HK1111155B - Non-nucleoside reverse transcriptase inhibitors - Google Patents

Description

Non-nucleoside reverse transcriptase inhibitors

The application is a divisional application with application date of 2002, 3, 4 and application number of 02806027.

Technical Field

The present invention relates to non-nucleoside reverse transcriptase inhibitors having anti-HIV-1 activity and having improved tolerability and pharmacokinetic profiles the present invention further relates to novel intermediates in the synthesis of such compounds and to the use of such compounds in antiviral processes and compositions.

Background

International patent application WO93/03022 discloses thiourea NNRTIs, which were later identified as "PETT" (phenylethylthioureas) compounds in J Med Chem 3961329-1335 (1995) and J Med Chem 39214261-4274 (1996). International patent applications WO99/47501, WO/0039095, WO/0056736, WO00/78315 and WO00/78721 describe thiourea PETT derivatives, which are said to be preferred against mixed RT binding sites.

International patent applications WO95/06034 and J Med Chem 424150-4160 (1999) disclose urea isosteres of PETT NNRTI International patent application WO99/36406 discloses urea NNRTI with a separate cyclopropyl bridge, where the phenyl group has the requisite 6-hydroxy function on the left side; international patent application WO00/47561 discloses prodrugs of this class of compounds.

Although the urea and thiourea NNRTIs disclosed in the above documents have activity against reverse transcriptase, in particular against HIV-1 reverse transcriptase, the nature of the HIV virus is such that it is poorly reproducible in replication and thus has a tendency to rapidly tolerate new drugs, which has prompted the need for other anti-retroviral agents which have improved antiviral properties against the problematic drug escape mutants, in particular at RT100, 103 and/or 181.

Furthermore, modern HIV treatment modalities, denoted HAART, highly effective anti-retroviral therapy, deliver an antiviral combination of three or more different classes of antiviral agents that can be used to extend the period of morbidity if not life-extending.

Summary of The Invention

According to a first aspect of the invention, there is provided a compound of formula I:

wherein:

R₁is O, S;

R₂is an optionally substituted nitrogen-containing heterocycle wherein the nitrogen is located at the 2-position relative to the (thio) urea linkage;

R₃is H, C₁-C₃An alkyl group, a carboxyl group,

R₄-R₇independently selected from H, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halo C₁-C₆Alkyl radical, C₁-C₆Alkanoyl, halo C₁-C₆Alkanoyl radical, C₁-C₆Alkoxy, halo C₁-C₆Alkoxy radical, C₁-C₆alkoxy-C₁-C₆Alkyl, halo C₁-C₆alkoxy-C₁-C₆Alkyl hydroxy-C₁-C₆Alkyl, amino-C₁-C₆Alkyl, carboxy-C₁-C₆Alkyl, cyano-C₁-alkyl, amino, carboxyl, carbamoyl, cyano, halogen, hydroxy, keto, and the like;

x is (CH)₂)_n-D-(CH₂)_n，

D is-NR₈-, -O-, -S (═ O) -, or-S (═ O)₂-，

R₈Is H, C₁-C₃An alkyl group, a carboxyl group,

n and m are independently 0 or 1;

and pharmaceutically acceptable salts and prodrugs thereof.

In general R₁Is preferably 0, i.e. a urea derivative, although R is₁It is also very effective to be S (i.e., thiourea derivative).

R₂Typically include thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl, tetrazolyl, piperidinyl, piperazinyl and fused rings such as benzothiazolyl, benzopyridyl, benzodiazolyl, benzimidazolyl, quinolinyl, purinyl and the like, which may be optionally substituted.

Preferably R₂Including pyridin-2-yl and thiazol-2-yl.

R₂The above optional substituents may include up to three substituents, such as C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₈Alkynyl, C₂-C₈Alkenoxy group, C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₁-C₆Alkanoyl, halo C₁-C₆Alkyl radical, C₁-C₄Alkanoyloxy group, C₁-C₄Alkyl mercapto, amino (including C)₁-C₃Alkyl-substituted amino), carboxy, carbamoyl, cyano, halogen, hydroxy, aminomethyl, carboxymethyl, hydroxymethyl, nitro, aryl (such as phenyl, pyrrol-1-yl, tetrazol-5-yl, triazol-4-yl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, indolyl, piperidinyl, piperazinyl, and the like), substituted (as defined herein) aryl, or-SO₂Q or- (═ 0) Q, where Q is C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl, aryl (as defined herein), substituted (as defined herein) aryl or amino₂The hetero atom in (A) may be derivatized, such as with C₁-C₆Alkyl, oxo, etc. optionally R₂The substituents may be ortho or meta to the (thio) urea functionality, but are preferably para.

Preferably R₂Optional substitutions include ethynyl, phenoxy, pyridin-1-yl, cyclopropyl, phenyl, halo-substituted phenyl (especially p-and m-chloro and fluoro-substituted phenyl) and dimethylamino₂The substituents of (A) include halogen (F, Br, Cl and I) and cyano.

R₃H is generally preferred.

Preferably R₄Is hydrogen, halogen or hydroxy, especially fluorine.

Preferably R₅Is halogen, C_1-3Alkylcarbonyl group, C_1-3Alkoxy or H, especially fluoro, most preferably H.

Preferably R₆Is hydrogen, C₁-C₃Alkoxy radical, C_1-3Alkylcarbonyl, cyano or ethynyl, in particular methoxy or fluoro, most preferably H.

Preferably R₇Is hydrogen, halogen, C_1-3Alkoxy or C_1-3Alkylcarbonyl, most preferably fluoro.

Preferably R₅And R₆Is H and R₄And R₇Is halogen, most preferably both are fluorine.

Preferably D is-0-, n is 0, m is 1, R₁Is 0, R₂Is a substituted pyridin-2-yl group and R₃Is H. Another preferred embodiment includes compounds wherein D is-O-, n is 0, m is 1, R is₁Is S, R₂Is a substituted pyridin-2-yl group and R₃Is H.

The compounds of formula I may be administered as a racemic mixture, but preferably the cyclopropyl moiety intermediate (thio) urea function, X and the phenyl ring (denoted Y below) are at least 75% relative to the configuration, such as about 90% enantiomerically pure:

or

Preferably, the optical isomers of formula I exhibit negative optical rotation values₂Tend to elute more slowly from chiral chromatography, e.g. chiral 150x10mm, 5 μm; crom Tech LTD Colomn, flow rate 4 ml/min, mobile phase 89% by volume 10mM OAc/NH in acetonitrile₄On the basis of preliminary X-ray crystal diffraction analysis, the absolute configuration that is currently favored appears to be:

generally preferred suitable values for D being-0-. n and m include 1: 0 and 1:1, n: preferred values of m include 0: 2, in particular 0: particularly preferred compounds have a stereochemical structure corresponding to (1S, 1aR, 7bR) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl.

Expression C₁-C_nAlkyl, wherein n is 3, 6, 7, etc., or lower alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, threo-butyl, tert-butyl, n-pentyl, n-hexyl, 3-methylpentyl, and the like₁-C_nAlkoxy relates to radicals such as methoxy, ethoxy, propoxy, tert-butoxy, C₂-C_nAlkenyl relates to radicals such as vinyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl, C₁-C_nThe alkyl mercapto group includes methylthio, ethylthio, tert-butylthio and the like C₁-C_nAlkanoyloxy includes acetoxy, propionyloxy, formyloxy, butanoyloxy, and the like C₂-C_nAlkenyloxy includes vinyloxy, propenyloxy, isobutoxyvinyl and the like, halo C₁-C_nAlkyl (including complex substituents containing such moieties, e.g. halo C)₁-C_nAlkoxy) includes alkyl groups as defined herein substituted with 1 to 3 halogen, including trifluoromethyl, 2-dichloroethyl, 3-difluoropropyl, and the like₂、NHMe、N(Me)₂Optionally substituted by halogen, C₁-C₇Acyloxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, nitro, carboxyl, carbamoyl, carbamoyloxycyano, methylsulfonylamino and the like, carboxyl, carboxymethyl and carbamoyl including the corresponding pharmaceutically acceptable C₁-C₆Alkyl esters and aryl esters.

Prodrugs of compounds of formula I are those which release the compound of formula I in vivo upon administration to a patient, typical prodrugs,when R is₄-R₇Or R₂Where the optional substituents represent hydroxy functions, are pharmaceutically acceptable ethers, particularly esters (including phosphate esters); when R is₂The above optional substituent or R₄-R₇When representing an amine function, is a pharmaceutically acceptable amide or carbamate; when R is₂Substituent or R₄-R₇When carboxyl functional, is indicated, it is a pharmaceutically acceptable ester.

Suitable pharmaceutically acceptable salts of the compounds of formula I include salts of organic acids, particularly carboxylic acid salts, including without limitation acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, disaccharide (digluconate), cypionate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate (palmoate), levate (pectinate), 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivalate, camphorate, undecanoate and succinate; salts of organic sulfonic acids such as methylchlorobenzene sulfonate and p-toluene sulfonate; and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, metabisulfate, thiocyanate, persulfate, phosphate and sulfonate.

As used herein, hydroxy protecting Groups refer to Groups that protect a hydroxy group from undesired reactions during the synthetic process, such as those disclosed In Greene, "Protective Groups In organic Synthesis", John Wiley & Sons, New York (1981.) hydroxy protecting Groups include substituted methyl ethers, such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, and other lower alkyl ethers, such as isopropyl, ethyl, and particularly methyl, benzyl, and trityl; tetrahydropyranyl ether; substituted ethyl ethers, such as 2, 2, 2-trichloroethyl; silyl ethers such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting a hydroxyl group with a carboxylic acid, such as acetates, propionates, benzoates, and the like.

Other aspects of the invention provide methods of inhibiting HIV comprising administering a compound of formula I to a subject afflicted with HIV-1 or exposed to HIV-1, HIV-1 may include drug escape mutants, such as HIV lines including mutations at 100, 103 and/or 181, particularly the K103N mutation.

The invention also provides the use of a compound of formula I in therapy, such as in the manufacture of a medicament for the treatment of HIV infection.

In the treatment of conditions caused by HIV, the compound of formula I is preferably administered in an amount to achieve a plasma concentration of about 100-5000nM, such as 300-2000nM, depending on the bioavailability of the formulation, which corresponds to a dosage level of 0.01-10 mg/kg/day, preferably 0.1-2 mg/kg/day for normal adults, typically a dosage level of about 0.05-5g per day, preferably 0.1-2g, such as 500-750mg, divided into 1-4 dosage units per day.

Consistent with the usual methods of use of HIV inhibitors, it is advantageous that one to three other antiviral agents be co-administered, providing a synergistic response and ensuring complementation of tolerance profiles, such other antiviral agents may include AZT, dd1, ddC, D4T, 3TC, DAPD, alovudine, abacavir, adefovir dipivoxil, bis-POC-PMPA, GW420867X, foscarnet, hydroxyurea, Hoechst-Bayer y097, efavirenz, trovidine, capravirine, nevirapine, delavirididine, tipranavir, emtricitabine, PFA, H2G (omociclovir), MIV-606 (valacyclovir stearate), TMC-126, TMC-125, TMC-120, dmavirenz, dmirip 450, dolorivir, hbavirenz, beravirenz, bereavir phosphate, their typical bioavailability, their ratio relative to their bioavailability, their ratio of activity: 1 to 1: 25, but possibly lower, for example in the case of using cytochrome antagonists such as ritonavir.

The compounds of the invention are generally prepared as follows:

route 1

(a) DPPA, Et3N, toluene; (b) substituted 2-aminopyridines; (c) aqueous HCl, dioxane; (d) substituted 2-pyridyl isothiocyanates.

A compound of the general formula (I) wherein R₁Is O (urea) or S (thiourea), R₂Is, for example, 5-substituted pyridin-2-yl, R₃Is H, prepared by the method shown in scheme 1 cyclopropanecarboxylic acid,1-route-1Converted to acyl azide and heated to 120 ℃ to induce Curtius rearrangement to give isocyanate,2-route-1A source of urea,3-route-1Obtained by coupling of an isocyanate with an appropriately substituted 2-aminopyridine, hydrolysis of the isocyanate in step (c) to form cyclopropylamine,4-route-1Then reacting with 2-pyridyl isothiocyanate to obtain thiourea,5-route-1Isothiocyanates can be prepared from optionally ring-substituted 2-aminopyridines by known methods, such as treatment with thiophosgene or thiocarbonyldiimidazole₃Variants correspondingly substituted amino-R with suitable amines₂Preparation, i.e. preparation of R from 2- (N-methylamino) pyridine₃Many 2-aminopyridines are commercially available as modifications of methyl, others are described in the literature, e.g., those shown in scheme 2₁Compounds which either correspond to S or may be substituted by2-route 2From isothiocyanates of3-route 2Amine and amine of (2)amino-R of combined RC (═ S) R₂Preparation of the latter two is described in WO9303022 although scheme 1 is illustrated with substituted pyridyl groups, the corresponding couplings can be used for other R₂Variants, such as optionally substituted thiazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl, and the like, are apparent.

Route 2

(a) Phenol, NaH, DMF; (b) 10% Pd/C, H₂latm、EtOH；(c)PdCl₂(PPh₃)₂Trimethylsilyl acetylene, CuI, diisopropylamine; (d) tert-butyl ammonium fluoride

Substituting the bromine of 5-bromo-2-nitropyridine with phenoxy followed by reduction of the nitro group to form 2-amino-5-phenoxypyridine in step (c) with a terminal alkyne SiMe in the presence of a catalytic amount of bis (triphenylphosphine) palladium dichloride and cuprous iodide₃Coupling of 2-amino-5-iodopyridine with C ═ CH Sonogashira to give 2-amino-5- (2-trimethylsilylethynyl) pyridine silyl with TBAF to give 2-amino-5-ethynylpyridine, which can be coupled with isocyanate as described in scheme 13-route-1Or thiourea5-route-1Wherein R is₁₀is-C ═ CSiMe₃Is converted into R₁₀is-C ═ CH.

Route 3

(a) Diazo ethyl acetate, catalyst, CH₂C₁₂(ii) a (b) Separating by chromatography, and then separating with LiOH, H₂O, MeOH refluxing; (c) with LiOH, H₂O, MeOH reflux and then chromatographic separation; (d) rt, NaOH, H₂O, MeOH, then LiOH, H₂O, MeOH reflux

A compound of the general formula (I) wherein R₁Is O (urea) or S (thiourea), R₂Is, for example, 5-substituted pyridin-2-yl, R₃Is H, X is-D-CH₂And wherein the cyclopropyl moieties have a relative configuration

Prepared by the method shown in scheme 3 using monovalent copper or rhodium (II) salts such as CuI, (CuOTf)₂-benzene and Rh₂(OAc)₄Catalytic cyclopropanation of benzopyran with diazoacetic acid ethyl ester in solvent such as dichloromethane, 1, 2-dichloroethane or chloroform1-route-3The reaction provides cyclopropanecarboxylic acid ethyl ester2-route-3Diastereomer mixtures of (1), having all cis-relative configurations and trans isomers thereof3-route-3Separation of the cis and trans diastereomers by column chromatography can be accomplished in this step, followed by hydrolysis of the separated ones as described in step (b)2-route-3Such as by refluxing in aqueous methanol-containing LiOH to produce all cis cyclopropanecarboxylic acids4-route-3Or, as described in step (c), a diastereomeric mixture of the ethyl esters may be hydrolyzed and the mixture of cyclopropanecarboxylic acids separated to yield all the cis-isomers separated2-route-3Can also be isolated by selective hydrolysis of the trans form at lower temperatures3-route-3This is accomplished, for example, by treatment with aqueous, methanol-containing NaOH at room temperature4-route-3Cyclopropanecarboxylic acids via the process outlined in route 1 to give ureas or thioureas5-route-3Benzopyran1-route-3Although scheme 3 is illustrated with the D ═ O variant, it is clear that the corresponding procedure can be used for D ═ S, S ═ O; s (═ 0)₂And D ═ NR₈Variants when R₈When H, the nitrogen is generally protected by a conventional secondary amine protecting group, such as in Greene&Those described in Wuts Protective Groups in Organic Synthesis2ed, Wiley NY 1991.

Route 4

(a) 3-Bromopropyne, K₂CO₃Acetone; (b) n, N-diethylaniline or PEG-200, 225 ℃.

Scheme 4 describes the preparation of benzopyrans, including a number of commercially available disubstituted phenols, such as those described below, wherein the phenyl ring is substituted: r₄And R₇Is halogen; r₄And R₆Is halogen; r₅And R₇Is halogen; r₄Is halogen and_R7is C_1-3An alkylcarbonyl group; and R₄Is hydroxy with R₅Is C_1-3Available disubstituted phenols1-route-4The reaction with 3-bromopropyne is carried out in the presence of a base, such as K in acetone₂CO₃Or NaH in DMF, leading to nucleophilic substitution of the halide to the ether2-route-4The ring closure can be accomplished by heating the ether in N, N-dimethylaniline or polyethylene glycol, which produces benzopyran3-route-4.

Route 5

NaBH₄EtOH; (b) refluxing the p-toluenesulfonic acid and the toluene;

scheme 5 describes the preparation of benzopyrans useful as starting materials for scheme 3 from appropriately substituted chroman-4-ones,suitably substituted chroman-4-ones can be prepared from readily commercially available chroman-4-ones, e.g. wherein R is₄To R₇In one position by halogen or C_1-3Alkoxy substitution, conversion of chroman-4-ones1 a-route-5And converted to the corresponding alcohol by a suitable reducing agent, such as sodium borohydride in ethanol, to give2-route-5Refluxing the alcohol with a small amount of acid, such as p-TsOH in toluene, allows2-route-5Dehydration to form the desired benzopyran1-route-3Corresponding 2H-1-thiochroman can be readily prepared from commercially available (substituted) thiochroman-4-ones, for example, by reaction of the (substituted) thiochroman-4-ones with a reducing agent, such as a metal hydride, e.g., lithium aluminum hydride, in an organic solvent such as diethyl ether, followed by dehydration, such as reflux with an acid, e.g., tartaric acid, sulfate, and the like.

Route 6

(a) Allyl bromide, K₂CO₃Acetone; (b) ph₃PCH₃Br，NaH，THF；(c)Cl₂[Pcy₃]₂Ru＝CHPh，CH₂Cl₂；(d)Ph₃PCH＝CH₂Br，DBU

Benzopyrans used as starting materials in scheme 3 are prepared from substituted o-hydroxybenzaldehydes using the procedure described in scheme 6.1-route-6K with allyl bromide in a base, such as in acetone₂CO₃-reaction in the presence of a catalyst resulting in nucleophilic substitution of the halide to give the ether2-route-6Witting reaction converts aldehyde groups to olefins to give3-route-6In step (c), the terminal double bond can undergo intramolecular metathesis by treatment with a catalyst, such as a ruthenium complex Grubb's catalyst or,1-route-6As can be seen in the above figureDirect cyclization in step d).

Route 7

(a)Pd(0)，DPPP，Et₃N，(CH₃)₃SiC ═ CH; (b) pd (0), butyl vinyl ether, DMF; (c) pd (0), Zn (CN)₂，DMF；(d)NaOH，H₂O，MeOH

Pd (0) -catalyzed triflates1-route-7Resulting in the replacement of the trifluoromethanesulfonyloxy group and is present at R₆Thus, scheme 7 provides a method for the preparation of the synthetic intermediates used in scheme 3 to give ureas or thioureas5-route-3In which R is₆Is cyano, ethynyl, or C_1-3An alkylcarbonyl group.

Route 8

(a)BuLi/ZnCl₂，THF；Pd(OAc)₂，BrCH＝CHCOOEt；DIBAL

(b)TsNHN＝CHCOCI；PhNMe₂，NEt₃，CH₂Cl₂

(c)Rh₂(5-R-MEPY)₄Completely degassed methylene chloride

(d)30％HBr，AcOH

(e)NaOH，H₂O

(f)NaOH；CO₂；1-Prl/DMSO

(g)IPrOH，HCI；DEAD，PPh₃，THF

(h)NaOH，MeOH：H₂O

(i)1.BBr₃，CH₂Cl₂2.CH₃CN3.NaOH, Water

(i)1.BuLi/ZnCl₂THF; pd (OAc)2.cpd9-Scheme-83.Jones reagent (chromic acid, sulfuric acid in acetone)

Scheme 8 describes the preparation of compounds wherein X is-CH₂Suitable routes to compounds of the formula-O-, in which Ra and Rb are optional substituents R₄-R₇Optionally substituted phenols having hydroxy groups protected by protecting groups such as methyl, MOM and the like1-route-8With a base such as BuLi in a solvent such as THF, converted to the zinc salt by addition of zinc chloride or the like₂Etc. are added with the activated acrylate, such as a lower alkyl cis-3-haloacrylate, e.g., BrCH ═ CHCOOEt, etc. the reaction mixture is cooled, a reducing agent, such as DIBAL, etc., is added in portions and the reaction is quenched to give2-route-8Hydrazones, p-toluenesulfonylhydrazones such as glyoxylic acid chloride, and the like, and bases such as N, N-xylidine, and the like are added to a solvent such as CH₂Cl₂Etc., and then another base, such as Et, is added₃N, etc. to obtain3-route-8The reaction product is dissolved in a solvent such as dichloromethane, which is preferably degassed₂(5-R-MEPy)₄(U.S. Pat. No.5,175,311, available from Aldrich or Johnson Matthey) and the like: obtained in high enantiomeric excess4-route-8Such as greater than 80% ee, preferably greater than 90% ee. preferably the compound is first contacted with BBr₃Reaction in dichloromethane: then adding acetonitrile into the reaction mixture, and finally adding sodium hydroxide to obtain6-route-8Alternatively, the product is treated with an electrophile, preferably HBr or the like, in combination with an acid such as AcOH (R) ((R))4-route-8) Under acid condition, self-generated ring closure is carried out to form benzopyrone5-route-8When treated under alkaline conditions such as NaOH, benzoReforming pyrones to benzopyran cyclopropyl carboxylic acids6-route-8Or, alternatively,4-route-8For example, when the protecting group of the phenol is MOM, the lactone can be opened by treatment with basic conditions such as NaOH, carbon dioxide, and lower alkyl halides such as iPrI in a solvent such as DMSO to give the alkyl ester7-route-8Replacement of the hydroxyl protecting group and ring closure with the free hydroxymethyl moiety is performed under acidic conditions, such as iPrOH/HCl, etc., followed by reaction with DEAD; PPH3 treatment in an organic solvent such as THF1-route-8Reacted with BuLi to convert to zinc salt, the salt with cyclopropyl iodide9-route-8Reaction in a palladium-catalyzed reaction: reacting with Jone's reagent to obtain the compound4-route-8The carboxylic acid is then converted to an isocyanate and subsequently a heteroaryl urea or heteroaryl thiourea of formula I is formed, as shown in scheme 1.

A preferred group of intermediates includes compounds of formula II:

wherein X and R₄-R₇As defined above, R₁₁is-C (O) OR₁₂Wherein R is₁₂Is H or a carboxyl protecting group, such as a lower alkyl ester; -NCO, -NCS or amines, e.g. NH₂Preferred compounds of formula II have formula III:

wherein R is₄And R₇Independently halogen, most preferably fluorine, R₁₁is-COOH, a lower alkyl ester thereof, isocyanate, isothiocyanate or amino.

Another group of preferred intermediates include compounds of formula IV:

wherein R is₄To R₇PG is a hydroxy protecting group, PG^·Is a hydroxyl protecting group or forms a ketone functional group together with an adjacent O.

Preferred compounds of formula IV are compounds of formula V:

wherein R is₄And R₇Independently halogen, most preferably fluorine; PG is lower alkyl, such as isopropyl, ethyl, most preferably methyl; PG (Picture experts group)^·Is lower alkyl, such as isopropyl, ethyl, most preferably methyl, or forms a keto group with an adjacent O.

Another group of preferred intermediates include compounds of formula VI:

wherein R is₄-R₇PG is a hydroxy protecting group, R is as defined above₁₃Is H, an ester thereof or a hydroxy protecting group preferred compounds in formula VI are compounds of formula VII:

wherein R is₄And R₇Independently isHalogen, preferably fluorine, PG is lower alkyl, such as isopropyl, ethyl, most preferably methyl, R₁₂Is H or-C (═ O) CH ═ N.

Preferred compounds of formula I include:

cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1 yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] naphthalen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c 1-1-yl) -urea,

Cis-1- (6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (5-cyanopyridin-2-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-bromopyridin-2-yl) -3- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1 yl) -3- (5-cyanopyridin-2-yl) -urea,

Cis-1- (5-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1 yl) -3- (5-cyanopyridin-2-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (N-acetyl-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] quinolin-1-yl) -urea,

Cis-1- (5-cyano-3-methyl-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

Cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (5-ethynyl-pyridin-2-yl) -urea,

Cis-1- (5-bromopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (5-phenoxypyridin-2-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -thiourea,

1- (6-chloro-5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

1- (5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (5-cyanopyridin-2-yl) -urea,

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyanopyridin-2-yl) -urea,

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 6 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (5-cyanopyridin-2-yl) -urea,

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyanopyridin-2-yl) -urea,

Cis-1- (5-cyanopyridin-2-yl) -3- (6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

cis-N- [1a, 6 b-dihydro-1H-benzo [ b ] cyclopropa [ d ] thiophen-1-yl ] -N' - (5-cyano-2-pyridinyl) -urea,

N- [ (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] - [1] benzothiopyran-1-yl ] -N' - (5-cyano-2-pyridyl) urea,

cis-N- (5-bromo-2-pyridyl) -N' - (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -N' - (5-chloro-2-pyridyl) urea,

cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -N' - (5-cyano-2-pyridyl) urea,

cis-N- (5-phenoxy-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

cis-N- (5-bromo-2-pyridinyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

cis-N- (5-chloro-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

cis-N- (5-cyano-2-pyridyl) -N' - (4, 7 dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N, - (5-fluoro-2-pyridyl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-diiodo-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (5-iodo-2-pyridinyl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-diiodo-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (3-isoxazolyl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - [4- (4-chlorophenyl) -1, 3-thiazol-2-yl ] urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (6-fluoro-1, 3-benzothiazol-2-yl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (4-pyrimidinyl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (2-pyrazinyl) urea,

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] -N' - (5-cyclopropyl-1H-pyrazol-3-yl) urea,

and pharmaceutically acceptable salts thereof, especially enantiomerically enriched, for example greater than 80% by weight, preferably greater than 90% by weight, such as > 97% ee, or pure preparations comprising the (-) enantiomer.

Thus, particularly preferred compounds include

(-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

(-) cis-1- (5-chloropyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea, or

(-) cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -thiourea,

(-) cis-1- (5-fluoropyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea,

(-) cis-1- (5-fluoropyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -thiourea,

and pharmaceutically acceptable salts thereof.

Although it is possible to administer the active agent alone, it is presently preferred that it form part of a pharmaceutical formulation.

Formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is one for oral administration.

If the manufacture of a pharmaceutical formulation involves intimately mixing pharmaceutical excipients and the active ingredient in salt form, it is often preferred to use non-basic excipients, i.e., acidic or neutral excipients; as a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; and as pills, etc.

For oral compositions (e.g., tablets and capsules), the term "suitable carrier" includes excipients such as conventional excipients, for example, binding agents, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and stearates of other metals, stearic acid, glyceryl stearate, silicone oil, talc, waxes, oils and colloidal silica, flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, and the like, may also be used. And may be formulated to provide sustained or controlled release of the active agent.

Other formulations suitable for oral administration include lozenges comprising the post-active agent in a flavoured base, usually sucrose and acacia or tragacanth; soft key agents, including active agents in an inert matrix such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

Detailed Description

Various aspects of the invention will now be described in more detail with reference to the following non-limiting examples.

Example 1

(±) cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -ureas

a) +/-cis-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

To 20 ℃ 2H-benzopyran (4.89g, 37mmol) and (CuOTf)₂-a mixture of benzene (186 mg, 0.37mmol) in 1, 2-dichloroethane (80ml) was added dropwise (3 hours) a solution of ethyl diazoacetate (8.44g, 74mmol) in 1, 2-dichloroethane (20ml) after 15 minutes at 20 ℃ with H₂O (100ml) Wash the reaction mixture H₂CH for O phase₂Cl₂(50mL) washing, combining the organic phases and removing the solvent under reduced pressure the crude product is subjected to column chromatography (silica gel, 20 → 50% EtOAc in hexane) to afford 1.96g (24%) of + -cis-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-carboxylic acid ethyl ester and 3.87g (48%) of ± -trans-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-carboxylic acid ethyl ester by-product.

¹H-NMR(CDCl₃)：7.26(d，1H)，7.10(dd，1H)，6.90(dd，1H)，6.78(d，1H)，4.49(dd，1H)，4.20(dd，1H)，3.97(q，2H)，2.44(dd，1H)，2.14(dd，1H)，2.07-1.95(m，1H)，1.02(t，3H).

b) (±) cis-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

(±) -cis-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]1.96g of benzopyran-1-carboxylic acid ethyl ester (9.0 mmol),LiOH (539 mg, 22.5mmol), H₂A mixture of O (10ml) and MeOH (20ml) was heated at reflux for 2h, the reaction mixture was concentrated to about 10ml, 4N HCl was added dropwise to give a white precipitate, the reaction mixture was taken up in CH₂Cl₂(3X 15mL), the organic phases were combined and the solvent was removed under reduced pressure the crude product was crystallized from EtOAc/hexane to give 435 mg (25%) of (. + -.) -cis-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-carboxylic acid white solid.

¹H-NMR(CDCl₃)：9.80(br s，1H)，7.22(d，1H)，7.10(dd，1H)，6.89(dd，1H)，6.77(d，1H)，4.45(dd，1H)，4.22(dd，1H)，2.45(dd，1H)，2.14-1.98(m，2H).

c) (±) cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea.

To (±) -cis-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c-]Diphenylphosphoryl azide (413mg, 1.5mmol) was added to a solution of benzopyran-1-carboxylic acid (285mg, 1.5mmol) and triethylamine (209. mu.l, 1.5mmol) in toluene (1.5ml) at 20 ℃ after 30 minutes the reaction mixture was heated to 120 ℃ for 15 minutes, after which a solution of 2-amino-5-cyanopyridine (197mg, 1.65mmol) in DMF (1ml) was added after 3 hours at 120 ℃ the reaction mixture was cooled to room temperature the reaction mixture was concentrated under reduced pressure, benzene (20ml) was added and 1NHCl (30ml), H₂O (30ml) and brine (30ml) the reaction mixture was washed, the solvent of the organic phase was removed under reduced pressure, the crude product was separated from EtOH/CH₂Cl₂Crystallization gave 133mg (29%) of (. + -.) -cis-1- (5-cyanopyridin-2-pyridyl) -3- (1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-yl) -urea.

¹H-NMR(DMSO-d₆)：9，78(s，1H)，8.31(d，1H)，7.99(dd，1H)，7.83(d，1H)，7.43(d，1H)，7.27(d，1H)，7.09(dd，1H)，6.89(dd，1H)，6.80(d，1H)，4.25(dd，1H)，4.14(dd，1H)，3.43(m，1H)，2.35(dd，1H)，1.92(m，1H).

Example 2

(±) cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a]Naphthalen-1-yl) -ureas

a) (±) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropa [ a ] naphthalene-1-carboxylic acid ethyl ester

(. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxetano [ a ] naphthalene-1-carboxylic acid ethyl ester synthesized in analogy to example 1a from 1H-isochroman (3.57g, 27mmol) to yield 910mg (15%) of (+) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxetano [ a ] naphthalene-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：7.34(d，1H)，7.25(dd，1H)，7.18(dd，1H)，7.03(d，1H)，4.81(d，1H)，4.51(d，1H)，4.28(dd，1H)，3.95(q，2H)，2.43(dd，1H)，2.05(dd，1H)，1.04(t，3H).

b) (±) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropa [ mono ] naphthalene-1-carboxylic acid

(±) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropa [ a]Naphthalene-1-carboxylic acid was prepared analogously to example 1b from (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropan [ a]Ethyl naphthalene-1-carboxylate (436mg, 2mmol) was synthesized to give 86mg (22%) of (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxetano [ a 1-naphthalene-1-carboxylate as a white solid and the crude product was subjected to column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂In (1).

¹H-NMR(CDCl₃)：8.50(br s，1H)，7.39(d，1H)，7.30(dd，1H)，7.21(dd，1H)，7.07(d，1H)，4.87(d，1H)，4.57(d，1H)，4.38(dd，1H)，2.59(dd，1H)，2.15(dd，1H).

c) (±) cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropa [ a ] naphthalen-1-yl) -urea

(±) -cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropa [ a]Naphthalen-1-yl) -urea from (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropane [ a ] in analogy to example 1c]Naphthalene-1-carboxylic acid (86mg, 0.45mmol) Synthesis the crude product was subjected to column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂To (b) gave 21mg (15%) of (. + -.) -cis-1- (5-cyanopyridin-2-yl) -3- (1, 1a, 3, 7 b-tetrahydro-2-oxacyclopropane [ a)]Naphthalen-1-yl) -urea.

¹H-NMR(DMSO-d₆)：9.62(s，1H)，8.29(d，1H)，7.98(dd，1H)，7.52-7.44(m，2H)，7.27-7.05(m，4H)，4.69(d，1H)，4.45(d，1H)，4.05(dd，1H)，3.25-3.10(m，1H)，2.22(dd，1H).

Example 3

(±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -ureas

a)1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -propan-1-one

2 ', 4' -dihydroxy-phenylethylketone (24.9g, 0.15 mole), 3-bromopropyne (24.2g, 0.20 mole) and K₂CO₃(20.7g, 0.15mol) in acetone (500ml) under reflux for 12H, the reaction mixture was cooled to room temperature, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, the crude product was purified by column chromatography (silica gel, 0 → 2% MeOH in H)₂O) to yield 26.2g (85%) of 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -prop-1-one.

¹H-NMR(CDCl₃)：12.80(s，1H)，7.69(d，1H)，6.52(m，2H)，4.72(d，2H)，2.96(q，2H)，2.56(t，1H)，1.23(t，3H).

3b)1- (5-hydroxy-2H-benzopyran-6-yl) -propan-1-one

A mixture of 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -propan-1-one (19.8g, 97mmol) and N, N-diethylaniline (100ml) was heated at reflux for 3H, the reaction mixture was concentrated under reduced pressure, the crude product was purified by column chromatography (silica gel, 5 → 10% EtOAc in hexane) and then recrystallized from EtOAc/hexane to give 8.91g (45%) of 1- (5-hydroxy-2H-benzopyran-6-yl) -propan-1-one.

¹H-NMR(CDCl₃)：13.00(s，1H)，7.49(d，1H)，6.75(dt，1H)，6.27(d，1H)，5.67(dt，1H)，4.86(dd，2H)，2.90(q，2H)，1.19(t，3H).

3c) 7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

To 1- (5-hydroxy-2H-benzeneAnd pyran-6-yl) -propan-1-one (511mg, 2.5mmol) and (Rh (II) Ac₂)₂(11mg, 0.025mmol) in a mixture of 1, 2-dichloroethane (8ml) at 20 ℃ A solution of ethyl diazoacetate (571mg, 5mmol) in 1, 2-dichloroethane (2ml) was added dropwise (3H) after 15 minutes at 20 ℃ with H₂O (10ml) Wash the reaction mixture H₂CH for O phase₂Cl₂(10mL), the organic phases are combined and the solvent is removed under reduced pressure and the crude product is purified by column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂In (b)) to yield 300mg (41%) of 7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-carboxylic acid ethyl ester (33/64 cis-trans isomer mixture).

¹H-NMR(CDCl₃)：13，13-13.07(m，1H)，7.57-7.49(m，1H)，6.41-6.38(m，1H)，4.65-3.92(m，4H)，3.01-1.95(m，5H)，1.29-1.08(m，6H).

3d) (±) -cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

+/-cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]Benzopyran-1-carboxylic acid starting from 7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] in analogy to example 2b]Synthesis of ethyl benzopyran-1-carboxylate (299mg, 1.03mmo1, 33/64 cis-trans isomer mixture) to yield 39.3mg (15%) of (. + -.) -cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] c]Benzopyran-1-carboxylic acid white solid and (+ -) -trans-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]The crude product was purified by column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂In (1).

¹H-NMR(DMSO-d₆)：7.67(d，1H)，6.35(d，1H)，4.57(dd，1H)，4.36(dd，1H)，2.98(q，2H)，2.55-2.46(m，1H)，2.18-2.00(m，2H)，1.10(t，3H).

3e) (±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] chromen-1-yl) -Urea

(±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -urea from + -cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] in analogy to example 1c]Synthesis of benzopyran-1-carboxylic acid (39.3mg, 0.15 mmol.) the crude product was purified by HPLC (C)₁₈In H₂5 → 95% Ether in O) to give 2.9mg (5.1%) (+ -) -cis-1- (5-cyanopyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] (5.1%)]Benzopyran-1-yl) -urea.

¹H-NMR(DMSO-d₆)：13.15(s，1H)，9.71(s，1H)，8.30(d，1H)，8.01(dd，1H)，7.73(d，1H)，7.57(d，1H)，7，50(d，1H)，6.43(d，1H)，4.42(dd，1H)，4，13(dd，1H)，3.45-3.32(m，1H)，3.01(q，2H)，2.49-2.42(m，1H)，1.97-1.86(m，1H)，1.12(t，3H).

Example 4

+/-cis-1- (6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [0159 ]]Benzopyran-1-yl) -3- (5-cyanopyridin-2-yl) -urea

4a)1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone

1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone was synthesized in analogy to example 3a from 1- (2, 4-dihydroxy-phenyl) -ethanone (20g, 131mmol) to yield 22g (88%) of 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone.

¹H-NMR(CDCl₃)：12.70(s，1H)，7.66(d，1H)，6，52(m，2H)，4.72(d，2H)，2.58-2.55(m，4H).

4b)1- (5-hydroxy-2H-benzopyran-6-yl) -ethanone

1- (5-hydroxy-2H-benzopyran-6-yl) -ethanone was synthesized in analogy to example 3b from 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone (17g, 89mmol) to yield 6.0g (35%) of 1- (5-hydroxy-2H-benzopyran-6-yl) -ethanone.

¹H-NMR(CDCl₃)：12，92(s，1H)，7.51(d，1H)，6.79(dt，1H)，6.32(d，1H)，5.71(dt，1H)，4.89(dd，2H)，2.55(s，3H).

4c) 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester (40/60 cis-trans isomer mixture) was synthesized in analogy to example 3c from 1- (5-hydroxy-2H-benzopyran-6-yl) -ethanone.

¹H-NMR(CDCl₃)：13.05-12.97(m，1H)，7.54-7.47(m，1H)，6，43-6.33(m，1H)，4.63-3.94(m，4H)，3.02-1.96(m，6H)，1.31-1.08(m，3H).

4d) 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-carboxylic acid starting from 6-acetyl-7-hydroxy 1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] in analogy to example 1b]Synthesis of ethyl benzopyran-1-carboxylate (2g, 8.1mmol, 40/60 cis-trans isomer mixture) to give 300mg (17%) of 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-carboxylic acid (40/60 cis-trans isomer mixture). The crude product was purified by column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂In (1).

¹H-NMR(CDCl₃)：7.55-7.45(m，1H)，6.45-6.30(m，1H)，4.65-4.00(m，2H)，3.05-1.95(m，6H).

4e) (±) -cis-1- (6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-yl) -3- (5-cyanopyridin-2-yl) -urea

(±) -cis-1- (6-acetyl-1-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -3- (5-cyanopyridin-2-yl) -urea from 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] in analogy to example 1c]Synthesis of benzopyran-1-carboxylic acid (300mg, 1.21mmol, 40/60 cis-trans isomer mixture) the crude product was purified by HPLC (C)₁₈5 → 95% of the Yifu organs, in H₂O) to yield 7.7mg (17%) of (. + -.) -cis-1- (6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -3- (5-cyanopyridin-2-yl) -urea and 9.0mg (20%) of (. + -.) -trans-1- (6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl) -3- (5-cyanopyranPyridin-2-yl) -urea by-product.

¹H-NMR(CDCl₃+CD₃OD)：7.98(d，1H)，7.74(dd，1H)，7.60(d，1H)，7.01(d，1H)，6.40(d，1H)，4.43(dd，1H)，4.29(dd，1H)，3.57(dd，1H)，2.69(m，1H)，2.61(s，3H)，2.00-1.86(m，1H).

Example 5

(±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -ureas

5a)1- (4-fluoro-2-prop-2-ynyloxy-phenyl) -prop-1-one

To a mixture of NaH (95%, 278mg, 11mmol) in OC in DMF (20ml) was added 1- (4-fluoro-2-hydroxyphenyl) -propan-1-one (1.68g, 10mmol) in DMF (5 ml.) after 15 minutes at 0 deg.C 3-bromopropyne (3.02g, 20mmol) was added as the reaction mixture after 1 hour at 0 deg.C the reaction mixture was cooled to room temperature the reaction mixture was quenched with H₂O (100ml) extraction H₂Et for O phase₂O (3X 100mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, CH)₂Cl₂) 1.40g (68%) of 1- (4-fluoro-2-prop-2-ynyloxy-phenyl) -prop-1-one are obtained.

¹H-NMR(CDCl₃)：7.64(dd，1H)，6.69(dd，1H)，6.60(ddd，1H)，4.68(d，2H)，2.85(q，2H)，2.58(t，1H)，1.03(t，3H).

5b)1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one

1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one was synthesized in analogy to example 3b from 1- (4-fluoro-2-propan-2-alkynyloxy-phenyl) -propan-1-one (1.34g, 6.5mmol) to give 619mg (46%) of 1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one.

¹H-NMR(CDCl₃)：7，60(dd，1H)，6.67-6.58.(m，2H)，5，86(dt，1H)，4.76(dd，2H)，2.93(q，2H)，1.23(t，8H).

5c) (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid ethyl ester

(±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid Ethyl ester according to 3c) starting from 1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one (619mg, 3mmol) to yield 142mg (16%) of ethyl (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylate and ethyl (±) -trans-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylate as by-products.

¹H-NMR(DDCl₃)：7.59(dd，1H)，6.65(m，1H)，4.50-4.46(m，2H)，3.95(q，2H)；2.89(q，2H)，2.57(dd，1H)，2.20(dd，1H)，1.13-1.03(m，1H)，1.12-1.01(m，6H).

5d) (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

(+) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]Benzopyran-1-carboxylic acid was prepared analogously to example 1b from (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Synthesis of ethyl benzopyran-1-carboxylate (140.3mg, 0.48mmol) to give 83mg (65%) of (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzenephan-1-carboxylic acid white solid the crude product was purified by column chromatography (silica gel, 1 → 5% MeOH in CH)₂Cl₂In (1).

¹H-NMR(DMSO-d₆)：12.15(brs，1H)，7.46(dd，1H)，6.78(dd，1H)，4.57(dd，1H)，4.43(dd，1H)，2.93-2.80(m，2H)，2.55(dd，1H)，2.24(dd，1H)，2.20-2.10(m，1H)，1.02(t，3H).

5e) (±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

(±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -urea analogously to example 1c from (. + -.) cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c-]Synthesis of benzopyran-1-carboxylic acid (81.9mg, 0.31 mmol.) the crude product was purified by HPLC (C)₁₈In H₂5 → 95% acetonitrile in O) to yield 12mg (10%) of (. + -.) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -urea.

¹H-NMR(DMSO-d₆)：9.81(s，1H)，8.33(d，1H)，8.04(dd，1H)，7，83(br s，1H)，7.49-7.40(m，2H)，6.89(dd，1H)，4.41(dd，1H)，4.34(dd，1H)，3.46-3.38(m，1H)，2.76(q，2H)，2.56-2.46(m，1H)，2.09-1.98(m，1H)，0.93(t，3H).

Example 6

(±) -cis-1 (5-cyanopyridin-2-yl) -3- (7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Benzopyran-1-yl) -ureas

6a) 6-fluoro-2-hydroxy-3-methoxybenzaldehyde.

1M boron trichloride in dichloromethane (25 ml; 25mmol) was added to 6-fluoro-2, 3-dimethoxybenzaldehyde [ Cantrell, Amandeda S.; engelhardt, Per; hoegberg, Marita; jaskunas, s.richard; johansson, Nils Gunnar; et al.; med, chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23mmol) in dichloromethane (30ml) at-70 ℃ the reaction mixture is stirred at room temperature overnight and then hydrolyzed with water the organic phase is separated, washed with water and then evaporated in vacuo the residue is chromatographed (silica gel, EA: Hex 5: 1) to yield 3.72g (94%) of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde as yellow crystals.

¹H-NMR(CDCl₃)：11.61(s，1H)，10.23(s，1H)，7.02(dd，1H)，6.55(app.t，1H)，3.87(s，3H).

6b) 5-fluoro-8-methoxy-2H-benzopyran

6-fluoro-2-hydroxy-3-methoxybenzaldehyde (3.32g, 19mmol) was dissolved in acetonitrile (20ml), DBU (2.97ml, 19mmol) was added, vinyltriphenylphosphine bromide (7.2g, 19mmol) was added and the reaction mixture was heated at reflux for 48H, diluted with water, extracted with ether (3X 50ml), the organic phase was washed with water, 10% sodium hydroxide, water and brine, then evaporated in vacuo and the residue was column chromatographed (silica gel, EA: Hex, 1:20) to give 1.2g of 5-fluoro-8-methoxy-2H-benzopyran (34%).

¹H-NMR(CDCl₃)：6.65(m，2H)，6.54(t，1H)，5.83(dt，1H)，4.88(dd，2H)，3.83(s，3H).

6c) (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-Tetrahydrocyclopropano [ c ] benzopyran-1-carboxylic acid ethyl ester

The title compound was synthesized in analogy to example 3c from 5-fluoro-8-methoxy-2H-benzopyran.

¹H-NMR(CDCl₃)：6.7-6.5(m，2H)，4.48(m，2H)，3.99(m，2H)，3.80(s，3H)，2.57(app.t，1H)，2.20(app.t，1H)，2，05(m，1H)，1.08(t，3H)。

6d) (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

The title compound was synthesized in analogy to example 1b from (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：6.7-6.5(m，2H)，4.48(m，2H)，3.80(s，3H)，2.61(app.t，1H)，2.17(app.t，1H)，2.06(m，1H).

6e) (±) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

The title compound was synthesized in analogy to example 1c from (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (62mg, 0.17 mmol.) to yield 38mg (40%).

¹H-NMR(CDCl₃)：10.06(br.s，1H)，9.40(br.d，1H)，8.11(d，1H)，7.70(dd，1H)，6.91(d，1H)，6.68(m，2H)，4.48(dd，1H)，4.28(dd，1H)，3.90-3.72(m，4H)，2.64(app.T，1H)，1.96(m，1H).

Example 7

(±) -cis-1 (5-cyanopyridin-2-yl) -3- (7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c)]Benzopyran-1-yl) -ureas

7a) 1-chloro-4-fluoro-2-prop-2-ynyloxy-benzene

The title compound was synthesized in analogy to example 15a) from 2-chloro-5-fluorophenol (2.5 g.) yield 2.8g (90%).

¹H-NMR(CDCl₃)：7.32(dd，1H)，6.85(dd，1H)，6.68(m，1H)，4.77(d，2H)，2.58(t，1H).

7b) 5-fluoro-8-chloro-2H-benzopyran

The title compound was synthesized in analogy to example 15b) from 1-chloro-4-fluoro-2-prop-2-ynyloxy-benzene (2.8 g.) yield 0.97g (35%).

¹H-NMR(CDCl₃)：7.09(dd，1H)，6.63(dt，1H)，6.56(t，1H)，5.84(dt，1H)，4.95(dd，2H).

7c) (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid ethyl ester

The title compound was synthesized in analogy to example 15c) from 5-fluoro-8-chloro-2H-benzopyran.

¹H-NMR(CDCl₃)：7.14(dd，1H)，6.60(t，1H)，4.51(m，2H)，4.01(m，2H)，2.60(app.t，1H)，2.23(t，1H)，2.09(m，1H)，1.08(t，3H).

7d) (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

The title compound was synthesized in analogy to example 15d from (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester (850 mg.) yield 43mg (96%).

¹H-NMR(CDCl₃)：8.86(br.s，1H)，7.13(dd，1H)，6.59(t，1H)，4.50(m，2H)，2.63(t，1H)，2.23-2.05(m，2H).

7e) (±) -cis-1 (5-cyanopyridin-2-yl) -3- (7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

The title compound was synthesized in analogy to example 1c from (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (63 mg.) yield 52mg (56%).

¹H-NMR(CDCl₃)：9.79(br.s，1H)，9.34(br.s，1H)，8.22(d，1H)，7.72(dd，1H)，7.17(dd，1H)，6.87(d，1H)，6.67(t，1H)，4.54(dd，1H)，4.33(dd，1H)，3.84(app.q，1H)，2.68(dd，1H)，2.00(m，1H).

Example 8

(±) -cis-1 (5-cyanopyridin-2-yl) -3- (4-chloro-7-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c)]Benzopyran-1-yl) -ureas

+/-cis-1- (5-chloropyridin-2-yl) -3- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -urea (15mg, 24%) was prepared from +/-cis- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen) -1-carboxylic acid (40mg, 0.16mmol) and 2-amino-5-chloropyridine (76mg, 0.57mmol) according to the method described in example 1 c.

¹H NMR(400MHz，CDCl₃)δppm：9.29(brs，1H)，9.26(brs 1H)，7.84(d，1H)，7.47(dd，1H)，7.16(dd，1H)，6.76(d，1H)，6.67(dd，1H)，4.65(dd，1H)，4.34(dd，1H)，3.82(dd，1H)，2.62(dd，1H)，1.96(m，1H)

Example 9

(±) -cis-1 (5-bromopyridin-2-yl) -3- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c)]Benzopyran-1-yl) -urea.

+/-cis-1- (5-bromopyridin-2-yl) -3- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -urea (13mg, 19%) was prepared from +/-cis- (4-chloro-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen) -1-carboxylic acid (40mg, 0.16mmol) and 2-amino-5-bromopyridine (99mg, 0.57mmol) according to the method described for example 1 c.

¹H NMR(400MHz，CDCl₃)δppm：9.27(brs，1H)，9.02(brs，1H)，7.95(d，1H)，7.60(dd，1H)，7.16(dd，1H)，6.70(d，1H)，6.67(dd，1H)，4.50(dd，1H)，4.35.(dd，1H)，3.81(dd，1H)，2.63(dd，1H)，1.97(m，1H)

Example 10

(±) cis-1- (5-cyanopyridin-2-yl) -3- (5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -ureas

10a) 4-formyl 3-hydroxyphenyl trifluoromethanesulfonate.

A solution of trifluoromethanesulfonic anhydride (1.77ml, 10.5mmol) in dichloromethane (10ml) was added to a mixture of 2, 4-dihydroxybenzaldehyde (1.38g, 10mmol) and pyridine (0.85ml, 10.5mmol) in dichloromethane (30ml) at-70 deg.C, the dry ice bath was removed, the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, washed with water, brine, and then evaporated in vacuo, and the crude product was purified by column chromatography (silica gel, EA: Hex, 1:6) to give 1.55g of 4-formyl-3-hydroxyphenyl trifluoromethanesulfonate (57%).

¹H-NMR(CDCl₃)：11.28(s，1H)，9.93(s，1H)，7.67(d，1H)，6.95(m，2H).

10b) 3-allyloxy-4-formylphenyl trifluoromethanesulfonate

Potassium carbonate (1.6g, 11.5mmol) and allyl bromide (1ml, 11.5mmol) were added to a solution of 4-formyl-3-hydroxyphenyl trifluoromethanesulfonate (1.55g, 5.7mmol) in acetone (50 ml.) the reaction mixture was stirred at 55 ℃ for 2 hours, filtered and then evaporated in vacuo and the residue was chromatographed (silica gel, EA: Hex, 1:20) to give 1.3g (73%) of 3-allyloxy-4-formylphenyl trifluoromethanesulfonate.

¹H-NMR(CDCl₃)：10.47(s，1H)，7.93(d，1H)，6.95(d，1H)，6.90(s，1H)，6.05(m，1H)，5.47(d，1H)，5.40(d，1H)，4.69(d，2H).

10c) 3-allyloxy-4-vinylphenyl trifluoromethanesulfonate

Methyltriphenylbromide (1.95g, 5.45mmol) was added to a suspension of sodium hydride (60% in oil) (0.25g, 6.3mmol) in THF (35ml) at 0 ℃ and then stirred at room temperature for 30 minutes to the above solution was added a solution of 3-allyloxy-4-formylphenyl trifluoromethanesulfonate (1.3g, 4.2mmol) in THF (15ml), the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was diluted with hexane, extracted with water, the organic phase was washed with brine and then evaporated, and 3-allyloxy-4-vinylbenzene trifluoromethanesulfonate (0.68g, 53%) was extracted by silica gel column chromatography (EA: Hex, 1: 20).

¹H-NMR(CDCl₃)：7，51(d，1H)，7.02(dd，1H)，6.85(dd，1H)，6.77(d，1H)，6.05(m，1H)，5.76(dd，1H)，5.43(m，1H)，5.32(m，2H)，4.58(dt，2H).

10d) Trifluoromethanesulfonic acid 2H-benzopyran-7-yl ester

To a solution of 3-allyloxy-4-vinylphenyl trifluoromethanesulfonate (0.68g, 2.2mmol) in dichloromethane (5ml) was added a Ru-catalyst (Grubb's catalyst) (36mg, 2 mol%), and the reaction mixture was stirred at room temperature for 2 hours after completion of the reaction (GC), the reaction mixture was used for the next step without further treatment after removal of the solvent, and an analytical sample was obtained by silica gel column chromatography (EA: Hex, 1: 20).

¹H-NMR(CDCl₃)：6.97(d，1H)，6.76(dd，1H)，6.68(d，1H)，6.39(dt，1H)，5.81(dt，1H)，4.98(dd，2H).

10e) +/-cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

Rh(OAc)₂(19mg, 2 mol%) was added to the above solution (10d) and a solution of EDA (0.44ml, 4.4mmol) in 1ml of dichloromethane was added with a syringe pump over 5 hours at room temperature, when the reaction was complete (GC), dichloromethane was evaporated, the residue was dissolved in ethyl acetate, washed with saturated ammonium chloride solution and brine, the organic phase was evaporated and the mixture of cis-and trans-isomers (1:1.3) was separated by column chromatography (silica gel, EA: Hex, 1:6) to give 0.4g (50%) of. + -. cis-5-trifluoromethanesulfonyloxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ], +/-cis-5-trifluoromethanesulfonyloxy-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] (50%)]Benzopyran-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：7.29(d，1H)，6.82(dd，1H)，6.73(d，1H)，4.51(dd，1H)，4.29(dd，1H)，3.98(m，2H)，2.45(t，1H)，2.19(t，1H)，2.05(m1，1H)，1.03(t，3H).

10f) +/-cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

+/-cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]Benzopyran-1-carboxylic acid ethyl ester (154mg, 0.42mmol), Pd (OAc)₂(9mg, 10 mol%) and PPh₃(44mg, 40 mol%) was mixed in D (4m1) and a gentle stream of nitrogen was passed through the reaction mixture for 10 minutes Zn (CN) was added₂(74mg, 0.63mmol), vial sealed, reaction mixture stirred at 120 ℃ overnight the reaction mixture was diluted with ethyl acetate, extracted with saturated ammonium chloride the organic phase evaporated and the residue chromatographed (silica gel, EA: Hex1:5) to give 53mg (52%) of + -cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] c]Benzopyran-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：7.33(d，1H)，7.19(dd，1H)，7.05(d，1H)，4.50(dd，1H)，4.25(dd，1H)，3.99(q，2H)，2.46(t，1H)，2.25(t，1H)，2.11(m，1H)，1.06(t，3H).

10g) +/-cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

Ethyl + -cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate (53mg, 0.22mmol) and NaOH (35mg, 0.88mmol) are dissolved in a mixture (5ml) of methanol and water (1: 1). the reaction mixture is stirred at 60 ℃ for 30 minutes, methanol is evaporated in vacuo, 20ml water are added, the resulting solution is extracted with diethyl ether, the aqueous phase is concentrated, acidified to pH2 with 1M HCl, extracted with diethyl ether, the organic phase is washed with brine and evaporated to give 42mg (90%) of + -cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

¹H-NMR(CDCl₃)：7.33(d，1H)，7.19(dd，1H)，7.06(d，1H)，4.51(dd，1H)，4.31(dd，1H)，2.53(app.t，1H)，2.27(app.t，1H)，2.16(m，1H).

10h) (±) cis-1- (5-cyanopyridin-2-yl) -3- (5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

+/-cis-5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (42mg, 0.19mmol) and TEA (0.032ml, 0.21mmol) in 3ml toluene DPPA (0.046ml, 0.21mmol) and 2-amino 5-cyano-pyridine (25mg, 0.21mmol) are added the reaction mixture is heated under reflux while stirring for 3 hours the resulting precipitate is filtered off and washed with hot ethanol (3ml) to give 41mg (63%) of + -cis-1- (5-cyanopyridin-2-yl) -3- (5-cyano-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-yl) -urea.

¹H-NMR(DMSO-d₆)：9.86(s，1H)，8.48(d，.1H)，8.07(dd，1H)，7.97(br.s，1H)，7.51(d，1H)，7.43(d，1H)，7.37(d，1H)，7.34(dd，1H)，4.39(dd，1H)，4.19(dd，1H)，3.57(app.q，1H)，2.54(app.t，1H)，2.09(m，1H).

Example 11

(±) cis-1- (5-cyanopyridin-2-yl) -3- (5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c)]Benzopyran-1-yl) -ureas

11a) +/-cis-5-trimethylsilylethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

+/-cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]Benzopyran-1-carboxylic acid ethyl ester (152mg, 0.41mmol), DPPP (38mg, 20 mol%), Pd (dba)₂(24mg, 10 mol%), CuI (3mg, 4 mol%) in 3ml triethylamine, gently flow a stream of nitrogen through the reaction mixture for 10 minutes, adding trimethylsilylacetylene (0.088ml, 0.62mmol), sealing the vial, stirring the reaction mixture at 120 ℃ overnight, diluting the reaction mixture with ethyl acetate, washing with water, brine, and then evaporating the residue by column chromatography on silica gel (EA: Hex, 1:15) to give 0.1g (77%) of + -cis-5-trimethylsilaneEthynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Benzopyran-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：7.15(d，1H)，7.01(dd，1H)，6.88(d，1H)，4.47(dd，1H)，4.16(dd，1H)，3.96(q，2H)，2.38(t，1H)，2.13(t，1H)，2.01(m，1H)，1.04(t，3H)，0.22(s，9H).

11b) +/-cis-5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

Ethyl + -cis-5-trimethylsilylethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate (0.1g, 0.32mmol) and sodium hydroxide (0.076g, 1.9mmol) were dissolved in methanol: water (1:1) (5 ml.) the reaction mixture was heated at 60 ℃ for 5 h, then acidified to pH2 with 1m hci, extracted with diethyl ether the organic phase was washed with brine and evaporated to give 66mg (97%) of ± cis-5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

¹H-NMR(CDCl₃)：7.17(d，1H)，7.03(dd，1H)，6.91(d，1H)，4.45(dd，1H)，4.23(dd，1H)，3.02(s，1H)，2.46(t，1H)，2.13(t，1H)，2.07(m，1H).

11c) (±) cis-1- (5-cyanopyridin-2-yl) -3- (5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea the title compound was synthesized in analogy to example 10h from ± cis-5-ethynyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-carboxylic acid (66mg, 31mmol) yield 53mg (52%).

¹H-NMR(DMSO-d₆：9.88(s，1H)，8.41(d，1H)，8.06(dd，1H)，7.86(br.s，1H)，7.46(d，1H)，7.32(d，1H)，7.02(dd，1H)，6.93(d，1H)，4.31(dd，1H)，4.16(dd，1H)，4.12(s，1H)，3.47(q，1H)，2.43(app.t，1H)，2.00(m，1H).

Example 12

+/-cis-1- (5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -3- (5-cyanoPyridin-2-yl) -ureas

12a) +/-cis-5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

+/-cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c]Benzopyran-1-carboxylic acid ethyl ester (117mg, 0.32mmol), DPPP (7.3mg, 50 mol%), Pd Difference (OAc)₂(2mg, 25 mol%) and triethylamine (0.09ml, 0.64mmol) were mixed in DMF (3ml), a stream of nitrogen was gently passed through the reaction mixture for 10 minutes, butyl vinyl ether (0.21ml, 1.6mmol) was added, the vial was sealed, the reaction mixture was stirred at 100 ℃ for 2 hours, 5% HCl (5ml) was added, the reaction mixture was stirred at room temperature for 30 minutes, the resulting mixture was extracted with ethyl acetate, the organic phase was washed with saturated ammonium chloride and then evaporated, the residue was purified by column chromatography on silica gel (EA: Hex, 1:5) to give 76mg (91%) of. + -. cis-5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ], (EA: Hex, 1:5)]Benzopyran-1-carboxylic acid ethyl ester.

¹H-NMR(CDCl₃)：7.52(dd，1H)，7.36(d，1H)，7.34(d，1H)，4.51(dd，1H)，4.21(dd，1H)，3.98(q，2H)，2.53(s，3H)，2.47(t，1H)，2.23(t，1H)，2.08(m，1H)，1.05(t，3H).

12b) +/-cis-5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

The title compound was synthesized in analogy to example 10g from cis-5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester (76mg, 29mmol) yield 66mg (97%).

¹H-NMR(CDCl₃)：7.52(dd，1H)，7.37(d，1H)，7.34(d，1H)，4.52(dd，1H)，4.26(dd，1H)，2.55(s，3H)，2.53(t，1H)，2.25(t，1H)，2.13(m，1H).

12c) (±) cis-1- (5-cyanopyridin-2-yl) -3- (5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

The title compound was synthesized in analogy to example 10h from cis-5-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester (66mg, 28mmol) yield 58mg (59%).

¹H-NMR(DMSO-d₆): 9.87(s, 1H), 8.42(d, 1H), 8.05(dd, 1H), 7.88(br.s, 1H), 7.52(dd, 1H), 7.49-7.44(m, 2H), 7.37(d, 1H), 4.39(dd, 1H), 4.18(dd, 1H), 3.55(q, 1H), 2.55-2.50(m, 4H), superimposed on the residual DMSO-d₆On the peak), 2.07(m, 1H).

Example 13

+/-cis-1- (5-methoxy-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -3- (5-cyanopyridin-2-yl) -urea

The title compound was synthesized in analogy to example 10 from 2-hydroxy-4-methoxybenzaldehyde.

¹H-NMR(CDCl₃)：8.44(br.s，1H)，8.06(d，1H)，7.70(dd，1H)，7.18(d，1H)，6.82(br.d，1H)，6.55(dd，1H)，6.36(d，1H)，4.32(dd，1H)，4.24(dd，1H)，3.76(s，3H)，3.58(q，1H)，2.36(dd，1H)，1.86(m，1H).

Example 14

(±) cis-1- (5-cyanopyridin-2-yl) -3- (N-acetyl-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a]Quinolin-1-yl-ureas

a) N-acetyl-1, 2-dihydroquinoline.

Quinoline (19.37g, 150mmol) was dissolved in anhydrous diethyl ether (500ml), cooled to 0 ℃ under an inert atmosphere, 1.5M DIBAL (100ml, 150mmol) in toluene was added dropwise over 2 hours, the reaction mixture was stirred for 30 minutes at 0 ℃ acetic anhydride (500ml) was added dropwise over 30 minutes, the reaction mixture was stirred for 30 minutes at 0 ℃ H was added cautiously₂O. the reaction mixture was extracted with diethyl ether and concentrated to give N-acetyl-1, 2-dihydroquinoline (11.5g, 44%).

b) +/-cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] quinoline) -1-carboxylic acid ethyl ester.

+/-cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropano [ c ] quinoline) -1-carboxylic acid ethyl ester prepared from N-acetyl-1, 2-dihydroquinoline (10g, 58mmol) according to the procedure described in example 1a the product was purified by column chromatography on silica (Et0 Ac/hexane 5% → 50%) to give + -cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropano [ c ] quinoline) -1-carboxylic acid ethyl ester (2.0g, 13%).

c) +/-cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] quinoline) -1-carboxylic acid

+ -cis- (N-acetyl 1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] quinoline) -1-carboxylic acid (425mg, 24%) was prepared according to the method described for example 1b from cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] quinoline) -1-carboxylic acid ethyl ester (2.0mg, 7.7 mmol).

d) (±) cis-1- (5-cyanopyridin-2-yl) -3- (N-acetyl-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] quinolin-1-yl) -urea

+ -cis-1- (5-cyanopyridin-2-yl) -3- (N-acetyl-1, 1a, 3, 7 b-tetrahydro 2-oxacycloprop [ a ] quinolin-1-yl)) -urea (250mg, 40%) was prepared from + -cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro cycloprop [ c ] quinoline) -1-carboxylic acid (416mg, 1.8mmol) according to the method described for example 1 c.

¹H NMR(250MHz，DMSO-d₆)δppm：9.51(brs，1H)，8.30(d1H)，8.01(dd，1H)，7.54(dd，1H)，7.44，(dd，1H)，7.36(d，1H)，7.23-7.18(m，3H)，4.10(d，1H)，3.60(dd，1H)，3.12-3.05(m，1H)，2.37(tr，1H)，2.0-1.92(m，4H)

Example 15

+/- -cis-1- (5-cyanopyridin-2-yl) -3- (47-difluoro-11 a27 b-tetrahydrocyclopropan [ c]Benzopyran-1-yl) -ureas

15a)2, 4-difluoro-2-propynyloxybenzene

Commercially available 2, 5-difluorophenol (20g, 0.15mol), K₂CO₃(53g, 0.38mo1) and commercially available 3-bromopropyne (45g, 0.38mol) were dissolved in acetone (300ml), refluxed overnight, cooled and then filtered, the solvent was removed, the crude product was dissolved in diethyl ether, washed with water and brine, the organic phase was evaporated, the crude product was redissolved in a small amount of diethyl ether and purified by basic Al₂O₃Column filtration, evaporation and drying gave 20g (80%) of 2, 4-difluoro-2-propynyloxy-benzene.

15b)5, 8-difluoro-2H-benzopyran.

2, 4-difluoro-2-propynyloxybenzene (20g, 0.12 mol) was dissolved in N, N-diethylaniline (100ml), heated in an oil bath at 225 ℃ under a hydrogen atmosphere for 6 to 8 hours, diethyl ether (150ml) was added, aniline was removed by extraction with 2M HCl (aq), and purification by chromatography (silica gel, N-hexane) gave 5.8g (29%)

15c) +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

5, 8-difluoro-2H-benzopyran (5g, 0.03 mol), (Rh (II) Ac₂)₂(0.39g, 0.00089 mol)Mole) was dissolved in 1, 2-dichloroethane (60ml) or chloroform without ethanol, ethyl diazoacetate (9.4ml, 0089 mole) in the same solvent was added dropwise over about 5 hours under a nitrogen atmosphere, the solvent was removed under vacuum, the mixture was transferred to ethyl acetate, and the solvent was removed with NaHCO₃(aq), water and brine, then solvent was removed the product (33% cis, 66% trans) was purified with hromatographic (0 → 10% ethyl acetate in hexanes) to give 2.2g of the title compound (30%).

15d) +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

Cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester (2g, 0.008 mol) 1M was heated in LiOH in methanol-water (25%) at 80 ℃ for 2 hours the volume was reduced to half, then acidified, extracted with ether and then chromatographed (silica gel, ether) to give the pure title compound (35%).

15e) (/ -) cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

(+/-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -urea was prepared in analogy to example 1c, except using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (0.2g, 0.00088 mol) to give 0.130g (42%) of the pure title compound.

¹H-NMR(CDCl₃-MeOD)：8.16(d，1H)，7.72(dd，1H)，6.97-6.86(m，2H)，6.69-6.61(m，1H)，4.47(dd，1H)，4.31(dd，1H)，3.75(m，1H)，2.65(t，1H)，2.05-1.96(m，1H).

Example 16

(+/-) -cis-1- (5-cyano-3-methyl-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -ureas

(+/-) -cis-1- (5-cyano-3-methyl-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ] chromen-1-yl) -urea was prepared similarly to example 1c except using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ] benzopyran-1-carboxylic acid (168mg, 0.74mmol) and 6-amino-5-methyl-nicotinonitrile (109mg, 0.82mmol) to give 52mg (+/-) -cis-1- (5-cyano-3-methyl-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cycloprop [ c ] chromen-1-yl) -urea (20%). purification of the crude product employs extraction between 0.01M HCl (aq) and ethyl acetate followed by chromatographic separation (silica gel, 0 → 25% MeOH in ether). solvent is evaporated and the solid is washed with 25% acetone in n-hexane.

¹H NMR(CDCl3-MeOD)：8.02(d，1H)，7.61(dd，1H)，6.97-6.87(m，1H，6.70-6.62(m，1H)，4.48(dd，1H)，4.30(dd，1H)，3.78(t，1H)，3.37(s，3H)，2.66(t，1H)，2.03(m，1H).

Example 17

(+/-) -cis-1- (5-hydro-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropan [ c)]Benzopyran-1-yl) -ureas

(+/-) -cis-1- (5-chloro-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -urea was prepared in analogy to example 1c, except using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (90mg, 0.4mmol) and 6-amino-5-chloropyridine (51mg, 0.44mmol) to give (+/-) -cis-1- (5-chloro-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -urea (50mg, 35%). purification of the crude product employs extraction between 0.01M HCl (aq) and ethyl acetate (1:1) followed by chromatographic separation (silica gel, ether).

¹H NMR(CDCl₃)：9.2(broad s，NH)，8.6(broad s，NH)，7.81(dd，1H).7.48(dd，1H)，6.89(m，1H)，6.75(d，1H)，6.69(m，1H)，4.45(dd，1H)，4.33(dd，1H)，3.75(m，1H)，2.61(m，1H)，1.97(m，1H).

Example 18

(+/-) -cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c [ -c ]]Benzopyran-1-yl) -3- (5-ethynyl-pyridin-2-yl) -urea

+/-cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ]]Benzopyran-1-yl) -3- (5-ethynyl-pyridin-2-yl) -urea was prepared analogously to example 1c) but using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c)]Benzopyran-1-carboxylic acid (100mg, 0.40.44mmol) and 5-t trimethylsilylethynyl-pyridin-2-ylamine (93mg, 0.49mmol) to give (25mg, 17%) of the product purification of crude was between 0.01M HCl (aq) and ethyl acetate-ether (1:1)And then chromatographed (silica gel, diethyl ether) the resulting mixture (containing the title compound and silylated compound) with 25% Bu in water₄N⁺F^-Stirring in THF for 30 min, then repeating the chromatographic separation to give pure +/-cis 1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c)]Benzopyran-1-yl) -3- (5-ethynyl-pyridin-2-yl) -urea.

¹H NMR(CDCl₃)：9.2(broad s，NH)，7.95(d，1H)，7.59(dd，1H)，7，48(broad s，1H)，6，89(td，1H)，6，64(td，1H)，6，57(d，1H)，4，46(dd，1H)，4，33(dd，1H)，3.78(q，1H)，3.11(s，1H)，2.62(t，1H)，1.99-1.97(m，1H)

Example 19

(+/-) -cis-1- (5-bromo-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropan [ c)]Benzopyran-1-yl) -ureas

+/- -cis-1- (5-bromo-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -urea was prepared similarly to example 1c, except using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol) and 6-amino-5-bromo-pyridine (42mg, 0.24mmol) to give +/- -cis-1- (5-bromo-pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -urea (50mg, 35%). purification of the crude product employs extraction between 0.01M HCl (aq) and ethyl acetate followed by chromatographic separation (silica gel, ether).

¹H NMR(CDCl₃)：9.2(broads，NH)，7.88(d，1H)，7.75(broads，1H)，7.60(dd，1H)，6.89(m，1H)，6.63(td，1H)，6.59(d，1H)，4.45(dd，1H)，4.33(dd，1H)，3.78(q，1H)，2.62(t，1H)，1.98(m，1H).

Example 20

+/-cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ]]Benzopyran-1-yl) -3- (5-phenoxy-pyridin-2-yl) -urea

(+/-) -cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (5-phenoxy-pyridin-2-yl) -urea was prepared in analogy to example 1c), but using cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (60mg, 0.26mmol) and 6-amino-5-phenoxypyridine (56mg, 0.29mmol) to yield 32mg (30%) of the title compound purification of the crude product was by extraction between 0.01MHCl (aq) and ethyl acetate followed by chromatography (silica gel, 20% diethyl ether in n-hexane).

¹H NMR(CDCl₃)：7.60(d，1H)，7.45(broads，1H)，7.37-7.34(m，2H)，7.27-7.24(m，2H)，7.14-7.11(m，1H)，6.94-9.92(m，2H)，6.79-7.74(m，1H)，6.63(d，1H)，6.59-6.55(m，1H)，4.43(dd，1H)，4.36(dd，1H)，3.75(q，1H)，2.59(t，1H)，1.98-1.94(m，1H).

Example 21

(+/-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c)]Benzopyran-1-yl) -thioureas

Cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (113mg, 0.5mmol), DPPA (118.6 μ l, 0.55mmol) and TEA (70.7 μ l, 0.55mmol) were refluxed in toluene (2ml) for 1 hour, then dioxane (3ml) and hcl (aq) (1.5ml, 6M) were added, the reaction mixture was left at 50 ℃ for 1 hour, then diethyl ether and water were added, the layers were separated, the aqueous phase was washed with diethyl ether, then basified with ammonia (aq), extracted with dichloromethane and dried to give intermediate 4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-ylamine which was treated directly with 6-isothiocyanatotoniumnicotinonitrile (34mg, 0.55mmol) in acetonitrile (4ml) at room temperature overnight filtered crystals, washing with cold acetonitrile gave 30mg (17%) of pure (+/-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -thiourea.

LC-MS：m/z358.9.

Example 22

(+/-) -cis-1- (6-Nitrogen-5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -ureas

1- (6-chloro-5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) urea was prepared analogously to example 1c) except using cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (280mg, 1.21mmol) and 6-amino-2-chloro-3-cyanopyridine (203mg, 1.33mmol) to yield a small amount of the title compound.

¹H NMR(DMSO-d₆)：10(br s，NH)，8.20(d，1H)，7.70(d，1H)，6.9(br s，NH)，6.8(m，1H)，6.6(m，1H)，4.4(dd，1H)，4.2(dd，1H)，3.2(m，1H)，2.4(t，1H)，1.9(m，1H).

Example 23

1- (5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c]Benzopyran-1-yl) -ureas

1- (5-cyanopyridin-2-yl) -3- (5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) urea was prepared analogously to example 1c) except that cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] benzopyran-1-carboxylic acid (390mg, 1.72mmol) and 2-amino-5-cyanopyridine (226mg, 1.89mmol) were used and the crude product was purified by extraction between 0.01M HCl (aq), recrystallization, washing several times with acetone and acetonitrile and then chromatography (silica gel, 1% EtOAc in ether) to give 28mg of the title compound.

¹H NMR(CDCl3-MeOD)：8.16(t，1H)，7.78(dd，1H)，7.09(d，1H)，6.56-6.34(m，2H)，4.34(m，2H)，3.54(t，1H)，2.57(dd，1H)，2.00-1.90(m，1H).

Example 24

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -3- (5-cyano-pyridin-2-yl) -urea

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cycloprop [ c ] chromen-1-yl) -3- (5-cyano-pyridin-2-yl) -urea was prepared in analogy to example 1c), except using cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cycloprop [ c ] chromen-1-carboxylic acid (178mg, 0.62mmol) and 2-amino-5-cyanopyridine (0.81mg, 0.68mmol). the crude product was chromatographed (silica, ether), acetone was washed to give 40mg (16%) of cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (5-cyanopyridin-2-yl) -urea.

¹H NMR(CDCl₃)：9.85(s，1H)，9.3(s，1H)，7.75(dd，1H)，7.33(dd，1H)，6.95(d，1H)，6.65(t，1H)，4.05(dd，1H)，4.32(dd，1H)，3.35(t，H)，2.65(t，1H)，2.05-1.95(m，1H).

Example 25

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -3- (6-chloro-5-cyano-pyridin-2-yl) -urea

Cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyano-pyridin-2-yl) -urea was prepared in analogy to example 1c), except using cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-carboxylic acid (178mg, 0.62mmol) and 2-amino-6-chloro-5-cyanopyridine (105mg, 0.68mmol), the crude was purified by chromatography (silica, 0 → 1% MeOH in ether), washed with acetone-hexane to give 40mg (13%) of cis-1- (4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyanopyridin-2-yl) -urea.

¹H NMR(CDCl₃)：9.90(s，1H)，8.30(s，1H)，7，75(d，1H)，7，25(d，1H)，6.60(t，1H)，4，5(dd，1H)，4.35(dd，1H)，3.5(m，1H)，2.65(m，1H)，2.1-1.95(m，1H).

Example 26

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -3- (5-cyano-pyridin-2-yl) -urea

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ] chromen-1-yl) -3- (5-cyano-pyridin-2-yl) -urea was prepared in analogy to example 1c), except using cis-4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ] chromen-1-carboxylic acid (177mg, 0.62mmol) and 2-amino-5-cyanopyridine (81mg, 0.68mmol) the purification of the crude product was performed by extraction between diethyl ether and 0.02M HCl (aq), chromatography (silica, 0 → 1% MeOH in diethyl ether), washing with acetone-hexane to give 42mg (17%) of cis-1- (4-bromo-6-fluoro-1-yl) -urea 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyanopyridin-2-yl) -urea.

¹H NMR(CDCl3-MeOD)：8.37(m，1H)，7.75(dd，1H)，7.14(dd，1H)，7.05(dd，1H)，6，93(d，1H)，4.56(dd，1H)，4.21(dd，1H)，3.77(t，1H)，2，42(dd，1H)，2.00(m，1H).

Example 27

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropan [ c ]]Benzopyran-1-yl) -3- (6-chloro-5-cyano-pyridin-2-yl) -urea

Cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyano-pyridin-2-yl) -urea was prepared analogously to example 1c) except using cis-4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-carboxylic acid (177mg, 0.62mmol) and 2-amino-6-chloro-5-cyanopyridine (105mg, 0.68 mmol.) purification of the crude product was performed by extraction between diethyl ether and 0.01M HCl (aq), chromatography (silica, 0 → 1% MeOH in diethyl ether), washing with acetone-hexane gave 46mg (17%) of cis-1- (4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -3- (6-chloro-5-cyanopyridin-2-yl) -urea.

¹H NMR(CDCl3)：9.41(s1H，)，8.28(dd，1H)，7.04(dd，1H)，4，54(dd，1H)，4.25(dd，1H)，3.50(m，1H)，2.41(dd，1H)，2.06-1.98(m，1H).

Example 28

Cis-1- (5-cyanopyridin-2-yl) -3- (6-fluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c]Benzopyran-1-yl) -ureas

Cis-1- (5-cyanopyridin-2-yl) -3- (6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) urea was prepared similarly to example 1c) except that cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (168mg, 0.8mmol) and 2-amino-5-cyanopyridine (105mg, 0.88mmol) were used and the crude product was extracted between diethyl ether and 0.01MHCl (aq), chromatographed (silica, 0 → 1% MeOH in diethyl ether) and then washed with acetone-hexane to give only 10mg (4%) of cis-1- (5-cyanopyridin-2-yl) -3- (6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea.

¹H NMR(CDCl3-MeOD)：8.16(d，1H)，7.73(dd，1H)，7.05(dd，1H)，6.96(d，1H)，6.84(td，1H)，6.76(dd，1H)，4.39(dd，1H)，4.17(dd，1H)，3.67(t，1H)，2.39(dd，1H)，1.96-1.92(m，1H).

Example 29

Intermediates

29a) 6-fluoropyran-4-ol

6-Fluorobenzopyran-4-one (10g, 61mmol) was dissolved in ethanol (100 ml.) NaBH was added₄(excess) and cooled on an ice bath the mixture was then left at room temperature for 2 hours, then refluxed for 4 hours and chromatographed (silica gel, ether-hexane, 1:5) to give 8g (80%) of pure 6-fluoropyran-4-ol.

29b) 6-fluoro-2H-benzopyrans

6-Fluorobenzopyran-4-ol (8g, 48mmol) and toluene-4-sulfonic acid (1g) were dissolved in toluene, refluxed overnight, then water was removed, then the mixture was cooled, and NaHCO was used₃(aq) washing and chromatographic purification (silica gel, n-hexane) gave 4.2g (52%) of pure 6-fluoro-2H-benzopyran.

29c) +/-cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

This compound was prepared analogously to cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester, except that 6-fluoro-2H-benzopyran was used to give 1.9 (29%) of the title compound.

29d) Cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

This compound was prepared analogously to cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid, except that ethyl cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate (1.9g, 8mmol) was used to give 350mg (21%) of pure cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

29e) 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene

This compound was prepared analogously to 2, 4-difluoro-2-prop-ynyloxy-benzene, except that 2-bromo-5-fluorophenol (15g, 78mmol) was used to give 15.6g (87%) of 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene.

29f) 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene

This compound was prepared analogously to 2, 4-difluoro-2-prop-ynyloxy-benzene, except that 2-bromo-4-fluorophenol (15g, 78mmol) was used to give 15g (84%) of 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene.

29g)1, 3-difluoro-5-prop-2-ynyloxy-benzene

This compound was prepared analogously to 2, 4-difluoro-2-propynyloxybenzene except that 3, 5-difluoro-phenol (14g, 107mmol) was used to give 12g (67%) of 1, 3-difluoro-5-prop-2-ynyloxy-benzene.

29h) 8-bromo-6-fluoro-2H-benzopyran

This compound was prepared analogously to 5, 8-difluoro-2H-benzopyran, except that 2-bromo-4-fluoro-1-prop-2-ynyloxybenzene was used (15g, 65mmol) to give the title compound (7g, 46%).

29i) 8-bromo-5-fluoro-2H-benzopyran

This compound was prepared analogously to 5, 8-difluoro-2H-benzopyran, except that 2-bromo-4-fluoro-1-prop-2-ynyloxybenzene was used (15g, 65mmol) to give the title compound (3.7g, 25%).

29j)5, 7-difluoro-2H-benzopyrans

This compound was prepared analogously to 5, 8-difluoro-2H-benzopyran, except that 1, 3-difluoro-5-prop-2-ynyloxybenzene (18g, 107mmol) and PEG-200 were used as solvents to give the title compound (4g, 23%).

29k) +/-cis-4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

This compound was prepared analogously to +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester, except that 5g (22mmol) of 8-bromo-6-fluoro-2H-benzopyran were used to give 1.9g (30%) of cis-6-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

291) +/-cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester

This compound was prepared analogously to +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester, except that 3.5g (15.3mmol) of 8-bromo-5-fluoro-2H-benzopyran were used to give 1.6g (33%) of +/-cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

29m) +/-cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid ethyl ester.

This compound was prepared analogously to ethyl +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate, except that 2g (12mmol) of 5, 7-difluoro-2H-benzopyran were used, giving 0.9g (29%) of ethyl +/-cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate.

Example 30

Cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Optical isomers of benzopyran-1-yl-ureas

Racemic (+/-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyrans-1-yl) -urea (see example 15) chiral AGP150 x10mm, 5 μm; the flow rate was set at 4 ml/min.the mobile phase was 89 vol% 10mM HOAc/NH in acetonitrile₄The second eluting isomer generally exhibits negative spin and is particularly active.

Without wishing to be bound in any way to this observation, it is believed that the slower eluting isomer has the absolute configuration described below, which is established with reference to the coordinates of the x-ray crystal of the unsubstituted analogue of example 1 coordinated internally in the reverse transcriptase.

Example 31

(-) cis-1- (5-Chloropyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -ureas

Racemic (+/-) -cis-1- (5-chloropyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) -urea (see example 17) chiral AGP150 x10mm, 5 μm; the flow rate was set at 4 m/min.the mobile phase was 89 vol% 10mM HOAc/NH in acetonitrile₄Oac. two peaks appeared at 27.7 minutes and 33.2 minutes the title isomer eluted at 33.2 minutes, generally showing negative spin and being particularly active.

Example 32

(-) -cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Benzopyran-1-yl) -ureas

a) Resolution of racemic cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

0.32g (1.32mmol) of racemic cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid was dissolved in hot acetonitrile (50ml), then (1R, 2R) -2-benzyloxycyclopentylamine (0.25g, 1.32mmol) was added, the resulting solution was left to crystallize, after a few hours, the mother liquor was decanted, the crystals washed with acetonitrile, the second crystallization from acetonitrile gave 92mg of the pure diastereomeric salt, the salt was treated with 1M HCl, the resulting mixture was extracted with ethyl acetate, the organic phase was washed with water, brine and evaporated to give 0.05g of the enantiomer cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

b) (-) cis-1- (5-cyanopyridin-2-yl) -3- (7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -urea

The title compound was synthesized in analogy to example 1c) using the enantiomer cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg) yield 60.2mg (84%).

[α]_D＝-0.388(c＝0.5，CHCl₃).

Example 33

+/- -cis-N- (5-cyano-2-pyridyl) -N' - (4, 7-dichloro-1, a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) ureas

a)1, 4-dichloro-2- (2-propynyloxy) benzene

2, 5-dichlorophenol (8g, 49mmol) was mixed with potassium carbonate (13.6g, 98mmol) and 80% solution of bromopropyne in toluene (11ml, 98mmol) in acetone (100ml) and stirred overnight at room temperature the precipitate was removed by filtration, washed with acetone the resulting acetone solution was concentrated by rotary evaporation and kept under vacuum for 5 hours the yellow oil was quantitatively obtained for further conversion without further purification.

b)5, 8-dichloro-2H-benzopyran

1, 4-dichloro-2- (2-propynyloxy) benzene was degassed and heated with stirring at 224 ℃ for 4 hours under argon and then distilled in a Kugelrohr apparatus (150-.

c) +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxyethyl ester

5, 8-dichloro-2H-benzopyran (3.15g, 16mmol), (Rh (II) Ac2)2(30mg, 0.1 mol%) was dissolved in degassed dry dichloromethane (3 ml.) the reaction mixture was then washed with NH4Cl (aq), water and brine, and the solvent removed by addition of ethyl diazoacetate (3ml, 2eq.) in the same solvent under nitrogen atmosphere by syringe at a flow rate of 0.4 ml/H over about 5 hours, the product (45% cis, 55% trans) was chromatographed on silica (200g, ethyl acetate/n-hexane 1:15) to give 0.9g pure cis product (racemate.) yield 20%. M⁺＝287.

¹H-NMR(CDCl₃)：7.15(d，1H，J＝8.5Hz)，6.91(d，1H，J＝8.8Hz)，4.59(dd，1H，J₁＝12，02，J₂＝7.03)，4.48(dd，1H，J₁＝12.02，J₂＝4.10)，4，07-3.94(m，3H)，2.62(t，1H，J＝8.8Hz)，2.27(t，1H，J＝8.36Hz)，2.20-2.12(m，1H)，1.1(t，3H).

d) +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ d ] benzopyran-1-carboxylic acid

+/-cis-4, 7-dichloro 1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxyethyl ester was mixed with methanol (3ml) and aqueous NaOH (1.5eq., 3ml), heated with stirring at 60 ℃ for 1.5 h extraction of the basic reaction mixture in hexane indicated that no starting material was present the reaction mixture was acidified with excess 3M HCl solution (pH 1) the precipitate formed was filtered through a cell phone, washed with water and the white solid obtained was dried under high vacuum (yield 80%).

e) +/-cis-N- (5-cyano-2-pyridinyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea

+/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ d ] benzopyran-1-carboxylic acid (100mg, 0.39mmol) was mixed with toluene (3ml), triethylamine (1.1eq.), 5-cyano-2-aminopyridine (1.1eq.), DPPA (1.1eq), bubbled with argon for about 5 minutes the reaction mixture was then heated under argon at 115 ℃ for 3 hours with stirring, rotary evaporation concentrated the reaction mixture, then mixed with a small amount of dry ethanol, the precipitate formed was collected by suction filtration, washed with ethanol (2 x 2ml) to give the desired product (+/-cis-isomer) as a beige-white powder (65mg, 45% yield).

¹H-NMR(DMSO-d₆): 9.83(s, 1H), 8.34(d, 1H), 8.03(dd, 1H), 7.75(brs, 1H), 7.44(d, 1H), 7.30(d, 1H), 7.10(d, 1H), 4.43(dd, 1H), 4.18(dd, 1H), 3.55-3.45(m, 1H by H)₂Overlap of the O signal), 2.54(dd, 1H), 2.10-2.02(m, 1H).

Example 34

+/-cis-N- (5-chloro-2-pyridinyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) ureas

Synthesis of +/-cis-N- (5-chloro-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea in analogy to example 33, using +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-carboxylic acid (100mg, 0.39mmol) and 2-amino-5-chloropyridine (1.1eq) gave 66mg of the product as a white powder in 44% yield.

¹H-NMR(DMSO-d₆)：9.47(s，1H)，7.98(d，1H)，7.86(brs，～1H)，7.83(dd，1H)，7.30(d，1H)，7.23(d，1H)，7.10(d，1H)，4.44(dd，1H)，4.18(dd，1H)，3.55-3.48(m，1H)，2.54(dd，1H)，2.10-2.02(m，1H).

Example 35

+/-cis-N- (5-bromo-2-pyridinyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) ureas

Synthesis of +/-cis-N- (5-bromo-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) urea in analogy to example 33, using +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-carboxylic acid (100mg, 0.39mmol) and 2-amino-5-bromopyridine (1.1eq) gave 35mg of product as a gray powder in 21% yield.

¹H-NMR(DMSO-d₆): 9.47(s, 1H), 7.97(d, 1H), 7.86(br s,. about.1H), 7.83(dd, 1H), 7.30(d, 1H), 7.2, 3(d, 1H), 7.10(d, 1H), 4.43(dd, 1H), 4.18(dd, 1H), 3.55-3.48(m, 1H), 2.54(dd, 1H is overlapped by the signal of DMSO), 2.08-2.01(m, 1H).

Example 36

+/-cis-N- (5-phenoxy-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) ureas

Synthesis of +/-cis-N- (5-phenoxy-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) urea in analogy to example 33, using +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-carboxylic acid (58mg, 0.22mmol) and 2-amino-5-phenoxypyridine (1.1eq) gave 49mg of the product as a brownish powder with a yield of 49%.

¹H-NMR(CDCl₃): 9.30(br s, 1H), 8.26(s, 1H), 7.53(d, 1H), 7.35(m, 2H), 7.25(dd, 1H), 7.16-7.10(dd, 1H substituted by CHCl)₃Signal overlap), 7.05(d, 1H), 6.97-6.90(m, 3H), 6.72(d, 1H), 4.46(dd, 1H), 4.30(dd, 1H), 2.73(m, 1H), 2.63(dd, 1H), 2.05-1.95(m, 1H).

Example 37

+/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-yl) -N' - (5-cyano-2-pyridyl) urea

a) 5-chloro-2-fluorophenol

5-chloro-2-fluoroaniline (10g, 68mmol) was dissolved in 6M sulfuric acid, cooled in an ice/salt bath to-5 deg.C, NaNO in minimal water₂The solution (5.2g, 76mmol) was added dropwise to the stirred suspension at a temperature not higher than-2 deg.C after addition, the clear yellow solution formed was stirred for a further 30 minutes under cooling CuSO₄Dissolved in water (80ml) and then mixed with sulfuric acid (32 ml.) the diazonium solution was added dropwise to a preheated (160 ℃) cuprous sulfate solution and the product removed from the reaction flask by steam distillation the reaction was completed for 2 hours₂SO₄Drying and concentration gave 4g of crude phenol (40%).

b) 4-chloro-1-fluoro-2- (2-propynyloxy) benzene

Synthesis of 4-chloro-1-fluoro-2- (2-propynyloxy) benzene Using (4g, 27mmol) 4-chloro-1-fluoro-phenol analogously to example 33a, 4.6g of a yellow oil with good yield (column chromatography, silica, ethyl acetate/n-hexane 1:15) were obtained 90%.

c) 5-chloro-8-fluoro-2H-benzopyran

Synthesis of 5-chloro-8-fluoro-2H-benzopyran analogously to example 33b), using 4-chloro-1-fluoro 2- (2-propynyloxy) benzene (4.6g, 25mmol), 1g of the product are obtained (column chromatography, alumina, ethyl acetate/n-hexane 1:15) as colorless oil in 22% yield.

d) +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxyethyl ester

Synthesis of +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxyethyl ester in analogy to example 33c, using 5-chloro-8-fluoro-2H-benzopyran (1g, 5.4mmol) gives 360mg of +/-cis product (column chromatography purification, silica, ethyl acetate/n-hexane 1:20) as a white solid in 25% yield.

e) +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

Synthesis of +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid Using +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxyethyl ester (360mg, 1.3mmol) in analogy to example 33d, 259mg of +/-cis acid (80%) was obtained.

f) +/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl) -N' - (5-cyano-2-pyridyl) urea

Synthesis of +/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -N' - (5-cyano 2-pyridyl) urea in analogy to example 33e, using +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (60mg, 0.25mmol) and 2-amino-5-chloropyridine (1.1eq) gave 59mg of the product as a white powder in 66% yield.

¹H-NMR(DMSO-d₆): 9.47(br s, 1H), 7.89(d, 1H), 7.80(br s, 1H), 7.74(dd, 1H), 7.32(d, 1H), 7.16-7.05(m, 2H), 4.39(dd, 1H), 4.16(dd, 1H), 3.55-3.48(m, 1H), 2.51(dd, 1H are overlapped by DMSO signal), 2.08-2.01(m, 1H).

Example 38

+/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-yl) -N' - (5-chloro-2-pyridyl) urea

Synthesis of +/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -N' - (5-chloro-2-pyridyl) urea in analogy to example 5, using +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (60mg, 0.25mmol) and 2-amino-5-chloropyridine (1.1eq) gave 59mg of the product as a white powder in 65% yield.

¹H-NMR(DMSO-d₆): 9.47(br s, 1H), 7.89(d, 1H), 7.80(br s, 1H), 7.74(dd, 1H), 7.32(d, 1H), 7.16-7.04(m, 2H), 4.39(dd, 1H), 4.16(dd, 1H), 3.55-3.48(m, 1H), 2.51(dd, 1H are overlapped by DMSO signal), 2.06-2.01(m, 1H).

Example 39

+/-cis-N- (5-bromo-2-pyridinyl) -N' - (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-yl) ureas

Synthesis of +/-cis-N- (5-bromo-2-pyridyl) -N' - (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) urea in analogy to example 32e, using +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (60mg, 0.25mmol) and 2-amino-5-bromopyridine (1.1eq) gave 56mg of the product as a white powder in 55% yield.

¹H-NMR(DMSO-d₆): 9.46(br s, 1H), 7.96(d, 1H), 7.83(dd, 1H), 7.81(br s, 1H), 7.27(d, 1H), 7.16-7.04(m, 2H), 4.38(dd, 1H), 4.17(dd, 1H), 3.55-3.48(m, 1H), 2.51(dd, 1H are overlapped by DMSO signal), 2.07-2.00(m, 1H).

Example 40

+/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Benzopyran-1-yl) -N' - (5-phenoxy-2-pyridinyl) ureas

Synthesis of +/-cis-N- (7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] chromen-1-yl) -N' - (5-phenoxy-2-pyridyl) urea in analogy to example 32E, using +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid (60mg, 0.25mmol) and 2-amino-5-phenoxypyridine (1.1eq) gave 76mg of the product as a pale brown powder in 73% yield.

¹H-NMR(CDCl₃): 9.33(br s, 1H), 7.93(s, 1H), 7.51(d, 1H), 7.38-7.32(m, 2H), 7.25(dd, 1H substituted by CHCl)₃Signal overlap), 7.16-7.10(m, 1H), 6.96-6.88(m, 3H), 6.79(dd, 1H), 6.68(d, 1H), 4.45(dd, 1H), 4.25(dd, 1H), 3.75-3.70(m, 1H), 2.61(dd, 1H), 2.05-1.95(m, 1H).

EXAMPLE 41

N- [ (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] - [1] benzothiopyran-1-yl ] -N' - (5-cyano-2-pyridinyl) urea

A)3, 4-dihydro-2H-1-benzothiopyran-4-ols

A solution of thiochroman-4-one (9g) was slowly added to a mixture of aluminum hydride (53g) in ether (54ml), refluxed for 2 hours, cooled, iced, then water and 20% sulfuric acid were added, the aqueous phase was washed twice with ether, the ether phase was washed twice with 2 n.oh and once with water, dried over magnesium sulfate, evaporated to give an oil (8.9g), crystallized after several hours, Rdt ═ 97%.

B) 2H-1-benzothiopyran and 4H-1-benzothiopyran

4-benzothiopyranol (8.9g) and potassium hydrogen sulphate were placed in a flask and evacuated to 1mm, heated at 90 ℃ until the alcohol melted, magnetically stirred and heated to 120 ℃, dehydrogenated, a mixture of product and water was distilled off, the product was dissolved in ether and dried, the crude product (7g, RDT 88%) was not purified NMR showed the presence of 10% 4H-1-benzothiopyran.

C) (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] - [1] thiochroman-1-carboxylic acid ethyl ester

Ethyl diazoacetate was slowly added to 500mg thiochroman at 140 ℃ the reaction was checked by gas chromatography and stopped after all starting material had been consumed (about 7 hours), purified by flash chromatography (5% ether: ethane) and identified by NMR spectroscopy as the cis isomer (46mg, Rdt ═ 6%).

D) (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] - [1] benzothiopyran-1-carboxylic acid

A mixture of the cis isomer (46.5mg), LiOH (4eq, 19mg) was refluxed in 25% methanol-water for 1h, the solvent was evaporated in vacuo, the residue was dissolved in water, washed with ether, the aqueous phase was acidified with concentrated hydrochloric acid, extracted twice with dichloromethane, dried and the organic phase was evaporated to give the desired acid (30mg) · Rdt 73%.

E) N- [ (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] - [1] benzothiopyran-1-yl ] -N' - (5-cyano-2-pyridinyl) urea

The above acid was refluxed in toluene for 4 hours in the presence of triethylamine (0.02ml), diphenylphosphine azide (0.03mg) and 2-amino-6-CN-pyridine (19.5mg), cooled, washed with water and then with hydrochloric acid solution (0.01M), the organic phase was dried and evaporated, and the residue was purified by flash chromatography (ethyl acetate: hexane ═ 2: 1) to give 10mg of the desired compound Rdt ═ 22%.

¹H(DMSO-d₆)：1.96(1H，m)；2.30(1H，t，8.6)；2.71(1H，ddt，13.65，6.24)；3.24(2H，m)；7.19(3H，m)；7.37(1H，dd，7.4，1.56)；7.42(1H，dd，9.0，3.1)；7.60(1H，NH)；8.02(1H，dd，9.0，2.3)；8.15(1H，s)；9.89(1H，NH)Mass：322(M⁺·)，321(M-H)

Example 42

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid

A) (2Z) -3- (3, 6-difluoro-2-methoxyphenyl) -2-propen-1-ol

A solution of BuLi (2.5M) in hexane (9.6ml, 0.024mol) was added to a solution of 2, 5-difluoroanisole (2.88 g; 0.02ml) in anhydrous THF (30ml) at-70 ℃ with stirring and after 2 hours ZnCl was added₂(0.36 g;, 0.026 mol) in dry tetrahydrofuran (50ml) the reaction temperature was raised to room temperature, followed by stirring at room temperature for 30 minutes, addition of Pd (OAc)₂(8 mg; 0.2 mol%), ethyl cis-3-bromoacrylate (3.58 g; 0.02mol) was added and the reaction mixture was placed in a preheated oil bath, then heated under reflux for 1 hour, the resulting reaction mixture was cooled to-78 deg.C, 60ml (0.06 mole) of DIBAL (1M solution in hexane) was added dropwise, stirring was continued at-78 deg.C for 2 hours, then stirred at room temperature for 1 hour, the reaction was quenched with water, HCl was added to dissolve all solids, the organic phase was diluted with ether, separated, washed with 5N HCl, brine, the residue was then subjected to Kugelrohr distillation (1.5 x10 mbar, 150 ℃) yielding 3.7g (92%) of crude (2Z) -3- (3, 6-difluoro-2-methylphenyl) -2-propen-1-ol, containing 6% of the other regioisomer (regioisomer).

¹H-NMR(CDCl₃)：7.00(m，1H)；6.77(m，1H)；6.31(app.d，1H)；6.12(app.dt，1H)；4.08(br.t，2H)；3.89(d，3H)；1.80(br.t，1H).

b) (2Z) -3- (3, 6-difluoro-2-methylphenyl) prop-2-enyldiazoacetate

Glyoxylic acid chloride of p-toluenesulfonylhydrazone (5.16 g; 0.02mol) was added to (2Z) -3- (3, 6-difluoro-2-methylphenyl) -2-propen-1-ol (3.6 g; 0.018 mol) in dry CH₂Cl₂(50ml) in a-5 ℃ solution, N-dimethylaniline (2.5 ml; 0.02mol) was then slowly added, stirred at-5 ℃ for 30 minutes and then Et was slowly added₃N (12 ml; 0.09 mol.) the resulting mixture is stirred at-5 ℃ for 15 minutes and then at room temperature for 30 minutes, whereupon water (50ml) is added, the organic phase is separated, washed with water, brine, and then concentrated in vacuo, flash chromatography (silica, EA: Hex; 1:15) gives 3.86g (80%) of the product as a yellow solid.

¹H-NMR(CDCl₃)：7.00(m，1H)；6.76(m，1H)；6.41(app.d，J＝12.2Hz；1H)；6.00(app.dt，J＝12.2；6.10Hz；1H)；4.71(br.s，1H)；4，67(dt，2H)；3.89(d，3H).

c) (1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -3-oxabicyclo [3.1.0] octan-2-one

(2Z) -3- (3, 6-difluoro-2-methylphenyl) prop-2-enyldiazoacetate (3.45g, 0.013 mol) was dissolved in 100ml of dry degassed dichloromethane and then added dropwise at room temperature over 6 hours under argon to a solution of chiral polyDoyle catalyst (Aldrich, also available from Johnson Mathey, 10mg, 0.1 mol%) in 50ml of dichloromethane the initial blue color turned to olive color at the end of the addition the reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (silica purification, EA: Hex, 1:5 → 1:1) to give 2.72g (88%) of (1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -3-oxabicyclo [3.1.0] octan-2-one colorless solid A Chiracel OD column was used in this step, enantiomeric purity was measured in hexane at 10% IPA to-94% ee.

¹H-NMR(CDCl₃)：7.00(m，1H)；6.72(m，1H)；4.33(dd，1H)；4.10(d，1H)；4.02(d，3H)；2.66(m，2H)；2.37(t，1H).

d) (1S, 1aR, 7bS) -1- (bromoethyl) -4, 7-difluoro-1 a, 7 b-dihydrocyclopropa [ c ] chromen-2 (1H) -one

(1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -3-oxabicyclo [3.1.0] octan-2-one (130mg, 0.55mmol) was mixed with 1.2ml of 30% HBr/AcOH (6mmol) and then heated with stirring at 90 ℃ for about 4 hours in a sealed vessel, then the reaction mixture was cooled, mixed with water, extracted with diethyl ether (3X 20ml). Ether extract was washed with saturated sodium bicarbonate solution, then with brine, dried over magnesium sulfate and concentrated to give 160mg of a white solid with 98% yield.

¹H-NMR(CDCl₃)：7.08(m，1H)；6.88(m，1H)；3.44(dd，1H)；3，06(t，1H)；2.96(dd，1H)；2.64(dd，1H)；2.46(m，1H).

e) (1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid.

(1S, 1aR, 7bS) -1- (bromoethyl) -4, 7-difluoro-1 a, 7 b-dihydrocyclopropa [ c ] chromen-2 (1H) -one (360mg, 1.2mmol) was combined with a solution of NaOH (0.1g, 2.5mmol) in 5ml of water, heated at 90 ℃ with stirring for 1 hour.

¹H-NMR(CDCl₃)：6.86(m，1H)；6.54(m，1H)；4.48(m，2H)；2.62(t，1H)；2.20(t，1H)；2.11(m，1H).

Example 43

(+/-) cis-N- [1a, 6 b-dihydro-1H-benzo [ b)]Cyclopropyl [ d ]]Thien-1-yl]-N' - (5-cyano-2-pyridinyl) -urea

a) Cis-1 a, 6 b-dihydro-1H-benzo [ b ] cyclopropa [ d ] thiophene-1-carboxylic acid ethyl ester, (1S, 1aS, 6bR) or (1R, 1aR, 6bS)

Ethyl diazoacetate was slowly added to 10g of thiophene at 140 ℃, the reaction was monitored by gas chromatography and stopped after 7 hours, the residue was purified by flash chromatography (5% diethyl ether in hexane), the cis isomer (917mg, Rdt ═ 6%) was confirmed by NMR spectroscopy.

Reference material:

Badger G.M.et al，J.Chem.Soc.，1958，1179-1184.

Badger G.M.et al，J.Chem.Soc.，1958，4777-4779.

b) cis-1 a, 6 b-dihydro-1H-benzo [ b ] cyclopropa [ d ] thiophene-1-carboxylic acid, (1S, 1aS, 6bR) or (1R, 1aR, 6bS)

Cis isomer (443mg), LiOH (193mg) in 15ml methanol/25% H₂The mixture in O was refluxed for 1h after evaporation of the solvent in vacuo, the residue was dissolved in water and then washed with diethyl ether the aqueous phase was acidified with concentrated HCl, extracted twice with dichloromethane and after drying the organic phase was evaporated to give the desired acid (313.6mg).

c) (+/-) cis-N- [1a, 6 b-dihydro-1H-benzo [ b ] cyclopropa [ d ] thiophen-1-yl ] -N' - (5-cyano-2-pyridinyl) -urea

Cis-acid (313mg) in toluene (20ml) in Et₃Refluxing in the presence of N (0.25ml), diphenylphosphoryl azide (0.3ml) and 2-amino-6-cyanopyridine (220mg) for 4h after cooling, the toluene phase was washed with water then HCl solution (0.01M), dried and the organic phase evaporated₂Hexane 1) and 10mg of the desired compound are obtained, Rdt 2%.

¹H(DMSO-d₆)：3.32(1H，m)；3.39(1H，td，8.05；7.69)；3.52(1H，dd，7.69，6.22)；7.08(1H，td，7.32，1.1)；7.15(1H，td，7.32，1.1)；7.22(1H，dd，8.4，0.8)；7.39(2H，m)；7.50(1H，NH)；8.00(1H，dd，8.79，2.2)；8.23(1H，d，2.2)；9.76(1H，NH)

¹³C(DMSO-d₆)：25.6(CH)，29.5(CH)，33.7(CH)，101.5(C)，112.1(CH)，118.0(C)，122.1(CH)，124.9(CH)，127.3(CH)，128.0(CH)，136.3(C)，141.7(CH)，143.7(C)，151.6(CH)，155.1(C)，156.1(C)Mass：310(M+2)，309(M+H)

Example 44

(-) -cis-1- (5-chloro-Pyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c ]]Benzopyran-1-yl) -ureas

This compound was prepared analogously to example 1c, except using chiral (+) -cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (see example 42e) (1.3g, 5.75 mmol.) silica gel purified product was recrystallized from acetonitrile to yield 0.95g (47%) of the title product absolute stereochemical configuration as shown in example 30.

¹H-NMR(CDCl₃)：9.25(broad s，1H)，8.67(s，1H)，7.79(d，1H)，7.48(dd，1H)，6.92-6.86(m，1H)，6.71(d，1H)，6.65-6.60(m，1H)，4.45(dd，1H)，4.34(dd，1H)，3.80(q，1H)，2.61(t，1H)，2.00-1.98(m，1H).

Example 45

(-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c]Benzopyran-1-yl) -ureas

(+) -cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (see example 42e) (1, 18g, 5.2mmol), diphenylphosphoryl azide [ 1340. mu.l, 6.3mmol (d ═ 1.277) ], triethylamine (870. mu.l, 6.3mmol) and 2-amino-5-cyanopyridine (740mg, 6.3mmol) were dissolved in toluene (15ml) and refluxed for 4 hours, then the solvent was removed in vacuo and the crude product was dissolved in ether, then washed (3. mu.100 ml0.01M HCl) and purified by chromatography (silica gel, 0 → 1% methanol in ether) to give pure (-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] chromen-1-yl) -urea (1.1g, 64%). The 92% was determined by HPLC on a chiral AGP column using an eluent of 11% acetonitrile in sodium phosphate buffer at a flow rate of 0.9 ml/min.

¹H-NMR(CDCl₃)：9(s，NH)，8.42(s，NH)，8.16(d，1H).7.72(dd，1H)，6.97-6.76(m，2H)，6.69-6.61(m，1H)，4.47(dd，1H)，4.31(dd，1H)，3.75(m，1H)，2.65(t，1H)，2.05-1.96(m，1H).

Example 46

(-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 27 b-tetrahydro-cyclopropa [ c]Benzopyran-1-yl) -thioureas

(+) -cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (2.2g, 9.7mmol), DPPA [2380 μ l, 10.7mmol 97% (d ═ 1.277) ] and TEA (1510 μ l, 11.7mmol) were refluxed in toluene (20ml) for 2h then dioxane (26ml) and hcl (aq) (26ml, 6M) were added, the reaction mixture was left to stand for 1-2 h water (50ml) was added at 50 ℃, the aqueous phase was washed with diethyl ether (2: -25 ml) and then basified with ammonia (aq) and extracted with dichloromethane and dried to give the intermediate 4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-ylamine (1.37g, 71%) which was directly treated with 6-isothiocyanato nicotinonitrile (1.25M) 7.7mmol) in acetonitrile (2ml) at room temperature without filtration of the precipitated crystals, removal of the solvent in vacuo and purification by chromatography (silica, 20% diethyl ether in pentane). The product crystals obtained were combined and the crude product (900mg) was recrystallized (ethanol-acetone), pure (-) -cis-1- (5-cyanopyridin-2-yl) -3- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -thiourea (590mg 18%). the absolute stereochemical configuration is as shown in example 30.

¹H-NMR(CDCl₃-MeOD)：8.1(d，1H)，7.77(dd，1H)，6.99-6.91(m，1H)，6.74(dd，1H)6.73-6.66(m，1H)，4.48(dd，1H)，4.33(dd，1H)，4.20(dd，1H)，2.78(t，1H)，2.16-2.1(m，1H).

Example 47

(+/-) -cis-1-bromopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 27 b-tetrahydro-cyclopropan [ c)]Benzopyran-1-yl) -ureas

a)1- (4-fluoro-2-prop-2-ynyloxy-phenyl) -propan-1-one.

To a mixture of NaH (95%, 278mg, 11mmol) in DMF (20mL) was added 1- (4-fluoro-2-hydroxyphenyl) -propan-1-one (1.68g, 10mmol) in DMF (5mL) at 0 deg.C after 15 minutes at 0 deg.C 3-bromopropyne (3.02g, 20mmol) was added to the reaction mixture after 1 hour at 0 deg.C the reaction mixture was warmed to room temperature, the reaction mixture was extracted with H2O (100mL H O (100mL) was added₂Et for O phase₂O (3 x 100ml) wash, remove the solvent of the combined organic phases under reduced pressure, column chromatography of the crude product (silica gel, CH)₂Cl₂) Purification gives 1.40g (68%) of 1- (4-fluoro-2-prop-2-ynyloxy-phenyl) -prop-1-one.

¹H-NMR(CDCl₃)：7.64(dd，1H)，6.69(dd，1H)，6.60(ddd，1H)，4.68(d，2H)，2.85(q，2H)，2.58(t，1H)，1.03(t，3H).

b)1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one

Synthesis of 1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one Using 1- (4-fluoro-2-propan-2-alkynyloxy-phenyl) -propan-1-one (1.34g, 6.5mmol) in analogy to example 3b, 619mg (46%) of 1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one was obtained.

¹H-NMR(CDCl₃)：7.60(dd，1H)，6.67-6.58(m，2H)，5.86(dt，1H)，4.76(dd，2H)，2.93(q，2H)，1.23(t，3H).

c) (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-Tetrahydrocyclopropan [ c ] benzopyran-1-carboxylic acid ethyl ester

Synthesis of ethyl (+ -) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate according to method 3c), 1- (5-fluoro-2H-benzopyran-8-yl) -propan-1-one (619mg, 3mmol) to yield 142mg (16%) of ethyl (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate and ethyl (±) -trans-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylate as by-products.

¹H-NMR(CDCl₃)：7.59(dd，1H)，6.65(m，1H)，4.50-4.46(m，2H)，3.95(q，2H)；2.89(q，2H)，2.57(dd，1H)，2.20(dd，1H)，1.13-1.03(m，1H)，1.12-1.01(m，6H).

d) (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ d ] benzopyran-1-carboxylic acid

(±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c ]]Synthesis of benzopyran-1-carboxylic acid analogously to example 1b, using (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropan [ c)]Benzopyran-1-carboxylic acid ethyl ester (140.3mg, 0.48mmol) to give 83mg (65%) of (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-carboxylic acid as white solid the crude product was purified by column chromatography (silica gel on CH)₂Cl₂Medium 1 → 5% MeOH).

¹H-NMR(DMSO-d₆)：12.15(br s，1H)，7.48(dd，1H)，6.78(dd，1H)，4.57(dd，1H)，4.43(dd，1H)，2.93-2.80(m，2H)，2.55(dd，1H)，2.24(dd，1H)，2.20-2.10(m，1H)，1.02(t，3H).

e) (+/-) -cis-1- (5-bromopyridin-2-yl) -3- (7-fluoro-4-propionyl-1, 1a, 27 b-tetrahydro-cyclopropa [ c ] chromen-1-yl) -urea

The title compound was synthesized in analogy to example 1c) by reacting 1 equivalent of (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid and 1eq of triethylamine in toluene with 1eq of diphenylphosphoryl azide at room temperature for 30 minutes the reaction mixture was heated to 120 ℃, approximately equimolar solution of 2-amino-5-bromopyridine was added, after 3 hours the solution was cooled to room temperature and the title compound was extracted as described above.

Example 48

(1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -2-methoxy-3-oxabicyclo [3.1.0]Hexane (C)

a) Iodo-3-oxabicyclo [3.1.0] hex-2-one

The title compound was synthesized using the stereochemistry described in Doyle J Amer Chem Soc 117 (21)5763-5775 (1993).

b) Iodo-2-methoxy-3-oxabicyclo [3, 1, 0] hexane

The title compound was synthesized stereochemically as described by Martin et al, Tett Lett 391521-1524 (1998).

c) (1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -2-methoxy-3-oxabicyclo [3.1.0] hexane

2, 4-Difluorophenylmethylether (90mg, 0.62mmol) was dissolved in anhydrous degassed THF (7ml), cooled to-78 ℃ under nitrogen, 2, 5M nBuLi in hexane (0.30ml, 0.77mmol) was added and the reaction mixture stirred at-78 ℃ for 2h ZnCl₂(150mg, 1.1mmol) was added as a solution in anhydrous THF (7ml) and the reaction mixture warmed to room temperature for 2h iodo-2-methoxy-3-oxacyclohexane (150mg, 0.63mmol), Pd (OAc)₂(1.5mg, 6.2. mu. mol) and the ligand tris (2, 4-di-tert-butylphenyl) phosphite (40mg, 62. mu. mol) were mixed in anhydrous tetrahydrofuran (7ml) and then the reaction mixture was added and the reaction mixture was heated at reflux for 3 days, quenched with water, diethyl ether was added, the layers were separated, the organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the title compound, otherwise designated 2, 4-difluoro-5- (cyclopropylacetal) anisole, purified by column chromatography on silica (EtOAc/hexane 1:3) to give (4)50mg, 31%.

¹H NMR(CDCl₃)δ(ppm)：6.88-6.94(m，1H，ArH)，6.68-6.73(m，1H，ArH)，4.82(s，1H，CHOCH₃)，3.97-3.98(m，1H，CHOCH)3.94(s，3H，OCH₃)，3.79-3.81(m，1H，CHOCH)3.30(s，3H，OCH₃) 2.13-2.19(m, 2H, 2x CH-cyclopropyl), 1.89(tr, J ═ 7.81Hz, 1H, CH cyclopropyl).

Example 49

Cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Benzopyran-1-carboxylic acid

BBr₃In CH₂Cl₂1M solution (5.8 ml; 5.8 mmole 2.1eq) the starting lactone (1S, 5R, 6S) -6- (3, 6-difluoro-2-methylphenyl) -3-oxabicyclo [ 3.1.0) from example 42c) was added at 0 deg.C]Hex-2-one (0.66 g; 2.75mmol). The reaction mixture is stirred at 0 ℃ for 1 hour, acetonitrile (5.8ml) is added, stirring is continued at 0 ℃ for 3 hours, the reaction mixture is quenched with water, the organic phase is separated, CH is used₂Cl₂The aqueous phase was extracted, the organic phases combined, evaporated, NaOH (0.33 g; 8.25 mmol; 3eq) in water (5ml) was added to the residue obtained, stirred at 80 ℃ for 45 minutes, the reaction mixture was extracted with diethyl ether to remove non-acidic impurities, the diethyl ether remaining in the aqueous phase was evaporated in vacuo, concentrated HCl was added to pH3.1 hours, the solid was filtered off to give 0.497g (80%) of the final crude acid product, a tan solid, the crude acid was EtOH/H dissolved in 6ml₂O (40/60v/v), treated with activated carbon, the hot solution was filtered and crystallized on standing, yield 0.4g (64%).

Example 50

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (5-fluoro-2-pyridinyl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 2-amino-5-fluoropyridine (28mg, 1.1eq), DPPA (0.054ml, 1.1eq), then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, purified by column chromatography on silica (50g, ethyl acetate/hexane 1:1) to give 30mg of a white solid product.

¹H-NMR(DMSO-d₆)：9.34(br s，～1H)，7.85(br d，2H)，7.6(dt，1H) 7.33(dd, 1H), 7.06(m, 1H), 6.77(dt, 1H), 4.29(m, 2H), 3.48(m, 1H), 2.48(m, 1H/signal overlap by DMSO), 2.00(m, 1H). LC-MS: m⁺336

Example 51

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (5-iodo-2-pyridinyl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 2-amino-5-iodopyridine (54mg, 1.1eq), DPPA (0.054ml, 1.1eq), then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, purified by column chromatography on silica (50g, ethyl acetate/hexane 1:1) to give 35mg of a white solid product.

¹H-NMR(DMSO-d₆): 9.4(br s,. about.1H), 8.07(d, 1H), 8.02(br s,. about.1H), 7.91(dd, 1H), 7.11(d, 1H), 7.06(m, 1H), 6.77(dt, 1H), 4.29(br d, 2H), 3.5(m, 1H), 2.46(m, 1H/signal overlap by DMSO), 2.00(m, 1H). LC-MS: m⁺444.

Example 52

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (3-isoxazolyl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 3, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 3-aminoisoxazole (0.018ml, 1.1eq), DPPA (0.054ml, 1.1eq), then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, purified by column chromatography on silica (50g, ethyl acetate/hexane 1:1) to give 10mg of a white solid product.

¹H-NMR(DMSO-d₆: 9.45(br s,. about.1H), 8.6(d, 1H), 7.06(m, 1H), 6.75(dt, 1H), 6.63(d, 1H), 6.33(br s,. about.1H), 4.29(m, 2H), 3.37 (signal overlap by water), 2.43(m, 1H), 1.98(m, 1H). LC-MS: m⁺308.

Example 53

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - [ (4-chlorophenyl) -1, 3-thiazol-2-yl]Urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 2-amino-4- (4-chlorophenyl) -1, 3-thiazole (52mg, 1.1eq), DPPA (0.052ml, 1.1eq) and then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, the product crystallized from ethanol and collected by filtration to give 50mg of the product as a white solid.

¹H-NMR(CDCl₃)：10.32(br s，～1H)，7.68(d，2H)，7.37(s，1H)，7.32(d，2H)，6.96(s，1H)，6.87(m，1H)，6.62(dt，1H)，4.44(dd，1H)，4.33(dd，1H)，3.53(m，1H)，2.56(m，～1H)，1.96(m，1H).LC-MS：M⁺434.

Example 54

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl 1-N' - (5-fluoro-1, 3-benzothiazol-2-yl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 2-amino-6-fluoro-1, 3-benzothiazole (41mg, 1.1eq), DPPA (0.041ml, 1.1eq) and then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, the product crystallized from ethanol and collected by filtration to give 20mg of the product as a white solid.

¹H-NMR(CDCl₃)：10.58(br s，～1H)，7.78(br d，1H)，.7.52(dd，1H)，7.45(dd，1H)，7.05(dt，1H)，6.94(m，1H)，6.65(dt，1H)，4.44(dd，1H)，4.33(dd，1H)，3.53(m，1H)，2.58(m，～1H)，2.03(m，1H).LC-MS：M⁺434.

Example 55

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (4-pyrimidinyl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 4, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 4-aminopyrimidine (25mg, 1.1eq), DPPA (0.054ml, 1.1eq) and then the reaction mixture was heated at 110 ℃ for 3 hours with stirring, the reaction mixture was concentrated by rotary evaporation, the product crystallized from ethanol and collected by filtration to give 20mg of white solid product.

¹H-NMR(DMSO-d₆): 9.71(br s, 1H), 8.4(br s, 1H), 8.39(d, 1H), 7.86(br s, 1H), 7.31(d, 1H), 7.08(m, 1H), 6.77(dt, 1H), 4.31(m, 2H), 3.48(m, 1H), 2.48(m, 1H, overlapped by DMSO signal), 2.02(m, 1H).

Example 56

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (2-pyrazinyl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 4, 7 b-tetrahydrocyclopropa [ c ] benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 4-aminopyrazine (25mg, 1.1eq), DPPA (0.054ml, 1.1 eq). The reaction mixture was then heated with stirring at 110 ℃ for 3 hours. The reaction mixture was concentrated by rotary evaporation and the product crystallized from ethanol and collected by filtration to yield 5mg of product as a white solid.

¹H-NMR(DMSO-d₆)：9.57(br s，1H)，8.67(br s，1H)，8.10(d，1H)，7.95(br s，1H)，7.64(br s，1H)，7.05(m，1H)，6.77(dt，1H)，4.31(m，2H)，3.49(m，1H)，2.48(m，～1H，overlapped with DMSO signal)，2.02(m，1H).

Example 57

N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Benzopyran-1-yl]-N' - (5-cyclopropyl-1H-pyrazol-3-yl) urea

(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c]Benzopyran-1-carboxylic acid (50mg, 0.22mmol, ee 90%) was mixed with toluene (1ml), triethylamine (0.034ml, 1.1eq), 3-amino-5-cyclopropyl-1H-pyrazole (30mg, 1.1eq), DPPA (0.030ml, 1.1 eq). The reaction mixture was then heated with stirring at 110 ℃ for 3 hours. The reaction mixture was concentrated by rotary evaporation and the two compounds were separated by column chromatography on silica (50g, ethyl acetate/hexane 1:3) to give 3mg of the title product. By using¹³C. The gHMBC, gHMQC and NOESY NMR experiments confirmed the structure.

¹H-NMR(CDCl₃)：7.05(br d，～1H)，6.88(m，1H)，6.64(dt，1H)，5.24(d，1H)，4.49(dd，1H)，4.33(dd，1H)，3.63(m，1H)，2.61(m，～2H)，1.99(m，1H)，0.99(m，2H)，0.58(m，2H).

Biological Effect

Various guidelines for analyzing test compounds at the enzyme level and in cell culture are found in DAIDS virology Manual for HIV Laboratories, according to the Division of AIDS, NIAID USA1997, including isolation and/or selection of mutant HIV strains and mutants RT., corrected HIV Resistance colour group data Analysis Plan for Resistance Studies on day 8/31 1999, including reasonable tolerance Studies on various drug escape mutants, the determination of HIV activity by the compounds of the invention, for example using multiple determinations with XTT in MT-4 cells (Weislow et al, J NatInst1989, vol81no8, 577et seq), preferably in the presence of 40-50% human serum, indicating that protein binding affects the present XTT cell line 4, in the supplementation of human serum with 10% fetal bovine serum or with 40-50% human serum (suitable for this case, if briefly summarized below, Penicillin and streptomycin were grown in RPMI medium, which was plated in 96-well microplates (2 x 104 cells)Cell/pocket), HIV-1IIIB (native type) or mutant viruses such as those with RTI Ie100, Cys181 or Asn103 mutations infected with 10-20TCID50 per pocket serially diluted test compounds were added to each pocket at 37 ℃ in CO₂The cells were propagated in enriched atmosphere cultures and the viability of the cells was determined on day 5 or 6 using XTT vital stain₅₀Compounds of the invention were analyzed in the XTT assay described above using natural HIV-1IIIB, with the results shown in table 1:

TABLE 1

Examples	ED(nM)
		Example 7	7
Example 16	6
		Example 18	6
Example 19	10
		Example 20	7
Example 23	7
		Example 24	20
Example 30	3
		Example 31	2.5
Example 33	9
		Example 43	2

The above-cited data analysis protocol outlines corresponding drug escape mutants for each antiviral drug type currently on the market, drug escape cell lines are readily isolated from HIV patients who have failed specific antiviral therapy, or, alternatively, the preparation of RT mutants of known genetic background are described in WO97/27319, WO99/61658 and WO00/73511, which also show the use of such mutants in sensitivity profiles.

K103 is a drug escape mutant of particular relevance in the context of NNRTI therapy, and the compounds of the invention preferably have a low ED50 resistance to this mutant, particularly in assays mimicking the presence of human serum.

Claims (2)

1. A compound of formula III:

wherein R is₄And R₇Independently is halogen; and

R₁₁is COOH or C thereof_1-6An alkyl ester.

2. According to claim1, wherein R is₄And R₇Is fluorine.