layer and with the organic layer 1N hydrochloric acid and the salt water washing that merge, dry and concentrated on sodium sulfate.Residue is obtained (R)-3-cyclohexyl-2 by the flash column chromatography purification with the 0-10% in the heptane (v/v) eluent ethyl acetate, and the 3-pyrrolin is [1,2,3-de]-1 also, and the 4-benzoxazinyl (984mg, 4.08mmol).
With trifluoroacetic anhydride (TFAA) (0.311ml 2.73mmol) is added to N under 0 ℃, (the R)-3-cyclohexyl-2 in the dinethylformamide (5.0ml), the 3-pyrrolin is [1,2,3-de]-1 also, (600mg is 2.49mmol) in the solution for the 4-benzoxazinyl.At room temperature stirred the mixture 5 hours, and subsequently it was distributed between dichloromethane and water.Use the dichloromethane extraction water layer, and with the organic layer salt water washing that merges, at Na 2SO 4Last dry and concentrated.Residue is obtained (R)-3-cyclohexyl-6-trifluoromethyl carbonyl-2 by the flash column chromatography purification with the 0-25% in the heptane (v/v) eluent ethyl acetate, and the 3-pyrrolin is [1,2,3-de]-1 also, and the 4-benzoxazinyl (628mg, 1.86mmol).
4N NaOH (5.0ml) is added to 1, (the R)-3-cyclohexyl in the 4-diox (20ml)-6-trifluoromethyl carbonyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, and (628mg is 1.86mmol) in the solution for the 4-benzoxazinyl.Mixture was refluxed 42 hours, use 5N hydrochloric acid that it is acidified to pH1 subsequently and between dichloromethane and water, distribute.Use the dichloromethane extraction water layer, and with the organic layer salt water washing that merges, at Na 2SO 4Last dry also concentrating obtains (R)-3-cyclohexyl-2, and the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazinyl-6-carboxylic acid (572mg).
Method according to embodiment 7, with (R)-3-cyclohexyl-2,3-pyrrolin also [1,2,3-de]-1,4-benzoxazinyl-6-carboxylic acid amide is (from (R)-3-cyclohexyl-2,3-pyrrolin also [1,2,3-de]-1,4-benzoxazinyl-6-carboxylic acid preparation) replace 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide to prepare title compound.Es IMS:m/411.0[M+H] +[α] D 22-30.7 ° (c=1.50mg/ml is in chloroform).
Embodiment 14
According to the method for embodiment 7, replace 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide and prepare following chemical compound with 7-fluoro-1-(tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide.
According to the method for embodiment 1, replace 7-methoxyl group indole and use toluene-4-sulfonic acid tetrahydropyran-4-base methyl ester to replace the cyclohexyl methyl bromine to prepare 7-fluoro-1 (tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide with the 7-fluoro indole.
The method that is used for synthetic toluene-4-sulfonic acid tetrahydropyran-4-base methyl ester intermediate
With paratoluensulfonyl chloride (29.8g, 157mmol) partly be added to tetrahydrochysene-2H-pyrans-4-base-methanol in the dichloromethane (200ml) (20.0g, 172mmol) and pyridine (25.2mL is in mixture 313mmol).At room temperature stirred the mixture 17 hours, and used aqueous hydrochloric acid solution (2M subsequently; 100ml) cancellation.Stratum disjunctum is also used dichloromethane (2 * 100ml) aqueous layer extracted.Merge organic layer and it is concentrated in a vacuum.From dichloromethane: recrystallize obtains toluene-4-sulfonic acid Pentamethylene oxide .-4 bases-methyl ester the heptane (5:1).Mother solution is further produced more the toluene-4-sulfonic acid tetrahydrochysene-pyrans-4 bases-methyl ester of volume by the silica gel chromatography with 50% dichloromethane eluting in the normal heptane, and (total output is 41.6g, 154mmol).
The 14A:3-{5-[(diethylamino) methyl-[1,2,4] thiadiazoles-3-yl]-7-fluoro-1-(tetrahydrochysene Pyrans-4-yl) Methyl-1H-indole, hydrochlorate
Title compound can use the diethylamine preparation.Es?IMS：m/z?403.1[M+H] +。
14B:7-fluoro-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2,4]-thiadiazoles-3-yl }-1- (tetrahydropyran-4-base) Methyl-1H-indole, hydrochlorate
Title compound can use pyrrolidine to replace the diethylamine preparation.
Es?IMS：m/z?401.0[M+H] +。
14C:3-{5-[(diformazan ammonia) methyl]-[1,2,4] thiadiazoles-3-yl }-7-fluoro-1-(four Hydrogen pyrans-4-yl) Methyl-1H-indole, hydrochlorate
Title compound can use dimethylamine to replace the diethylamine preparation.Es?IMS：m/z?375.0[M+H] +。
Embodiment 15
According to the method for embodiment 7, replace 1-(cyclohexyl) methyl-7-methoxyl group-following chemical compound of 1H-indole-3-carboxylic acid amide preparation with 7-chloro-1-(tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide.
According to the method for embodiment 1, replace 7-methoxyl group indole and replace the cyclohexyl methyl bromine to prepare 7-chloro-1-(tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide with toluene-4-sulfonic acid tetrahydropyran-4-base methyl ester with the 7-chloro-indole.
15A:7-chloro-3-(5-{[N-ethyl-N-(2-methoxy ethyl) amino] methyl }-[1,2, 4]-thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole, hydrochlorate
Title compound can use N-ethyl-N-(2-methoxy ethyl) amine to replace the diethylamine preparation.Es?IMS：m/z?451.0，449.0[M+H] +。
15B:7-chloro-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2,4]-thiadiazoles-3-yl }-1- (tetrahydropyran-4-base) Methyl-1H-indole, hydrochlorate
Title compound can use pyrrolidine to replace the diethylamine preparation.Es?IMS：m/z?419.3，417.3[M+H] +。
15C:7-chloro-3-(5-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,2,4]- Thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
Title compound can use N-ethyl (2-ethoxy) amine to replace the diethylamine preparation.Es?IMS：m/z?437.1，435.1[M+H] +。
Embodiment 16
1-(cyclohexyl) methyl-7-methoxyl group-3-(4-{[N-(2-methoxy ethyl)-N- Methylamino] methyl }-[1,3]-thiazol-2-yl)-the 1H-indole, hydrochlorate
1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide (is prepared from 7-methoxyl group indole as describing among the embodiment 1; 5.10g, 17.8mmol), Lawesson ' s reagent (7.92g, 19.6mmol) and the mixture of toluene (150ml) at room temperature stirred 4 days.In a vacuum concentrated reaction mixture and with the residue that obtains by with the column chromatography purification of dichloromethane eluting to obtain 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carbothioic acid amide (3.58g).
With 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carbothioic acid amide (200mg, 0.66mmol), 1, the 3-dichloroacetone (126mg, 0.99mmol) and the mixture of ethanol (2.0ml) stirred 1 hour down at 60 ℃.Reactant mixture concentrated in a vacuum and the residue that obtains is mixed with 5% aqueous carbonic acid sodium (100ml).With the dichloromethane (mixture that 4 * 100ml) extractions obtain.Merge organic layer, use the salt water washing, dry and concentrated in a vacuum on magnesium sulfate.By the residue that obtains with the column chromatography purification of 25% in the normal heptane (v/v) eluent ethyl acetate to obtain 3-[4 (chloromethyl) thiazol-2-yl]-1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (200mg).
With 3-[4 (chloromethyl) thiazol-2-yl]-1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (100mg, 0.27mmol), (2-methoxy ethyl) methylamine (119mg, 1.33mmol), 1, the mixture of 4-diox (2ml) and acetonitrile (1ml) is accepted 160 ℃ microwave irradiation 10 minutes.Reactant mixture concentrated in a vacuum and with the residue and the aqueous NaOH (1M that obtain; 50ml) mix and (4 * 50ml) extract with dichloromethane.With the organic layer salt water washing that merges, dry and concentrated in a vacuum on magnesium sulfate.The residue that obtains is obtained the free alkali oily product of title compound by the column chromatography purification with eluent ethyl acetate.By adding hydrogen chloride (the 1M solution in the diethyl ether; 3ml) (15ml) forms hydrochlorate in this free base solution to the diethyl ether.Concentrate the 1:1 hydrochlorate (95.1mg) that this mixture obtains title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)δ?1.00-1.30(5H，m)，1.55-1.94(6H，m)，3.00(3H，s)，3.32-3.66(5H，m)，3.80(2H，t，J?5.0)，3.97(3H，s)，4.29(2H，d，J?7.2)，4.52(2H，s)，6.81(1H，d，J?8.0)，7.16(1H，dd，J?8.0，8.0)，7.62(1H，s)，7.80(1H，d，J?8.0)，7.85(1H，s)。
Es?IMS：m/z?428.1[M+H] +，339.0。
Embodiment 17
Replace (2-methoxy ethyl) methylamine with alternative amine, the method for embodiment 16 is further used for preparing following chemical compound.
17A:1-(cyclohexyl) methyl-7-methoxyl group-3-{4-[(morpholine-4-yl) methyl]-[1, 3]-thiazol-2-yl }-the 1H-indole, hydrochlorate
Title compound can be with morpholino for the preparation of (2-methoxy ethyl) methylamine.Es?IMS：m/z426.3[M+H] +，339.1。
17B:1-(cyclohexyl) methyl-3-{4-[(4-hydroxy piperidine-1-yl) methyl]-[1, 3]-thiazol-2-yl }-7-methoxyl group-1H-indole, hydrochlorate
Title compound can replace the preparation of (2-methoxy ethyl) methylamine with the 4-hydroxy piperidine.Es?IMS：m/z?440.1[M+H] +，399.0。
17C: 1-(cyclohexyl) methyl-3-(4-{[N-isopropyl-N-(2-methoxy ethyl) Amino] methyl }-[1,3] thiazol-2-yl)-7-methoxyl group-1H-indole, hydrochlorate
Title compound can use N-isopropyl-N-(2-methoxy ethyl) amine to replace the preparation of (2-methoxy ethyl) methylamine.Es?IMS：m/z?456.4[M+H] +，339.1。
17D:(S)-1-(cyclohexyl) methyl-3-{4-[(2-hydroxymethyl pyrrolidine-1-yl) Methyl]-[1,3]-thiazol-2-yl }-7-methoxyl group-1H-indole
Title compound can use (S)-(+)-dried meat ammonia alcohol to replace the preparation of (2-methoxy ethyl) methylamine and separate with free alkali.
Es IMS:m/z 440.1[M+H] +, 339.1; [α] D 22-10.0 ° (c=0.65mg/ml in the chloroform).
17E:1-(cyclohexyl) methyl-7-methoxyl group-3-{4-[(thiomorpholine-4-yl) first Base]-[1,3]-thiazol-2-yl }-the 1H-indole, hydrochlorate
Title compound can replace the preparation of (2-methoxy ethyl) methylamine with thiomorpholine.Es?IMS：m/z?442.0[M+H] +，339.0。
Embodiment 18
1-(cyclohexyl) methyl-7-methoxyl group-3-{4-[1-(pyrrolidine-1-yl) ethyl]-[1, 3]-thiazol-2-yl }-the 1H-indole, hydrochlorate
With the 1-chloro-2 in the ethanol (3ml), and the 3-diacetyl (0.717g, 5.95mmol) solution at room temperature drops to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carbothioic acid amide in the ethanol (12ml) (as embodiment 16 preparations; 1.20g, 3.97mmol) in the solution, and at room temperature the mixture that obtains was stirred 3 days subsequently.Reactant mixture is concentrated in a vacuum and the residue that obtains is mixed with dichloromethane (50ml) and water and salt water washing successively, dry also concentrated in a vacuum on magnesium sulfate.With the residue that obtains by with the column chromatography purification of 33% in the normal heptane (v/v) eluent ethyl acetate to obtain 1-{2-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] thiazole-4-yl ethyl ketone brown solid (1.11g).
With 1-{2-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] thiazole-4-yl } ethyl ketone (100mg, 0.27mmol), pyrrolidine (193mg, 2.71mmol), acetic acid (163mg, 2.71mmol) and the mixture of acetonitrile (3ml) at room temperature stirred 2 hours.Add macropore triethyl ammonium methylated polystyrene cyano group boron hydride (MP-cyano group boron hydride, last sample: 2.35mmol/g, 231mg, 0.543mmol) and allow the microwave irradiation 10 minutes of 130 ℃ of the mixture acceptance that obtain.By removing by filter resin, it is washed also concentrating filtrate in a vacuum with dichloromethane.With residue and the aqueous NaOH (1M that obtains; 100ml) mix and extract with dichloromethane (4 x 100ml).Merge organic layer, subsequently it is used the salt water washing, dry and concentrated in a vacuum on magnesium sulfate.The residue that obtains by in ethyl acetate with the column chromatography purification of 5% methanol-eluted fractions.The oil that obtains is dissolved in the diethyl ether (10ml), subsequently with hydrochloric acid (the 1M solution in the diethyl ether; 3ml) be added to this solution.Concentrate 1: 1 hydrochlorate (30.1mg) that the mixture that obtains obtains title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)δ；0.98-1.32(5H，m)，1.54-2.22(13H，m)，3.22-3.44(3H，m)，3.66-3.84(1H，m)，3.97(3H，s)，4.29(2H，d，J?7.2)，4.60-4.72(1H，m)，6.81(1H，d，J?7.6)，7.15(1H，dd，J?7.6，8.0)，7.51(1H，s)，7.79-7.90(2H，m)。Es?IMS：m/z?424.1[M+H] +，353.1。
Embodiment 19
1-(cyclohexyl) methyl-7-fluoro-3-(4-{[N-isopropyl-N-(2-methoxy ethyl) Amino] methyl }-[1,3] thiazol-2-yl)-the 1H-indole, trifluoroacetate
According to the method for embodiment 16, use 1-(cyclohexyl) methyl-7-fluoro-1H-indole-3-carboxylic acid amide (from the preparation of 7-fluoro indole) and N-isopropyl-N-(2-methoxy ethyl) amine to prepare title compound.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.Es?IMS：m/z?444.3[M+H] +，327.3。
Embodiment 19A
1-(cyclohexyl) methyl-6-fluoro-3-[4-(diethylamino) methyl]-[1,3] thiazole-2- Base)-and the 1H-indole, trifluoroacetate
According to the method for embodiment 16, use 1-(cyclohexyl) methyl-6-fluoro-1H-indole-3-carboxylic acid amide (from the preparation of 6-fluoro indole) and diethylamine to prepare title compound.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.Es?IMS：m/z?400.1[M+H] +，327.1。
Embodiment 20
7-chloro-1-(cyclohexyl) methyl-3-(4-{[N-isopropyl-N-(2-methoxy ethyl) Amino] methyl }-[1,3] thiazol-2-yl)-the 1H-indole, hydrochlorate
According to the method for embodiment 16, using 7-chloro-1-(cyclohexyl) methyl--1H-indole-3-carboxylic acid amide (from the preparation of 7-chloro-indole) and N-isopropyl-N-(2-methoxy ethyl) amine prepare title compound.Es?IMS：m/z?462.3，460.3[M+H] +，343.1。
Embodiment 21
1-(cyclohexyl) methyl-7-ethyl-3-(4-{[N-isopropyl-N-(2-methoxy ethyl) Amino] methyl }-[1,3] thiazol-2-yl)-the 1H-indole, trifluoroacetate
According to the method for embodiment 16, prepare title compound with 1-(cyclohexyl) methyl-7-ethyl-1H-indole-3-carboxylic acid amide (from the preparation of 7-ethylindole) and N-isopropyl-N-(2-methoxy ethyl) amine.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.Es?IMS：m/z?454.5[M+H] +，337.3。
Embodiment 22
Method according to embodiment 16, with (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazinyl-6-carboxylic acid amide is (from (R)-3-cyclohexyl-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazinyl-6-carboxylic acid preparation is as describing among the embodiment 13) replace 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide to prepare following chemical compound.
22A:(R)-and 3-cyclohexyl-6-{4-[(diethylamino) methyl]-[1,3]-thiazole-2- Base }-2, the 3-pyrrolin is [1,2,3-de]-1 also, 4-benzoxazinyl, hydrochlorate
Title compound can replace (2-methoxy ethyl) methylamine with diethylamine and prepares.Es IMS:m/z 410.3[M+H] +, 337.3; [α] D 22-37.5 ° (c=1.30mg/ml in the chloroform).
22B:(R)-and 3-cyclohexyl-6-{4-[(N-ethyl-N-isopropylamino) methyl]-[1, 3]-thiazol-2-yl-2, the 3-pyrrolin also-[1,2,3-de]-1,4-benzoxazinyl, three Fluoroacetate
Title compound can and prepare with N-ethyl-N-2-aminopropane. replacement (2-methoxy ethyl) methylamine.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.Es IMS:m/z 424.3[M+H] +, 337.3; [α] D 22-27.4 ° (c=1.25mg/ml in the chloroform).
22C:(R)-and 3-cyclohexyl-6-{4-[(pyrrolidine-1-yl) methyl]-[1,3]-thiazole -2-yl }-2, the 3-pyrrolin also-[1,2,3-de]-1,4-benzoxazinyl, trifluoroacetate
Title compound can replace (2-methoxy ethyl) methylamine with pyrrolidine and prepares.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.
Es IMS:m/z 408.3[M+H] +, 337.3; [α] D 22-32.6 ° (c=2.15mg/ml in the chloroform).
22D:(R)-3-cyclohexyl-6-(4-{[N-isopropyl-N-(2-methoxy ethyl) ammonia The base] methyl-[1,3]-thiazol-2-yl)-2, the 3-pyrrolin also-[1,2,3-de]-1, The 4-benzoxazinyl, trifluoroacetate
Title compound can and prepare with N-isopropyl-N-(2-methoxy ethyl) amine replacement (2-methoxy ethyl) methylamine.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.Es IMS:m/z 454.3[M+H] +, 337.3; [α] D 22-58.4 (c=2.09mg/ml in the chloroform).
22E:(R)-3-cyclohexyl-6-(4-{[two-(2-methoxy ethyl) amino] methyl }-[1, 3]-thiazol-2-yl)-2, the 3-pyrrolin also-[1,2,3-de]-1,4-benzoxazinyl, three Fluoroacetate
Title compound can and prepare with two-(2-methoxy ethyl) amine replacement (2-methoxy ethyl) methylamine.By partly preparing HPLC[method (i)] this free alkali of purification obtains the trifluoroacetate of the 1:1 of title compound.
Es IMS:m/z 470.3[M+H] +, 337.3; [α] D 22-28.5 ° (c=1.20mg/ml in the chloroform).
Embodiment 23
According to the method for embodiment 16, replace 1-(cyclohexyl) methyl-7-methoxyl group-following chemical compound of 1H-indole-3-carboxylic acid amide preparation with 7-chloro-1-(tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide.
According to the method for embodiment 1, replace 7-methoxyl group indole and replace the cyclohexyl methyl bromine to prepare 7-chloro-1 (tetrahydropyran-4-base) Methyl-1H-indole-3-carboxylic acid amide with toluene-4-sulfonic acid tetrahydropyran-4-base methyl ester (as describing preparation among the embodiment 14) with the 7-chloro-indole.
23A:7-chloro-3-{4-[(diethylamino) methyl]-[1,3]-thiazol-2-yl }-1-(tetrahydrochysene pyrrole Mutter-the 4-yl) Methyl-1H-indole, hydrochlorate
Title compound can use the diethylamine preparation.EIMS：m/z?420.0，418.4[M+H] +，347.0，345.0。
23B:7-chloro-3-(4-{[N-(2-ethoxy)-N-isopropylamino] methyl }-[1,3]-thiophene Azoles 2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole
Title compound can use different third ammonia preparation of N-(2-ethoxy)-N-.EIMS：m/z?448.4[M+H] +，347.1，345.1。
23C:7-chloro-3-(4-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,3]-thiazole -2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole
Title compound can use the preparation of N-ethyl-N-(2-ethoxy) amine.EIMS：m/z436.3，434.4[M+H] +，347.0，345.0。
23D:7-chloro-3-(4-{[N-(2-methoxy ethyl)-N-methylamino] methyl }-[1,3]-thiophene Azoles-2-yl)-and 1-(tetrahydropyran-4-base) Methyl-1H-indole, hydrochlorate
Title compound can use N-(2-methoxy ethyl)-N-methylamine preparation.EIMS：m/z436.1，434.1[M+H] +，347.0，345.0。
Embodiment 24
1-(cyclohexyl) methyl-3-{4-[(dimethylamino) methyl]-5-ethyl-[1,3]- Thiazol-2-yl }-7-methoxyl group-1H-indole hydrochloride
(0.68g, 9.94mmol) portioning is added to ethyl dichloroacetate (1.22ml stirred 30 minutes down at 0 ℃ 9.94mmol) and in the mixture of diethyl ether (10ml) and with the mixture that obtains with Sodium ethylate under ice-water cooling.Add then propionic aldehyde (0.79ml, 10.93mmol) and allow reactant mixture slowly be warming up to room temperature and continue to stir 72 hours.Then reactant mixture is inclined to water (10ml) and upward and with diethyl ether extracted (2 * 15ml).Merge organic layer, dry on magnesium sulfate, and concentrate in a vacuum and obtain thick 3-chloro-2-oxygen-ethyl valerate (1.8g), use it for next step and need not to be further purified.
With 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carbothioic acid amide (0.227g, 0.754mmol) and thick 3-chloro-2-oxygen-ethyl valerate (1.34g, 7.52mmol) mixture in dimethyl formamide carried out microwave irradiation 25 minutes at 140 ℃.In the vacuum concentrated reaction mixture and by silica gel column chromatography with the residue that 25% acetone eluting purification in the heptane obtains, obtain thick 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-5-ethyl-thiazole-4-carboxylic acid ethyl ester (0.490g).This material is used for next step and need not to be further purified.
With lithium borohydride (200mg, 9.09mmol) portioning is added to 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-5-ethyl-thiazole-4-carboxylic acid ethyl ester (490mg stirred 2 hours down at 0 ℃ 1.15mmol) and in the mixture of oxolane (5ml) and with the mixture that obtains under ice-water cooling.With aqueous hydrochloric acid (2M; 2ml) the cancellation reactant mixture is also with dichloromethane (2 * 100ml) aqueous layer extracted.Merge organic layer, dry on magnesium sulfate, and concentrate in a vacuum and obtain thick product.Silica gel column chromatography with 66% eluent ethyl acetate in the heptane produces thick [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-5-ethyl-thiazole-4-yl]-methanol (210mg).This material is used for next step and need not to be further purified.
With methylsufonyl chloride (90 μ l, 1.16mmol) under ice-water cooling, be added to [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-5-ethyl-thiazole-4-yl]-methanol (210mg, 0.547mmol), (150 μ l are 0.91mmol) and in the mixture of dichloromethane (5ml) and allow the mixture that obtains slowly be warming up to room temperature for diisopropylethylamine.Continue to stir 22 hours.With aqueous carbonic acid sodium (2ml) cancellation reactant mixture, and with dichloromethane (2 * 10ml) aqueous layer extracted.Merge organic layer, dry on magnesium sulfate, and concentrate in a vacuum and obtain thick product.Flash column chromatography with the acetone eluting of 10% in the normal heptane obtains 3-(4-chloromethyl-5-ethyl-thiazol-2-yl)-1-cyclohexyl ethyl-7-methoxyl group-1H-indole (109mg).
With the dimethylamine (solution of the 2.2M in oxolane; 0.50ml) be added to 3-(4-chloromethyl-5-ethyl-thiazol-2-yl)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (38mg in acetonitrile (2ml), 0.095mmol), potassium carbonate (16mg, 0.113mmol) and sodium iodide (14mg, mixture 0.095mmol).Accepted microwave irradiation 5 minutes with under 160 ℃ in the mixture, be allowed to condition at then between dichloromethane (20ml) and the 5% aqueous carbonic acid sodium (5ml) and distribute.With dichloromethane (10ml) aqueous layer extracted and the organic layer that merges is dry and concentrated in a vacuum on magnesium sulfate.The oil that obtains is dissolved in the diethyl ether, then with the hydrogen chloride (solution of the 1M in diethyl ether; 3ml) add to this solution.Concentrate in a vacuum the hydrochlorate that the mixture obtain obtains the 1:1 of title compound (40mg, 0.089mmol). 1H?NMR(400MHz，CD 3OD)δ?1.04-1.15(2H，m)，1.16-1.30(3H，m)，1.43(3H，t，J?7.0)，1.55-1.78(5H，m)，1.82-1.92(1H，m)，3.05(8H，m)，3.99(3H，s)，4.33(2H，d，J?7)，4.62(2H，s)，6.91(1H，d，J?8.0)，7.29(1H，t，J?8.0)，7.62(1H，d，J?8)，8.30(1H，s)EIMS：m/z?412.3[M+H] +，367.0。
Embodiment 25
1-(cyclohexyl) methyl-3-{5-[(diethylamino) methyl]-4-methyl-[1,3]- Thiazol-2-yl }-7-methoxyl group-1H-indole, hydrochlorate
With ethyl 2-chloro-3-oxobutanoic acid esters (0.332ml, 2.40mmol) be added to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carbothioic acid amide among the EtOH (5.0ml) (604mg, 2.00mmol).Mixture was refluxed 1 hour.After being cooled to 0 ℃, by filter the collecting precipitation thing obtain 1-cyclohexyl methyl-3-(5-carbethoxyl group-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (505mg, 1.22mmol).
(125mg 3.30mmol) adds to 1-cyclohexyl methyl-3-(5-carbethoxyl group-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (680mg, 1.65mmol) solution among the THF (20ml) with lithium aluminium hydride under 0 ℃.Under 0 ℃, stirred the mixture 1 hour, then with the frozen water cancellation and use dichloromethane extraction.With the organic layer that the salt water washing merges, dry and concentrated on sodium sulfate.By use the purification by flash chromatography residue of 10% in the dichloromethane (v/v) methanol-eluted fractions then with the 25-50% in the heptane (v/v) ethyl acetate, obtain 1-cyclohexyl methyl-3-(5-methylol-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (532mg, 1.44mmol).
With methanesulfonyl fluoride (28mg, 0.24mmol) add to 1-cyclohexyl methyl-3-(5-methylol-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole in the dichloromethane (1.0ml) (74mg, 0.20mmol) and triethylamine (26mg, solution 0.26mmol).Stirred the mixture under the room temperature 40 minutes.And it is distributed between the aqueous carbonic acid hydrogen sodium of dichloromethane and 5%.Use the dichloromethane extraction water layer, the organic layer that merges with the salt water washing then, on sodium sulfate dry and concentrate obtain thick 1-cyclohexyl methyl-3-(5-methylsulfonyl yloxymethyl-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (65mg, 0.15mmol).With the thick 1-cyclohexyl methyl-3-in THF (1.5ml) and the acetonitrile (1.5ml) (5-methylsulfonyl yloxymethyl-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (64mg; 0.14mmol), potassium carbonate (29mg; 0.21mmol), sodium iodide (31mg; 0.21mmol) and diethylamine (21mg, 0.28mmol) mixture is accepted 160 ℃ microwave irradiation 5 minutes.The mixture that produces is distributed between dichloromethane and water.With the organic layer that the dichloromethane extraction water layer also merges with the salt water washing, dry and concentrated on sodium sulfate.With residue by purification by flash chromatography with 50-100% (v/v) eluent ethyl acetate in the heptane, obtain 1-cyclohexyl methyl-3-(5-diethyl amino methyl-4-methylthiazol-2-yl)-7-methoxyl group-1H-indole (27mg, 0.064mmol).By adding the hydrogen chloride (solution of the 1M in diethyl ether; 1ml) this free base solution to diethyl ether (1ml) and the ethanol (2ml) forms hydrochlorate.Remove in a vacuum desolvate and dry sediment obtain the 1:1 of title compound hydrochlorate (26mg, 0.056mmol). 1H?NMR(400MHz，DMSO-d 6)δ?0.95-1.25(5H，m)，1.29(6H，t，J?7.2)，1.40-1.52(2H，m)，1.55-1.70(3H，m)，1.72-1.84(1H，m)，3.10-3.25(4H，m)，3.93(3H，s)，4.27(2H，d，J?7.0)，4.56(2H，d，J?5.0)，6.82(1H，d，J?7.6)，7.14(1H，t，J?7.6)，7.72(1H，d，J?7.6)，8.00(1H，s)，9.90(1H，brs)；Es?IMS：m/z?426.3[M+H] +，353.1。
Embodiment 26
1-(cyclohexyl) methyl-3-{2-[(diethylamino) methyl]-[1,3]-thiazole-4- Base }-7-methoxyl group-1H-indole, hydrochlorate
(60% is scattered in the mineral oil with sodium hydride under nitrogen; 1.50g, 37.4mmol) add to 7-methoxyl group indole (5.00g, 34.0mmol) solution in the dimethyl formamide (50ml).Adding bromomethyl cyclohexane extraction after stirring the mixture under the room temperature 10 minutes (5.20ml, 37.4mmol).Stir the mixture 42 hours and the distribution between ethyl acetate (150ml) and water (150ml) then that obtain under the room temperature.Wash with saline (150ml) with ethyl acetate (150ml) aqueous layer extracted and with the organic layer that merges, drying also concentrates in a vacuum on magnesium sulfate.The intermediate that this is thick is by the flash column chromatography purification with 0-10% (v/v) eluent ethyl acetate in the normal heptane, obtain 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (7.48g, 30.7mmol).
In in 1.5 hours, be added dropwise under 55 ℃ chloracetyl chloride (8.66ml, 109mmol) pyridine to the toluene (50ml) (2.20ml, 27.2mmol) and 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (6.60g, agitating solution 27.2mmol).At the mixture 0.5h that 55 ℃ of following reheat obtain, allow it be cooled under the room temperature then.Add entry (60ml) and methanol (10ml).Separate organic layer and under reduced pressure concentrate and obtain coffee-like residue.Column chromatography purification residue with 5% in the normal heptane (v/v) eluent ethyl acetate.With the solid that obtains repeatedly from ether recrystallize obtain 2-chloro-1-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] ethyl ketone white solid (1.40g).
With 2-chloro-1-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl] ethyl ketone (0.73g, 2.30mmol) and 2-(tert-butyl group ketonic oxygen base) thioacetamide (1.21g 6.89mmol) is suspended in the ethanol (10ml) and uses Emrys TMOptimizer EXP allows the mixture that obtains accept 150 ℃ microwave irradiation 10 minutes.In a vacuum concentrated reaction mixture and with the residue that obtains by flash column chromatography purification with 5% (v/v) eluent ethyl acetate in the normal heptane, obtain 1-(cyclohexyl) methyl-7-methoxyl group-3-{2-[(tert-butyl group ketonic oxygen base) methyl] thiazole-4-yl-1H-indole yellow oil (1.01g).
With 1-(cyclohexyl) methyl-7-methoxyl group-3-{2-[(tert-butyl group ketonic oxygen base) methyl] thiazole-4-yl }-(0.92g 2.10mmol) is dissolved in the methanol (20ml) and adds the sodium hydroxide (5ml) of 4N the 1H-indole.Agitating solution is 2 hours under the room temperature.Concentrated reaction mixture and residue is absorbed in the dichloromethane under the vacuum.Add entry (10ml) and separate organic layer.Obtain 1-(cyclohexyl) methyl-3-[2-(methylol) thiazole-4-yl with dichloromethane extraction water layer and the concentrated in a vacuum organic layer that merges]-7-methoxyl group-1H-indole Melon yellow color foam (0.55g).
With methylsufonyl chloride (174 μ l 2.25mmol) add to 1-(cyclohexyl) methyl-3-[2-(methylol) thiazole-4-yl in the dichloromethane (8ml)]-7-methoxyl group-1H-indole (0.40g, 1.12mmol) and pyridine (182 μ l, 2.25mmol) solution.Stir the mixture overnight that obtains under the room temperature.(87 μ l 1.12mmol) also continue to stir 0.5 hour to add other methylsufonyl chloride.The concentrated reaction mixture and the orange-yellow residue that will obtain obtain 3-[2-(chloromethyl) thiazole-4-yl by the flash column chromatography purification with the dichloromethane eluting in the vacuum]-yellow oil (0.415g) of 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole.
With 3-[2-(chloromethyl) thiazole-4-yl]-1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (0.08g, 0.214mmol) and diethylamine (221 μ l 2.14mmol) are dissolved in the acetonitrile (2ml).The mixture that obtains is exposed to 100 ℃ following 5 minutes of microwave irradiation.The residue that enriched mixture also obtains by the column chromatography purification with 33% in the normal heptane (v/v) eluent ethyl acetate in the vacuum.The product that obtains is absorbed in the diethyl ether, adds the hydrogen chloride (solution of the 1M in diethyl ether then; 1ml).The solid that concentrates this solution in the vacuum and obtain with the ether development, the dry then 1:1 hydrochlorate (0.034g) that obtains title compound. 1H NMR (400MHz, CD 3OD) δ 0.99-1.25 (5H, m), 1.43 (J 7.5 for 6H, t), 1.56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (J 7.5 for 2H, d), (2H, s is by H for 4.75-4.80 2The peak of O shields), 6.75 (J 8.0 for 1H, d), 7.08 (J 8.0,8.0 for 1H, dd), 7.64-7.68 (3H, m).Es?IMS：m/z?412.1[M+H] +，339.0。
Embodiment 27
1-(cyclohexyl) methyl-7-methoxyl group-3-{2-[(pyrrolidine-1-yl) methyl]-[1, 3]-thiazole-4-yl }-the 1H-indole, hydrochlorate
Replace diethylamine with pyrrolidine, prepare this title compound by the method for embodiment 26.Es?IMS：m/z?410.3[M+H] +，339.1。
Embodiment 28
1-(cyclohexyl) methyl-3-{2-[(dimethylamino) methyl]-[1,3]-thiazole-5- Base }-7-methoxyl group-1H-indole, hydrochlorate
(3.04ml, (5g 17.4mmol) spends the night in the suspension and with the solution stirring that obtains 34.8mmol) to add to 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid in the dichloromethane (100ml) with oxalyl chloride.Remove excessive solvent and reagent by evaporation then.With Cupricin. (6.2g, 69.6mmol), toluene (200ml) and acetonitrile (10ml) add to the residue that obtains and will obtain under the reaction mixture refluxed heating 7 hours.(1.6g is 17.9mmol) and with heated overnight under the reaction mixture refluxed to add a in addition Cupricin. then.Reaction mixture is also filtered by the dicalite pad.Be left red solid with the filtrate that acetonitrile washing dicalite and evaporation merge.By flash column chromatography purification solid with 50% (v/v) dichloromethane eluting in the heptane, obtain (1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-oxo acetonitrile (4.7g, 14.7mmol).
Under nitrogen, 10% palladium on the active carbon (90mg) is added in the acetic acid (40ml) (1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-(975mg is 3.29mmol) in the solution for the oxo acetonitrile.Place reaction under the hydrogen atmosphere and stirred 14 hours.Then by dicalite pad filter reaction mixture.Be left reddish oil with the filtrate that acetic acid washing dicalite and evaporation merge.Be absorbed in this reddish oil in the dichloromethane (50ml) and be added dropwise to methyl chloride oxo ethyl ester (0.393ml, 4.28mmol), be added dropwise to then the N-ethyl diisopropylamine (1.7ml, 9.87mmol).In stirred reaction mixture 1 hour and the impouring separatory funnel.Use the aqueous hydrochloric acid (50ml) of 2M, 5% aqueous carbonic acid sodium (50ml) and saline (50ml) washing Organic substance successively.Dry Organic substance on sodium sulfate filters and removes in a vacuum the remaining brown oil of desolvating.Should pass through to use dichloromethane by oil, use the purification by flash chromatography of 66% in the heptane (v/v) dimethyl ether then, obtain N-[(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-2-oxygen-ethyl] oxalic acid (oxalamic acid) methyl ester (573mg, 1.48mmol) yellow/brown solid.
With phosphorus pentasulfide (538mg 1.21mmol) adds to N-[(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl in the chloroform (20ml))-2-oxygen-ethyl]-methyl oxalate (429mg, 1.11mmol) and will be under the reaction mixture refluxed heating 3.5 hours.Reaction mixture, with in its impouring separatory funnel and water use the salt water washing then.Then on magnesium sulfate dry organic layer, filter and remove in a vacuum and desolvate.The solid that obtains by the flash column chromatography purification with the dichloromethane eluting, is obtained 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl) thiazole-2-carboxylate methyl ester (418mg, 1.09mmol) brown solid.
(83mg, 2.18mmol) portioning adds to 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl) thiazole-2-carboxylate methyl ester (418mg, solution 1.09mmol) in methanol (10ml) and the oxolane (10ml) in 2 minutes with sodium borohydride.Other 1 hour of reaction stirred is also used aqueous hydrochloric acid (1M then; 10ml) cancellation.In mixture impouring separatory funnel, with dichloromethane (50ml) dilution and water (20ml) washing.The dry organic layer that merges filters and removes in a vacuum the remaining yellow oil that desolvates.This oil is obtained [5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl) thiazol-2-yl]-methanol (308mg, 0.86mmol) rice white foam by the flash column chromatography purification with the 50-100% in the heptane (v/v) diethyl ether.
With methylsufonyl chloride (80 μ l, 1.03mmol), then with triethylamine (0.156ml, 1.12mmol) add in the dichloromethane (20ml) [5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl) thiazol-2-yl]-(308mg is 0.86mmol) in the solution for methanol.Reaction stirred 30 minutes in the impouring separatory funnel, with 5% aqueous carbonic acid sodium, is used the salt water washing and drying on magnesium sulfate then then.Removing in a vacuum desolvates obtain methanesulfonic acid 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-thiazol-2-yl methyl ester (411mg, 0.94mmol).
With dimethylamine (2M in the oxolane; 1ml 2mmol) adds to methanesulfonic acid 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-thiazol-2-yl methyl ester in the oxolane (2ml) (93mg, 0.215mmol) solution and allow reactant mixture be exposed to 150 ℃ following 15 minutes of microwave irradiation.With dichloromethane (40ml) diluted reaction mixture and with the mixture washing of 1:1 (v/v) saline and saturated sodium bicarbonate, dry on magnesium sulfate, filter and remove in a vacuum and desolvate.The oil that obtains is obtained title compound (70mg, 0.18mmol) free alkali by the flash column chromatography purification.This free alkali is dissolved in dichloromethane (5ml), adds hydrogen chloride (the 2M solution in the diethyl ether; 1ml 2mmol) and in a vacuum obtains 1: 1 hydrochlorate of title compound except that desolvating.
1H?NMR(400MHz，CD 3OD)：0.96-1.12(2H，m)，1.13-1.26(3H，m)，1.5-1.62(2H，m)，1.62-1.78(3H，m)，1.78-1.92(1H，m)，3.01(6H，s)，3.96(3H，s)，4.26(2H，d，J?5.5)，4.71(2H，s)，6.78(1H，d，J?8.0)，7.11(1H，t，J?8.0)，7.41(1H，d，J?8.0)，7.52(1H，s)，8.08(1H，s)；Es?IMS：m/z?384.0[M+H] +，339.0，243.1。
Embodiment 29
1-(cyclohexyl) methyl-3-{4-[(diethylamino) methyl]-[1,3]-oxazoles-2- Base }-7-methoxyl group-1H-indole, hydrochlorate
With 1, (333mg, (500mg is 1.75mmol) in the solution and allow reactant mixture accept 150 ℃ microwave irradiation 30 minutes 2.62mmol) to add to 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide in the toluene (4ml) for the 3-dichloroacetone.The dark solution that obtains with dichloromethane (50ml) dilution and with 5% aqueous carbonic acid sodium solution (5 * 20ml) washings, dry on the magnesium sulfate, filter and in a vacuum except that desolvating.The brown oil that obtains by using the flash column chromatography purification of 5% (v/v) acetone among the petroleum ether 40-60, is obtained 3-(4-chloromethyl-oxazoles-2-yl)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (510mg, 1.42mmol) white solid.
(0.29ml, ((100mg, (1ml) solution of oxolane 0.28mmol) also allows reactant mixture accept 150 ℃ microwave irradiation 15 minutes to 4-chloromethyl-oxazoles-2-base-1-cyclohexyl methyl-7-methoxyl group-1H-indole 2.8mmol) to add to 3-with diethylamine.In reactant mixture impouring separatory funnel, with dichloromethane (40ml) dilution and with 5% aqueous carbonic acid sodium solution (2 * 25ml), saline (20ml) washing, on the magnesium sulfate dry and in a vacuum evaporating solvent to being left orange oil.Should oil by using the flash column chromatography purification of 10% (v/v) methanol in the dichloromethane, obtain title compound (92mg, 0.23mmol) free alkali.Be dissolved in this free alkali in the dichloromethane and add the hydrogen chloride (solution of 1M in the diethyl ether; 2ml, 2mmol).Concentrate the hydrochlorate that this mixture obtains the 1:1 of title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)：0.97-1.28(5H，m)，1.44(6H，t，J?7.0)，1.5-1.8(5H，m)，1.8-1.95(1H，m)，3.3-3.5(4H，m)，3.97(3H，s)，4.29(2H，d，J?7.0)，4.38(2H，s)，6.8(1H，d，J?8.0)，7.2(1H，t，J?8.0)，7.8(1H，s)，7.82(1H，s)，8.2(1H，s)；Es?IMS：m/z?396.0[M+H] +，323.4，295.4，268.3。
Embodiment 30
1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(pyrrolidine-1-yl) methyl]-[1, 3]-oxazoles-2-yl }-the 1H-indole, trifluoroacetate
Use Emrys TMOptimizer EXP allow 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide (563mg, 1.97mmol), 2-chloro-3-oxygen-methyl propionate (Gangjee etc., J.Med.Chem. 44, 1993-2003,2001; 1.48g, 9.85mmol) and dimethyl acetylamide (10ml) accept 90 ℃ microwave irradiation 2 * 5 minutes.With dichloromethane (150ml) diluted reaction mixture, use 5% aqueous magnesium sulfate (2 * 100ml) and saline (150ml) washing then.Dry organic extract and concentrated in a vacuum on magnesium sulfate.By the flash column chromatography purification with 25% (v/v) eluent ethyl acetate in the heptane, (it is 87:13 that HPLC measures ratio to obtain inseparable mixture of 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-oxazoles-5-carboxylate methyl ester and 1-cyclohexyl methyl-7-methoxyl group-3-oxazole-2-base-1H-indole with the residue that obtains; 0.613g).
With lithium aluminium hydride solution (the 1M solution in the diethyl ether; 2.88ml, 2.88mmol) under ice-methanol cooling, drop to 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-oxazoles-5-carboxylate methyl ester that is dissolved in the oxolane (10ml) and the mixture of 1-cyclohexyl methyl-7-methoxyl group-3-oxazole-2-base-1H-indole (557mg).The mixture that stirring obtains under 0 ℃ 30 minutes is used diethyl ether (40ml) dilution then.Add the mixture 18 hours that stirring obtains under excessive sal glauberi and the room temperature then.Filter this mixture and use diethyl ether (100ml) washing by the dicalite pad; Concentrated filtrate in a vacuum then.With the residue that obtains by column chromatography purification with 50% eluent ethyl acetate in the normal heptane, obtain [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-oxazoles-5-yl]-methanol yellow solid (242mg, 0.71mmol).
Under ice-methanol cooling with methylsufonyl chloride (98mg, 0.85mmol) drop to [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-oxazoles-5-yl]-methanol (242mg that is dissolved in the dichloromethane (15ml), 0.71mmol) solution, be added dropwise to triethylamine (93mg then, 0.92mmol), remove cooling bath and stirred the mixture l16 hour.In hydrophobic glaze porcelain tube, use dichloromethane (30ml) diluted mixture thing then, with saturated sodium carbonate solution (30ml) washing.Dry organic extract on magnesium sulfate concentrates then in a vacuum.Allow the residue that obtains (110mg, 0.26mmol), pyrrolidine (185mg, 2.60mmol) and the mixture of oxolane (2.5ml) accept 150 ℃ microwave irradiation 15 minutes.Concentrate the mixture that obtains in the vacuum and obtain brown size by flash column chromatography (ammonia of 2% (v/v) in the ethanol/methylene of 1:49 ratio is as eluent) purification.With this glue by partly preparing HPLC[method (i)] be further purified and obtain 1-cyclohexyl methyl-7-methoxyl group-3-(5-pyrrolidine-1-ylmethyl-oxazoles-2-yl)-1H-indole trifluoroacetate (14mg). 1H?NMR(400MHz，CD 3OD)δ?0.99-1.27(5H，m)，1.54-1.78(5H，m)，1.86(1H，m)，2.00-2.24(4H，m)，3.25-3.44(2H，m)，3.53-3.74(2H，m)，3.97(3H，s)，4.29(2H，d，J?7.0)，4.64(2H，s)，6.81(1H，s，J?7.0)，7.15(1H，t，J?8.0)，7.41(1H，s)，7.79(1H，d，J?7.5)，7.82(1H，s)。Es?IMS：m/z?394.1[M+H] +，323.1。
Embodiment 31
1-(cyclohexyl) methyl-3-{5-[(diethylamino) methyl]-4-methyl-[1,3]- Oxazole-2-yl }-7-methoxyl group-1H-indole, hydrochlorate
Use Emrys TMOptimizer EXP allows 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-carboxylic acid amide (500mg, 1.75mmol), ethyl-2-chloro acetoacetic ester (2.88g, 17.6mmol) and the mixture of dimethyl formamide (10ml) accept 185 ℃ microwave irradiation 15 minutes.With dichloromethane (100ml) diluted reaction mixture, use then 5% aqueous magnesium sulfate (2 * 50ml), the washing of water (50ml) and saline (50ml).Dry organic extract and concentrated in a vacuum on magnesium sulfate.The residue that obtains is obtained inseparable mixture of 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methyl-oxazoles-5-carboxylic acid, ethyl ester and 1-cyclohexyl methyl-7-methoxyl group-3-(4-methyl-oxazoles-2-yl)-1H-indole by the column chromatography purification with 33% (v/v) dichloromethane eluting in the normal heptane, and (it is 78:22 that HPLC measures ratio; 0.586g).Repeat this reaction with identical scale.
With lithium aluminium hydride solution (the 1M solution in the diethyl ether; 5.8ml, 5.8mmol) under ice-methanol cooling, drop to 2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methyl-oxazoles-5-carboxylic acid, ethyl ester that is dissolved in the oxolane (20ml) and the mixture of 1-cyclohexyl methyl-7-methoxyl group-3-(4-methyl-oxazoles-2-yl)-1H-indole (1171mg).The mixture that stirring obtains under 0 ℃ 20 minutes is used diethyl ether (40ml) dilution then.Add the mixture 18 hours that stirring obtains under excessive sal glauberi and the room temperature then.Filter this mixture by the dicalite pad, wash also concentrated filtrate in a vacuum with diethyl ether (100ml).Residue is obtained [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methyl-oxazoles-5-yl]-methanol white solid (774mg) by the flash column chromatography purification with 50% eluent ethyl acetate in the normal heptane.
Under nitrogen under-78 ℃ with methylsufonyl chloride (281mg, 2.45mmol) drop to [2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methyl-oxazoles-5-yl]-methanol (724mg, 2.04mmol) solution that is dissolved in the dichloromethane (40ml).(269mg 2.66mmol) and allow this mixture be warming up to room temperature, stirred 2 hours simultaneously to be added dropwise to triethylamine.Use dichloromethane (100ml) to dilute this mixture then, with saturated sodium carbonate liquor (2 * 100ml) and saline (100ml) washing.Dry organic extract on magnesium sulfate concentrates then in a vacuum.Allow the residue that obtains (100mg, 0.23mmol), diethylamine (169mg, 2.30mmol) and the mixture of oxolane (2ml) accept 150 ℃ microwave irradiation 15 minutes.Concentrate the mixture that obtains in the vacuum and obtain brown size by flash column chromatography (with the ammonia eluting of 2% in the ethanol/methylene of 1:49 ratio (v/v)) purification.This glue is dissolved in dichloromethane (0.5ml), adds hydrogen chloride (the 1M solution in the diethyl ether then; 0.5ml) and in a vacuum enriched mixture obtain the 1:1 hydrochlorate (32mg) of title compound. 1H?NMR(400MHz，CD 3OD)δ?0.85-1.38(6H，m)，1.46(6H，t，J?7.5)，1.55-1.78(4H，m)，1.88(1H，m)，2.39(3H，s)，3.34(4H，q，J?7.6)，3.98(3H，s)，4.34(2H，d，J?6.9)，4.65(2H，s)，6.88(1H，d，J?8.2)，7.23(1H，t，J?8.0)，7.74(1H，d，J?8.0)，8.00(1H，s)
Es?IMS：m/z?410.3[M+H] +，337.1。
Embodiment 32
1-(cyclohexyl) methyl-3-{2-[(diethylamino) methyl]-[1,3]-oxazoles-5- Base }-7-methoxyl group-1H-indole, hydrochlorate
Under nitrogen, 10% palladium on the active carbon (240mg) is added to the 1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl of acetic acid (50ml))-(28 descriptions prepare the oxo acetonitrile as embodiment; 2.39g, 8.06mmol) in the solution.Reaction is placed under the hydrogen atmosphere and stir and spend the night.Then reactant mixture is filtered by the dicalite pad.The extremely remaining reddish oil of filtrate with acetic acid washing dicalite and evaporation merging.Be absorbed in this reddish oil in the dichloromethane (50ml) and be added dropwise to chloracetyl chloride (0.77ml, 9.67mmol), dropwise add then triethylamine (3.4ml, 24.2mmol).In stirred reaction mixture 30 minutes and the impouring separatory funnel.Use successively 5% aqueous carbonic acid sodium (2 * 30ml) and saline (30ml) wash this Organic substance.Dry Organic substance on magnesium sulfate filters and removes in a vacuum and desolvate to remaining redness/brown oil.With this oil by using 20-100% (v/v) dichloromethane in the heptane, use the purification by flash chromatography of 25-50% (v/v) diethyl ether in the heptane subsequently, obtain 2-chloro-N-[2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-2-oxygen ethyl]-acetamide (2.32g, 6.1mmol).
With diethylamine (0.55ml, 5.3mmol) add to 2-chloro-N-[2-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-2-oxygen ethyl in oxolane (2ml)]-acetamide (200mg, 0.53mmol) solution and allow reactant mixture accept 150 ℃ microwave irradiation 15 minutes.With in the reactant mixture impouring separatory funnel and add dichloromethane (30ml).Use 5% aqueous carbonic acid sodium and this Organic substance of salt water washing successively.Dry Organic substance on magnesium sulfate filters also and obtains brown solid except that desolvating in a vacuum.This brown solid is dissolved in oxolane (2ml) and (methoxycarbonyl sulfamoyl) triethyl group ammonium hydroxide, and the adding inner salt (505mg, 2.12mmol).Allow the reactant mixture that obtains accept 150 ℃ microwave irradiation 15 minutes and to use methanol (20ml) cancellation.Remove in a vacuum desolvate and with residue by using the flash chromatography of 50% (v/v) ethyl acetate in the heptane, subsequently by partly preparing the HPLC[method (ii)] purification obtains white solid.With this solid be dissolved in dichloromethane (～5ml) in and add the hydrogen chloride (solution of 1M in the diethyl ether; 1ml).Concentrate in a vacuum the hydrochlorate that this mixture obtains the 1:1 of title compound (77mg, 0.2mmol). 1H?NMR(400MHz，CD 3OD)δ H?0.97-1.12(2H，m)，1.15-1.25(3H，m)，1.44(6H，t，J?6.9)，1.52-1.62(2H，m)，1.62-1.77(3H，m)，1.77-1.9(1H，m)，3.36(4H，q，J?6.7)，3.95(3H，s)，4.26(2H，d，J?7)，4.64(2H，s)，6.77(1H，d，J?8)，7.11(1H，t，J?8)，7.38(1H，s)，7.41(1H，d，J?8)，7.56(1H，s)；Es?IMS：m/z?396.1[M+H] +，323.4，268.4。
Embodiment 33
1-(cyclohexyl) methyl-3-(5-ethyl-5, the different thiophene of 6-dihydro-4H-pyrroles [3,4-d] Azoles-3-yl)-and 7-methoxyl group-1H-indole, hydrochlorate
(0.2ml 1.25mmol) adds to 5-(1-cyclohexyl methyl-7-methoxyl group-1H-indole)-[1,3,4]-oxa-thiazole-2-ketone in the meta-xylene (0.5ml) and (describes preparation as embodiment 7 with the diethylacetylene dicarboxylic ester; 100mg, 0.25mmol) suspension and allow this reaction accept 200 ℃ microwave irradiation 5 minutes.With the flash column chromatography direct purification of reactant mixture, obtain 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-isothiazole-4 then by 0-100% (v/v) dichloromethane in the use heptane, and the 5-diethyl dicarboxylate (141mg, 0.3mmol).Repeat this reaction and all merge with the scale of 1.255mmol, and the flash column chromatography purification by 50-60% (v/v) dichloromethane in the use heptane obtain identical intermediate (882mg, 1.87mmol).
With the lithium aluminium hydride (solution of 1M in THF; 1.91ml, 1.91mmol) being added to 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-isothiazole-4 in the oxolane (20ml), (400mg is in the cold solution (ice/methanol bath) 0.85mmol) for the 5-diethyl dicarboxylate.Excessive sal glauberi is added to this reactant mixture and reaction stirred 1.5 hours firmly.Filter the mixture that obtains by the dicalite pad, wash with diethyl ether.The oil that concentrated filtrate also will obtain in the vacuum produces 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methylol-isothiazole-5-yl by the flash column chromatography purification]-methanol (141mg, 0.3mmol).
With methylsufonyl chloride (0.182ml, 1.16mmol), then with triethylamine (0.175ml, 1.12mmol) add to 3-(1-cyclohexyl methyl-7-methoxyl group-1H-indol-3-yl)-4-methylol-isothiazole-5-yl in the dichloromethane (10ml)]-(194mg is 0.5mmol) in the solution and stirred reaction mixture 45 minutes for methanol.Add other a methylsufonyl chloride (0.07ml, 0.44mmol) and triethylamine (0.15ml 1mmol) and further stirred 2 hours.In reactant mixture impouring separatory funnel, the salt water washing is used in the aqueous carbonic acid sodium solution washing with 5% then, evaporating solvent in the dry also vacuum on the magnesium sulfate.With the residue that obtains by using 33%-100% (v/v) dichloromethane in the heptane, use the flash column chromatography purification of diethyl ether then, obtain methanesulfonic acid { 4-chloromethyl-3-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl]-isothiazole-5-yl } methyl ester (113mg, 0.23mmol).
With ethamine (0.186ml, 0.37mmol) and triethylamine (0.05ml, 0.37mmol) add to methanesulfonic acid in oxolane (1ml) { 4-chloromethyl-3-[1-(cyclohexyl) methyl-7-methoxyl group-1H-indol-3-yl]-isothiazole-5-yl } methyl ester (90mg, 0.19mmol) solution and allow reactant mixture accept 150 ℃ microwave irradiation 15 minutes.In reactant mixture impouring separatory funnel, with dichloromethane (30ml) dilution and with 5% aqueous carbonic acid sodium solution (2 * 10ml), saline (10ml) washing, dry and on the magnesium sulfate in a vacuum except that desolvating.Repeat this reaction with the scale of 0.166mmol and obtain identical intermediate.Merge crude product and obtain title compound (36mg, free alkali 0.09mmol) by the flash column chromatography purification that uses ethyl acetate.Be dissolved in this free alkali in the dichloromethane and add the hydrogen chloride (solution of 2M in the diethyl ether; 1ml, 2mmol).Concentrate the hydrochlorate that this mixture obtains the 1:1 of title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)：0.97-1.15(2H，m)，1.15-1.27(3H，m)，1.47(3H，t，J?7)，1.52-1.61(2H，m)，1.62-1.77(3H，m)，1.81-1.95(1H，m)，3.63(2H，q，J?7)，3.95(3H，s)，4.28(2H，d，J?7)，4.62-4.75(2H，m)，4.95-5.12(2H，m)，6.77(1H，d，J?8)，7.09(1H，t，J?8)，7.43(1H，s)，8.01(1H，d，J?8)；Es?IMS：m/z?396.0[M+H] +，353.4，351.3，320.3。
Embodiment 34
1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(pyrrolidine-1-yl) methyl]-different Oxazole-3-yl }-the 1H-indole, trifluoroacetate
(12ml 0.13mol) slowly was added in 30 minutes in the dimethyl formamide (30ml) with phosphoryl chloride phosphorus oxychloride in-10 ℃.In 1 hour, allow this solution be warming up to 0 ℃, then 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole (is prepared as embodiment 26; 3.2g, 13mmol) stirred this solution 16 hours under portioning adding and the room temperature.Cooling this solution and dilute with water in ice bath is then carefully with the sodium bicarbonate neutralization and with ethyl acetate extraction (3 * 50ml).Merge to remove in organic extract and the vacuum and desolvate.(3.5g) is dissolved in aqueous naoh solution (5M with residue; Refluxed other 16 hours down at 100 ℃ 100ml) and with mixture.Also (3 * 50ml) extractions merge organic extract and obtain 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-formaldehyde (2.2g, 8.12mmol) white solid except that desolvating in a vacuum with ethyl acetate to cool off this solution.
With oxammonium hydrochloride. (403mg, 5.8mmol) and sodium acetate (713mg, 8.7mmol) (780mg 2.9mmol) stirred this solution 64 hours under solution and the room temperature to add to 1-(cyclohexyl) methyl-7-methoxyl group-1H-indole-3-formaldehyde in the mixture of ethanol (8ml) and water (2ml).Concentrate this mixture and water (50ml) dilution residue in the vacuum, and (3 * 50ml) extract with ethyl acetate.Product recrystallize from diethyl ether/heptane is produced 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carbaldehyde oxime (380mg, 1.3mmol) yellow powder.
With N-chlorosuccinimide (119mg, 0.89mmol) add to the 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carbaldehyde oxime (170mg in the dichloromethane (5ml) that is cooled to 0 ℃, 0.59mmol) solution, and allow mixture be warming up to room temperature, stirred simultaneously 1 hour.Add propargyl bromide (8 μ l, 0.65mmol) and triethylamine (9 μ l, this mixture of stirring is 16 hours 0.65mmol) and under the room temperature.Remove the flash column chromatography purification residue that desolvates and pass through to use 60-80% (v/v) the dichloromethane eluting in the normal heptane in the vacuum, obtain 3-(5-bromomethyl-isoxazole-3-bases)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (150mg, 0.37mmol) yellow solid.
(0.024ml 0.34mmol) adds to 3-(5-bromomethyl-isoxazole-3-bases)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (120mg, 0.31mmol) solution in the acetonitrile (3ml) with diethylamine.Stirred the mixture under the room temperature 16 hours.Filter this mixture also in a vacuum except that desolvating.With partly preparing the HPLC[method (ii)] the purification residue obtains the trifluoroacetate (20mg) of title compound 1H NMR (400MHz, CD 3OD) δ 1.03-1.09 (2H, m), 1.21 (3H, m), 1.57-1.74 (5H, m), 1.83-1.89 (1H, m), 2.14 (4H, m), 3.38-3.60 (4H, m), 3.96 (3H, s), 4.27-4.29 (2H, d, J 6.9), 4.69 (2H, s), 6.78 (1H, d, J 7.5), 7.02 (1H, s), 7.08-7.12 (1H, m), 7.67 (1H, s), 7.67-7.69 (J 8.1 for 1H, d) Es IMS:m/z 394.1[M+H] +, 323.4.
Embodiment 35
1-(cyclohexyl) methyl-7-methoxyl group-3-(5-{[two-(2-ethoxy) amino] first Base }-isoxazole-3-bases)-the 1H-indole, trifluoroacetate
Replace pyrrolidine with diethanolamine, prepare this title compound by the method for embodiment 34.Es?IMS：m/z?428.4[M+H] +，323.4。
Embodiment 36
1-(cyclohexyl) methyl-7-fluoro-3-{5-[(pyrrolidine-1-yl) methyl]-thiophene-2- Base)-and the 1H-indole, hydrochlorate
(60% is scattered in the mineral oil with sodium hydride; 0.88g, 22.2mmol) add to 7-fluoro indole in the dimethyl formamide (50ml) (2.0g, ice-cold solution 14.8mmol), and stirring the mixture 15 minutes, be added dropwise to then benzene sulfonyl chloride (2.26ml, 17.8mmol).Stirred the mixture under the room temperature 18 hours.Water (200ml) dilutes this suspension then, and ((organic layer that 3 * 100ml) washings merge is with concentrating in dried over sodium sulfate and the vacuum for 3 * 100ml) extractions and water with t-butyl methyl ether.With residue by the flash column chromatography purification with 20% in the isoheptane (v/v) eluent ethyl acetate obtain 1-benzenesulfonyl-7-fluoro indole colorless solid (3.96g, 14.4mmol).
(0.75ml, 14.55mmol) solution dropped to 1-benzenesulfonyl-7-fluoro indole (2.0g, 7.27mmol) solution in the dimethyl formamide (10ml) in 3 minutes with the bromine in the dimethyl formamide (25ml).Stir this mixture 10 minutes then under the room temperature and incline on the mixture of sodium metabisulfite (2g), Ammonia (3ml), water (100ml) and rubble ice (100g).The suspension that stirring obtains advances t-butyl methyl ether (in 2 * 100ml) until whole color fade (discharged) and extraction.Water (organic layer that 2 * 100ml) washings merge, with dried over sodium sulfate and remove in a vacuum desolvate obtain 1-benzene sulfonyl-3-bromo-7-fluoro indole salmon solid (2.35g, 6.64mmol).
Allow 1-benzene sulfonyl-3-bromo-7-fluoro indole (0.5g in the ethanol (4ml), 1.41mmol), 5-formyl-2-thienyl boric acid (0.24g, 1.55mmol), two (triphenylphosphine) dichloro palladium (II) (0,06g, 0.08mmol) and triethylamine (0.39ml, 2.82mmol) solution is accepted 150 ℃ of microwave irradiations 420 seconds.Under reduced pressure concentrate the suspension obtain and obtain thick 5-(1-benzene sulfonyl-7-fluoro indole-3-yl)-thiophene-2-formaldehyde brown solid (0.42g) by residue by tripoli pad (silica pad), use it for next step and need not to be further purified with the dichloromethane eluting.
Successively will
Figure C200580007120D00571
Molecular sieve (1g), pyrrolidine (0.44ml, 5.36mmol), sodium cyanoborohydride (0.034g, 0.54mmol) and glacial acetic acid (1) be added to thick 5-(1-benzene sulfonyl-7-fluoro indole-3-yl)-thiophene-2-formaldehyde.Stirred the mixture obtain then under the room temperature 18 hours, and filtered and with methanol (2 * 30ml) and dichloromethane (2 * 30ml) washing leaching cakes.Concentrate the filtrate that merges under the vacuum, be dissolved in the dichloromethane (20ml), with aqueous NaOH (2M; 15ml) washing is with concentrating under dried over sodium sulfate and the vacuum.Then with residue by the flash column chromatography purification with the 0-10% in the dichloromethane (v/v) methanol-eluted fractions obtain 1-benzene sulfonyl-7-fluoro-3-(5-pyrrolidine-1-ylmethyl-thiophene-2-yl)-indole yellow oil (0.22g, 0.46mmol).
With 1-benzene sulfonyl-7-fluoro-3-(5-pyrrolidine-1-ylmethyl-thiophene-2-yl)-indole (0.20g, 0.46mmol) and potassium carbonate (0.25g is 1.82mmol) with first alcohol and water (3:1 v/v; Mixture process 4ml) is also accepted 100 ℃ microwave irradiation 600 seconds.Then the suspension that obtains is under reduced pressure concentrated and distribution between dichloromethane (10ml) and water (10ml).Separate organic facies and wash water with dichloromethane (10ml).The organic layer that merges is dry and concentrated in a vacuum on magnesium sulfate.With residue by the flash column chromatography purification with the 0-10% in the dichloromethane (v/v) methanol-eluted fractions obtain 7-fluoro-3-(5-pyrrolidine-1-ylmethyl-thiophene-2-yl)-indole colorless solid (0.10g, 0.35mmol).
(60% is scattered in the mineral oil with sodium hydride; 0.03g (0.10g 0.35mmol) stirred this mixture 15 minutes under solution and the room temperature 0.71mmol) to add to 7-fluoro-3-(5-pyrrolidine-1-ylmethyl-thiophene-2-yl)-indole in the dimethyl formamide (3ml).(0.05ml 0.39mmol) and under 60 ℃ stirred the mixture 18 hours to add the bromomethyl cyclohexane extraction.Water (30ml) dilutes this suspension then, and t-butyl methyl ether is advanced in extraction, and (in 2 * 30ml), (organic layer that 2 * 20ml) washings merge is with dried over mgso and vapourisation under reduced pressure for water.With residue by the purification by flash chromatography with 5% in the methanol (v/v) dichloromethane eluting obtain title compound (free alkali) colorless solid (0.05g, 0.13mmol).Be dissolved in it in diethyl ether (3ml) and usefulness hydrogen chloride (solution of 1M in the diethyl ether) processing, evaporation obtains title compound (1:1 hydrochlorate) colorless solid. 1H?NMR(400MHz，CD 3OD)δ H?1.02-1.34(5H，m)，1.57-1.93(6H，m)，2.11-2.19(4H，m)，3.38-3.57(4H，m)，4.19(2H，d，J?7.4)，4.65(2H，s)，6.91-7.36(4H，m)，7.58(1H，s)，7.71(1H，d，J?8.1)；Es?IMS：m/z?396.9[M+H] +，326.0
Embodiment 37
1-(cyclohexyl) methyl-3-{5-[(dimethylamino) methyl]-[1,3,4]-Evil Diazole-2-yl }-7-methoxyl group-1H-indole, hydrochlorate
(0.6ml 6.96mmol) adds to 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid in the dichloromethane (20ml) (1.0g, 3.48mmol) suspension and stir this reaction 3.5 hours with oxalyl chloride.Decompression is descended evaporating solvent and the residue that obtains is dissolved in the dichloromethane (20ml) again.With the monoxone hydrazine (1.3g, 8.97mmol) and triethylamine (2.9ml 20.9mmol) is added to this solution and stirred reaction mixture 4 hours and let alone then to place and spend the night.The vapourisation under reduced pressure solvent and with the residue that obtains by the flash column chromatography purification with the 50-100% in the heptane (v/v) eluent ethyl acetate obtain 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid N '-(2-chloracetyl) hydrazine (397mg, 1.05mmol).
With (methoxycarbonyl sulfamoyl) triethyl group ammonium hydroxide; inner salt (315mg; 1.32mmol) (250mg is 0.662mmol) in the solution and allow reactant mixture accept 150 ℃ microwave irradiation 15 minutes to add to 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid N '-(2-chloracetyl) hydrazine in the oxolane (3ml).With methanol cancellation reactant mixture and evaporating solvent.The purification by flash chromatography of the residue that obtains 33-50% (v/v) ethyl acetate by using heptane is obtained 3-(5-chloromethyl-[1,3,4] oxadiazole-2-yls)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (169mg, 0.47mmol) yellow solid.With the amount of 0.53mmol repeat this reaction obtain identical intermediate (276mg altogether, 0.77mmol).
With diethylamine (0.134ml, 1.28mmol) add to 3-(5-chloromethyl-[1 in the oxolane (1ml), 3,4] oxadiazole-2-yl)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (92mg, 0.26mmol) solution and allow reactant mixture accept 150 ℃ microwave irradiation 15 minutes.The oil that obtains is obtained title compound (87mg, 0.22mmol) free alkali by the flash column chromatography purification.Be dissolved in this free alkali in the dichloromethane and add the hydrogen chloride (solution of 2M in the diethyl ether; 1ml, 2mmol).Remove excess reagent and remaining title compound (1:1 hydrochlorate) white solid of solvent by evaporation. 1H?NMR(400MHz，CD 3OD)：0.97-1.12(2H，m)，1.15-1.26(3H，m)，1.46(6H，t，J?7)，1.53-1.63(2H，m)，1.63-1.78(3H，m)，1.8-1.95(1H，m)，3.44(4H，q，J?7)，3.98(3H，s)，4.33(2H，d，J?7)，4.84(2H，s)，6.85(1H，d，J?7)，7.19(1H，t，J?7.9)，7.73(1H，d，J8)，7.94(1H，s)；Es?IMS：m/z?397.1[M+H] +，324.4，270.5。
Embodiment 38
1-(cyclohexyl) methyl-7-methoxyl group-3-{5-[(pyrrolidine-1-yl) methyl]-[1, 3,4]-thiadiazoles-2-yl }-the 1H-indole, hydrochlorate
(62mg 0.139mmol) adds to 1-cyclohexyl methyl-7-methoxyl group-1H-indole-3-carboxylic acid N '-(2-chloracetyl) hydrazine in the oxolane (0.5ml) and (describes preparation as embodiment 37 with phosphorus pentasulfide; 50mg is 0.139mmol) in the solution and allow reactant mixture accept 150 ℃ microwave irradiation 5 minutes.Amount with 0.7mmol repeats twice of this reaction.To dilute (60ml) in the reactant mixture impouring separatory funnel that merge and with dichloromethane.With organic layer with 5% aqueous carbonic acid sodium (2 * 30ml), saline (30ml) washing, dry and remove in a vacuum and desolvate on sodium sulfate.With the residue that obtains by the flash column chromatography purification obtain 3-(5-chloromethyl-[1,3,4] thiadiazoles-2-yl)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (186mg, 0.49mmol).
With pyrrolidine (0.101ml, 1.235mmol) add to (the 5-chloromethyl-[1 of 3-in the oxolane, 3,4] thiadiazoles-2-yl)-1-cyclohexyl methyl-7-methoxyl group-1H-indole (93mg, 0.25mmol) solution and allow reactant mixture accept 150 ℃ microwave irradiation 5 minutes.The reactant mixture that obtains is obtained title compound (42mg, 0.1mmol) free alkali by the flash column chromatography purification.Be dissolved in this free alkali in the dichloromethane and add the hydrogen chloride (solution of 1M in the diethyl ether; 1ml, 1mmol).Remove the hydrochlorate that excessive reagent and solvent obtain the 1:1 of title compound in a vacuum.
1H?NMR(400MHz，CDCl 3)：0.94-1.1(2H，m)，1.13-1.23(3H，m)，1.5-1.75(8H，m)，1.8-1.9(5H，m)，2.66-2.73(4H，m)，3.95(3H，s)，4.12(2H，s)，4.23(2H，d，J?7)，6.73(1H，d，J?7.8)，7.17(1H，t，J?8)，7.66(1H，s)，7.77(1H，d，J?8)；Es?IMS：m/z?411.1[M+H] +，340.0，324.4，286.1，270.5。
Embodiment 39
7-chloro-3-{5-[(2,2-dimethyl-pyrrolidine-1-yl) methyl]-[1,2,4] oxadiazoles -3-yl }-1-(tetrahydropyran-4-base) Methyl-1H-indole, hydrochlorate
Be used for Synthetic 2, the method for 2-dimethyl-ketopyrrolidine:
(3.36g, 89mmol) portioning is added to the NiCl in the methanol (200ml) with sodium borohydride 2.6H 2The stirring of O with refrigerative solution (0 ℃).Stir this reactant mixture and add methyl-4-methyl-4-nitro valerate solution in the methanol (100ml) after 30 minutes.Keep 0 ℃ reaction temperature, then portioning add sodium borohydride (7.86g, 208mmol).Allow reaction stir then 72 hours, filter by Celite pad afterwards.The filter cake that obtains is extremely dry with methanol (150ml) washing and evaporated filtrate.The solid that obtains with dichloromethane (400ml) development also filters by Celite pad.Obtain product 2 with evaporated filtrate behind dichloromethane (200ml) washing leaching cake, 2-dimethyl-ketopyrrolidine pale green coloring agent (6.8g).
Be used for Synthetic 2, the method for 2-dimethyl-pyrrolidine hydrochloride:
With the lithium aluminium hydride (solution of the 1M in the oxolane; 120ml 120mmol) slowly adds to 2 in the oxolane (150ml) of stirring, 2-dimethyl-ketopyrrolidine (6g, 53mmol) solution.In a single day reinforced finishing is warming up to backflow with reaction, and reflux under the argon atmosphere and stirred 16 hours.After this, allow reaction be cooled to 0 ℃, to add at interval entry (2.2ml), 10% sodium hydroxide solution (2.2ml) and water (6.6ml) in 45 minutes.The slurry that obtains is filtered with diethyl ether (150ml) dilution and by Celite pad.Use hydrochloric acid (the 1M solution in the diethyl ether, 63ml) acidify with diethyl ether (250ml) washing leaching cake and with filtrate.The yellow solid that obtains is leached, obtain 2,2-dimethyl-pyrrolidine hydrochloride (4.8g).
Be used to synthesize the method for (2,2-dimethyl-pyrrolidine-1-yl)-ethyl acetate:
With the ethyl chloride acetas (0.15ml, 1.37mmol), (416mg, 1.5mmol) and 2, (0.280mg 2.06mmol) is suspended in the ethanol (3ml) and allows it accept 120 ℃ microwave irradiation 45 minutes 2-dimethyl-pyrrolidine potassium carbonate.The mixture that obtains is suspended in the diethyl ether (30ml), and (30ml) extracts and abandons organic layer with 2M hydrochloric acid.Handle water layer and use diethyl ether (3 * 30ml) extractions with excessive slightly 4N sodium hydroxide solution.Merge organic layer, dry on sodium sulfate, filter also and under reduced pressure obtain (2,2-dimethyl-pyrrolidine-1-yl)-ethyl acetate (156mg) except that desolvating.
With 7-chloro-indole replacement 7-methoxyl group indole, with toluene-4-sulfonic acid tetrahydropyran-4-base methyl ester (as describing preparation among the embodiment 14) replacement cyclohexyl methyl bromine and with (2,2-dimethyl-pyrrolidine-1-yl)-ethyl acetate replacement N, N-dimethylglycine methyl ester prepares title compound according to the method for embodiment 1.
1H?NMR(400MHz，CD 3OD)δ?1.45(10H，m)，2.22(5H，m)，3.35(2H，m)，3.59(1H，br?s)，3.91(2H，d，J11.1)，4.12(1H，br?s)，4.52(2H，d，J?7.1)，4.71(1H，br?s)，4.95(1H，br?s)；7.23(1H，t，J?7.6)，7.32(1H，d，J?7.6)，8.08(1H，s)，8.13(1H，d，J?7.6)。Es?IMS：m/z?429.5[M+H] +。
Embodiment 40
1-(cyclohexyl) methyl-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2,4] thiophene Diazole-3-yl }-1H-indole-7-nitrile, hydrochlorate
Use Emrys TMOptimizer EXP, ([3-(7-bromo-1-cyclohexyl methyl-1H-indol-3-yl)-[1,2,4] thiadiazoles-5-yl]-methanol in 2 * 4ml) (is described as embodiment 7 and to be prepared from the 7-bromo indole to allow DMF; 2 * 250mg, 0.16mmol), zinc cyanide (II) (2 * 72mg, 0.61mmol) and tetrakis triphenylphosphine palladium (0) (2 * 21mg, 18.3 μ mol) suspension accept 200 ℃ microwave irradiation 5 minutes.Merge in reactant and the impouring separatory funnel, the adding dichloromethane (～50ml).
Successively water (2 * 20ml), the moisture HCl of 1M (20ml) and saline (20ml) washs this Organic substance, and is dry on magnesium sulfate, filter, and remove in a vacuum and desolvate.The grease that obtains obtains 1-cyclohexyl methyl-3-(5-methylol-[1 by the flash column chromatography purification with the 50-100% in the heptane (v/v) dichloromethane eluting, 2,4] thiadiazoles-3-yl)-(416mg, 1.18mmol) light yellow oil leave standstill and make its crystallization 1H-indole-7-nitrile.
Successively with methylsufonyl chloride (0.110ml, 1.42mmol) and triethylamine (0.214ml 1.53mmol) adds to 1-cyclohexyl methyl-3-(5-methylol-[1,2 in the dichloromethane (40ml), 4] thiadiazoles-3-yl)-(416mg is in solution 1.18mmol) for 1H-indole-7-nitrile.Allow reaction stir 1 hour and then in the impouring separatory funnel.This Organic substance is washed with 2M aqueous carbonic acid sodium solution (20ml), saline (20ml), dry on magnesium sulfate, filter, and obtain methanesulfonic acid 3-(7-cyano group-1-cyclohexyl methyl-1H-indol-3-yl)-[1 except that desolvating in a vacuum, 2,4] thiadiazoles-(503mg, 1.17mmol), it need not to be further purified and can use 5-base methyl ester.
With pyrrolidine (0.12ml, 1.4mmol) add to the methanesulfonic acid 3-(7-cyano group-1-cyclohexyl methyl-1H-indol-3-yl)-[1 in the dichloromethane (3ml), 2,4] thiadiazoles-5-base methyl ester (120mg, 0.28mmol) solution and allow reaction accept 100 ℃ microwave irradiation 5 minutes.Directly by with the dichloromethane in the heptane, use the flash column chromatography purification of 25-50% (v/v) eluent ethyl acetate to obtain title compound (71mg, 0.175mmol) free alkali then reactant.(35mg 0.086mmol) is dissolved in the dichloromethane (2ml) and adds hydrogen chloride (solution of 1M in the diethyl ether) with this free alkali.Concentrate the hydrochlorate that this mixture obtains the 1:1 of title compound in a vacuum. 1H?NMR(400MHz，CD 3OD)：1.06-1.36(7H，m)，1.62-1.80(5H，m)，1.91-2.07(1H，m)，2.09-2.34(2H，br?m)，3.35-4.20(4H，br?m)，4.42(2H，d，J?7)，5.07(2H，s)，7.37(1H，t，J?8)，7.69(1H，dd，J?7，1)，8.23(1H，s)；8.84(1H，dd，J?8，1)Es?IMS：m/z?406.4[M+H] +。
Embodiment 41
External test is to the effect and the effectiveness of the human CB1 receptor of expressing in Chinese hamster ovary celI
With Chinese hamster ovary cell (CH0) cell suspension of expressing human CB1 receptor and luciferase reporter gene in the phenol red/serum-free DMEM/F-12 nut mix that contains penicillin/streptomycin (50U/50 μ g/ml) and amphotericin (1 μ g/ml) and with 3 * 10 4The density of cells/well (100 μ l final volume) is inoculated in 96 orifice plates.(37 ℃ were descended 5% CO about 18 hours with the cell overnight incubation before mensuration 2/ 95% air).
Test compounds (the 10mM solution in the dimethyl sulfoxide) is diluted in the stock solution that obtains the 0.11mM-0.11nM scope among the F12 Nut Mix.(10 μ l) directly is added in the corresponding hole with stock solution.Plate hatched under 37 ℃ allowed the expression of agonist induction luciferase in 5 hours.Under soft light, with LucLite substrate (Packard; The description reconstruct that provides according to manufacturer; 100 μ l) be added to every hole.Also at room temperature hatched then 5 minutes with Top Seal overlay, then counting (single photon counting, 0.01 minute gate time, 5 minutes count delay) on Packard TopCount.
The curve that obtains per second counting (CPS) relativization compound concentration (M) by least square and method match " the best-match " curve is to obtain EC 50Value.Table 1 shows the pEC of the representative compounds of the present invention that obtains 50Value.
Table 1
Figure C200580007120D00631
Figure C200580007120D00641
Embodiment 42
The TFL of mice
The training mice undisturbedly is sitting in the whipping device (Ugo Basile, Italy), measures TFL simultaneously.Allow the tail of mice be exposed to photothermal focused beam acts at point from the about 2.5cm of tail point.TFL is defined as and applies thermostimulation and tail and remove interval between contracting.The cutoff that adopts 12 seconds is to avoid tissue injury.Four groups of eight mices are used (carrier: 10% Tween-80 in the saline with a kind of processing of three kinds of dosage of carrier or test compounds by intravenous; Volume injected 10ml/kg).Before using test compounds, measure TFL and behind administered compound, (be generally 20,40 and 60 minutes) at regular intervals and measure TFL.At T MaxCalculate ED 50
Embodiment 2G, 13, 14B, 15A, 15B, 15C, 20, 23B, 23C, 23DWith 39Obviously increased TFL, ED 50＜5 μ mol/kg.

Claims (9)

1. (the indol-3-yl)-Hete rocyclic derivatives that has general formula I
Figure C200580007120C00031
General formula I
Wherein
A represents 5-membered aromatic heterocycle, wherein X 1, X 2And X 3Be independently selected from N, O, S and CR;
R is hydrogen or C 1-4Alkyl; Or
R is being present in X 2Or X 3In the time can with R 3Form 5-8 unit ring together;
R 1Be the saturated carbocyclic ring of 5-8 unit, the optional hetero atom that is selected from O and S that contains;
R 2Be H, CH 3Or CH 2-CH 3Perhaps
R 2With R 7Be joined together to form 6 yuan of rings, these 6 yuan rings are chosen wantonly and are contained the hetero atom that is selected from O and S, and this hetero atom is bonded to the position 7 of indole ring;
R 3And R 4Be H, C independently 1-6Alkyl or C 3-7Cycloalkyl, this alkyl is by OH, C 1-4Alkoxyl, C 1-4Alkylthio group, C 1-4Alkyl-sulfonyl, CN or halogen are optional to be replaced; Perhaps
R 3With R 4And their bonded N form the optional heteroatomic 4-8 of other that be selected from O and S unit ring that contains together, and should ring by OH, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy-C 1-4Alkyl or halogen are optional to be replaced; Perhaps
R 3And R 5Forming optional containing together is selected from 0 and the heteroatomic 4-8 of other of S unit ring, and should ring by OH, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy-C 1-4Alkyl or halogen are optional to be replaced; Perhaps
R is being present in X 2Or X 3Among the time and R 3Form 5-8 unit ring;
R 5Be H or C 1-4Alkyl; Perhaps
R 5With R 3Form together to choose wantonly and contain the first ring of other heteroatomic 4-8 that is selected from O and S, and be somebody's turn to do ring by OH, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy-C 1-4Alkyl or halogen are optional to be replaced;
R 5' be H or C 1-4Alkyl;
R 6Expression is independently selected from H, C 1-4Alkyl, C 1-4The 1-3 of alkoxyl, a CN and halogen substituent group;
R 7Be H, C 1-4Alkyl, C 1-4Alkoxyl, CN or halogen; Perhaps
R 7With R 2Connect and form 6 yuan of rings, these 6 yuan rings are chosen wantonly and are contained other hetero atom that is selected from O and S, and this hetero atom is connected to the position 7 of indole ring; Or its pharmaceutically acceptable salt.
2. (indol-3-yl)-Hete rocyclic derivatives as claimed in claim 1, wherein R 2Be H or and R 7Connect and form 6 yuan of rings, these 6 yuan rings are chosen wantonly and are contained the hetero atom that is selected from O and S, and this atom is bonded to the position 7 of indole ring.
3. (indol-3-yl)-Hete rocyclic derivatives as claimed in claim 1 or 2, wherein R, R 5, R 5' and R 6Be H.
4. (indol-3-yl)-Hete rocyclic derivatives as claimed in claim 3, wherein R 1Be cyclohexyl or THP trtrahydropyranyl.
5. (indol-3-yl)-Hete rocyclic derivatives as claimed in claim 4, wherein heterocycle A is 1,2,4-oxadiazole, i.e. X 1Be N, X 2Be O, X 3Be N; 1,2,4-thiadiazoles, i.e. X 1Be N, X 2Be S, X 3Be N; Or thiazole, i.e. X 1Be S, X 2Be CR, X 3Be N.
6. (the indol-3-yl)-Hete rocyclic derivatives of claim 1, it is selected from:
7-chloro-3-(5-{[N-ethyl-N-(2-methoxy ethyl) amino] methyl }-[1,2,4]-thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-{5-[(pyrrolidine-1-yl) methyl]-[1,2,4]-thiadiazoles-3-yl }-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-(5-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,2,4]-thiadiazoles-3-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-(4-{[N-(2-ethoxy)-N-isopropylamino] methyl }-[1,3]-thiazol-2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-(4-{[N-ethyl-N-(2-ethoxy) amino] methyl }-[1,3]-thiazol-2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-(4-{[N-(2-methoxy ethyl)-N-methylamino] methyl }-[1,3]-thiazol-2-yl)-1-(tetrahydropyran-4-base) Methyl-1H-indole;
7-chloro-3-{5-[(2,2-dimethyl-pyrrolidine-1-yl) methyl]-[1,2,4]-oxadiazoles-3-yl }-1-(tetrahydropyran-4-base) Methyl-1H-indole;
Or its pharmaceutically acceptable salt.
7. pharmaceutical composition, it contains (the indol-3-yl)-Hete rocyclic derivatives that can accept one of any of the blended claim 1-6 of auxiliary agent with pharmacy.
8. (indol-3-yl)-Hete rocyclic derivatives of the formula I that defines in the claim 1 is used to prepare the purposes of the medicine for the treatment of pain.
9. the purposes of claim 8, wherein said pain is perioperative pain, chronic pain, neuropathic pain, cancerous pain and pain and the spasticity relevant with multiple sclerosis.
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