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HK1101400B - Non-nucleotide reverse transcriptase inhibitors - Google Patents

Non-nucleotide reverse transcriptase inhibitors Download PDF

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Publication number
HK1101400B
HK1101400B HK07109407.1A HK07109407A HK1101400B HK 1101400 B HK1101400 B HK 1101400B HK 07109407 A HK07109407 A HK 07109407A HK 1101400 B HK1101400 B HK 1101400B
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Hong Kong
Prior art keywords
cis
tetrahydro
carboxylic acid
difluoro
cyclopropane
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Application number
HK07109407.1A
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Chinese (zh)
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HK1101400A1 (en
Inventor
Christian Sund
Nathalie Roue
Stefan LINDSTRÖM
Dmitry Antonov
Christer Sahlberg
Katarina Jansson
Original Assignee
Medivir Aktiebolag
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Priority claimed from SE0400021A external-priority patent/SE0400021D0/en
Priority claimed from SE0400585A external-priority patent/SE0400585D0/en
Application filed by Medivir Aktiebolag filed Critical Medivir Aktiebolag
Priority claimed from PCT/SE2004/002034 external-priority patent/WO2005066131A1/en
Publication of HK1101400A1 publication Critical patent/HK1101400A1/en
Publication of HK1101400B publication Critical patent/HK1101400B/en

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Description

Non-nucleotide reverse transcriptase inhibitors
Technical Field
The present invention relates to non-nucleoside reverse transcriptase inhibitors (NNRTIs) effective against HIV-1 and having improved resistance and pharmacokinetic profiles. The invention also relates to novel intermediates in the synthesis of such compounds and to the use of said compounds in antiviral methods and compositions.
Background
Our earlier filed PCT applications WO02/070516 and WO 03/020705 require novel NNRTIs of formula I and pharmaceutically acceptable salts and prodrugs thereof,
wherein:
R1o, S;
R2is an optionally substituted, nitrogen-containing heterocycle, such as pyridyl;
R3is H, C1-C3An alkyl 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 radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl, hydroxy C1-C6Alkyl, amino C1-C6Alkyl, carboxyl C1-C6Alkyl, cyano C1-C6Alkyl, amino, carboxyl, carbamoyl, cyano, halo, hydroxy, keto, and the like;
x is- (CH)2)n-D-(CH2)m-or X is- (CRaRb)c-；
D is-NR8-, -O-, -S (═ O) -, or-S (═ O)2-；
R8Is H, C1-C3An alkyl group;
Raand RbIndependently is H, C1-C3Alkyl, OH or RaAnd RbTogether are ═ O;
n and m are independently 0 or 1;
c is 1, 2 or 3.
Example 20 of WO02/070516 discloses the following compounds,
the compounds are said to inhibit wild type HIV (HIV)IIIB) ED (D)50Was 7 nM.
The same thing as wePending, but unpublished PCT application WO04/021969 as of priority date discloses compounds of the general formula I above, but in which R is2Is represented by the formula- (CHR) at the 5-position11)p-E-(CHR11)q-R10Substituted pyridin-2-yl wherein E is-CH2-、-CHOH-、-C＝O-、-NR9-、-O-、-S-、-S(＝O)2-；
P and q are independently 0, 1 or 2, where P + q ≦ 2;
R10is a monocyclic ring optionally substituted by halo, cyano, morpholinomethyl-or morpholinoketo-group; and
R11independently is H, C1-C3Alkyl, halo-substituted C1-C3Alkyl or hydroxy.
Although the urea and thiourea NNRTIs disclosed in the above documents are ingeniously effective against reverse transcriptase, especially that of HIV-1, with an extreme lack of replication fidelity, with consequent propensity for rapid development of drug resistant HIV virus properties, suggesting the need for additional antiviral agents with enhanced antiviral properties to combat problematic drug escape mutants, especially at RT100, 103 and/or 181 positions.
Brief description of the invention
According to a first aspect of the present invention there is provided a compound of formula Z:
wherein:
a is CH or N;
R1is a substituent on a carbon atom in the ring containing A, said substituent being selected from the group consisting of-S (═ O)pRa，
Wherein Ra is-C1-C4Alkyl, -ORx, -NRxRx, -nhrxrx, -nhnhch (═ O) ORx, -NRxOH;
-C(＝O)-Rb，
wherein Rb is-C1-C4-alkyl, ORx, -NRxRx, -NRxNRxRx, -NHC1-C3-alkyl-C (═ O) ORx;
-NRxRc，
wherein Rc is H, C1-C4Alkyl, -NRxRx; -C (═ O) Rd, -CN, S (═ O)pRx
Wherein Rd is C1-C4-alkyl, -ORx, -NRxRx-C1-C3-alkyl-O-C1-C3Alkyl C (═ O) ORx;
-C1-C3-alkyl-COORx;
-C1-C3alkyl-OH or C thereof1-C4An alkyl ether or ester;
-(O-C1-C3alkyl radical)q-O-Rx；
A 5-or 6-membered aromatic ring having 1-3 heteroatoms;
p and q are independently selected from 1 or 2;
rx is independently selected from H, C1-C4Alkyl or acetyl; or a pair of Rx may form together with the adjacent N atom a pyrrolidine, piperidine, piperazine or morpholine ring;
R2is a substituent on a carbon atom in the ring containing A, and is H, halo, cyano, C1-C4Alkyl, halo C1-C4-an alkyl group;
l is-O-, -S (═ O)r-or-CH2-, where r is 0, 1 or 2;
R3is H, C1-C3An alkyl 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 radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl, hydroxy C1-C6Alkyl, amino C1-C6Alkyl, carboxyl C1-C6Alkyl, cyano C1-C6Alkyl, amino, carboxyl, carbamoyl, cyano, halo, hydroxy, keto;
x is- (CR)8R8’)n-D-(CR8R8’)m-；
T is O or S;
d is a bond, -NR9-, -O-, -S (═ O) -, or-S (═ O)2-；
n and m are independently 0, 1 or 2, provided that when D is a bond, they cannot both be 0;
R8and R8' independently is H, C1-C3Alkyl, halo C1-C3Alkyl, hydroxy, or R8And R8' together with its adjacent C atom is-C (═ O) -;
R9independently is H, C1-C3An alkyl group;
provided that R is1When — C (═ O) Rb is not morpholinonyl-.
The preferred value for T is O, i.e., a urea derivative, although T is S (i.e., a thiourea derivative) is also highly effective.
To R3The preferred value of (b) is H.
Preferably R4Is hydrogen, halo C1-C3Alkyl or hydroxy, especially fluoro.
Preferably R5Is halo, C1-C3Alkylcarbonyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or H, especially fluoro and most preferably H.
Preferably R6Is hydrogen, halo C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-3Alkylcarbonyl, cyano or ethynyl, especially methoxy or fluoro and most preferably H.
Preferably R7Is hydrogen, halo C1-C3Alkyl, halo, C1-C3Alkoxy or C1-3Alkylcarbonyl, most preferably fluoro.
Preferably R5And R6Is H and R4And R7Most preferably both are fluorinated. Alternative preferred configurations include those wherein R5And R6Is H, R4Is fluoro and R7In the acetyl or cyano configuration.
R4-R7Is suitably at least one of halo C1-C3Alkyl radicals, e.g. CF2H、-CFH2、-CH2CF3or-CF2CF3And especially-CF3。
R1Preferred of (1) — S (═ O)pRa groups include those wherein p is 2 or especially 1, and wherein Ra is an alkyl group, such as cyclopropyl, methylcyclopropyl, and most preferably methyl. Preferred groups therefore include methylsulfonyl or methylsulfinyl.
Additionally preferred is-S (═ O)pNRxRx groups include those groups, rings, wherein Rx are each H or Me or one of them is H and the other is MePropyl or methylcyclopropyl, most preferably NH2. Preferred groups therefore include sulphonamides.
R1preferred-C (═ O) -Rb groups of (a) include those where Rb is NRxRx or NHNRxRx, especially N-methylcarboxamide, hydrazinocarbon group and-C (═ O) NHNHC (═ O) Me. Other preferred-C (═ O) -Rb groups include-C (═ O) NRx '-N-morpholine, -C (═ O) NRx' -N-piperidine, -C (═ O) NRx '-N-pyrrolidine, -C (═ O) NRx' -N-piperazine, where Rx is methyl, acetyl or preferably H.
R1preferred-NRxRc groups of (a) include those wherein Rx is H or Me and those wherein Rc is-C (═ O) Rd, wherein Rd is alkyl and S (═ O) pRx, especially cyclopropylamide and acetamide.
R1Preferred of (1)1-C3the-alkyl-COORx group includes carboxyethyl and C thereof1-C2An alkyl ester.
R1Preferred of (1)1-C3alkyl-ORx groups including hydroxyethyl and C1-C2Alkyl ethers and esters.
R1Preferred of (A) is- (O-C)1-C3Alkyl radical)qthe-O-Rx groups include ethoxy-containing groups, especially the ethoxy group of the 2- (methoxyethoxy) ethoxy group.
R1Exemplary heteroatom rings of (a) include furyl, thienyl, pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, especially 5-membered rings such as thiazolyl, thiadiazolyl, pyrazolyl, oxadiazolyl and most preferably triazolyl.
A preferred value for L is-O-.
The compound of formula Z may be administered as a racemic mixture, but preferably the cyclopropyl moiety intermediate (thio) urea functionality, X and the phenyl ring (hereinafter Y) are at least 75% such as about 90% enantiomerically pure in terms of configuration:
preferred optical isomers of the compounds of formula I exhibit negative optical rotation values. Such isomers, for example, when X is-O-CH2-when there is a tendency to elute less rapidly from chiral chromatography (chromatagram), such as chiral AGP 150 x 10mm, 5 μm; crom TechLTD column, flow 4ml/min, mobile phase 89% volume 10mM HOAc/NH in acetonitrile4And OAc. On the basis of preliminary x-ray crystallographic analysis, the currently preferred absolute configuration is shown as:
a preferred value for D is-O-. Suitable values for n and m include 1: 0 and 1: 1. Preferred values of n: m include 0: 2 and especially 0: 1, which are derivatives of chromans. Each R8And R8' suitably is H. Alternatively, R is 0 and m is 18Advantageously H and R8' is OH.
Particularly preferred compounds have a stereochemistry corresponding to the (1S, 1aR, 7bR) -1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromen-1-yl group. For clarity, its structure is noted:
C1-Cnalkyl (where n is 3 or 4), or lower alkylThe expression "group" includes such groups as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, methylcyclopropyl and the like. The term halo refers to chloro, bromo, fluoro and iodo, especially fluoro. C1-CnAlkoxy refers to groups such as methoxy, ethoxy, propoxy, cyclopropoxy, t-butoxy, and the like. C2-CnAlkenyl refers to groups such as vinyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl and the like. C1-CnAlkylthio includes methylthio, ethylthio, tert-butylthio and the like. C1-CnThe alkanoyloxy group includes acetyloxy, propionyloxy, formyloxy, butyryloxy and the like. C2-CnThe alkenyloxy group includes vinyloxy, propenyloxy, isobutoxyvinyl and the like. Halogen substituted C1-CnAlkyl (including containing such moieties as halo C)1-CnA complex substituent of alkoxy) includes alkyl as defined herein substituted 1 to 3 times with halogens including trifluoromethyl, 2-dichloroethyl, 3-difluoropropyl, and the like. The term amine includes, for example, C, optionally substituted with halogen1-C7Acyloxy, C1-C6Alkyl radical, C1-C6NH substituted by alkoxy, nitro, carboxyl, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or the like2、NHMe、N(Me)2A group. Carboxy, carboxymethyl and carbamoyl radicals include the corresponding pharmaceutically acceptable C1-C6Alkyl 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 are when any R4-R7Or R1Or R2When representing a hydroxy functional group, are pharmaceutically acceptable ethers and especially esters (including phosphates), when any R1Substituent or R4-R7When representing an amine function, is a pharmaceutically acceptable amide or carbamate or when R1、R2Substituent or R4-R7When a carboxyl functional group is indicated, it is a pharmaceutically acceptable ester. Pharmaceutical preparationsThe above acceptable esters include alkyl esters including acetyl, acetyl (ethanoyl), butyryl, tert-butyryl and pivaloyl, phosphate esters and sulfonate esters (i.e., those derived from RSO)2Esters of OH, wherein R is lower alkyl or aryl). Pharmaceutically acceptable esters include lower alkyl esters and ethers as disclosed in WO 00/47561, especially methoxyaminoacyl and ethoxyaminoacyl.
The compounds of formula Z may form salts which constitute further aspects of the invention. Suitable pharmaceutically acceptable salts of compounds of formula I include salts of organic acids, especially salts of carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cypionate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate, pectate (pectate), 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, vollate, camphorate, undecanoate and succinate, salts of organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, butanesulfonate, butanedioate, and the like, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphate and sulfonate.
As used herein, hydroxy protecting Groups refer to substituents which protect a hydroxy group from unwanted reactions during Synthesis, such as those O-protecting Groups disclosed in Greene, "Protective Groups organic Synthesis," John Wiley & Sons, New York (1981). Hydroxy protecting groups include substituted methyl ethers such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tert-butyl and other lower alkyl ethers such as isopropyl, ethyl and especially methyl, benzyl and triphenylmethyl ethers; a tetrahydropyranyl ether; substituted 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.
Similarly, N-protecting groups as used herein refer to those conventional N-protecting groups disclosed in Greene, "protective groups in Organic Synthesis", John Wiley & Sons New York 1981.
The invention also provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent therefor. Other aspects of the invention also provide methods for inhibiting HIV comprising administering to a patient suffering from HIV-1 infection or exposure to HIV-1 a compound of formula Z. HIV-1 may comprise drug escape mutants, such as HIV strains comprising mutations at the 100, 103 and/or 181 mutations, in particular the K103N and/or L100I mutants.
The invention also extends to the use of a compound of formula Z in therapy, for example in the manufacture of a medicament for the treatment of HIV infection.
In treating conditions caused by HIV, it is preferred to administer the compound of formula Z in an amount to achieve plasma levels of about 100 to 5000nM, e.g., 300 to 2000 nM. Corresponding dose ratios of 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day, are established depending on the bioavailability of the formulation. Typical dosage rates for normal adults will be about 0.05 to 5g, preferably 0.1 to 2g, e.g. 500-750mg, per day in one to four dosage units per day. As with all drugs, the dosage rate will vary depending on the weight and metabolic status of the patient and the severity of the infection, and adjustments may be necessary for concomitant drug use.
To match the conventional practice of HIV inhibitors, it is advantageous to combine one to three other antiviral agents to provide a synergistic response and to ensure a complementary mode of resistance. Such other antiviral agents may include AZT, ddI, ddC, D4T, 3TC, DAPD, alovudine, abacavir (abacavir), adefovir (adefovir), adefovir dipivoxil (adefovir dipivoxil), di-POC-PMPA, GW420867X, foscarnet (foscarnet), hydroxyurea, Hoechst-Bayer HBY 097, efavirenz (efavirenz), troviradine, MIV-150, capravirine, nevirapine (nevirapine), delaviridine, tipranavir (tipranavir), emtricitabine (emtricitabine), PFA, H2G (omaciclicovir), MIV-606 (valaciclovir), TMC-126, TMC-125, TMC-120, ritavir (ritavir), amprenavir (dmavirenz), amprenavir (amprenavir), amprenavir (dmavir, amprenavir), amprenavir (fosalvir), amprenavir (dmavir-450, amprenavir), amprenavir (dmavir, amprenavir), amprenavir (dminavir), amprenavir (dminavir), typically reflecting their respective activities and bioavailability in molar proportions. Typically such ratios relative to the compound of formula I will be tailored from 25: 1 to 1: 25, but may be lower, for example in the case of cytochrome p450 antagonists such as ritonavir.
The compounds of the invention are typically prepared as follows:
scheme 1
(a)DPPA、Et3N, toluene; (b) substituted 2-aminopyridines; (c) aqueous HCl, dioxane; (d) substituted 2-pyridine isothiocyanates.
Compounds of the general formula (I) wherein T is O (urea) or S (thiourea), Re is a (substituted) oxyphenyl or oxypyridyl moiety, or a thio, sulpholine, sulphone or methylene analogue of such an ether and R3Is H, prepared by the method shown in scheme 1. Making cyclopropane carboxylic acid1-scheme- 1Conversion to acyl azide and heating to 120 ℃ to promote Curtius rearrangement and provide isocyanate2-scheme-1. By reacting isocyanates withCoupling of correspondingly substituted 2-aminopyridines to give ureas3-scheme-1. Such as hydrolysis of isocyanate to form cyclopropylamine in step (c)4-scheme-1Followed by reaction with 2-pyridyl isocyanate to form thiourea5-scheme-1. The isothiocyanates can be prepared from optionally ring-substituted 2-aminopyridines by known methods, for example treatment with thiophosgene or thiocarbonyldiimidazole. Using the appropriate for R accordingly3Preparation of R of formula I from 2- (N-methylamino) pyridine, an amine-substituted amino-pyridine as methyl3Variants. Many 2-aminopyridines are commercially available and others are described in the literature or readily derived therefrom, such as those shown in scheme 2. Alternatively, the compounds of T ═ S can be derived from the isocyanates corresponding to 2-scheme 2A or from amines 3, 3 a-scheme 2 and amino-R attached to RC (═ S) R2Preparation, both described in WO 9303022.
Scheme 2A
(a) Alkali, DMF, heating; (b) reduction; (c) oxidizing; (d) alkali, Cu catalyst, heating
The preparation of suitable 5-O-or 5-S-substituted-2-aminopyridines is outlined in scheme 2A. Will be provided with1-scheme-2AAnd suitably R1And R2Substituents, or precursors (synthons) of these substituents, are reacted in step (a) with 5-bromo-2-nitropyridine and a base, e.g. NaH or Cs2CO3Reaction to obtain bromine substitution and generate nitro compound2-scheme-2A. The nitro group is then reduced to the amine in step (b), typically by hydrogenation at atmospheric pressure in the presence of a catalyst such as Pd or Raney nickel (Raney nickel). The precursor becomes the desired R1、R2The conversion of the substituents may be carried out before the reduction step (b) in the nitro compound2-scheme-2AThe above process is carried out. In sulfanyl2-procedure- 2ADifferent oxidizing agents, e.g. in the case of hydrogen peroxideIn step (c), the sulfide group is then converted to S ═ O) r, followed by reduction of the nitro group to form5-scheme-2A. Thio compounds3 a-scheme-2AIt is also possible, as in step (d), to react with Cu or CuI in DMF and a base such as K in the presence of a copper catalyst, for example at 150 ℃2CO3Is directly prepared by coupling 2-amino-5-bromopyridine with thiol 1 a-scheme-2A.
Scheme 2B
(a)NH3EtOH, heating; (b) et (Et)3SiH、TFA、H2SO4
The preparation of suitable 5-substituted methyl-2-aminopyridines is outlined in scheme 2B. With the appropriate R1And R2Ketones of substituents or precursors (synthons) of these substituents1-scheme- 2BReaction with ammonia in step (a) to obtain displacement of chlorine and to obtain amino compound2-procedure- 2B. Then reducing the keto group to CH in step (b)2To obtain3-scheme-2B。
Scheme 3
(a) Azoacetic acid ethyl ester, catalyst, CH2Cl2(ii) a (b) By chromatography, followed by LiOH, H2O, MeOH refluxing; (c) with LiOH, H2O, MeOH reflux, then chromatography; (d) rt, NaOH, H2O, MeOH, then using LiOH, H2O, MeOH reflux
The compounds of general formula (I) were prepared by the method shown in scheme 3. In the compoundT is O (urea) or S (thiourea), R1' and R2' is R1And R2If desired, with conventional hydroxy, carboxyl groups of amino protecting groups or for R1/R2Conventional synthon protection of R3Is H, X is-D-CH2And wherein the cyclopropyl moiety has the relevant configuration
Chromenes and derivatives thereof1-scheme-3The three-membered ring reaction (cyclization) of the double bond in (A) with ethyl azoacetate is carried out from cuprous or rhodium (II) salts, e.g. CuI, (CuOTf)2-benzene, and Rh2(OAc)4In a solvent such as dichloromethane, 1, 2-dichloroethane or chloroform. This reaction provides ethyl cyclopropylcarboxylate2-scheme-3In all relevant cis-configurations and in their trans-isomers3-scheme-3. Separation of the cis and trans diastereoisomers by column chromatography may be effected at this stage, followed by separation of the separated2-scheme-3Hydrolysis, for example by refluxing in methanolic aqueous LiOH solution, gives all cis-cyclopropylcarboxylic acid4-scheme-3The racemic mixture of (a), as described in step (b). Alternatively, a mixture of diastereomers of ethyl acetate may be subjected to hydrolysis and separation performed on a mixture of cyclopropylcarboxylic acids to provide all of the cis isomers separated, as in step (c). Step (d) comprises cis-ethyl acetate2-scheme-3Can also be separated by selective hydrolysis of the trans form at lower temperatures3-scheme-3This is done, for example, by treatment with aqueous methanol NaOH at room temperature. The separated cis-ethyl acetate can then be hydrolyzed to form cyclopropylcarboxylic acid in a conventional manner4-scheme-3. Cyclopropylformic acid is subjected to the procedure outlined in scheme 1 to give urea or thiourea5-scheme-3. Chromenes and their use1-scheme-3Prepared by the methods shown in schemes 4, 5 and 6.
Although this scheme 3 has beenDescribed in the D ═ O variant, it is clear that for D ═ S, S ═ O; s (═ O)2 and D ═ NR8Variants will be useful to handle accordingly. When R is8For H, the nitrogen is protected with a typically conventional secondary amine protecting group, such as those described in Greene& Wuts Protective Groups inOrganic Synthesis 2nded, Wiley NY 1991).
Scheme 4
(a) 3-Bromopropyne, K2CO3Acetone; (b) n, N-diethylaniline or PEG-200, 225 deg.C
Scheme 4 describes the preparation of chromenes, which include a number of commercially available disubstituted phenols, such as those in which the substitution pattern on the phenyl ring is as follows: r4And R7Is halo; r4And R6Is halo; r5And R7Is halo; r4Is halo; and R7Is C1-3An alkylcarbonyl group; and R4Is hydroxy, with R5Is C1-3An alkylcarbonyl group. Useful disubstituted phenols1-scheme-4With 3-bromopropyne in the presence of a base, e.g. K2CO3In acetone or NaH in the presence of DMF, resulting in nucleophilic substitution of the halide to form the ether2-scheme-4. The ring closure can be accomplished by heating diethyl ether in N, N-dimethylaniline or polyethylene glycol to obtain chromene3-scheme-4。
Scheme 5
NaBH4EtOH; (b) p-toluenesulfonic acid and toluene, wherein the toluene is a mixture of p-toluenesulfonic acid and toluene,refluxing;
scheme 5 describes the preparation of chromenes useful as starting materials in scheme 3 from appropriately substituted chromanones, which are readily commercially available chromanones, such as those wherein R is4To R7One of the positions being from halo or C1-3Alkoxy-substituted chromanones. By means of a suitable reducing agent, for example sodium borohydride in ethanol, in 4-chromanone1 a-scheme-5Conversion of the carbonyl group in (A) to the corresponding alcohol to give2-scheme-5. Refluxing the alcohol with a small amount of an acid, such as p-TsOH, in toluene causes2-scheme-5Dehydration to form the desired chromene1-scheme-3. Corresponding treatments will be useful for other D variants (variants). For example, the corresponding 2H-1-benzothiopyran is readily prepared from commercially available (substituted) thiochroman-4-ones by reaction with a reducing agent, e.g., a metal hydride, e.g., lithium aluminum hydride, in an organic solvent, e.g., diethyl ether, followed by dehydration, e.g., reflux with an acid, e.g., potassium hydrogen sulfate, and the like.
Scheme 6
(a) Allyl bromide, K2CO3Acetone; (b) ph3PCH3Br、NaH、THF；(c)Cl2[Pcy3]2Ru＝CHPh、CH2Cl2；(d)Ph3P+CH＝CH2Br-、DBU
For the chromenes used as starting materials in scheme 3, they were prepared from substituted o-hydroxybenzaldehydes as shown by the method outlined in scheme 6. Make it1-scheme-6With allyl bromide in bases, e.g. K2CO3In the presence of acetone, resulting in nucleophilic substitution of the halide to the ether2-scheme-6. Witting reaction converts aldehyde group (aldehydic group) into olefin and gives3-scheme-6. In step (b)In step (c), a pair of terminal double bonds may undergo intramolecular metathesis (metathesis) to produce chromenes by treatment with a catalyst such as a ruthenium complex Grubb's catalyst. As an alternative to this, the first and second,1-scheme-6Can be cyclized directly as shown in step d) of the above figure.
Scheme 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-scheme-7Resulting in the replacement of the trifluoromethanesulfonyloxy group and the coupling at R6Introduction of other substituents on the above. Thus, scheme 7 provides for the preparation of synthetic intermediates useful in scheme 3 to yield compounds wherein R is6Is cyano, ethynyl or C1-3Urea or thiourea of alkylcarbonyl groups5-scheme-3。
Scheme 8
(a)BuLi/ZnCl2、THF；Pd(OAc)2、BrCH＝CHCOOEt；DIBAL
(b)TsNHN＝CHCOCl；PhNMe2、NEt3、CH2Cl2
(c)Rh2(5-R-MEPY)4Abs degassed dichloromethane
(d)30％HBr、AcOH
(e)NaOH、H2O
(f)NaOH；CO2；I-PrI/DMSO
(g)IPrOH、HCl；DEAD、PPh3、THF
(h)NaOH、MeOH:H2O
(i)1.BBr3、CH2Cl2 2.CH3CN 3 NaOH, Water
(j)1.BuLi/ZnCl2THF; pd (OAc)2.cpd 9-scheme-83. Jones reagent (chromic acid, sulfuric acid in acetone)
For compounds in which X is-CH2A convenient route for compounds of-O-, wherein R is depicted in scheme 8aAnd RbOptional substituents R, suitably protected if desired with conventional protecting groups4-R7And RcIs a lower alkyl ester. Optionally substituted phenols with protecting groups such as methyl, MOM, etc. to protect the hydroxy group1-scheme-8With a base such as BuLi or the like in a solvent such as THF or the like, and converted to a zinc salt by the addition of zinc chloride or the like. Catalysts such as Pd (OAc)2Etc. are added together with activated acrylates such as lower alkyl-cis-3-haloacrylates, e.g. BrCH ═ CHCOOEt, etc. The reaction mixture is cooled, a reducing agent such as DIBAL and the like is added dropwise and quenched to give2-scheme-8. Adding a hydrazone such as p-toluenesulfonylhydrazone chloride (glyoxylic acid chloride) or the like and a base such as N, N-dimethylaniline or the like to a solvent such as CH2Cl2Etc., followed by addition of another base such as Et3N etc. are obtained3-scheme-8. The reaction product is dissolved in a preferably degassed solvent such as dichloromethane or the like. Addition of chiral Doyle's catalysts, e.g. Rh2(5-R-MEPy)4(US 5175311, available from Aldrich or Johnson Matthey) and the like, e.g.with a high enantiomeric excess of, for example, greater than 80, preferably greater than 90% ee4-scheme-8. Preferably, the compound is first contacted with BBr3Reaction in dichloromethane, subsequent addition of acetonitrile, addition of the reaction mixture and finally addition of hydrogenSodium oxide to obtain6-scheme-8. Alternatively, the product (4-scheme-8) is ring-opened by an electrophile, preferably HBr or the like, in combination with an acid, e.g., AcOH or the like. Spontaneous ring closure under acid conditions to form chromenone5-scheme-8. Chromenone, when subjected to alkaline conditions such as NaOH and the like, re-sticks to form chromene cyclopropyl carboxylic acid6-scheme-8. As an alternative to this, the first and second,4-scheme-8For example, when the protecting group of the phenol is MOM, the lactone can be opened and the alkyl ester obtained by subjecting it to basic conditions such as NaOH, carbon dioxide and lower alkyl halides such as iPrI in a solvent such as DMSO7-scheme-8. Replacement of the hydroxyl protecting group and ring closure with a free hydroxymethyl moiety occurs under acidic conditions, e.g., in the presence of iPrOH/HCl or the like, followed by DEAD; PPH in organic solvents such as THF and the like3In the presence of a catalyst. Alternatively, the compound is polymerized (convergent)1-scheme-8Reacted with BuLi and converted to the zinc salt. The salt is reacted with cyclopropyl iodide in a palladium-catalyzed reaction,9-scheme-8Reaction with Jone's reagent to give compound 4-scheme-8. This carboxylic acid is in turn converted to an isocyanate and subsequently to a heteroaryl urea or heteroaryl thiourea of formula Z as depicted in scheme 1.
R of the formula Z3Variants are accordingly used with the appropriate amine-substituted (substituted) pyridyloxy (pyridyloxy) or phenyloxypyridine, i.e. for R3And 5-substituted-2- (N-methylamino) pyridine derivatives which are methyl.
Compounds wherein X is optionally substituted alkylene are conveniently prepared by scheme 9:
scheme 9
(a)NaBH4EtOH; (b) refluxing p-toluenesulfonic acid and toluene;
scheme 9 depicts the use of 1, 2, 3, 4-tetrahydronaphthalenes, indanes and the like as starting materials in the above schemes from position R4To R7Is, for example, halogenated or C1-3Known monosubstituted tetralones substituted with alkoxy, and the like. 1-Tetrahydronaphthalenone by reaction of a suitable reducing agent such as sodium borohydride in ethanol1 b-scheme-9The carbonyl group in (A) is converted into the corresponding alcohol to obtain2-scheme-9. Refluxing the alcohol with a small amount of acid, e.g., p-TsOH in toluene, causes2-scheme-9To obtain the desired 1, 2, 3, 4-tetralin1-scheme-9. The corresponding reactants can be applied to n ═ 1 or 3.
Although it is possible for the active agent to be administered alone, it is preferred that it be present as part of a pharmaceutical formulation. Such formulations will comprise the active agent as defined above, together with one or more acceptable carriers or excipients, and optionally other therapeutically useful ingredients. The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Although formulations include those suitable for rectal, nasal, topical (including buccal or sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, preferred formulations are oral. The formulations may conveniently be presented in unit dosage form, such as tablets and sustained release capsules, and may be prepared by any of the methods well known in the art of pharmacy.
Such methods include the step of associating an active agent as defined above with a carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to a process for the preparation of a pharmaceutical composition which comprises mixing or bringing into association a compound of formula Z or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or medium. If the preparation of a pharmaceutical formulation comprises intimate mixing of a pharmaceutical excipient and the active ingredient in salt form, it is generally preferred to use an excipient which is non-basic, i.e. acidic or neutral, in nature. Formulations suitable for oral administration in the present invention may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active agent; as a powder or granule; 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 a bolus infusion (bolus), and the like.
With respect to compositions suitable for oral administration (e.g., tablets and capsules), the term suitable carrier includes media such as common excipients for example binding agents such as syrup, gum arabic, 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 other metal salts of stearic acid, glyceryl stearate, silicone oil (silicone oil), talc waxes, oils and colloidal silicon dioxide. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, and the like may also be used. It may be desirable to add a colorant to make the dosage form easily distinguishable. Tablets may also be coated by methods well known in the art.
Tablets may optionally be prepared by compressing or molding one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as a powder or granules, optionally together with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the active agent in an aromatic base, usually sucrose and acacia or tragacanth; lozenges comprising the active agent in an inert base 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 summarized by way of illustration only with reference to the following non-limiting examples.
Example 1
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (sulfonamido) phenoxy) -2-pyridinyl]Urea
a)5- (4- (N-tert-butylsulfonylamino) phenoxy) -2-nitropyridine
To a solution of 4-hydroxy- (N-tert-butyl) benzenesulfonamide (3.01g, 13.2mmol) in DMF (48ml) was added cesium carbonate (5.67g, 17.4mmol), followed by 5-bromo-2-nitropyridine (2.36g, 11.6mmol) and the mixture was stirred at 50 ℃ for 12 hours. The suspension was filtered and the solvent evaporated, then saturated NaHCO3The residue was extracted between aqueous solution and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The resulting mixture was purified by silica gel column chromatography (0-1/2-1% EtOH/dichloromethane gradient) to give 3.47g of material of which about 70% was the title compound (LC-MS, API-ES)+: 352.4, respectively; calc.351.38) and about 30% 2- (4- (N-tert-butylsulfonylamino) phenoxy) -5-bromopyridine (LC-MS, API-ES) as a by-product+：386.3；Calc.385.24)。
1H-NMR(CDCl3)：8.37(d，1H)，8.31(d，1H)，7.98(d，2H)，7.54(dd，1H)，7.20(d，2H)，4.51(s 1H)，1.28(s，9H)。
b)5- (4- (N-tert-butylsulfonylamino) phenoxy) -2-pyridinamine
The product mixture obtained in example 1a (3.47g) was dissolved in ethanol (70ml) and ethyl acetate (18 ml). 10% palladium on charcoal (680mg) was then added and the black suspension was hydrogenated under normal hydrogen pressure for 11/2 hours with stirring. The catalyst was filtered off and the filtrate evaporated. The residue obtained is purified by column chromatography on silica gel (gradient 0-10% EtOH in dichloromethane) to yield 2.42g of the title compound (57% yield in two steps). (LC-MS, API-ES)+：322.0；Calc.320.41)
1H-NMR(d6-DMSO)：7.77(d，1H)，7.73(d，2H)，7.20(dd，1H)，7.39(s，1H)，7.25(dd，1H)，6.99(d，2H)，6.50(d，1H)，5.97(br，s 1H)，1.06(s，9H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (N-tert-butylsulfonylamino) phenoxy) -2-pyridyl]Urea
(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] prepared as shown in WO 02/705163]Chromene-1-carboxylic acid (68mg, 0.301mmol), 5- (4- (N-tert-butylsulfonamido) phenoxy) -2-pyridylamine (109mg, 0.0.341mmol) and triethylamine (47. mu.l, 0.341mmol) were mixed together in dry toluene (2ml) and introduced into an argon atmosphere. DPPA (74. mu.l, 0.341mmol) was then added and the reaction solution was stirred at 110 ℃ for 3 hours. By reaction between dichloromethane and 5% citric acidExtraction was performed followed by saturated NaHCO3The reaction mixture is worked up by aqueous extraction. Column chromatography on silica gel (1-2% EtOH/dichloromethane gradient) afforded 143mg of material, which was chromatographed by preparative TLC (10% MeOH/CHCl)3) Further purification gives 100mg of pure product as a white powder (61% yield). (LC-MS, API-ES +: 545.0; Calc.544.48).
1H-NMR(CDCl3)：9.29(br s，1H)，7.85(d，2H)，7.64(d，1H)，7.62(s，1H)，7.29(dd，1H)，6.96(d，2H)，6.79(d tr，1H)，6.70(d，1H)，6.59(d tr，1H)，4.52(s，1H)，4.47(dd，1H)，4.33(dd，1H)，3.79(q，1H)，2.62(tr，1H)，1.98(m，1H)，1.26(s，9H)。
d) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (sulfonamido) phenoxy) -2-pyridyl]Urea
Reacting anhydrous N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N' - [5- (4- (N-tert-butylsulfonylamino) phenoxy) -2-pyridinyl]Urea (36mg, 0.066mmol) was dissolved in a 1% trifluoromethanesulfonic acid/acetonitrile solution (5.8ml), and the reaction solution was stirred at room temperature for 30 minutes. The reaction was quenched with a small amount of pyridine and the acetonitrile was removed by evaporation. By reaction in dichloromethane and saturated NaHCO3The extraction between the aqueous solutions is carried out for the post-treatment. The organic phase was dried over sodium sulfate and evaporated. Column chromatography on silica gel (gradient 1-4% EtOH in dichloromethane) gave 26mg of pure product as a white powder (yield 71%).
1H-NMR(d6-DMSO)：9.41(s，1H)，8.06(br，s 1H)，7.77(d，2H)，7.73(d，1H)，7.52(dd，1H)，7.32(d，1H)，7.29(s，1H)，7.05(d，2H)，6.79(d tr，1H)，7.02(d tr，1H)，4.32(dd，1H)，4.28(dd，1H)，3.51(q，1H)，2.47(tr，1H)，2.00(m，1H)。
Example 2
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (N-methylcarboxyamido) phenoxy) -2-pyridinyl]Urea
a)5- (4- (N-methylcarboxyamido) phenoxy) -2-nitropyridines
Potassium tert-butoxide (191mg, 1.70mmol) was added to a solution of 4-hydroxy-N-methylbenzamide (257mg, 1.70mmol) in DMF (2.5ml) and the mixture was stirred at room temperature for 1 hour. The mixture was then heated to 65 ℃ and 5-bromo-2-nitropyridine (305mg, 1.50mmol) was added and the mixture stirred at 65 ℃ for 12 h. The solvent was then evaporated and the residue was extracted between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The resulting mixture was purified by silica gel column chromatography (gradient 0-11/2% EtOH in methylene chloride) to give 358mg of the title compound (LC-MS, API-ES) at about 60%+: 273.9, respectively; calc.273.25) and about 40% of 2- (4- (N-methylformamide) phenoxy) -5-bromopyridine (LC-MS, API-ES) as a by-product+：307.8，308.8；Calc.307.15)。
1H-NMR(d6-DMSO)：8.46(br q，1H)，8.45(d，1H)，8.34(d，1H)，7.93(d，2H)，7.71(dd，1H)，7.28(d，2H)，2.78，2.77(2x s，3H)。
b)5- (4- (N-methylcarboxamido) phenoxy) -2-pyridinamines
The product mixture (358mg) obtained in step a) was dissolved in ethanol (10 ml). 10% palladium on charcoal (110mg) was then added and the black suspension was hydrogenated under normal hydrogen pressure with stirring for 11/2 hours. The catalyst was filtered off and the filtrate evaporated. The residue was purified by silica gel column chromatography (2-6% EtOH/dichloromethane gradient) to give 118mg of the title compound (32% yield in the above two steps) (LC-MS, API-ES)+：244.4；Calc.243.27)
1H-NMR(CDCl3)：7.93(d，1H)，7.71(d，2H)，7.21(dd，1H)，7.25(dd，1H)，6.94(d，2H)，6.55(d，1H)，6.01(br，s 1H)，4.41(br s，2H)，3.01(2x s，3H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (N-methylcarboxamido) phenoxy) -2-pyridyl]Urea
The title compound was synthesized in analogy to example 1, from 5- (4- (N-methylcarboxamido) phenoxy) -2-pyridylamine (37mg, 0.15 mmol). Column chromatography on silica gel (gradient 0-2% EtOH in dichloromethane) afforded 41mg of pure product as a white powder (yield 65%). (LC-MS, API-ES)+：467.1；Calc.466.45)。
1H-NMR(CDCl3)：9.33(br s，1H)，7.99(s，1H)，7.75(d，2H)，7.61(d，1H)，7.28(dd，1H)，6.93(d，2H)，6.78(d tr，1H)，6.72(d，1H)，6.57(d tr，1H)，6.07(br q，1H)，4.45(dd，1H)，4.33(dd，1H)，3.78(q，1H)，3.03(d，3H)，3.66(tr，2H)，2.61(tr，1H)，2.01-1.95(m，1H)。
Example 3
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (N-methylsulfonylamino) phenoxy) -2-pyridyl]Urea
a)5- (4- (N-methylsulfonylamino) phenoxy) -2-nitropyridine
The title compound was synthesized in analogy to example 1a from N- (4-hydroxyphenyl) methanesulfonamide (150mg, 0.802 mmol). Column chromatography on silica gel (gradient 0-0.75% EtOH in dichloromethane) gave 63mg of material, of which > 90% was the title compound (LC-MS, API-ES)+: 308.0; calc.307.25). (formation of 2- (4- (N-methylsulfonylamino) phenoxy) -5-bromopyridine (LC-MS, API-ES as a by-product+：307.8，308.8；Calc.307.15))。
1H-NMR(d6-DMSO)：8.52(d，1H)，8.36(d，1H)，7.85(d，2H)，7.83(dd，1H)，7.48(q，1H)，7.40(d，2H)，2.43，2.42(2x s，3H)。
b)5- (4- (N-methylsulfonylamino) phenoxy) -2-pyridineamine
The title compound was synthesized in analogy to example 2b) from (5- (4- (N-methylsulfonylamino) phenoxy) -2-nitropyridine (63mg, 0.204 mmol). Filtration and evaporation gave 73mg of crude product. (LC-MS, API-ES)+：280.0；Calc.279.34)。
1H-NMR(d6-DMSO)：7.78(d，1H)，7.70(d，2H)，7.25(dd，1H)，7.02(d，2H)，6.50(dd，1H)，5.97(s 1H)，2.37，2.36(2x s，3H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (N-methylsulfonylamino) phenoxy) -2-pyridyl]Urea
The title compound was synthesized in analogy to example 1c) from 5- (4- (N-methylsulfonylamino) phenoxy) -2-pyridylamine (76mg, 0.204 mmol). Column chromatography on silica gel (gradient 1-21/2% EtOH/dichloromethane) gave a pure fraction containing 36mg of pure product as a white powder (yield 40%). (LC-MS, API-ES)+：503.0；Calc.502.32)。
1H-NMR(CDCl3)：9.47(br s，1H)，8.68(s，1H)，7.85(s，1H)，7.57(d，1H)，7.30-7.24(m，3H)，6.83-6.77(m，2H)，6.56(d tr，1H)，4.45(dd，1H)，4.32(dd，1H)，3.81(q，1H)，3.02(s，3H)，2.60(tr，1H)，1.99-1.93(m，1H)。
Example 4
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4-Aminophenoxy) -2-pyridinyl]Urea
a)5- (4- (N-tert-butoxycarbonylamino) phenoxy) -2-nitropyridine
Analogously to example 1a), from 4- (N-tert-butoxy-)Carbonylamino) phenol (581mg, 2.78mmol) the title compound was synthesized. Column chromatography on silica gel (gradient 0-2% EtOH in dichloromethane) afforded 704mg of the title compound (LC-MS, API-ES) at about 50%+: 332.0; calc.331.25). The other half was prepared from (2- (4- (N-tert-butoxycarbonylamino) phenoxy) -5-bromopyridine (LC-MS, API-ES)+: 364.9, 366.0; calc.363.15) which is formed as a by-product.
1H-NMR(d6-DMSO)：9.47(br s，1H)，8.35(d，1H)，8.29(d，1H)，7.55(d，2H)，7.51(dd，1H)，7.15(d，2H)，1.47(s，9H)。
b)5- (4- (N-tert-Butoxycarbonylamino) phenoxy) -2-pyridylamine
The title compound was synthesized in analogy to example 2b) from the mixture containing (5- (4- (N-tert-butoxycarbonylamino) phenoxy) -2-nitropyridine (total weight 704mg) obtained from step a). After the reaction, the residue obtained was filtered and evaporated and purified by silica gel column chromatography (gradient of 2-10% EtOH/dichloromethane) to yield 418mg of the title compound (two steps yield 57%) (LC-MS, API-ES)+：302.0；Calc.301.35)
1H-NMR(CDCl3)：7.69(d，1H)，7.32(d，2H)，7.31(d，1H)，6.90(d，2H)，6.68(d，1H)，6.47(br，s 1H)，4.98(br s，2H)，1.51(s，9H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (N-tert-butoxycarbonylamino) phenoxy) -2-pyridinyl]Urea
The title compound was synthesized in analogy to example 1c) from 5- (4- (N-tert-butoxycarbonylamino) phenoxy) -2-pyridylamine (418mg, 1.39 mmol). Column chromatography on silica gel (gradient 1-4% EtOH in dichloromethane) afforded 479mg of the product as a white powder (74% yield). (LC-MS, API-ES)+：525.1；Calc.524.30)。1H-NMR(CDCl3)：9.32(br s，1H)，7.34(d，2H)，7.20(dd，1H)，6.88(d，2H)，6.79(d tr，1H)，6.58(d tr，1H)，6.45(s，1H)，4.41(dd，1H)，4.34(dd，1H)，3.75(q，1H)，2.59(tr，1H)，1.98-1.93(m，1H)，1.52(s，9H)。
d) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4-aminophenoxy) -2-pyridinyl]Urea
Reacting anhydrous N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N' - [5- (4- (N-tert-butoxycarbonylamino) phenoxy) -2-pyridinyl]Urea (242mg, 0.46mmol) was dissolved in methyl chloride (2ml), and then 1M HCl/AcOH (4.6ml) was added and the reaction solution was stirred at room temperature for 60 minutes. The volatile material was removed by evaporation. By reaction between methyl chloride and saturated NaHCO3Extraction between aqueous solutions worked up the residue. The organic phase was dried over sodium sulfate and evaporated. Column chromatography on silica gel (gradient 1-3% EtOH in dichloromethane) afforded 139mg of pure product as a white powder (71% yield).
1H-NMR(CDCl3)：9.33(br s，1H)，7.44(d，1H)，7.24(s，1H)，7.17(dd，1H)，6.79(d，2H)，6.77(d tr，1H)，6.68(d，2H)，6.60-6.54(m，2H)，4.40(dd，1H)，4.35(dd，1H)，3.73(q，1H)，3.61(br s，2H)，2.57(tr，1H)，1.98-1.92(m，1H)。
Example 5
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (methylsulfonyl) phenoxy) -2-pyridinyl]Urea
a)5- (4- (methylsulfonyl) phenoxy) -2-nitropyridines
The title compound was synthesized in analogy to example 1a) from 4-hydroxyphenyl methylsulfone (288mg, 1.67 mmol). Silica gel column chromatography (0-2% EtOH/dichloromethane gradient) afforded 300mg of the title compound (LC-MS, API-ES) in which more than 90% was-：353.0(m+AcO-) (ii) a Calc.294.29). There is a few percent of 2- (4- (methylsulfonyl) phenoxy) -5-bromopyridine (LC-MS, API-ES)+: 327.9, 330.0; calc.328.19) contaminants.
1H-NMR(CDCl3)：8.41(d，1H)，8.33(d，1H)，8.04(d，2H)，7.58(dd，1H)，7.27(d，2H)，3.10(s，3H)。
b)5- (4- (methylsulfonyl) phenoxy) -2-pyridineamines
The title compound was synthesized in analogy to example 2b) from the mixture containing (5- (4- (methylsulfonyl) phenoxy) -2-nitropyridine (300mg) obtained from step a). This material was dissolved in a mixture of ethyl acetate (10ml), isopropanol (3ml) and methanol (3ml) while heating. After continuing the reaction at room temperature, the residue obtained after filtration and evaporation is removedThe residue was purified by silica gel column chromatography (gradient of 2-4% EtOH in dichloromethane) to give 160mg of the title compound (LC-MS, API-ES)+: 265.0; calc.264.31).
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (methylsulfonyl) phenoxy) -2-pyridyl]Urea
The title compound was synthesized in analogy to example 1c) from 5- (4- (methylsulfonyl) phenoxy) -2-pyridylamine (31mg, 0.118 mmol). Silica gel column chromatography (1-3% EtOH/dichloromethane gradient) followed by preparative TLC (10% MeOH/CHCl)3) 10.7mg of pure product are obtained in the form of a white powder (yield 19%). (LC-MS, API-ES)+：488.0；Calc.487.48)。1H-NMR(CDCl3)：9.41(br s，1H)，8.99(s，1H)，7.91(d，2H)，7.68(d，1H)，7.31(dd，1H)，7.04(d，2H)，6.87(d，1H)，6.80(d tr，1H)，6.58(d tr 1H)，4.48(dd，1H)，4.32(dd，1H)，3.82(q，1H)，2.62(tr，1H)，2.01-1.95(m，1H)。
Example 6
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (2-hydroxyethyl) phenoxy) -2-pyridinyl]Urea
a)5- (4- (2-hydroxyethyl) phenoxy) -2-nitropyridine
In analogy to example 2a, from 2- (4-hydroxyphenyl) ethanol (234 mg)1.70mmol) the title compound was synthesized. Silica gel column chromatography (0-2% EtOH/dichloromethane gradient) afforded 237mg of material, of which more than 80% was the title compound (LC-MS, API-ES)-：319.0(m+AcO-) (ii) a Calc.260.25). About 10-15% of 2- (4- (2-hydroxyethyl) phenoxy) -5-bromopyridine (LC-MS, API-ES) is present+: 294.0, 296.0; calc.295.25) contaminants.
b)5- (4- (2-hydroxyethyl) phenoxy) -2-pyridinamine
The title compound was synthesized in analogy to example 2b, from the mixture obtained from step a) containing (5- (4- (2-hydroxyethyl) phenoxy) -2-nitropyridine (197 mg). The residue obtained after filtration and evaporation was purified by silica gel column chromatography (gradient 2-10% EtOH in dichloromethane) to yield the title compound (LC-MS, API-ES) containing 65mg+: 231.1; calc.230.27).
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (2-hydroxyethyl) phenoxy) -2-pyridyl]Urea
The title compound was synthesized in analogy to example 1c) from 5- (4- (2-hydroxyethyl) phenoxy) -2-pyridylamine (62mg, 0.282 mmol). Silica gel column chromatography (0-4% EtOH/dichloromethane gradient) gave a fraction from which 8mg of pure product was obtained as a white powder and additional fractions (LC-MS, API-ES)+：454.2；Calc.453.45)。
1H-NMR(CDCl3)：9.38(br s，1H)，8.28(s，1H)，7.54(d，1H)，7.24(dd，1H)，7.20(d，2H)，6.88(d，2H)，6.77(d tr，1H)，6.71(d，1H)，6.56(d tr，1H)，4.43(dd，1H)，4.34(dd，1H)，3.87(t，2H)，3.77(q，1H)，2.86(t，2H)，2.59(tr，1H)，1.98-1.93(m，1H)，1.51(br，1H)。
Example 7
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N’-[5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-pyridinyl]Urea
a)5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-nitropyridine
The title compound was synthesized in analogy to example 2a) from 4- (2- (2-methoxy-ethoxy) phenol (300mg, 1.42 mmol). Silica gel column chromatography (0-1/2% EtOH/dichloromethane gradient) afforded 173mg of the title compound (LC-MS, API-ES) in excess of 70%+: 335.1; calc.334.33). Contamination with about 20-30% of 2- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -5-bromopyridine (LC-MS, API-ES) was present+：368.0，370.0；Calc.369.33)。
b)5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-pyridylamine
The title compound was synthesized in analogy to example 2b) from the mixture containing 5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-nitropyridine (173mg) obtained in example 22. Residue obtained after filtration and evaporationThe residue was purified by silica gel column chromatography (gradient 0-6% EtOH/dichloromethane) to give a pure fraction (LC-MS, API-ES) containing 92mg (yield 60%) of the title compound+：305.1；Calc.304.35)。
1H-NMR(CDCl3)：7.85(d，1H)，7.16(dd，1H)，6.90-6.85(m，4H)，6.68(d，1H)，6.50(d，1H)，4.40(br，2H)，4.11(t，2H)，3.85(t，2H)，3.72(t，2H)，3.58(t，2H)，3.39(s，3H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]- N' - [5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-pyridinyl]Urea
The title compound was synthesized in analogy to example 1c) from 5- (4- (2- (2-methoxyethoxy) ethoxy) phenoxy) -2-pyridylamine (46mg, 0.15 mmol). Silica gel column chromatography (0-11/2% EtOH/dichloromethane gradient) gave a fraction from which 14mg of the pure product was obtained as a white powder and a further few mixed fractions (. about.40 mg) (LC-MS, API-ES)+528.1；Calc.527.53)。
1H-NMR(CDCl3)：9.35(br s，1H)，7.82(s，1H)，7.48(d，1H)，7.18(d，1H)，6.89(m，4H)，6.77(d tr，1H)，6.63(d，1H)，6.57(d tr 1H)，4.42(dd，1H)，4.35(dd，1H)，4.14(t，2H)，3.87(t，1H)，3.75(q，1H)，3.74(t，2H)，3.59(t，2H)，3.40(s，3H)，2.58(tr，1H)，1.98-1.92(m，1H)。
Example 8
5- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical] Amino } carbonyl) amino]-3-pyridinyl } oxy) -N-methyl-2-pyridinecarboxylic acid methyl esterAmides of carboxylic acids
a) N-methyl-5- [ (6-nitro-3-pyridyl) oxy]-2-pyridinecarboxamides
5- [ (6-Nitro-3-pyridyl) oxy ] -2-pyridinecarboxylic acid (260mg, 1mmol) was refluxed in thionyl chloride (10ml) overnight. Evaporation of excess thionyl chloride quenched the crude acid chloride with aqueous methylamine to give pure N-methyl-5- [ (6-nitro-3-pyridyl) oxy ] -2-pyridinecarboxamide (190mg, 70%)
1H NMR(CDCl3+MeOD)：8.4(d，1H)，8.32(d，1H)，8.31(d，1H)，7.42(br s，1H)，7.55(m，2H)。
b)5- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromene-1- Base of]Amino } carbonyl) amino]-3-pyridinyl } oxy) -N-methyl-2-pyridinecarboxamide
N-methyl-5- [ (6-nitro-3-pyridyl) oxy ] -2-pyridinecarboxamide (190mg, 0.7mmol) was dissolved in methanol (20 ml). The mixture was hydrogenated using Ra/Ni under hydrogen atmosphere. When the starting material was consumed according to TLC (diethyl ether), the mixture was filtered through celite and concentrated under reduced pressure.
To the crude product was added (1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid (0.170mg, 0.76mmol) and the mixture was co-evaporated to half volume with toluene (10 ml). Diphenylphosphoryl azide (179. mu.l, 0.76mmol) and triethylamine (106. mu.l, 0.76mmol) were added. The mixture was then refluxed for 4h under argon atmosphere. The solvent was then removed under reduced pressure and the crude product was dissolved in ethyl acetate and washed with a small portion of aqueous hydrochloric acid (0.01M), saturated sodium bicarbonate and water. Purification by flash chromatography (1% methanol in ether) afforded the desired compound (158mg, 48%).
1H NMR(CDCl3)：9.27(br s，1H)，8.25(d，1H)，8，17(d，1H)，8.16-8.10(br s，1H)，7.88-7.82(m，1H)，7.67(d，1H)，7.31(dd，1H)，7.26(dd，1H)，6.83-6.75(m，2H)，6.61-6.55(m，1H)，4.48(dd，1H)，4.32(dd，1H)，3.81(q，1H)，3.02(d，3H)，2.62(t，1H)，2.02-1.94(m，1H)。
Example 9
4- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical] Amino } carbonyl) amino]-3-pyridyl } oxy) benzamide
a)4- [ (6-Nitro-3-pyridyl) oxy group]Benzamide derivatives
4-hydroxybenzamide (150mg, 1.1mmol) and cesium carbonate (394mg, 1.21mmol) were dissolved in dimethylformamide (7 ml). 5-bromo-2-nitropyridine (244mg, 1.21mmol) was then added. The mixture was left at 50 ℃ until the starting material was consumed according to TLC (1% methanol in ether). Purification by flash chromatography to give 4- [ (6-nitro-3-pyridyl) oxy ] benzamide (110mg, 38%)
1H NMR(CDCl3)：8，37(d，1H)，8.29(d，1H)，7.94(m，2H)，7.51(dd，1H)，7.18(m，2H)。
b)4- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropan)Alkyl [ c ]]Chromene-1- Base of]Amino } carbonyl) amino]-3-pyridyl } oxy) benzamide
The compound was prepared by essentially the same procedures as described for example 8 starting from 4- [ (6-nitro-3-pyridinyl) oxy ] benzamide (100mg, 0.38mmol) and (1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid (65mg, 0.29mmol) to give 20mg (12%) of the pure title compound.
1H NMR(CDCl3+MeOD)：7.82(m，2H)，7.63(d，1H)，7.30(dd.1H)，6.96(d，2H)，6.90-6.76(m，2H)，6.62-5.59(m，1H)，4.45(dd，1H)，4.35(dd，1H)，2.6(t，1H)，2.0-1.92(m，1H)
Example 10
5- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical] Amino } carbonyl) amino]-3-pyridinyl } oxy) -2-pyridinecarboxamide
a)5- [ (6-Nitro-3-pyridyl) oxy group]-2-pyridinecarboxamides
5- [ (6-Nitro-3-pyridyl) oxy ] -2-pyridinecarboxylic acid (100mg, 1mmol) was refluxed in thionyl chloride (5ml) overnight. Evaporation of excess thionyl chloride and quenching of the crude acid chloride with aqueous methylamine gave pure 5- [ (6-nitro-3-pyridyl) oxy ] -2-pyridinecarboxamide (60mg, 60%)
1H NMR(DMSO)：8.60(d，1H)，8.57(d，1H)，8.13(s，1H)，8.11(br s，1H)，7.67(br s，1H)。
b)5- ({6- [ ({ [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromene-1- Base of]Amino } carbonyl) amino]-3-pyridinyl } oxy) -2-pyridinecarboxamide
The compound was prepared by essentially the same method as described for example 8 starting from 5- [ (6-nitro-3-pyridinyl) oxy ] -2-pyridinecarboxamide (60mg, 0.38mmol) and (1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid (65mg, 0.29mmol) to give 18mg (18%) of the pure title compound.
1H NMR(CDCl3+MeOD)：9.35(br s，1H)，8.28(d.1H)，8.17(d，1H)，7.75(br s，1H)，7.69(d，1H)，7.33(dd，1H)，7.27(dd，1H)，6.96(d，1H)，6.8(m，1H)，6.58(m，1H)，4.48(dd，1H)，4.32(dd，1H)，3.80(q，1H)，2.62(t，1H)，2.02-1.96(m，1H)。
Example 11
N- [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N′-{5- [4- (hydrazinocarbonyl) phenoxy group]-2-pyridinyl } urea
a)2- [4- (benzyloxy) benzoyl]Hydrazine carboxylic acid tert-butyl ester
4-Benzyloxybenzoic acid (0.780g, 3.42 mmo) was added at room temperaturel), tert-butyl carbazate (0.443g, 3.35mmol), Et3A mixture of N (0.5mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.05g, 5.47mmol) and 1-hydroxybenzotriazole hydrate (0.778g, 5.76mmol) in N, N-dimethylformamide (27mL) was stirred for 2 days. The reaction was concentrated and diluted with dichloromethane. The organic phase was washed twice with water and MgSO4Drying and concentrating. The residue is purified by column chromatography (silica gel, 5% MeOH in CH)2Cl2Middle) purification and determination of 2- [4- (benzyloxy) benzoyl group by NMR spectroscopy]Tert-butyl hydrazinecarboxylate (0.998g, yield: 85%).
1H-NMR(CDCl3)：8.21(s，1H)，7.76(d，2H)，7.37(m，5H)，6.95(d，2H)，6.76(s，1H)，5.08(s，2H)，1.48(s，9H)。
b)2- (4-hydroxybenzoyl) hydrazinecarboxylic acid tert-butyl ester
2- [4- (benzyloxy) benzoyl in the presence of a catalytic amount of Pd-C10% in ethanol (40mL)]A solution of tert-butyl hydrazinecarboxylate (975mg, 2.85mmol) was hydrogenated for 3 hours. After filtration over celite, the residue is purified by column chromatography (silica gel, 10% MeOH in H)2Cl2Middle) and determination of tert-butyl 2- (4-hydroxybenzoyl) hydrazinecarboxylate (0.688g, yield: 96%).
1H-NMR(CD3OD)：7.73(d，2H)，6.82(d，2H)，4.84(s，2H)，1.48(s，9H)
c)2- {4- [ (6-Nitro-3-pyridyl) oxy]Benzoyl hydrazine carboxylic acid tert-butyl ester
A mixture of tert-butyl 2- (4-hydroxybenzoyl) hydrazinecarboxylate (0.688g, 2.73mmol) and 5-bromo-2-nitropyridine (0.554mg, 2.73mmol) and cesium carbonate (1.33g, 4.08mmol) in N, N-dimethylformamide (7mL) was stirred at 80 ℃ overnight. The solution was concentrated and the residue was extracted with dichloromethane and water. Organic phase over MgSO4Drying and concentrating. The crude product was purified by column chromatography (silica gel, 5% MeOH in H)2Cl2Middle) to yield 736mg of a mixture of nitropyridine and bromopyridine.
d)2- {4- [ (6-amino-3-pyridyl) oxy]Benzoyl hydrazine carboxylic acid tert-butyl ester.
A mixture of nitropyridine and bromopyridine (0.700g) was hydrogenated in the presence of catalytic amounts of Pd-C10% ethanol (20mL) and EtOAc (20mL) for 1 h. After filtration over celite, the residue is purified by column chromatography (silica gel, 5% MeOH in H)2Cl2Middle) purification and determination of 2- {4- [ (6-amino-3-pyridinyl) oxy group by NMR spectroscopy]Benzoyl } hydrazinecarboxylic acid tert-butyl ester (0.326g, yield: 35%).
1H-NMR(CD3OD)：7.73(d，2H)，6.64(d，1H)，7.17(dd，1H)，6.86(dd，2H)，6.55(d，1H)，4.74(s，4H)，1.39(s，9H)。
e)2- [4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Chromene- 1-radical]Amino } carbonyl) amino]-3-pyridinyl } oxy) benzoyl]Hydrazine carboxylic acid tert-butyl ester
Chiral acid (155mg, 0.687mmol), 2- {4- [ (6-amino-3-pyridyl) oxy]Benzoyl hydrazine carboxylic acid tert-butyl ester (267mg, 0.776mmol), diphenylphosphoryl azide (0.162mL, 0.756mmol) and Et3A mixture of N (0.105mL, 0.756mmol) in toluene (10mL) was refluxed for 4 hours. The solution was reduced and the residue was diluted in dichloromethane and washed once with HCl (0.001N) and brine. The organic phase is MgSO4Drying and evaporating. The residue is purified by column chromatography (silica gel, 5% MeOH in H)2Cl2Middle (b)) to yield the title compound (0.227g, yield: 52%).
1H-NMR(CDCl3)：9.36(s，1H)，9.05(s，1H)，8.99(s，1H)，7.80(d，2H)，7.62(d，1H)，7.28(s，1H)，7.25(d，1H)，6.89(d，1H)，6.86(d，2H)，6.78(m，1H)，6.55(m，1H)，4.43(dd，1H)，4.30(dd，1H)，3.76(m，1H)，2.59(m，1H)，1.95(m，1H)，1.46(s，1H)。
f) N- [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N′- {5- [4- (hydrazinocarbonyl) phenoxy]-2-pyridinyl } urea
2- [4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]) at room temperature]Chromen-1-yl radical]Amino } carbonyl) amino]-3-pyridinyl } oxy) benzoyl]A mixture of tert-butyl hydrazinecarboxylate (49mg, 0.089mmol) in dichloromethane (0.5mL) and trifluoroacetic acid (0.5mL) was stirred for 30 min. Concentrate the reaction and column chromatographe (silica gel, 2% MeOH in H)2Cl2Middle (1) to obtain a compound N- [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N' - {5- [4- (hydrazinocarbonyl) phenoxy]-2-pyridinyl } urea (17.6mg, yield:42％)。
1H-NMR(CD3OD)：7.80(d，2H)，7.62(d，1H)，7.39(dd，1H)，6.97(d，3H)，6.83(m，1H)，6.62(m，1H)，4.41(m，1H)，4.29(dd，1H)，3.61(m，1H)，2.59(t，1H)，2.02(m，1H)。
example 12
4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Chromen-1-yl radical]Ammonia Yl } carbonyl) amino]-3-pyridinyl } oxy) -N-cyclopropylbenzamide
a)4- (benzyloxy) -N-cyclopropylbenzamide
In analogy to example 11a, from 4-benzyloxybenzoic acid (0.759g) 4- (benzyloxy) -N-cyclopropylbenzamide (0.774g, 83%) was synthesized.
1H-NMR(CDCl3)：7.70(d，2H)，7.38(m，5H)，6.97(d，2H)，6.17(s，1H)，5.10(s，2H)，2.88(m，1H)，0.85(m，2H)，0.6(m，2H)。
b) N-cyclopropyl-4-hydroxybenzamide
In analogy to example 11b, from 4- (benzyloxy) -N-cyclopropylbenzamide (0.774g) N-cyclopropyl-4-hydroxybenzamide (0.332g, 68%) was synthesized.
1H-NMR(CD3OD)：8.26(s，1H)，7.67(d，2H)，6.80(d，2H)，4.88(s，1H)，2.79(m，1H)，0.75(m，2H)，0.60(m，2H)。
c) N-cyclopropyl-4- [ (6-nitro-3-pyridyl) oxy]Benzamide derivatives
In analogy to example 11c, a mixture of nitropyridine and bromopyridine was synthesized from N-cyclopropyl-4-hydroxybenzamide (0.330 g).
1H-NMR(CD3OD)：8.33(d，1H)，8.32(d，1H)，7.92(d，2H)，7.66(dd，1H)，7.24(d，2H)，2.85(m，1H)，0.81(m，2H)，0.64(m，2H)。
d)4- [ (6-amino-3-pyridyl) oxy group]-N-cyclopropylbenzamide
In analogy to example 11d, 4- [ (6-amino-3-pyridinyl) oxy ] -N-cyclopropylbenzamide (0.128g, 25%) was synthesized from a mixture of nitropyridine and bromopyridine.
1H-NMR(CDCl3)：7.92(s，1H)，7.68(d，2H)，7.20(d，1H)，6.92(d，2H)，6.54(d，1H)，6.12(s，1H)，4.41(s，2H)，2.89(m，1H)，0.81(m，2H)，0.64(m，2H)。
e)4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Chromene-1- Base of]Amino } carbonyl) amino]-3-pyridinyl } oxy) -N-cyclopropylbenzamide
In analogy to example 11e, 4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromen-1-yl ] amino } carbonyl) amino ] -3-pyridinyl } oxy) -N-cyclopropylbenzamide (0.090g, 38%) was synthesized from 4- [ (6-amino-3-pyridinyl) oxy ] -N-cyclopropylbenzamide (0.128 g).
1H-NMR(CDCl3)：9.36(s，1H)，8.56(s，1H)，7.73(d，2H)，7.62(d，1H)，7.27(dd，1H)，6.91(m，3H)，6.78(m，1H)，6.57(m，1H)，6.23(s，1H)，4.45(dd，1H)，4.33(dd，1H)，3.72(m，1H)，2.90(m，1H)，2.60(t，1H)，1.97(m，1H)，0.87(m，2H)，0.63(m，2H)。
Example 13
N- [4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Chromen-1-yl radical] Amino } carbonyl) amino]-3-pyridyl } oxy) phenyl]Acetamide
a) N- {4- [ (6-nitro-3-pyridyl) oxy]Phenyl acetamide
The title compound was synthesized in analogy to example 11c, from N- (4-hydroxyphenyl) acetamide.
1H-NMR(DMSO-d6)：10.05(s，1H)，8.36(d，1H)，8.29(d，1H)，7.67(d，2H)，7.54(dd，1H)，7.18(d，2H)，2.03(s，3H)。
b) N- {4- [ (6-amino-3-pyridyl) oxy group]Phenyl acetamide
The title compound was synthesized in analogy to example 11d, from N- {4- [ (6-nitro-3-pyridyl) oxy ] phenyl } acetamide.
1H-NMR(CDCl3)：7.87(d，1H)，7.41(d，2H)，7.29(s，1H)，7.17(dd，1H)，6.89(d，2H)，6.51(d，1H)，4.47(s，2H)，2.14(s，3H)。
d) N- [4- ({6- [ ({ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ]]Chromene- 1-radical]Amino } carbonyl) amino]-3-pyridyl } oxy) phenyl]Acetamide
The title compound was synthesized in analogy to example 11e, from N- {4- [ (6-amino-3-pyridinyl) oxy ] phenyl } acetamide.
1H-NMR(CDCl3)：9.39(s，1H)，8.82(s，1H)，7.54(m，3H)，7.47(d，2H)，7.20(dd，1H)，6.88(d，2H)，6.79(m，2H)，6.55(m，1H)，4.42(dd，1H)，4.32(dd，1H)，3.76(m，1H)，2.57(t，1H)，2.04(m，1H)。
Example 14
N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N′-{5- [4- (1H-1, 2, 4-triazol-1-yl) phenoxy group]Pyridin-2-yl-urea
a) 2-nitro-5- [4- (1H-1, 2, 4-triazol-1-yl) phenoxy]Pyridine compound
Cesium carbonate (1.3g, 4.03mmol) was mixed with 3ml of anhydrous dimethylformamide, 4- (1H-1, 2, 4-triazol-1-yl) phenol (0.5g, 3.1mmol) and 5-bromo-2-nitropyridine (0.63g, 3.1mmol) and the reaction mixture was heated at 70 ℃ with stirring in a closed flask. The reaction mixture was then mixed with 40ml of water and extracted into dichloromethane (3X 20 ml). The organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting green-brown solid was washed thoroughly with dichloromethane to give 280mg of the desired compound (yield 32%).
1H-NMR(DMSO-d6)：9.3(s，1H)，8.47(d，1H)，8.35(d，1H)，8.24(s，1H)，7.98(d，2H)，7.71(dd，1H)，7.45(d，2H)。
b)5- [4- (1H-1, 2, 4-triazol-1-yl) phenoxy]Pyridin-2-amines
2-Nitro-5- [4- (1H-1, 2, 4-triazol-1-yl) phenoxy ] pyridine (100mg, 0.35mmol) was mixed with 15-20ml of ethanol and argon was bubbled through. About 20mg of Pd/C was added to the reaction mixture, and hydrogen was applied at normal pressure and room temperature for 3-12 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was bubbled with argon, filtered through celite and the resulting solution was concentrated by rotary evaporation to give 42mg of the desired aminopyridine after purification by silica gel column chromatography (EtOAc/EtOH 100: 1). The yield thereof was found to be 47%.
1H-NMR(CDCl3)：8.4(s，1H)，8.01(s，1H)，7.85(d，～1H)，7.50(d，2H)，7.35(s，1H)，6.96(d，2H)，6.48(d，1H)，4.55(br s，2H)。
c) N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]Chromen-1-yl radical]-N′- {5- [4- (1H-1, 2, 4-triazol-1-yl) phenoxy group]Pyridin-2-yl-urea
(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid (33mg, 0.15mmol,. about.95% ee) was mixed with toluene (1.5ml), triethylamine (1.1eq), 5- (3-fluorophenyl) -2-aminopyridine (1.1eq), DPPA (1.1eq) and argon bubbled through for about 5 min. The reaction mixture was then heated in a closed flask with stirring at 110 ℃ for 3 h. The reaction mixture was concentrated by rotary evaporation and purified by silica gel column chromatography (30g of YMC silica, ethyl acetate/n-hexane 1: 1). The desired product was obtained as a beige-white powder (40mg, 57.5% yield).
1H-NMR(CDCl3)：9.42(br s，1H)，9.35(br s，1H)，8.52(s，1H)，8.10(s，1H)，7.65(m，3H)，7.30(dd，1H)，7.03(d，2H)，6.87(d，1H)，6.80(m，1H)，6.65(d tr，1H)，4.45(dd，1H)，4.33(dd，1H)，3.80(q，1H)，2.60(br tr，1H)，1.94-2.00(m，1H)。
And additionally left wing structures (wings).
Similar to examples 1 to 14, the following left wing structures were matched to any of the new right wing structures (right hand wings) described above.
Example 15
a) +/-cis-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
2H-chromene (4.89g, 37mmol) and (CuOTf) were reacted at 20 ℃ with2To a mixture of benzene (186mg, 0.37mmol) and 1, 2-dichloroethane (80mL) was added dropwise (3h) a solution of ethyl azoacetate (8.44g, 74mmol) in 1, 2-dichloroethane (20 mL). After 15min at 20 ℃ with H2The reaction mixture was washed with O (100 mL). H2O phase is CH2Cl2(50mL) the combined organic phases were washed and the solvent was removed under reduced pressure. Column chromatography of the crude product (silica gel, 20 → 50% EtOAc in n-hexane) afforded 1.96g (24%) of. + -. cis-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester and 3.87g (48%) of ± -trans-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] as by-product]Chromene-1-carboxylic acid ethyl ester.
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-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
Reacting (+/-) -cis-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c)]Chromene-1-carboxylic acid ethyl ester (1.96g, 9.0mmol), LiOH (539mg, 22.5mmol), H2A mixture of O (10mL) and MeOH (20mL) was heated to reflux for 2 h. The reaction mixture was concentrated to about 10mL and 4N HCl was added dropwise to give a white precipitate. By CH2Cl2The reaction mixture was extracted (3X 15mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was crystallized from EtOAc/hexanes to give 435mg (25%) of (. + -.) -cis-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] as a white solid]Chromene-1-carboxylic acid.
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)。
Example 16
a) (±) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 15a, (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] naphthalene-1-carboxylic acid ethyl ester was synthesized from 1H-isochromene (3.57g, 27mmol) to give 910mg (15%) of (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ 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-oxa-cyclopropa [ a ] naphthalene-1-carboxylic acid
Analogously to example 15b, starting from (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropane [ a-]Synthesis of (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropa [ a ] using ethyl naphthalene-1-carboxylate (436mg, 2mmol)]Naphthalene-1-carboxylic acid, 86mg (22%) of (. + -.) -cis-1, 1a, 3, 7 b-tetrahydro-2-oxa-cyclopropane [ a ] as a white solid]Naphthalene-1-carboxylic acid. The crude product is purified by column chromatography (silica gel, 1 → 5% MeOH in H)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)。
The product of step b
Example 17
(±) -cis-1- (5-cyano-pyridin-2-yl) -3- (7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane And [ c ]]Chromen-1-yl) -urea.
a)1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -propan-1-one
2 ', 4' -dihydroxy-phenyl-ethyl ketone (24.9g, 0.15mol), 3-bromo-propyne (24.2g, 0.20mol) and K2CO3A mixture of (20.7g, 0.15mol) in acetone (500mL) was refluxed for 12 h. The reaction mixture was allowed to come to room temperature and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 0 → 2% MeOH in H)2O to) 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-chromen-6-yl) -propan-1-one.
A mixture of 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -prop-1-one (19.8g, 97mmol) and N, N-diethylaniline (100mL) was heated to reflux for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5 → 10% EtOAc in n-hexane) followed by recrystallization from EtOAc/n-hexane to give 8.91g (45%) of 1- (5-hydroxy-2H-chromen-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-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
To 1- (5-hydroxy-2H-chromen-6-yl) -propan-1-one (511mg, 2.5mmol) and (Rh (II) Ac at 20 deg.C2)2(11mg, 0.025mmol) to a mixture in 1, 2-dichloroethane (8mL) was added dropwise (3h) a solution of ethyl azoacetate (571mg, 5mmol) in 1, 2-dichloroethane (2 mL). After 15min at 20 ℃ with H2The reaction mixture was washed with O (10 mL). H2CH for O phase2Cl2The combined organic phases were washed (10mL) and the solvent was removed under reduced pressure. The crude product is purified by column chromatography (silica gel, 1 → 5% MeOH in H)2Cl2Middle (b) to yield 300mg (41%) of 7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester (mixture of cis and trans isomer ratio 33/64).
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-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
In analogy to example 16b, from 7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester (299mg, 1.03mmol, cis and trans isoMixture of structures ratio 33/64) synthesis of + -cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c]Chromene-1-carboxylic acid, 39.3mg (15%) of (. + -.) -cis-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] as a white solid]Chromene-1-carboxylic acid and (±) -trans-7-hydroxy-6-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] as by-product]Chromene-1-carboxylic acid. The crude product was purified by column chromatography (silica gel, 1 → 5% MeOH in CH)2Cl2Middle) purification.
1H-MR(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)。
Example 18
a)1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone
In analogy to example 17a, 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone was synthesized 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)。
b)1- (5-hydroxy-2H-chromen-6-yl) -ethanone
In analogy to example 46b, 1- (5-hydroxy-2H-chromen-6-yl) -ethanone was synthesized from 1- (2-hydroxy-4-prop-2-ynyloxy-phenyl) -ethanone (17g, 89mmol) to give 6.0g (35%) of 1- (5-hydroxy-2H-chromen-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)。
c) 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
In analogy to example 17c, 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester (mixture of the cis and trans isomers 40/60) was synthesized from 1- (5-hydroxy-2H-chromen-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)。
d) 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
In analogy to example 15b, from 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Synthesis of 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] using chromene-1-carboxylic acid ethyl ester (2g, 8.1mmol, mixture of the cis and trans isomers in 40/60 ratio)]Chromene-1-carboxylic acid to give 300mg (17%) of 6-acetyl-7-hydroxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid (mixture of cis and trans isomers 40/60). The crude product is purified by column chromatography (silica gel, 1 → 5% MeOH in H)2Cl2Middle) purification.
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)。
Example 19
5a)1- (4-fluoro-2-prop-2-ynyloxy-phenyl) -propan-1-one.
To a mixture of NaH (95%, 278mg, 11mmol) in DMF (20mL) at 0 deg.C was added a solution of 1- (4-fluoro-2-hydroxy-phenyl) -propan-1-one (1.68g, 10mmol) in DMF (5 mL). After 15min at 0 ℃ 3-bromo-propyne (3.02g, 20mmol) was added to the reaction mixture. After 1 hour at 0 ℃, the reaction mixture was allowed to warm to room temperature. With H2The reaction mixture was extracted with O (100 mL). H2Et for O phase2O (3X 100mL) and the combined organic phases were stripped of solvent under reduced pressure. The crude product is purified by column chromatography (silica gel, CH)2Cl2) Purification gave 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-chromen-8-yl) -propan-1-one.
In analogy to example 17b, 1- (5-fluoro-2H-chromen-8-yl) -propan-1-one was synthesized 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-chromen-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，3H)。
c) (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
According to method 17c), ethyl (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromene-1-carboxylate was synthesized from 1- (5-fluoro-2H-chromen-8-yl) -propan-1-one (619mg, 3mmol) to give 142mg (16%) ethyl (±) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromene-1-carboxylate and ethyl (±) -trans-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromene-1-carboxylate as a by-product.
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-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
In analogy to example 15b, from (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Synthesis of (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] using chromene-1-carboxylic acid ethyl ester (140.3mg, 0.48mmol)]Chromene-1-carboxylic acid, 83mg (65%) of (. + -.) -cis-7-fluoro-4-propionyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] as a white solid]Chromene-1-carboxylic acid. The crude product is purified by column chromatography (silica gel,1 → 5% MeOH in H2Cl2Middle) purification.
1H-NMR(DMSO-d6)：12.15(br s，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)。
Example 20
a) 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde.
A solution of 1M boron trichloride in dichloromethane (25 ml; 25mmol) was added to 6-fluoro-2, 3-dimethoxy-benzaldehyde [ 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) to and maintaining the reaction temperature at-70 ℃. The reaction mixture was stirred at room temperature overnight and hydrolyzed with water. The organic phase was separated, washed with water and evaporated in vacuo. The residue is chromatographed (silica gel, EA: Hex 5: 1) to give 3.72g (94%) of 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde 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)。
b) 5-fluoro-8-methoxy-2H-chromene.
6-fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32g, 19mmol) was dissolved in acetonitrile (20ml), DBU (2.97ml, 19mmol) was added followed by vinyltriphenylphosphine bromide (7.2g, 19 mmol). The reaction mixture was heated at reflux for 48h, diluted with water and extracted with diethyl ether (3X 50 ml). The organic phase was washed with water, 10% sodium hydroxide, water and brine and evaporated in vacuo. Column chromatography of the residue (silica gel, EA: Hex 1: 20) gave 1.2g of 5-fluoro-8-methoxy-2H-chromene (34%).
1H-NMR(CDCl3)：6.65(m，2H)，6.54(t，1H)，5.83(dt，1H)，4.88(dd，2H)，3.83(s，3H)。
c) (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
The title compound was synthesized in analogy to example 17c, from 5-fluoro-8-methoxy-2H-chromene.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)。
d) (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
The title compound was synthesized in analogy to example 15b, from (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-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)。
e) (±) -cis-1- (5-cyano-pyridin-2-yl) -3- (7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromen-1-yl) -urea.
The title compound was synthesized in analogy to example 15c, from (±) -cis-7-fluoro-4-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid (62mg, 0.17 mmol). 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 21
a) 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)。
b) 5-fluoro-8-chloro-2H-chromene.
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)。
c) +/-cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
The title compound was synthesized in analogy to example 15c) from 5-fluoro-8-chloro-2H-chromene.
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)。
d) (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
The title compound was synthesized in analogy to example 15d) from (±) -cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-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)。
Example 22
a) Trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester.
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 ℃. The dry ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane, washed with water, brine and evaporated in vacuo. The crude product was purified by column chromatography (silica gel, EA: Hex 1: 6) to give 1.55g of 4-formyl-3-hydroxy-phenyl trifluoro-methanesulfonate (57%).
1H-NMR(CDCl3)：11.28(s，1H)，9.93(s，1H)，7.67(d，1H)，6.95(m，2H)。
b) Trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester.
Potassium carbonate (1.6g, 11.5mmol) and allyl bromide (1ml, 11.5mmol) were added to a solution of 4-formyl-3-hydroxy-phenyl trifluoro-methanesulfonate (1.55g, 5.7mmol) in acetone (50 ml). The reaction mixture was stirred at 55 ℃ for 2h, filtered and evaporated in vacuo. The residue is chromatographed (silica gel, EA: Hex 1: 20) to give 1.3g (73%) of 3-allyloxy-4-formyl-phenyl trifluoro-methanesulfonate.
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)。
c) 3-allyloxy-4-vinyl-phenyl trifluoro-methanesulfonate.
Methyltriphenylphosphine bromide (1.95g, 5.45mmol) was added to a suspension of sodium hydride (60% in oil) (0.25g, 6.3mmol) in THF (35ml) at 0 deg.C and stirred at room temperature for 30 min. To the above solution was added a solution of 3-allyloxy-4-formyl-phenyl trifluoro-methanesulfonate (1.3g, 4.2mmol) in THF (15ml), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with n-hexane and extracted with water. The organic phase was washed with brine and evaporated. Silica gel column chromatography (EA: Hex 1: 20) gave 3-allyloxy-4-vinyl-phenyl trifluoro-methanesulfonate (0.68g, 53%).
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)。
d) Trifluoro-methanesulfonic acid 2H-chromen-7-yl ester.
To a solution of 3-allyloxy-4-vinyl-phenyl trifluoro-methanesulfonate (0.68g, 2.2mmol) in dichloromethane (5ml) was added ruthenium-catalyst (Grubb's catalyst) (36mg, 2 mol%) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (GC), the reaction mixture was used in the next step without any work-up. The solvent was removed by silica gel column chromatography (EA: Hex 1: 20) to obtain a sample for analysis.
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)。
e) +/-cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
General formula 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 a period of 5h at room temperature. When the reaction was complete (GC) the dichloromethane was evaporated and the residue was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and brine. The organic phase is evaporated and the crude mixture of cis-and trans-isomers (1: 1.3) is separated by column chromatography (silica gel, EA: Hex 1: 6) to give 0.4g (50%) of + -cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] s]Chromene-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(m，1H)，1.03(t，3H)。
f) +/-cis-5-cyano-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
Reacting the mixture of + -cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester (154mg, 0.42mmol), Pd (OAc)2(9mg, 10 mol%) and PPh3(44mg, 40 mol%) was mixed in DMF (4ml) and a gentle stream of nitrogen was passed through the reaction mixture for 10 min. Adding Zn (CN)2(74mg, 0.63mmol), the vial was sealed and the reaction mixture was stirred at 120 ℃ overnight. The reaction mixture was diluted with ethyl acetate and extracted with saturated ammonium chloride. The organic phase is evaporated and the residue chromatographed (silica gel, EA: Hex 1: 5) to give 53mg (52%) of + -cis-5-cyano-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-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)。
g) +/-cis-5-cyano-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
Ethyl + -cis-5-cyano-1, 1a, 2, 7 b-tetrahydro-cyclopropaneo [ c ] chromene-1-carboxylate (53mg, 0.22mmol) and NaOH (35mg, 0.88mmol) were dissolved in a mixture of methanol and water (1: 1) (5 ml). The reaction mixture was stirred at 60 ℃ for 30 min. Methanol was evaporated in vacuo and 20ml of water were added. The resulting solution was extracted with diethyl ether. The aqueous phase was concentrated, acidified to pH-2 with 1M HCl and extracted with ether. The organic phase was washed with brine and evaporated to give 42mg (90%) of cis-5-cyano-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-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)。
Example 23
a) +/-cis-5-trimethylsilylethynyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
Reacting the mixture of + -cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester (152mg, 0.41mmol), DPPP (38mg, 20 mol%), Pd (dba)2(24mg, 10 mol%), CuI (3mg, 4 mol%) were mixed in 3ml of triethylamine and a gentle stream of nitrogen was passed through the reaction mixture for 10 min. Trimethylsilyl-acetylene (0.088ml, 0.62mmol) was added, the vial was sealed and the reaction mixture was stirred at 120 ℃ overnight. The reaction mixture was diluted with ethyl acetate, washed with water, brine and evaporated. The residue was purified by silica gel column chromatography (EA: Hex 1: 15) to give 0.1g (77%) of. + -. cis-5-trimethylsilylethynyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-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)。
b) +/-cis-5-ethynyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
Ethyl + -cis-5-trimethylsilylethynyl-1, 1a, 2, 7 b-tetrahydro-cyclopropa [ c ] chromene-1-carboxylate (0.1g, 0.32mmol) and sodium hydroxide (0.076g, 1.9mmol) were dissolved in a mixture of methanol: water (1: 1) (5 ml). The reaction mixture was heated at 60 ℃ for 5h, then acidified to pH-2 with 1M HCl and extracted with ether. The organic phase was washed with brine and evaporated to give 66mg (97%) of + -cis-5-ethynyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-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)。
Example 24
+/-cis-1- (5-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropaneAlkyl [ c ]]Chromen-1-yl) -3- (5-cyano-pyridines -2-yl) -urea
a) +/-cis-5-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
Reacting the mixture of + -cis-5-trifluoromethylsulfonyloxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid ethyl ester (117mg, 0.32mmol), DPPP (7.3mg, 50 mol%), Pd (OAc)2(2mg, 25 mol%) and triethylamine (0.09ml, 0.64mmol) were mixed in DMF (3ml) and a gentle stream of nitrogen was passed through the reaction mixture for 10 min. Butyl vinyl ether (0.21ml, 1.6mmol) was added, the vial sealed and the reaction mixture stirred at 100 ℃ for 2 h. 5% HCl (5ml) was added and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride and evaporated. The residue was purified by silica gel column chromatography (EA: Hex 1: 5) to give 76mg (91%) of. + -. cis-5-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-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)。
b) +/-cis-5-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
The title compound was synthesized in analogy to example 22g, from + -cis-5-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester (76mg, 29 mmol). 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)。
Example 25
+/-cis-5-methoxy-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c]Chromene-1-carboxylic acid.
The title compound was synthesized in analogy to example 22, from 2-hydroxy-4-methoxybenzaldehyde.
Example 26
a) N-acetyl-1, 2-dihydroquinoline.
Quinoline (19.37g, 150mmol) was dissolved in anhydrous ether (500ml) under an inert gas atmosphere and cooled to 0 ℃. DIBAL, a 1.5M solution in toluene (100ml, 150mmol) was added dropwise over a period of 2hrs and the reaction mixture was stirred at 0 ℃ for 30 min. Acetic anhydride (500ml) was added dropwise over a period of 30min and the reaction mixture was stirred at 0 ℃ for 30 min. Carefully add H2And O. The reaction mixture was extracted with ether and concentrated to give N-acetyl-1, 2-dihydroquinoline (11.5g, 44%).
b) + -cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid ethyl ester.
Following the procedure described in example 15a, ± cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid ethyl ester was prepared from N-acetyl-1, 2-dihydroquinoline (10g, 58mmol) and the product was purified by silica gel column chromatography (EtOAc/N-hexane 5% → 50%) to give ± cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid ethyl ester (2.0g, 13%).
c) +/-cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid.
. + -. cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid (425mg, 24%) was prepared from. + -. cis- (N-acetyl-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] quinoline) -1-carboxylic acid ethyl ester (2.0mg, 7.7mmol) according to the procedure described for example 15 b.
Example 27
a)2, 4-difluoro-2-propynyloxybenzene.
Commercially available 2, 5-difluorophenol (20g, 0.15mol), K2CO3(53g, 0.38mol) and commercially available 3-bromopropyne (45g, 0.38mol) were dissolved in acetone (300ml), refluxed overnight, cooled and filtered. The solvent was removed and the crude product was dissolved in ether and washed with water and brine. The organic phase is evaporated and the crude product is redissolved in a small amount of diethyl ether by basic Al2O3The column was filtered. Evaporation and drying gave 20g (80%) of 2, 4-difluoro-2-propynyloxy-benzene.
b)5, 8-difluoro-2H-chromene.
2, 4-difluoro-2-propynyloxybenzene (20g, 0.12mol) was dissolved in N, N-diethylaniline (100ml), and the mixture was heated in an oil-bath at 225 ℃ for 6 to 8 hours under an argon atmosphere. Ether (150ml) was added by addition of 2M HCl(aq)The aniline was removed by extraction. Purification by chromatography (silica gel, n-hexane) gave 5.8g (29%) of 5, 8-difluoro-2H-chromene.
c) +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
Reacting 5, 8-difluoro-2H-chromene (5g, 0.03mol), (Rh (II) Ac2)2(0.39g, 0.00089mol) was dissolved in 1, 2-dichloroethane (60ml) or ethanol-free chloroform. In N2Under the atmosphere, in a time period of more than about 5 hoursEthylazoacetate (9.4ml, 0089mol) in the same solvent was added dropwise. The solvent was then removed in vacuo and the mixture was extracted with ethyl acetate and then with NaHCO3(aq), water and brine and solvent removed. The product was purified by chromatography (0 → 10% ethyl acetate in hexanes) (33% cis, 66% trans) to give 2.2g of the title compound (30%).
d) Cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
Ethyl cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylate (2g, 0.008mol) was heated at 80 ℃ for 2h in a 1M solution of LiOH in methanol-water (25%). The volume was reduced to half and acidified. Extraction with ether followed by chromatography (silica gel, ether) gave the pure title compound (35%).
Example 28
Additional intermediates
a) 6-fluoro chroman-4-ols
6-fluoro chroman-4-one (10g, 61mmol)) was dissolved in ethanol (100 ml). Adding NaBH4(excess) and cooled on an ice bath. The mixture was then left at room temperature for 2h, followed by reflux for 4 h. Purification by chromatography (silica gel, ether-hexane, 1: 5) gave 8.g (80%) of pure 6-fluoro-chroman-4-ol.
b) 6-fluoro-2H-chromenes
6-fluoro chroman-4-ol (8g, 48mmol) and toluene-4-sulfonic acid (1g) were dissolved in toluene and refluxed overnight, followed by removal of water. The mixture was then cooled and NaHCO used3(aq) washing and purification by chromatography (silica gel, n-hexane) gave 4.2g (52%) of pure 6-fluoro-2H-chromene.
c) +/-cis-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
This compound was prepared analogously to cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester but using 6-fluoro-2H-chromene to give 1.9 (29%) of the title compound.
d) Cis-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid
This compound was prepared analogously to cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid but using ethyl cis-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylate (1.9g, 8mmol) to give 350mg (21%) of pure cis-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
e) 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene
This compound was prepared analogously to 2, 4-difluoro-2-propynyloxy-benzene but using 2-bromo-5-fluorophenol (15g, 78mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6g (87%).
f) 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene
This compound was prepared analogously to 2, 4-difluoro-2-propynyloxy-benzene but using 2-bromo-4-fluoro-phenol (15g, 78mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15.g (84%).
g)1, 3-difluoro-5-prop-2-ynyloxy-benzene
This compound was prepared analogously to 2, 4-difluoro-2-propynyloxybenzene but using 3, 5-difluoro-phenol (14g, 107mmol) to give 12g (67%) of 1, 3-difluoro-5-prop-2-ynyloxy-benzene.
h) 8-bromo-6-fluoro-2H-chromene
This compound was prepared analogously to 5, 8-difluoro-2H-chromene but using (15g, 65mmol) 2-bromo-4-fluoro-1-prop-2-ynyloxybenzene to give the title compound (7g, 46%).
i) 8-bromo-5-fluoro-2H-chromene
This compound was prepared analogously to 5, 8-difluoro-2H-chromene but using (15g, 65mmol) 1-bromo-4-fluoro-2-prop-2-ynyloxybenzene to give the title compound (3.7g, 25%).
j)5, 7-difluoro-2H-chromenes
This compound was prepared analogously to 5, 8-difluoro-2H-chromene but using (18g, 107mmol) 1, 3-difluoro-5-prop-2-ynyloxybenzene and PEG-200 as solvents to give the title compound (4g, 23%).
k) +/-cis-4-bromo-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
This compound was prepared analogously to +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester, but using 5g (22mmol) of 8-bromo 6-fluoro-2H-chromene to give 1.9g (30%) of cis-6-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
l) +/-cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
This compound was prepared analogously to +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester but using 3.5g (15.3mmol) of 8-bromo-5-fluoro-2H-chromene to give 1.6g (33%) of +/-cis-4-bromo-7-fluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
m) +/-cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
This compound was prepared analogously to +/-cis-4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester, but using 2g (12mmol) of 5, 7-difluoro-2H-chromene to give 0.9g (29%) of +/-cis-5, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid ethyl ester.
zs
Example 29
a) Resolution of racemic cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
0.32g (1.32mmol) of racemic cis-7-fluoro-4-chloro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid was dissolved in hot acetonitrile (50ml) and (1R, 2R) -2-benzyloxycyclopentylamine (0.25g, 1.32mmol) was added. The resulting solution was left to crystallize. After several hours the mother liquor was decanted and the crystals were washed with acetonitrile. A second crystallization from acetonitrile gave 92mg of the pure diastereoisomeric salt. The salt was treated with 1M HCl and 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-tetrahydro-cyclopropane [ c ] chromene-1-carboxylic acid.
Example 30
+/-cis-N- (5-cyano-2-pyridyl) -N' - (4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c)] Chromene-1-Yl) urea
a)1, 4-dichloro-2- (2-propynyloxy) benzene
2, 5-dichlorophenol (8g, 49mmol) was mixed with potassium carbonate (13.6g, 98mmol) and 80% propargyl bromide in toluene (11ml, 98mmol) in acetone (100ml) at room temperature and stirred overnight. The precipitate was removed by filtration and washed with acetone. The resulting acetone solution was concentrated by rotary evaporation and kept under vacuum for 5 h. A quantitative yield of yellow oily product was obtained. It was used for further transformation without additional purification.
b)5, 8-dichloro-2H-chromene
1, 4-dichloro-2- (2-propynyloxy) benzene was degassed and heated at 224 ℃ for 4h with stirring under argon. Then in a Kugelrohr apparatus (150 ℃ C./175 ℃ C./4.1X 10)-2mbar) the reaction mixture was distilled to give 3.58g of the desired product as a white solid. The yield from dichlorophenol was 36%.
c) +/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
5, 8-dichloro-2H-chromene (3.15g, 16mmol), (Rh (II) Ac)2)2(30mg, 0.1 mol%) was dissolved in degassed anhydrous dichloromethane (3 ml). In N2Under an atmosphere of air, byThe syringe was charged with ethyl azoacetate (3ml, 2eq.) in the same solvent over a period of about 5 hours at a flow rate of 0.4 ml/h. Then using NH4Cl (aq), water and brine the reaction mixture was washed and the solvent was removed. The product was purified by silica gel chromatography (200g, ethyl acetate/n-hexane 1: 15) (45% cis, 55% trans) to give 0.9g of pure cis-product (racemate). The yield was 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-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid
+/-cis-4, 7-dichloro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid ethyl ester was mixed with an aqueous solution of methanol (3ml) and NaOH (1.5eq., 3ml), and heated at 60 ℃ for 1.5h with stirring. The extract of the basic reaction mixture extracted into hexane showed no starting material present. The reaction mixture was acidified with excess 3M HCl solution (pH 1). The precipitate formed was collected by suction and washed with water. The resulting white solid was dried under high vacuum (yield 80%).
Example 59A
a) 5-chloro-2-fluorophenol
5-chloro-2-fluoroaniline (10g, 68mmol) was dissolved in 6M sulfuric acid and cooled to-5 ℃ in an ice/brine bath. Adding NaNO dropwise at a temperature of not higher than-2 deg.C2(5.2g, 76mmol) in a minimum amount of water to a stirred suspension. After additional clear yellow solution had formed, it was allowed to stir for an additional 30min while cooling. Make CuSO4Dissolved in water (80ml) and mixed with sulfuric acid (32 ml). The diazonium salt solution was added dropwise to a preheated (160 ℃) cuprous sulfate solution and the product was removed from the reaction flask by steam distillation. This reaction took about 2h to complete. The water/phenol solution was extracted into ether, washed with brine, and taken over Na2SO4And (5) drying. Concentration yielded 4g of crude phenol (40%).
b) 4-chloro-1-fluoro-2- (2-propynyloxy) benzene
In analogy to example 33a, 4-chloro-1-fluoro-2- (2-propynyloxy) benzene was synthesized from (4g, 27mmol) 4-chloro-1-fluorophenol to give 4.6g of the product as a yellow oil (purification by silica gel column chromatography, ethyl acetate/n-hexane 1: 15). The yield was 90%.
c) 5-chloro-8-fluoro-2H-chromene
In analogy to example 33b), 5-chloro-8-fluoro-2H-chromene was synthesized from 4-chloro-1-fluoro-2- (2-propynyloxy) benzene (4.6g, 25mmol) to give 1g of the product as a colorless oil (purification by column chromatography on alumina, ethyl acetate/n-hexane 1: 15). The yield was 22%.
d) +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid ethyl ester
In analogy to example 33c, from 5-chloro-8-fluoro-2H-chromene (1g, 5.4mmol) was synthesized +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid ethyl ester to give 360mg of +/-cis product as a white solid (purification by silica gel column chromatography, ethyl acetate/n-hexane 1: 20). The yield was 25%.
e) +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid
In analogy to example 33d +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid ethyl ester (360mg, 1.3mmol) was synthesized from +/-cis-7-chloro-4-fluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] chromene-1-carboxylic acid to give 259mg of +/-cis-disperse acid (80%).
Example 31
N- [ (1S, 1aR, 7bR) or (1R, 1aS, 7bS) -1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]]-[1]Benzo (b) is Thiopyran-1-yl]-N' - (5-cyano-2-pyridyl) urea
a)3, 4-dihydro-2H-1-benzothiopyran-4-ol
A solution of thiochroman-4-one (9g) in diethyl ether (27ml) was slowly added to a mixture of lithium aluminium hydride (0.53g) in diethyl ether (54 ml). After the end of the addition, the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool and ice was added followed by water and 20% H2SO4And (3) solution. The aqueous phase was washed twice with diethyl ether. The ether phase is washed twice with 2N NaOH and once with water over MgSO4Drying and evaporating. After a few hours, it crystallized as a clear oil (8.9 g). Rdt ═ 97%
b) 2H-1-benzothiopyrans and 4H-1-benzothiopyrans
4-Thiochromanol (Thiochromanol) (8.9g) and potassium hydrogen sulphate (0.89g) were placed in a flask and sucked to 1mm under vacuum. The flask was placed in a bath and heated at 90 ℃ until the alcohol melted. The magnetic stirrer was turned on and the bath temperature was slowly raised to 120 ℃. The mixture of product and water from the distillation was rapidly dehydrated and collected in an ice-cold receiver. The product was dissolved in diethyl ether and dried. The crude product (7g, Rdt ═ 88%) was not purified. NMR showed 10% 4H-1-thiochroman present.
c)1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] [1] benzothiopyran-1-carboxylic acid ethyl ester, (1S, 1aR, 7bR) or (1R, 1aS, 7bS)
Ethylazoacetate was slowly added to 500mg of thiochromene at 140 ℃. The reaction was monitored by gas chromatography and ended when all starting material was consumed (about 7 hours). The residue was purified by flash chromatography (5% ether in n-hexane). The cis isomer was determined by nmr spectroscopy (46.5mg, Rdt ═ 6%).
d)1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] [1] benzothiopyran-1-carboxylic acid, (1S, 1aR, 7bR) or (1R, 1aS, 7bS)
The cis isomer (46.5mg), LiOH (4eq., 19mg) were dissolved in 5ml of methanol/25% H2The mixture in O was refluxed for 1 hour. After evaporation of the solvent under vacuum, the residue was dissolved in water and washed with ether. The aqueous phase was acidified with concentrated HCl and extracted twice with dichloromethane. After drying, the organic phase was evaporated and the desired acid (30mg) was obtained. Rdt-73%.
Example 32
(1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane-o [ c]Chromene-1-carboxylic acid
a) (2Z) -3- (3, 6-difluoro-2-methoxyphenyl) -2-propen-1-ol.
A solution of BuLi (2.5M) in hexane (9.6 ml; 0.024mol) was added to a stirred solution of 2, 5-difluoroanisole (2.88 g; 0.02mol) in anhydrous THF (30ml) at-70 ℃ for 2h, after which a solution of zinc chloride (3.6 g; 0.026mol) in anhydrous THF (50ml) was added. The reaction temperature was allowed to rise to room temperature and then stirring was continued at room temperature for 30 min. Addition of Pd (OAc)2(8 mg; 0.2 mol%) followed by the addition of ethyl cis-3-bromoacrylate (3.58 g; 0.02 mol). The reaction mixture was placed in a preheated oil bath and heated at reflux for 1 h. The resulting reaction mixture was cooled to-78 ℃ and 60ml (0.06mol) of DIBAL (1M in n-hexane) was added dropwise. Stirring was continued at-78 ℃ for 2h and at room temperature for 1 h. The reaction was quenched with water and the solid was dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, brine and evaporated in vacuo. The residue was Kugelrohr distilled (1.5X 10)-2mbar, 150 ℃ C.) to3.7g (92%) of crude (2Z) -3- (3, 6-difluoro-2-methoxyphenyl) -2-propen-1-ol, containing 6% of the other positional isomers (regioisomers). The crude product was used in the next step without further purification.
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-methoxyphenyl) prop-2-enoic acid azoacetate
P-toluenesulfonylhydrazone glyoxyl chloride (5.16 g; 0.02mol) was added to anhydrous CH of (2Z) -3- (3, 6-difluoro-2-methoxyphenyl) -2-propen-1-ol (3.6 g; 0.018mol) at-5 deg.C2Cl2To a solution (50ml) was added N, N-dimethylaminoaniline (2.5 ml; 0.02mol) slowly. Stirring at-5 deg.C for 30min, and slowly adding Et3N (12 ml; 0.09 mol). The resulting mixture was stirred at-5 ℃ for 15min, then at room temperature for 30min, to which water (. about.50 ml) was added. The organic phase was separated and washed with water, brine and concentrated in vacuo. Flash chromatography (Celite, EA: Hex 1: 15) gave 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-methoxyphenyl) -3-oxabicyclo [3.1.0] hex-2-one.
(2Z) -3- (3, 6-difluoro-2-methoxyphenyl) prop-2-enylazoacetate (3.45g, 0.013mol) was dissolved in 100ml of anhydrous degassed dichloromethane and added dropwise over a period of 6h to a solution of chiral Doyle catalyst (Aldrich, also available from Johnson Matthey, 10mg, 0.1 mol%) in 50ml of dichloromethane under argon at room temperature. After the addition was complete, the initial blue color turned to olive. The reaction mixture is concentrated in vacuo and the crude product is purified by flash chromatography (Celite, EA: Hex 1: 5 → 1: 1) to give 2.72g (88%) of (1S, 5R, 6S) -6- (3, 6-difluoro-2-methoxyphenyl) -3-oxabicyclo [3.1.0] Hex-2-one as a colorless solid. Enantiomeric purity can be measured at this stage using a Chiracel OD column, 10% IPA in n-hexane-94% ee.
1H-NMR(CDCl3)：7.00(m，1H)；6.72m，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- (bromomethyl) -4, 7-difluoro-1 a, 7 b-dihydrocyclopropane [ c ] chromen-2 (1H) -one.
(1S, 5R, 6S) -6- (3, 6-difluoro-2-methoxyphenyl) -3-oxabicyclo [3.1.0] hex-2-one (130mg, 0.55mmol) was mixed with 1.2ml of 30% HBr/AcOH (6mmol) and the closed vessel was heated at 90 ℃ with stirring for about 4 h. The reaction mixture was then allowed to cool down, mixed with water and extracted into diethyl ether (3X 20 ml). The ether extract was washed with saturated sodium bicarbonate solution and brine. Dried over magnesium sulfate. Concentration gave 160mg of a white solid. The yield was 98%.
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-tetrahydrocyclopropane [ c ] chromene-1-carboxylic acid.
(1S, 1aR, 7bS) -1- (bromomethyl) -4, 7-difluoro-1 a, 7 b-dihydrocyclopropa [ c ] chromen-2 (1H) -one (360mg, 1.2mmol) was mixed with a solution of NaOH (0.1g, 2.5mmol) in 5ml of water and heated at 90 ℃ for 1H with stirring. After completion the reaction mixture was allowed to cool down and extracted into diethyl ether (2X 20 ml). The aqueous phase was acidified with concentrated HCl. The precipitate formed was collected by filtration to give 180mg of pure product. The mother liquor was extracted into ether and washed with brine, dried over magnesium sulfate. Concentration gave an additional 70mg of product (containing up to 15% impurities). The total yield is about 92%.
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 33
a) Cis-1 a, 6 b-dihydro-1H-benzo [ b ] cyclopropane [ d ] thiophene-1-carboxylic acid ethyl ester, (1S, 1aS, 6bR) or (1R, 1aR, 6bS)
Ethylazoacetate was slowly added to 10g of thiophene at 140 ℃. The reaction was monitored with gas phase color and ended after 7 hours. The residue was purified by flash chromatography (5% diethyl ether in hexanes). The cis isomer was determined by NMR spectroscopy (917mg, Rdt ═ 6%). Reference documents: badger G.M.et al, J.chem.Soc., 1958, 1179-1184, Badger G.M.et al, J.chem.Soc., 1958, 4777-4779.
b) Cis 1a, 6 b-dihydro-1H-benzo [ b ] cyclopropane [ d ] thiophene-1-carboxylic acid, (1S, 1aS, 6bR) or (1R, 1aR, 6bS)
The cis isomer (443mg), LiOH (193mg) were added to 15ml of methanol/25% H2The mixture in O was refluxed for 1 hour. After evaporation of the solvent under vacuum, the residue was dissolved in water and washed with ether. The aqueous phase was acidified with concentrated HCl and extracted twice with dichloromethane. After drying, the organic phase was evaporated to give the desired acid (313.6 mg). Rdt 81%.
Example 34
(1S, 5R, 6S) -6- (3, 6-difluoro-2-methoxyphenyl) -2-methoxy-3-oxabicyclo [3.1.0] hexane
a) Iodo-3-oxabicyclo [3.1.0] hex-2-one
The title compound was synthesized with the indicated stereochemistry as 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 with the stereochemistry shown as described in Martin et al Tett Lett 391521-.
c) (1S, 5R, 6S) -6- (3, 6-difluoro-2-methoxyphenyl) -2-methoxy-3-oxabicyclo [3.1.0] hexane
2, 4-Difluoroanisole (90mg, 0.62mmol) was dissolved in anhydrous, degassed THF (7ml) under N2Then cooled to-78 ℃. 2.5M hexane (0.30ml, 0.77mmol) of nBuLi was added and the reaction mixture was stirred at-78 ℃ for 2 hrs. Adding ZnCl2(150mg, 1.1mmol), as a solution in anhydrous THF (7ml), and the reaction mixture was allowed to warm to room temperature for 2 hrs. Iodo-2-methoxy-3-oxabicyclohexane (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 THF (7ml) and added to the reaction mixture. Heating the reaction mixture at reflux for 3 days with H2And quenching O. Adding diethyl ether and separating the layers, the organic layer is washed with H2O and saturated aqueous NaCl solution, over MgSO4Drying, filtration and concentration gave the title compound, 2, 4-di-fluoro-5- (cyclopropanal) anisole, also denoted as. Column chromatography over silica gel (EtOAc/hexanes 1: 3) afforded (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 35
Cis-4, 7-difluoro-11a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromene-1-carboxylic acid.
At 0 ℃ BBr3CH (A) of2Cl2(5.8 ml; 5.8mmol 2.1eq) of a 1M solution was added to the starting lactone and (1S, 5R, 6S) -6- (3, 6-difluoro-2-methoxyphenyl) -3-oxabicyclo [3.1.0] obtained in example 42c)]Hex-2-one (0.66 g; 2.75 mmol). The reaction mixture was stirred at 0 ℃ for 1 h. Acetonitrile (5.8ml) was added and stirring continued at 0 ℃ for 3 h. The reaction mixture was quenched by the addition of water and the organic phase was separated. Using CH as the aqueous phase2Cl2The combined organic phases were extracted and evaporated. To the resulting residue was added a solution of NaOH (0.33 g; 8.25 mmol; 3eq) in water (. about.5 ml) and stirred at 80 ℃ for 45 min. The reaction mixture was extracted with diethyl ether to remove non-acidic impurities. The ether remaining in the aqueous phase was evaporated in vacuo and concentrated HCl was added to pH 3. After about 1h the solid was filtered off to give 0.497g (80%) of the final crude acid as a brown solid. The crude acid was dissolved in 6ml EtOH/H2O (40/60v/v), treated with activated carbon. The hot solution was filtered and left to crystallize. The yield was 0.4g (64%).
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 36
a)1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid ethyl ester.
The indene is diluted with 100ml of dichloroethane. Adding about 10mg of CuI and about 10mg of Pd (OAc)2.25 ml of the resulting mixture was added dropwise to 25ml of ethyl azoacetate and refluxed for 30 minutes. Tong (Chinese character of 'tong')Perform Al2O3The solution eluted with an EtOAC/hexane gradient was filtered. The eluate was vigorously evaporated at 100 ℃ under 2mmHg to give the title compound (36 g).
b)1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] inden-1-amine.
With about 50g NaOH in 200ml 10: 1 MeOH: H2O boiled the product of step a) for 2 hours. The mixture was diluted with water, washed with dichloroethane, evaporated with HOAc, extracted with dichloroethane, washed with water, dried over sulphate, filtered and evaporated to give 25g of 95% pure acid. DPPA 275.2 δ 1.12810ml, 46.5mmol tea7.1ml 1.1ee and 7.3g of the acid (mass 174.12, 0.9ee) were mixed in 200ml toluene and refluxed for about 2 hours. The product was evaporated and dissolved in 200ml of dioxane. 25ml of HCl (aq) and 25ml of water were added and the mixture was stirred at room temperature for 60 minutes. The solution was partitioned between an acid/base water/dichloroethane solution. The organic phase was dried, filtered and evaporated. Column chromatography of the product over silica 60 column gave 660mg of 85% pure cis-amine with molecular weight 145.11.
Example 37
+/-cis-1- (5-cyano-pyridin-2-yl) -3- (1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a)]Inden-1-yl) -urea
a) +/-cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a ] indene-1-carboxylic acid ethyl ester
Indene (11.6g, 100mmol) and Cu at 80 deg.C2Br2(0.10g, 0.35mmol) to a mixture in 1, 2-dichloroethane (200mL) was added dropwise (3h) a solution of ethyl azoacetate (17.1g, 150mmol) in 1, 2-dichloroethane (35 mL). After 15min at 80 ℃ with H2The reaction mixture was washed with O (200 mL). H2O phase is CH2Cl2(50mL) and the combined organic phases were stripped of solvent under reduced pressure. Column chromatography of the crude product (silica gel, 5 → 10% EtOAc in hexanes) afforded 3.63g (18%) of + -cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a ]]Indene-1-carboxylic acid ethyl ester and 6.68g (33%) of. + -. trans-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a ] as by-product]Indene-1-carboxylic acid ethyl ester.
1H-NMR(CDCl3)：7.30-7.05(m，4H)，3.81(q，2H)，3.36(d，1H)，3.18(dd，1H)，2.92(m，1H)，2.24(m，1H)，1.99(dd，1H)，0.92(t，3H)。
b) +/-cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a ] indene-1-carboxylic acid
From + -cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a]Indene-1-carboxylic acid ethyl ester (3.53g, 15.5mmol), LiOH (539mg, 22.5mmol), H2Synthesis of. + -. cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a ] with MeOH (10mL)]Indene-1-carboxylic acid, heating the above materials to reflux for 2h, concentrating and acidifying to obtain + -cis-1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a]1.62g (62%) of a white solid precipitate of indene-1-carboxylic acid. The product did not crystallize.
1H-NMR(CDCl3)：10.95(br s，1H)，7.35-7.02(m，4H)，3.29(d，1H)，3.14(dd，1H)，2.96(m，1H)，2.27(m，1H)，1.91(dd，1H)。
The reaction mixture was concentrated under reduced pressure, benzene (20mL) was added, and 1N HCl (30mL), H2The reaction mixture was washed with O (30mL) and brine (30 mL). The organic phase was freed of solvent under reduced pressure. The crude product is purified by column chromatography (silica gel, 4 → 5% MeOH in CH)2Cl2To yield 25mg (5%) + -cis-1- (5-cyano-pyridin-2-yl) -3- (1, 1a, 6, 6 a-tetrahydro-cyclopropane [ a)]Inden-1-yl) -urea.
1H-NMR(DMSO-d6)：9.58(s，1H)，8.18(d，1H)，7.96(dd，1H)，7.40-7.25(m，3H)，7.17-7.05(m，3H)，3.27-3.13(m，2H)，2.80-2.73(m，2H)，2.05(dd，1H)。
Example 38
+/-cis-1- (5-cyano-pyridin-2-yl) -3- (1a, 2, 3, 7 b-tetrahydro-cyclopropane [ a)]Naphthalen-1-yl) -urea.
a)1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 37, synthesis of ethyl 1a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate from 1, 2-dihydronaphthalene (3.91g, 30mmol) gave 688mg (11%) of ethyl 1a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate (mixture of the cis and trans isomers 56/39).
1H-NMR(CDCl3)：7.35-6.95(m，4H)，4.30-3.85(m，2H)，2.90-1.00(m，10H)。
b)1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
In analogy to example 37b, 1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid was synthesized from ethyl 1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylate (688mg, 3.18mmol, mixture of the cis and trans isomers 56/39) to give 540mg (90%) of 1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid (mixture of the cis and trans isomers 56/39). The product did not crystallize.
1H-NMR(CDCl3)：11.36(br s，1H)，7.30-6.95(m，4H)，2.80-1.65(m，7H)。
Example 68
a)1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid ethyl ester.
In analogy to example 37a, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid ethyl ester was synthesized from 6, 7-dihydro-5H-benzocycloheptane (4.40g, 30.5mmol) to give 3.43g (49%) of 1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid ethyl ester (mixture of cis and trans isomers 1/10).
1H-NMR(CDCl3)：7.40-6.90(m，4H)，4.30-4.00(m，2H)，3.30-0.50(m，12H)。
b)1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid.
1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid was synthesized in analogy to example 37, from ethyl 1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cycloheptene-1-carboxylate (3.43g, 14.9mmol, mixture of cis and trans isomers at 1/10) to yield 2.81g (93%) of 1, 1a, 2, 3, 4, 8 b-hexahydro-benzo [ a ] cyclopropane [ c ] cycloheptene-1-carboxylic acid (mixture of 1/10 cis and trans isomers). The product did not crystallize.
1H-NMR(CDCl3)：10.76(br s，1H)，7.40-7.00(m，4H)，3.30-0.50(m，9H)。
Example 40
a) 6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-ol
6-Methoxytetralone (10g, 0.057mol) was mixed with 150ml of absolute ethanol, and sodium borohydride (1.2eq) was added to the stirred mixture in portions. The reaction mixture was left to stir at room temperature for 15 h. The reaction mixture was then concentrated by rotary evaporation, mixed with 100ml of water and heated at 45 ℃ for 1 h. The resulting mixture was extracted into diethyl ether (3X 80 ml). The combined organic extracts are purified over Na2SO4Dried and concentrated by rotary evaporation to give 10.39g of a yellow oil which was used in the next step without additional purification.
b) 7-methoxy-1, 2-dihydronaphthalene
Crude 6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-ol (10.3g, 0.058mol) was dissolved in 100ml of toluene and heated in an oil bath (115 ℃). To the reaction mixture was added p-toluenesulfonic acid (20mg) and refluxed for about 1 h. The reaction was monitored by GC. The reaction mixture was then cooled and saturated NaHCO3The solution, water and brine were washed, and the organic layer was washed with Na2SO4And (5) drying. Concentration gave 8.87g of a bright brown oil. The yield was 96%.
c) 5-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
7-methoxy-1, 2-dihydronaphthalene (8.8g, 0.055mol) was mixed with 10ml of degassed anhydrous dichloromethane and 20mg of rhodium acetate (ca. 0.1 mol%). To the reaction mixture was bubbled nitrogen, ethyl azoacetate (2eq, 50% degassed anhydrous dichloromethane solution) was slowly added at room temperature to the stirred solution via syringe (flow rate about 1 ml/hour). Gas starts to be generated when adding. The reaction was monitored by GC. An additional amount of catalyst (about 20mg) was added during the reaction. The GC-ratio of cis/trans isomers was 21: 48.
After completion of the reaction according to GC data, saturated NH4The reaction mixture was washed with Cl solution and brine. The dichloromethane solution is treated with Na2SO4And (5) drying. Concentration gave 13g of crude product as a yellow oil. Purification was carried out by silica gel column chromatography (200g, ethyl acetate/hexane 1: 20). The trans isomer is obtained only in pure form. The desired cis form cannot be purified by the technique used. Fractions enriched in the desired product (200mg, cis/trans ratio by GC 70: 30) were combined and used for further transformations.
d) 5-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
Reacting 5-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a]Ethyl naphthalene-1-carboxylate (0.2g, 0.8mmol) was dissolved in 2ml of methanol, and to the reaction mixture was added aqueous solution of sodium hydroxide (0.2g, 50mmol) in 2ml and stirred at room temperature overnight. The basic reaction mixture was extracted into hexane, indicating no starting material was present. The reaction mixture was acidified with excess 3M HCl solution (pH ═ 1) and extracted into ethyl acetate (3 × 15 ml). The combined extracts were washed with water and brineWashing with Na2SO4Drying and concentration by rotary evaporation gave 0.15g of cis/trans acid mixture as a white solid.
EXAMPLE 41
a) 7-methoxy-1, 2, 3, 4-tetrahydro-1-naphthol
In analogy to example 69a, 7-methoxy-3, 4-dihydro-1 (2H) -naphthol was synthesized from 7-methoxy-1, 2, 3, 4-tetrahydro-1-naphthalenone (5g, 28mmol) to give about 5g of crude product which was used in the next step without additional purification (quantitative yield).
b) 6-methoxy-1, 2-dihydronaphthalene
In analogy to example 40b, 6-methoxy-1, 2-dihydronaphthalene was synthesized from 7-methoxy-1, 2, 3, 4-tetrahydro-1-naphthol to give 4.4g of product as a tan-colored oil (96% yield from 7-methoxy-1, 2, 3, 4-tetrahydro-1-naphthalenone).
c) 6-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 38, ethyl 6-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate was synthesized from 6-methoxy-1, 2-dihydronaphthalene (4.4g, 28mmol) (feed rate 0.7ml/H) to give 9.68g of a crude product as an orange-brown oil. Purification was carried out by silica gel column chromatography (200g, ethyl acetate/hexane 1: 10). Three fractions were collected: a cis isomer (75% by GC) rich fraction of 0.16g, a mixed fraction of 1.76g and a pure trans isomer containing fraction of 1 g. The total yield is 45%.
d) 6-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
6-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid was synthesized in analogy to example 69d) from ethyl 6-methoxy-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylate (0.16g, 0.65mmol) to yield 0.1g of product as white crystals. The yield was 71%.
Example 42
a)7, 8-dihydro-2-naphthol
7-methoxy-1, 2-dihydronaphthalene (6.4g, 40mmol) was dissolved in anhydrous DMF and under bubbling argon, sodium ethyl mercaptide (2.5eq) was added and the reaction mixture was heated at 160 ℃ for about 4h while stirring. The reaction was monitored by GC. The reaction mixture was diluted with water, acidified with 3M HCl and extracted into ethyl acetate. The organic extracts were washed with water and brine, over Na2SO4Dried and concentrated by rotary evaporation. Purification by silica gel column chromatography (200g, EtOAc/hexane) afforded 5.36g of the desired phenol. The yield was 92%.
b)7, 8-dihydro-2-naphthalenyltrifluoromethanesulfonate
7, 8-dihydro-2-naphthol (5.3g, 37mmol) was mixed with triethylamine (6.2ml, 44mmol) in dry methyl chloride and cooled in an ice/brine bath under nitrogen. To the stirred solution was added triflic anhydride (7.4ml, 44mmol) by syringe over a period of 10 min. The temperature was allowed to slowly rise to room temperature. The reaction mixture was then washed with water and brine, over Na2SO4And (5) drying. The crude product was purified by silica gel column chromatography. 9g of a brown liquid are obtained. The yield thereof was found to be 88%.
c)5- { [ (trifluoromethyl) sulfonyl ] oxy } -1a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 40, from 7, 8-dihydro-2-naphthalenyltrifluoromethanesulfonate (9g, 32mmol) (feed rate 1ml/H) 5- { [ (trifluoromethyl) sulfonyl ] oxy } -1a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylic acid ethyl ester was synthesized to give 13g of crude product as an orange-brown oil. Purification was carried out by silica gel column chromatography (200g, ethyl acetate/hexane 1: 15). A fraction enriched in cis-isomer (80% by GC) of 0.64g was collected and used for the next conversion.
d) 5-cyano-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
Coupling 5- { [ (trifluoromethyl) sulfonyl]Oxy } -1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ]]Naphthalene-1-carboxylic acid ethyl ester (0.2g, 0.5mmol) with Zn (CN)2(0.82mmol) and Pd (Ph)3P)4(56mg, 10 mol%) were mixed in DMF (4ml), argon bubbled through for 5min, and heated at 100 ℃ for 14h in a closed bottle with stirring. The reaction was monitored by GC. The reaction mixture was concentrated by rotary evaporation with saturated NH4The Cl was mixed and extracted into ethyl acetate (3X 15 ml). The organic extracts were washed with water and brine, over Na2SO4And (5) drying. Concentration gave 0.12g of oily product (yield 90%).
d) 5-cyano-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
5-cyano-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid was synthesized in analogy to example 69d from ethyl 5-cyano-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylate (0.12g, 0.5mmol) to yield 0.1g of product as white crystals. The yield was 94%.
1H-NMR(DMSO-d6)：9.70(br s，1H)，8.32(br s，1H)，8.03(dd，1H)，7.46-7.63(m，4H)，7.32(br s，1H)，3.18-3.10(m，2H)，2.76-2.65(m，1H)，2.62-2.51(m，1H)，2.34(t，1H)，2.01-1.80(br m，2H)，1.78-1.69(br m，1H)。
Example 42A
a)5- [ (trimethylsilyl) ethynyl ] -1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
Coupling 5- { [ (trifluoromethyl) sulfonyl]Oxy } -1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ]]Naphthalene-1-carboxylic acid ethyl ester (0.2g, 0.5mmol) with trimethylsilylacetylene (0.2ml, 1.37mmol), DPP(35mg，10mol％)、Pd(dba)2(30mg, 10 mol%) and CuI (3mg) in Et3N (2.5ml) was mixed, argon bubbled through for 5min, and heated in a closed bottle at 95 ℃ for 14h with stirring. The reaction was monitored by GC. The reaction mixture was concentrated by rotary evaporation with saturated NH4Cl was mixed and extracted into ethyl acetate (3X 15 ml). The organic extracts were washed with water and brine, over Na2SO4And (5) drying. Concentration gave 0.15g of oily product (87% yield).
b) 5-ethynyl-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
Reacting 5- [ (trimethylsilyl) ethynyl group]-1a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a]Ethyl naphthalene-1-carboxylate (0.2g, 0.64mmol) was dissolved in 4ml of methanol and to the reaction mixture was added sodium hydroxide (0.05g, 1.2mmol) in 2ml of an aqueous solution and stirred at 65 ℃ for 6h with heating. The basic reaction mixture extracted into hexane showed no starting material present. The reaction mixture was acidified with excess 3M HCl solution (pH 1) and extracted into ethyl acetate (3 × 15 ml). The combined extracts were washed with water and brine, over Na2SO4Drying and concentration by rotary evaporation gave 0.12g of a mixture of cis/trans acids (85: 15) as a white solid. The yield was 88.7%.
Example 43
a)5, 8-difluoro-4-methyl-3, 4-dihydro-1 (2H) -naphthalenone
1, 4-difluorobenzene (22ml, 210mmol) was mixed with gamma-valerolactone (4ml, 42mmol) with stirringAdding AlCl into the stirred reaction mixture in portions3(28g, 210 mmol). The reaction mixture was then refluxed for 16h with stirring (oil bath 110 ℃). The reaction mixture was allowed to cool (ice/brine bath) and ice/concentrated HCl was added and stirred until a homogeneous mixture was obtained. The reaction mixture was then extracted into dichloromethane and washed with water (4X 10ml) and sodium bicarbonate solution (3X 100 ml). Subjecting the organic extract to Na2SO4And (5) drying. Concentration by rotary evaporation gave 6.7g of product as a yellow powder. The yield thereof was found to be 81%.
b)5, 8-difluoro-4-methyl-1, 2, 3, 4-tetrahydro-1-naphthol
In analogy to example 69a, synthesis of 5, 8-difluoro-4-methyl-1, 2, 3, 4-tetrahydro-1-naphthol from 5, 8-difluoro-4-methyl-3, 4-dihydro-1 (2H) -naphthalenone gave 1.8g of crude product, which was used in the next step without additional purification.
c)5, 8-difluoro-1-methyl-1, 2-dihydronaphthalene
In analogy to example 40b, synthesis of 5, 8-difluoro-1-methyl-1, 2-dihydronaphthalene from 5, 8-difluoro-4-methyl-1, 2, 3, 4-tetrahydro-1-naphthol (1.8g, 9.1mmol) gave 1.5g of product as a tan oil (90% yield from 5, 8-difluoro-4-methyl-1, 2, 3, 4-tetrahydro-1-naphthalenone).
d)4, 7-difluoro-3-methyl-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 40c, ethyl 4, 7-difluoro-3-methyl-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate was synthesized from 5, 8-difluoro-1-methyl-1, 2-dihydronaphthalene (3.5g, 19mmol) (feed rate 0.5ml/H) to give the crude product as a yellow-brown oil. Purification by silica gel column chromatography (200g, ethyl acetate/hexane 1: 15) gave 5.2g of a mixture of diastereomeric esters of EDA (GC ratio: trans-45%; 40%/trans: cis/, cis-11%; 2.3%/trans: cis) together with the colourless oily dimer.
e) +/-trans-cis-4, 7-difluoro-3-methyl-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a]Ethyl naphthalene-1-carboxylate (5.25g, 20mmol, a 50: 50 mixture of the cis and trans isomers) was dissolved in 2.5ml of methanol, and to the reaction mixture was added aqueous sodium hydroxide (0.4g, 10mmol) in 2.5ml and stirred at room temperature overnight. The reaction mixture was extracted into hexane (3X 30 ml). The combined extracts were washed with water and brine, over Na2SO4Drying and concentration by rotary evaporation gave 1.12g of cis-ester as a colourless oil (-94% mixture of ethyl and methyl esters according to GC). The resulting mixture was dissolved in 1.5ml of methanol, and an aqueous solution of sodium hydroxide (0.2g, 5mmol) in 1.5ml was added to the reaction mixture, followed by stirring at 95 ℃ for 40 min. The reaction mixture was acidified with excess 3M HCl solution (pH ═ 1) and extracted into ethyl acetate (3 × 15 ml). The combined extracts were washed with water and brine, over Na2SO4Drying and concentration by rotary evaporation gave 0.93g of light orange crystalline trans- +/-cis-acid. Yield 20% (approximate quantification calculated based on the starting cis isomer).
Example 44
a)4, 7-difluoro-3-methyl-1-indanone
In analogy to example 43a, synthesis of 4, 7-difluoro-3-methyl-1-indanone from butyrolactone (4ml, 52mmol) gave 7.19g of a yellow powder (85: 15 mixture of the corresponding indanone and tetralone (tertralone) according to GC). The product was purified by silica gel column chromatography (200g, EtOAc/hexane) to give 3.7g (yield 40%) of pure product together with the combined fractions and the fraction containing pure tetralone.
b)4, 7-difluoro-3-methyl-1-indanol
In analogy to example 40, 4, 7-difluoro-3-methyl-1-indanol was synthesized from 4, 7-difluoro-3-methyl-1-indanone (3.7g, 20mmol) to give about 3.75g of crude product (quantitative yield), which was used in the next step without additional purification.
c)4, 7-difluoro-1-methyl-1H-indene
In analogy to example 37, 4, 7-difluoro-1-methyl-1H-indene was synthesized from 4, 7-difluoro-3-methyl-1-indanol (3.75g, 9.1mmol) to give 2.36g of the product as a light brown liquid (yield 70%).
d)2, 5-difluoro-6-methyl-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid ethyl ester
In analogy to example 40c, ethyl 2, 5-difluoro-6-methyl-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylate was synthesized from 4, 7-difluoro-1-methyl-1H-indene (1.32g, 7.9mmol) (feed rate 0.4ml/H) to give the crude product as a yellow-brown oil. Purification by silica gel column chromatography (100g, ethyl acetate/hexane 1: 15) gave 0.61g of a mixture of the cis-and trans-esters as colorless oily diastereoisomeric esters (cis/trans ratio: 84: 16 according to MR). The yield was 30%.
e) Trans- +/-cis-2, 5-difluoro-6-methyl-1, 1a, 6, 6 a-tetrahydrocyclopropano [ a ] indene-1-carboxylic acid
In analogy to the procedure described above, trans- +/-cis-2, 5-difluoro-6-methyl-1, 1a, 6, 6 a-tetrahydrocyclopropano [ a ] indene-1-carboxylic acid ethyl ester (0.61g, 2.4mmol) was synthesized from 2, 5-difluoro-6-methyl-1, 1a, 6, 6 a-tetrahydrocyclopropano [ a ] indene-1-carboxylic acid by stepwise hydrolysis first with 20 mol.% NaOH, then with excess NaOH on heating to give 380mg of white crystalline product. Yield 70% (approximate quantification based on starting cis isomer).
Example 45
a)5, 8-difluoro-3, 4-dihydro-1 (2H) -naphthalenone
5, 8-difluoro-3, 4-dihydro-1 (2H) -naphthalenone was synthesized along with 4, 7-difluoro-3-methyl-1-indanone according to the method described in example 44 a. Separating by silica gel column chromatography. 0.77g of pure product is obtained, with a yield of 8%.
b)5, 8-difluoro-1, 2, 3, 4-tetrahydro-1-naphthol
In analogy to example 40a, 5, 8-difluoro-1, 2, 3, 4-tetrahydro-1-naphthol was synthesized from 5, 8-difluoro-3, 4-dihydro-1 (2H) -naphthalenone (0.77g, 4.2mmol) to give the crude product which was used in the next step without additional purification (quantitative yield).
c)5, 8-difluoro-1, 2-dihydronaphthalene
In analogy to example 40b, 5, 8-difluoro-1, 2-dihydronaphthalene was synthesized from 5, 8-difluoro-1, 2, 3, 4-tetrahydro-1-naphthol to give 0.67g of crude product as a brown liquid (yield 90% from 5, 8-difluoro-3, 4-dihydro-1 (2H) -naphthalenone).
Additional amounts of product were also obtained by reduction and subsequent dehydration from a mixture of 5, 8-difluoro-3, 4-dihydro-1 (2H) -naphthalenone and 4, 7-difluoro-3-methyl-1-indanone. The corresponding mixture of indene and naphthalene was easily separated by column chromatography on silica gel (ethyl acetate/hexane 1: 20).
d)4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid ethyl ester
In analogy to example 40c, ethyl 4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate was synthesized from 5, 8-difluoro-1, 2-dihydronaphthalene (0.7g, 4.2mmol) (feed rate 0.4ml/H) to give the crude product as a yellow-brown oil. Purification by silica gel column chromatography (100g, ethyl acetate/hexane 1: 15) gave 0.45g of a mixture of cis-and trans-esters as colorless oil (cis/trans ratio according to GC: 33: 67). 4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
e)4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropane [ a ] naphthalene-1-carboxylic acid
In analogy to example 43e, 4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylic acid was synthesized from ethyl 4, 7-difluoro-1 a, 2, 3, 7 b-tetrahydro-1H-cyclopropa [ a ] naphthalene-1-carboxylate (0.45g, 1.8mmol) by stepwise hydrolysis first with excess NaOH at r.t. and then with excess NaOH upon heating (60 ℃, 1.5H) to give 80mg of the product as white crystals (cis/trans ratio according to HPLC 78: 22).
Example 46
a) 6-bromoindene
This compound was prepared in analogy to examples 40a and 40b from 5-bromo-1-indanone (4.0g, 18.8mmol) to yield 2.4g (65%) of 6-bromoindene.
b) (±) -cis-4-bromo-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid ethyl ester
The compound was prepared in analogy to example 40c from 6-bromoindene (1.95g, 10 mmol). Purification on silica gel, starting with hexane, followed by hexane and 2% diethyl ether, and finally with hexane and 5% diethyl ether, yielded 670mg (24%) of the cis-ester.
c) (±) -cis-4-bromo-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid
The acid was synthesized in analogy to example 40d, starting from 330mg (1.77mmol) of the compound from example 75b to yield 232mg (79%) of (. + -.) -cis-4-bromo-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylic acid.
Example 47
a) (±) -cis-4-cyano-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid ethyl ester
This compound was prepared in analogy to example 42d from ethyl (±) -cis-4-bromo-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylate (200mg, 0.7mmol) to yield 73mg (46%) of ethyl (±) -cis-4-cyano-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylate after purification on silica gel using hexane and 10% ethyl acetate as eluent.
b) (±) -cis-4-cyano-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid
The acid was synthesized in analogy to example 40d, starting from 73mg (0.32mmol) of the compound from example 47a, to yield 59mg (95%) of (. + -.) -cis-4-cyano-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylic acid.
Example 48
a)4, 7-difluoro-1-indanones
2, 5-Difluorocyinnamic acid (5.0g, 27.2mmol) was dissolved in 25ml of ethanol and a catalytic amount of 10% palladium on carbon was added. The reaction mixture was hydrogenated at atmospheric pressure for 3 hrs. Filtration through celite and evaporation of the solvent gave crude 3- (2, 5-difluorophenyl) -propionic acid. The acid was dissolved in 75ml of toluene and 5ml of thionyl chloride was added. The reaction mixture was heated at +110 ℃ for 2 hrs. The solvent was evaporated to give crude 3- (2, 5-difluorophenyl) -propionyl chloride, which was dissolved in 25ml of carbon disulphide and 4g of aluminium chloride in 100ml of carbon disulphide were added dropwise to the suspension. The reaction mixture was refluxed for 2hrs, worked up and crystallized from ethanol to yield 975mg (22%) of 4, 7-difluoro-1-indanone.
b)4, 7-Difluorindene
The compound was prepared in analogy to examples 40a and 40b, from 4, 7-difluoro-1-indanone (975mg, 5.8mmol) to yield 475mg (54%) of 4, 7-difluoroindene.
c) (±) -cis-2, 5-difluoro-1, 1a, 6, 6 a-tetrahydrocyclopropane [ a ] indene-1-carboxylic acid ethyl ester
The compound was prepared in analogy to example 40c from 4, 7-difluoroindene (475mg, 3.13 mmol). Purification on silica gel starting with n-hexane, followed by n-hexane and 2% diethyl ether and finally with n-hexane and 5% diethyl ether gave 205mg of cis-ester containing 22% of the trans-ester.
d) (±) -cis-2, 5-difluoro-1, 1a, 6, 6 a-tetrahydrocyclopropa [ a ] indene-1-carboxylic acid
The acid was synthesized in analogy to example 40d, starting from 205mg of the cis-ester obtained in example 77c, to yield 120mg of (. + -.) -cis-2, 5-difluoro-1, 1a, 6, 6 a-tetrahydrocyclopropano [ a ] indene-1-carboxylic acid containing a small fraction of the corresponding trans-acid.
Example 49
4- [ [6- [ [ [ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ]][1]Benzopyran- 1-radical]Amino group]Carbonyl radical]Amino group]-3-pyridyl]Oxy radical]-N- (4-morpholinyl) -benzamide
a) N- (4-morpholinyl) -4- (phenylmethoxy) -benzamide
4-Benzyloxybenzoic acid (0.5g, 2.19mmol), 4-aminomorpholine (0.2mL, 2.13mmol), Et at room temperature3N(0.316mA mixture of L), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.671g, 3.5mmol) and 1-hydroxybenzotriazole hydroxide (0.5g, 3.7mmol) in N, N-dimethylaminocarboxamide (17mL) was stirred for 2 days. The reaction was concentrated and diluted with dichloromethane. The organic phase was washed twice with water and MgSO4Drying and concentrating. The residue is purified by column chromatography (silica gel, 5% MeOH in CH)2Cl2) Purification and determination of N- (4-morpholinyl) -4- (phenylmethoxy) -benzamide (0.615g, yield: 90%).1H-NMR(CD3OD)：7.99(s，1H)，7.78(d，J＝8.6Hz，2H)，7.45(m，2H)，7.39(m，2H)，7.33(m，1H)，7.07(d，J＝8.6Hz，2H)，5.16(s，2H)，3.82(m，4H)，2.91(m，4H)。
1b) 4-hydroxy-N- (4-morpholinyl) -benzamides
4-hydroxy-N- (4-morpholinyl) -benzamide (0.288g, 66%) was synthesized in analogy to example 11b from N- (4-morpholinyl) -4- (phenylmethoxy) -benzamide (0.615 g).1H-NMR(CD3OD)：7.67(d，J＝8.6Hz，2H)，6.81(d，J＝8.6Hz，2H)，3.80(m，4H)，2.8(m，4H)。
1c) N- (4-morpholinyl) -4- [ (6-nitro-3-pyridinyl) oxy ] -benzamide
In analogy to example 11c, from 4-hydroxy-N- (4-morpholinyl) -benzamide (0.288g) was synthesized a mixture of nitropyridine and bromopyridine (0.328 g).
1d)4- [ (6-amino-3-pyridinyl) oxy ] -N- (4-morpholinyl) -benzamide
In analogy to example 11d, 4- [ (6-amino-3-pyridinyl) oxy ] -N- (4-morpholinyl) -benzamide (0.234g, 57%) was synthesized from a mixture of nitropyridine and bromopyridine (0.328 g).
1H-NMR(CD3OD)：7.77(d，J＝8.2，2H)，7.73(d，J＝2.73Hz，1H)，7.28(m，1H)，6.95(d，J＝8.2Hz，2H)，6.65(d，J＝8.6Hz，1H)，3.80(m，4H)，2.89(m，4H)。
1e)4- [ [6- [ [ [ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] [1] benzopyran-1-yl ] amino ] carbonyl ] amino ] -3-pyridinyl ] oxy ] -N- (4-morpholinyl) -benzamide
In analogy to example 11e, 4- [ [6- [ [ [ [ (1S, 1aS, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropa [ c ] [1] benzopyran-1-yl ] amino ] carbonyl ] amino ] -3-pyridyl ] oxy ] -N- (4-morpholinyl) -benzamide (0.015g, 21%) was synthesized from 4- [ (6-amino-3-pyridinyl) oxy ] -N- (4-morpholinyl) -benzamide (0.041 g).
1H-NMR(CD3OD)：7.82(d，J＝8.6Hz，2H)，7.63(d，J＝2.73Hz，1H)，7.40(m，1H)，6.98(d，J＝8.6Hz，3H)，6.84(m，1H)，6.63(m，1H)，4.42(d，J＝11.3Hz，1H)，4.29(dd，J＝11.7，2.73Hz，1H)，3.80(m，4H)，3.62(t，J＝7.2Hz，1H)，2.91(m，4H)，2.6(t，J＝8.4Hz，1H)，2.03(m，1H)。(LC-MS，API-ES+：538.2；Calc.537.5)
Example 50
1- (4, 7-diFluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c]Chromen-1-yl) -3- [5- (4-methanesulfonyl-benzene Oxy) -pyridin-2-yl]-urea
a) 4-methanesulfonyl-phenol:
h is to be2WO4(0.029g, 0.114mmol) in H2O (10ml) was stirred. 50% NaOH (0.040ml) (pH > 12) was added first, followed by AcOH (0.040ml) to pH 5. 4-Methylsulfonyl-phenol (4g, 0.029mol) was added and the reaction mixture was heated to 65 ℃. Adding 30% H in portions over 10min2O2H of (A) to (B)2O (3 ml). The reaction mixture was allowed to stir at room temperature for 1 h. Adding 50% NaHSO3To quench the reaction. Addition of methyl chloride and the compound was washed with brine and purified by chromatography (0 → 10% EtOH methyl chloride) to give 1.9g of 4-methanesulfonyl-phenol (1) (42%) and 1.5g of 4-methanesulfonyl-phenol (2) (30%).
b)5- (4-methanesulfonyl-phenoxy) -2-nitro-pyridine:
to a solution of 4-methanesulfonyl-phenol (1.52g, 9.7mmol) in DMF (30ml) was added cesium carbonate (4.2g, 12.9mmol) followed by 5-bromo-2-nitropyridine (1.75g, 8.6mmol) and the mixture stirred at 50 ℃ overnight. The suspension was filtered and evaporated + re-evaporated with toluene. This compound was purified by chromatography (0 → 10% EtOH of methyl chloride) to give 1.5g (56%) of 5- (4-methanesulfonyl-phenoxy) -2-nitro-pyridine.
c)5- (4-methanesulfonyl-phenoxy) -pyridin-2-ylamine:
5- (4-methanesulfonyl-phenoxy) -2-nitro-pyridine (1.27g, 4.56mmol) was dissolved in EtOH (30ml) and EtOAc (8 ml). Pd/C (10%) (400mg) was added and the nitro group was reduced to the amine by hydrogenation at atmospheric pressure for 3 h. The catalyst was filtered off and the filtrate was evaporated to give 0.6g of 5- (4-methanesulfonyl-phenoxy) -pyridin-2-ylamine.
d)1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromen-1-yl) -3- [5- (4-methylsulfonyl) Radical-phenoxy) -pyridin-2-yl]-urea:
5- (4-methanesulfonyl-phenoxy) -pyridin-2-ylamine (0.049g, 0.197mmol) was dissolved in toluene (2 ml). (1S, 1aR, 7bS) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane-o [ c ] prepared as shown in WO 02/705163 was added]Chromene-1-carboxylic acid (0.041g, 0.179mmol), DPPA (0.04ml, 0.189mmol) and TEA (0.025ml, 0.180 mmol). The reaction mixture was heated to 110 ℃ and left to stir at the same temperature overnight. The reaction mixture was washed with methyl chloride and 5% citric acid followed by saturated NaHCO3The aqueous solution is extracted step by step. Column chromatography on silica gel (5% MeOH in chloroform) afforded 25mg (30%) of 1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ]]Chromen-1-yl) -3- [5- (4-methanesulfonyl-phenoxy) -pyridin-2-yl]-urea.
1H-NMR(CDCl3)：9.30(br s，1H)，7.65(m，2H)，7.30(m，2H)，7.05(m，2H)，6.80-6.70(m，2H)，6.60(d tr，1H)，4.47(dd，1H)，4.32(dd，1H)，3.80(q，1H)，2.75(s，3H)，2.60(tr，1H)，1.99(m，1H)。
Biological results
Extensive guidance on the analysis of test compounds at the enzyme level and in cell culture, including isolation and/or selection of mutant HIV strains and mutant RTs, was found in DAIDS virology Manual for HIV Laboratories complex by Division of AIDS, NIAID USA 1997. Drug Resistance Studies, including the rationale for different drug escape mutants, are described in the HIV Resistance laboratory reactive Group Data Analysis plant for Resistance students, reviewed 31 August 1999.
The compounds of the invention are useful for assaying the activity of HIV, for example using a multiplex assay of XTT in MT-4 cells (Weislow et al, J Nat Cancer Inst 1989, vol 81 no 8, 577et seq), preferably including an assay in the presence of 40-50% human serum to show contribution to protein binding. To shorten the XTT assay, MT4 cells, a human T cell line grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (or 40-50% human serum as appropriate), penicillin and streptomycin, were used to spread over 10-20TCID infected wells50HIV-1 ofIIIB(wild type) or mutant viruses, e.g.those mutant viruses which undergo RT IIe 100, Cys 181 or Asn 103 mutations (2.10) in 96-well microplates4Cells/well). Serial dilutions of test compounds were added to each well and cultures were incubated at 37 ℃ in CO-rich medium2Viability of cells was determined under atmosphere incubation and on day five or day six with XTT vital dye (visual dye). The results are in particular ED50μ M presentation.
Preferred are compounds effective against wild-type viruses and mutant HIV viruses, particularly viruses that contain drug escape mutations. Drug escape mutations are those that occur in patients that have been subject to the prior art selection pressures of antiviral agents and confer enhanced resistance to such antiviral agents. The Data Analysis Plan cited above summarizes the relevant drug escape mutants for each antiviral class on the market today. Drug-evading clones were easily isolated from HIV patients who failed individualized antiviral therapy. Alternatively, the preparation of RT mutations on a known genetic background is shown in WO 97/27319, WO 99/61658 and WO00/73511, which also show the use of such mutants in a sensitivity profiling assay.
K103N is a specifically related drug-escape mutant in the context of NNRTI therapy and the compounds of the invention preferably have a low ED against this mutant50And especially more preferably the double mutant L100I, K103, especially in assays mimicking the presence of human serum.
Suitable reverse transcriptase assays use reverse transcriptases that are responsible for escape mutations of key drugs, prepared as extensively as described in Unge et al Eur.J.biochem.269, 1670-.
For example, the preparation of K103N mutants using this methodology and primers
CATCCCGCAGGGTTAAAAAAGAACAAATCAGTAACAGTACTGGATG
CATCCAGTACTGTTACTGATTTGTICTTTTTTACCCTGCGGGATG
The L100I/K103N mutant was prepared by L100 mutated in the K103N enzyme:
CCACATCCCGCAGGGATTAAAAAGAACAAATCAGTAAC
GTTACTGATTTGTTCTTTTTAATCCCTGCGGGATGTGG
the cDNA was cloned into pET11d expression vector in the HIVRT DH10 clone to complete the mutation. The mutation occurs by amplification of the mutated DNA with the aid of the enzyme Pfu. Clones were then formed in E coli TOP10 cells and expression of mutated enzymes was formed in E coli BL21(DE3) cells after introduction of IPTG.
HIV-1 reverse transcriptase is detected using the SPA (scintillation proximity assay) system which relies on fluorescent microspheres coated with the receptor molecule streptoavidin (streptavidin) (Flashplates, Perkinelmer Life Science) capable of binding the radiolabelled ligand in the reaction solution. At the position ofIn the assay, the sequence obtained by pre-annealing (pre-annealed) the biotin-added primer (5'-GTC ATA GCT GTT TCC TG-3') with a DNA-heterogeneous template (synthesized by GENSE) in a ribonuclease-free environment was 5'-CGUCU GGC AUU GCG AGC GGA UAA CAA UUU CAC ACA GGAAAC AGC UAU GAC-3'. At room temperature, 50mM Tris-HCl pH 8.0, 80mM KCl, 10mM MgCl2HIV-1 reverse transcriptase (e.g., L100I + K103N) catalyzed RNA-dependent DNA activity was detected in the presence of 10mM dithiothreitol, 5mg/ml BSA and 0.05% Nonidet detergent (Nonidet) P40, in which tritium-labeled dGTP (Amersham, 35Ci/mmol) and 11. mu.M dNTPs (dATP, dCTP and dTTP) integrated together were monitored. Reactions were carried out for 120min in a reaction volume of 100. mu.l using a Km value of 0.25. mu.M dGTP concentration, using 10nM of RNA template and using 180ng/ml of mutant RT (e.g.L100I + K103N).
As outlined below, the compounds of the invention were used to assay HIV effectiveness against problematic L100I, K103N mutants in vitro assays. For reference, the most recent prior art compound, cis-1- (4, 7-difluoro-1, 1a, 2, 7 b-tetrahydro-cyclopropane [ c ] chromen-1-yl) -3- (5-phenoxy-pyridin-2-yl) -urea, was analyzed in the same system as described above in example 20 of WO 02/070516.
Examples Substituted phenyl (or pyridyl) ICnM
1 Sulfonamide group 29
2 N-methyl amide group 26
3 N-methylsulfonylamino group 60
4 Amino group 70
5 Methylsulfonyl radical 40
8 N-methylamido (on pyridyl) 70
9 Amino group 28
10 Amide (on pyridyl) 80
11 Hydrazinocarbonyl group 10
12 Cyclopropylamino group 27
13 Acetamide 40
14 Triazolyl radical 60
Description of the Prior Art Zero 600
It is therefore readily apparent that, in addition to the substituents in the right box, the effective resistance against the problematic double-escape mutants L100I and K103N is dramatically improved according to the invention.

Claims (5)

1. A compound or a pharmaceutically acceptable salt thereof; the compound is N- [ (1S, 1aR, 7bR) -4, 7-difluoro-1, 1a, 2, 7 b-tetrahydrocyclopropane [ c ] chromen-1-yl ] -N' - [5- (4- (sulfonamido) phenoxy) -2-pyridyl ] urea.
2. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier or diluent therefor.
3. Use of a compound as defined in claim 1 for the manufacture of a medicament for the prophylaxis or treatment of HIV-1 infection.
4. Use according to claim 3, wherein the HIV-1 infection is a drug escape mutant.
5. Use according to claim 4, wherein the drug escape mutant comprises the L100I and K103N mutations.
HK07109407.1A 2004-01-08 2004-12-30 Non-nucleotide reverse transcriptase inhibitors HK1101400B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE0400021-2 2004-01-08
SE0400021A SE0400021D0 (en) 2004-01-08 2004-01-08 Non-nucleoside reverse transcriptase inhibitors
SE0400585A SE0400585D0 (en) 2004-03-09 2004-03-09 NNRTI Antivirals
SE0400585-6 2004-03-09
PCT/SE2004/002034 WO2005066131A1 (en) 2004-01-08 2004-12-30 Non-nucleotide reverse transcriptase inhibitors

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HK1101400A1 HK1101400A1 (en) 2007-10-18
HK1101400B true HK1101400B (en) 2011-03-25

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