HK1184153B - Spiro-cyclic amine derivatives as s1p modulators - Google Patents

Description

Spiro-piperidine derivatives as S1P modulators

Technical Field

The present invention relates to novel spiro-cyclic amine heterocyclic derivatives having affinity for the S1P receptor, pharmaceutical compositions containing said compounds and the use of said compounds for the preparation of a medicament for the treatment, alleviation or prevention of diseases and disorders in which any S1P receptor is involved or in which modulation of the endogenous S1P signaling system by any S1P receptor is involved.

Background

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a variety of cellular responses, such as proliferation, cytoskeletal organization and migration, adhesion-and tight junction assembly, and morphogenesis. S1P binds to members of the endothelial cell differentiation gene family of plasma membrane-localized G protein-coupled receptors (EDG receptors). To date, 5 members of this family have been identified as the S1P receptor in different cell types, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8). S1P can produce cytoskeletal rearrangements in many cell types to regulate immune cell trafficking, vascular homeostasis, and cellular communication in the Central Nervous System (CNS) and peripheral organ systems.

It is well known that S1P is secreted by the vascular endothelium and is present in the blood at a concentration of 200-900 nanomolar and is bound by albumin and other plasma proteins. This provides both a stable reservoir in the extracellular fluid and efficient release to high affinity cell surface receptors. S1P binds with low nanomolar affinity to 5 receptors S1P 1-5. In addition, platelets also contain S1P and can be released locally to cause, for example, vasoconstriction. The receptor subtypes S1P1, S1P2 and S1P3 are widely expressed and represent dominant receptors in the cardiovascular system. In addition, S1P1 is also a receptor on lymphocytes. The S1P4 receptor is almost exclusively within the hematopoietic and lymphatic systems. S1P5 is expressed primarily (although not exclusively) in the central nervous system. Expression of S1P5 appears to be restricted to oligodendrocytes in mice, myelinogenic cells of the brain (myelinating cells), but expression at the astrocyte and endothelial levels is found in rats and humans rather than on oligodendrocytes.

S1P receptor modulators are compounds that signal as (antagonistic) agonists at one or more S1P receptors. The present invention relates to modulators, in particular agonists, of the S1P5 receptor, preferably to agonists selective in preference to the S1P1 and/or S1P3 receptor, in view of unwanted cardiovascular and/or immunomodulatory effects. It has now been found that S1P5 agonists are useful for the treatment of cognitive disorders, in particular age-related cognitive decline.

While research is ongoing to develop therapeutic agents useful in the treatment of age-related cognitive decline and dementia, many successful drug candidates have not yet been generated. Thus, there is a need for new therapeutic agents with desirable properties.

Disclosure of Invention

It has now been found that spiro-cyclic amine derivatives of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof or one or more N-oxides thereof

Wherein

R1 is selected from

The cyano group(s),

(2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkyl, each optionally substituted with CN or one or more fluorine atoms,

(3-6C) cycloalkyl, (4-6C) cycloalkenyl or (8-10C) bicyclic group, each optionally substituted with halogen or (1-4C) alkyl,

phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, (1-6C) alkyl optionally substituted with one or more fluorine atoms, (1-6C) alkoxy optionally substituted with one or more fluorine atoms, amino, (1-4C) alkylamino, and (3-6C) cycloalkyl optionally substituted with phenyl which may be substituted with (1-4C) alkyl or halogen,

Phenyl substituted with: phenoxy, benzyl, benzyloxy, phenethyl or monocyclic heterocycle, each optionally substituted with (1-4C) alkyl, wherein (1-4C) alkyl is optionally substituted with one or more fluorine atoms,

a monocyclic heterocycle, optionally independently substituted with: halogen, (1-6C) alkyl optionally substituted with one or more fluorine atoms, (3-6C) cycloalkyl, or phenyl optionally substituted with (1-4C) alkyl or halogen,

and

bicyclic heterocycle optionally substituted with halogen or (1-4C) alkyl, wherein (1-4C) alkyl is optionally substituted with one or more fluorine atoms;

-Y-(C_n-alkylene) -X-is a linking group, wherein,

y is linked to R1 and is selected from the group consisting of a direct bond, -O-, -CO-, -S-, -SO-, -SO₂-、-NH-、-CH=CH-、-C(CF₃)=CH-、-C≡C-、-CH₂-O-、-O-CO-、-CO-O-, -CO-NH-, -NH-CO-and trans-cyclopropylene;

n is an integer of 0 to 10; and is

X is attached to the phenylene/pyridyl moiety and is selected from the group consisting of direct bond, -O-, -S-, -SO-, -SO₂-, -NH-, -CO-, -CH = CH-and trans-cyclopropylene;

r2 is H or independently selected from one or more substituents selected from halogen, (1-4C) alkoxy, or (1-4C) alkyl optionally substituted with one or more fluorine atoms; and is

R3 is (1-4C) alkylene-R4, wherein the alkylene may be substituted by one or more halogen atoms or by (CH) ₂)₂Substituted to form a cyclopropyl moiety, or R3 is (3-6C) cycloalkylene-R4, -CH₂- (3-6C) cycloalkylene-R4, (3-6C) cycloalkylene-CH₂-R4 or-CO-CH₂-R4, wherein R4 is-OH, -PO₃H₂、-OPO₃H₂-COOH, -COO (1-4C) alkyl or tetrazol-5-yl;

q is a direct bond or-O-;

-W-T-is selected from-CH = CH-, -CH-₂-CH₂-、-CH₂-O-、-O-CH₂-、-O-CH₂-CH₂-and-CO-O-;

r5 is H or independently selected from one or more halogens;

z is CH, CR2 or N; and is

A represents a morpholine ring structure or a 5-, 6-or 7-membered cyclic amine,

showing affinity for the S1P receptor. In particular, the compounds of the invention show selective affinity for the S1P5 receptor relative to the S1P1 and/or S1P3 receptors.

In the prior art, the structure of spiroindoline (spiroindolone) derivatives is disclosed, for example, in WO2005063745, showing some similarities to the structure of the compounds of the present invention. However, those compounds are Mas receptor modulators. There is no suggestion or teaching that the spiroindoline compounds of WO2005063745 may show affinity for the S1P receptor.

The compounds of the present invention are modulators of the S1P receptor, in particular the S1P5 receptor. More specifically, the compounds of the present invention are S1P5 receptor agonists. The compounds of the invention are useful for the treatment, alleviation and prevention of diseases and disorders in which any S1P receptor is involved-in particular the S1P5 receptor-or in which modulation of the endogenous S1P signaling system by any S1P receptor is involved. In particular, the compounds of the invention are useful for the treatment, alleviation or prevention of CNS (central nervous system) dysfunctions such as neurodegenerative diseases, in particular-but not limited to-cognitive disorders (in particular age-related cognitive decline) and related conditions, alzheimer's disease, (vascular) dementia, cognitive deficits in niemann-pick disease and schizophrenia, obsessive-compulsive behaviour, major depression, autism, multiple sclerosis and pain, etc. Preferably, the compounds of the present invention are useful for the treatment, alleviation or prevention of cognitive disorders (particularly age-related cognitive decline) and related conditions.

In a particular embodiment of the invention, the compound has formula (I), wherein R3 is selected from- (CH)₂)₂-OH、-CH₂-COOH、-(CH₂)₂-COOH、-(CH₂)₃-COOH、-CH₂-CHCH₃-COOH、-CH₂-C(CH₃)₂-COOH、-CHCH₃-CH₂-COOH、-CH₂-CF₂-COOH、-CO-CH₂-COOH, 1, 3-cyclobutylidene-COOH, - (CH)₂)₂-PO₃H₂、-(CH₂)₃-PO₃H₂、-(CH₂)₂-OPO₃H₂、-(CH₂)₃-OPO₃H₂、-CH₂-tetrazol-5-yl, - (CH)₂)₂-tetrazol-5-yl and- (CH)₂)₃-tetrazol-5-yl. Preferred R3 groups are selected from- (CH)₂)₂-COOH、-CH₂-CHCH₃-COOH、-CH₂-C(CH₃)₂-COOH、-CHCH₃-CH₂-COOH、-CH₂-CF₂-COOH、-CO-CH₂-COOH and 1, 3-cyclobutylidene-COOH. Most preferably- (CH)₂)₂-COOH。

In another specific embodiment, Q is a direct bond.

In another embodiment, the compound has the structure of formula (I), wherein R2 is H, methyl, chloro, or fluoro. In other embodiments, R2 is H.

In other embodiments of the invention, Z is CH or CR 2.

In another embodiment, the compound has formula (I), -W-T-is selected from-CH₂-O-、-O-CH₂-、-O-CH₂-CH₂-and-CO-O-. In a preferred embodiment, -W-T-is-O-CH₂-。

In addition, in a particular embodiment of the invention, in the radical-Y- (C)_n-alkylene) -X-wherein Y is selected from the group consisting of a direct bond, -O-, -CO-, -CH = CH-, -C (CF)₃) = CH-, -C ≡ C-and trans-cyclopropylene; n is an integer of 0 to 6. Preferably, Y is selected from the group consisting of a direct bond, -O-, -CH = CH-, -C.ident.C-and trans-cyclopropylidene. In other embodiments, X is selected from the group consisting of a direct bond, -O-, -S-, -SO-, -SO-₂-, -NH-, -CO-, -CH = CH-and trans-cyclopropylene. Preferably, X is selected from the group consisting of a direct bond, -O-, -S-, -SO-, -Y-O-, -S-O-and-O-are ₂-, -NH-and-CO-. In a preferred embodiment, the group-Y- (C)_n-alkylene) -X-is selected from-CH₂-O-、-CH₂-S-and-CH = CH-and in particular-CH₂-O-。

In certain embodiments of the invention R1 is (1-4C) alkyl and Y is a direct bond, n is an integer selected from 1 to 6 and X is-O-or a direct bond. In other embodiments, R1 and- (CH)₂)_n-together are a straight-chain hexyl, heptyl or octyl group.

In other embodiments of the invention, R1 is selected from (1-4C) alkyl, cyclohexyl, cyclohexenyl, optionally substitutedHalogen-substituted biphenyl, phenyl optionally substituted with one, two or three substituents independently selected from halogen, (1-4C) alkyl, (1-4C) alkoxy, trifluoromethyl, trifluoromethoxy and cyclopropyl optionally substituted with phenyl, thienyl, pyridyl, tetrahydropyranyl, each optionally substituted with halogen, (1-4C) alkyl, cyclopropyl or phenyl optionally substituted with halogen, and indolyl, dihydrobenzofuranyl and benzodiazepineAlkyl, each optionally substituted with halogen or (1-4C) alkyl. In a preferred embodiment of the invention, R1 is selected from phenyl, optionally substituted with one or more substituents independently selected from halogen, (1-4C) alkyl, cyclopropyl and trifluoromethyl. More preferably, R1 is 2, 6-dichlorophenyl.

In other embodiments of the invention, each R5 is H.

In a preferred embodiment of the invention, a represents a piperidine structure.

In another embodiment, the compounds of the invention have the structure (II)

The compounds of the present invention can be suitably prepared by methods effective in the art, as well as the methods exemplified in the experimental section of this specification. Several new and useful intermediates have been found to be useful in the preparation of the compounds of the present invention. They are further embodiments of the invention.

Accordingly, another embodiment of the present invention is a compound of formula (III)

Where Br is attached at the position indicated by the asterisk.

Furthermore, a particular embodiment of the present invention is a compound of formula (IV)

Wherein OH is attached at the position indicated by #, and wherein, if OH is present¹At the position indicated, the compound may be used²Independently at one or both positions represented by (1-4C) alkyl or halogen selected from F or Cl; and W-T is-O-CH₂-or-CH₂-CH₂-; and A represents a morpholine ring structure or a 5-or 6-membered cyclic amine; a compound of formula (III) wherein-W-T-is-O-CH is useful for the preparation of a compound of formula (I)₂And the compound of formula (IV) is used for preparing the compound of formula (I), wherein-W-T-is-O-CH ₂-or-CH₂-CH₂-。

According to other embodiments of the invention, a very efficient process for the preparation of compounds of formula (I) is a process wherein R2 is H or one or two substituents selected from fluoro, (1-4C) alkyl and (1-4C) alkoxy; -W-T-is-O-CH₂-and Z is CH or CR2, comprising an intramolecular Heck cyclization step, wherein the compound of formula (V)

Wherein A' represents a 5-, 6-or 7-membered cyclic amine containing a double bond at the carbon atom indicated by the arrow, P1 is selected from-CO₂-benzyl and-CO₂Protecting group for- (1-4C) alkyl (preferably-CO)₂-benzyl), Bn is benzyl and the BnO-group can be attached in one position indicated by #, on silver carbonate (preferably in an amount of 1-2 moles with respect to the amount of compound V) and Herrmann-Beller catalyst (1-10 mol%, preferably3-6mol%) in a suitable solvent at elevated temperature (e.g. 140 ℃ in N-methyl-2-pyrrolidone (NMP),

wherein a "represents a 5-, 6-or 7-membered cyclic amine containing a double bond in one or (briefly) two positions (depending on the position of the nitrogen atom in the ring) displaced with respect to ring a', and then subjected to further process steps such as first deprotection and reduction to produce a compound of formula (IV) to produce a compound of formula (I).

The term halogen refers to fluorine, chlorine, bromine, or iodine. Preferred halogens are fluorine and chlorine, especially chlorine.

The terms (1-6C) alkyl and (1-4C) alkyl refer to branched or unbranched alkyl groups having 1-6 and 1-4 carbon atoms, respectively, such as methyl, ethyl, propyl, isopropyl and butyl. The preferred alkyl group is methyl.

The term (1-4C) alkoxy means an alkoxy group having 1-4 carbon atoms wherein the alkyl moiety is as defined above. The preferred alkoxy group is methoxy.

The terms (1-4C) alkylene and (C)_nAlkylene) means a branched or unbranched alkylene radical having 1 to 4 or n carbon atoms respectively, e.g. methylene, -CHCH₃-、-C(CH₃)₂-、-CHCH₃CH₂-and the like. In the definition of R3 where R3 is (1-4C) alkylene-R4, one or more carbon atoms in the alkylene group may be independently (among others) replaced by (CH)₂)₂Substitution to form a cyclopropyl moiety means forming a group such asR3 group.

The term (2-4C) alkynyl refers to a branched or unbranched alkynyl group having 2-4 carbon atoms in which the triple bond may be present at different positions in the group, e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, and the like.

The terms 5-, 6-or 7-membered cyclic amines used in the definition of formula (I) refer to pyrrolidinyl, piperidinyl and hexamethyleneimino structures, respectively.

The term (3-6C) cycloalkyl refers to a cycloalkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Preferred are cyclopentyl and cyclohexyl.

The term (4-6C) cycloalkenyl refers to cycloalkenyl groups having 4-6 carbon atoms and containing one or two double bonds, such as cyclohexenyl.

The term (3-6C) cycloalkylene refers to a cycloalkyl group having two points of attachment. Preferred is a 1, 3-cyclobutylene group having the structure

The term (8-10C) bicyclic group refers to a condensed ring system of two groups selected from aromatic and non-aromatic ring structures having a total of 8-10 carbon atoms, such as-in particular-indane groups.

The term monocyclic heterocycle includes monocyclic heteroaryl and non-aromatic heteromonocyclic groups, e.g. furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, imidazolyl, pyrazolyl, isopyrazolylAzolyl, isothiazolyl, triazolyl,Oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrahydrofuryl, tetrahydropyranyl, oxadiazolylAlkyl, morpholinyl, and the like.

The term bicyclic heterocycle includes bicyclic heteroaryl groups and non-aromatic heterobicyclic groups, such as indolyl, indazolyl, isoindolyl, indolizinyl, benzimidazolyl, imidazothiazolyl, imidazopyridinyl, benzofuranyl, dihydrobenzofuranyl, benzodiazepine Alkyl, quinolyl, isoquinolyl, quinolyl, tetrahydroisoquinolyl, and the like.

The term "independently" with respect to a substituent means that the substituents may be the same or different from each other in the same molecule.

The compounds of the invention may contain one or more asymmetric centers and may therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Other asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers, which means that all possible optical isomers and diastereomers in the form of mixtures and in the form of purified or partially purified compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be accomplished according to methods known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates derived, if necessary, from reagents containing asymmetric centers of known absolute configuration. If desired, racemic mixtures of the compounds can be separated so that the individual enantiomers can be separated. Separation can be carried out by methods well known in the art, such as by coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

The compounds may exist in polymorphic forms and are likewise included within the scope of the present invention. In addition, the compounds may form solvates with water (i.e., hydrates) or conventional organic solvents, and such solvates are also intended to be included within the scope of the present invention.

Isotopically-labeled compounds of formula (I) or pharmaceutically acceptable salts thereof, including isotopically labeled compounds of formula (I) so as to be detectable by PET or SPECT, are also within the scope of the present invention. The above applies to the use of¹³C]-、[¹⁴C]-、[³H]-、[¹⁸F]-、[¹²⁵I]-or other isotopically enriched atom labelled compounds of formula (I) suitable for receptor binding or metabolic studies.

The term "pharmaceutically acceptable salts" refers to those salts: are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. They may be prepared in situ during isolation and purification of the compounds of the invention or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.

The compounds of the invention may also be administered enterally or parenterally. The precise dosage and regimen of administration of these compounds and compositions thereof will depend upon the biological activity of the compound itself, the age, weight and sex of the patient, the needs, suffering or extent of need of the individual receiving the drug administration, and the judgment of the practitioner. Generally, parenteral administration requires lower doses than other methods of administration that are more dependent on absorption. However, the dosage is preferably 0.001-10mg/kg body weight for humans. Generally, the dosage for enteral and parenteral administration will be in the range of 0.1 to 1000mg of total active ingredient per day.

For example, according to the standard reference "Remington, the science and practice of pharmacy" (21)^stPlate, Lippincott Williams&Wilkins,2005, see especially Part 5: pharmaceuticalmafacturing) with pharmaceutically suitable excipients, and the compounds may be compressed into solid dosage units, such as pills or tablets, or processed into capsules or suppositories. The compounds can also be applied in the form of solutions, suspensions or emulsions with the aid of pharmaceutically suitable liquids.

For the preparation of dosage units, e.g. tablets, the use of conventional additives such as fillers, pigments, polymeric binders and the like is contemplated. In general, any pharmaceutically suitable additive that does not interfere with the function of the active compound may be used.

Suitable carriers with which the compounds of the invention can be administered include, for example, lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. Compositions for intravenous administration may, for example, be solutions of the compounds of the present invention in sterile isotonic aqueous buffer. The intravenous composition may also include, for example, solubilizers, stabilizers, and/or local anesthetics to reduce pain at the injection site, if desired.

The pharmaceutical compositions of the invention may be formulated for any route of administration and comprise at least one compound of the invention and pharmaceutically acceptable salts thereof, and any pharmaceutically suitable ingredient, excipient, carrier, adjuvant or vehicle (vehicle).

By "pharmaceutically suitable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In a particular embodiment of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more pharmaceutical compositions of the invention. Associated with such containers may be various written materials such as instructions for use, or a notice (notice) in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human or veterinary administration.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

Drawings

FIG. 1 percentage change in the small and large C57BL/6J male mice administered vehicle (control group) or a compound of the invention (dose expressed in mg/kg; oral) in maze type T.

The following examples are intended to further illustrate the invention in more detail.

Any novel intermediates disclosed herein are additional embodiments of the invention.

Examples

1. (analysis) method

Nuclear magnetic resonance spectrum (¹HNMR) Bruker Avance-I400 with a 9.4T magnet equipped with a BBIiversie broadband probe with Z-gradient and ATM (R) (¹H：400MHz,¹³C: 100 MHz), or bruker avance-DRX600 with 14.1T magnet equipped with TXI inverted triple resonance cryoprobe with Z-gradient and ATM, measured at 300K in the indicated solvent, unless otherwise indicated. In deuterated chloroform (CDCl) containing 99.8 atomic% D₃) Performing the following steps; or in dimethyl sulfoxide-d containing 0.03v/v% tetramethylsilane₆（DMSO-d₆) Both obtained from Aldrich chemical shift () given as ppm downfield from tetramethylsilane. The coupling constant J is given in Hz. The peak shape in the NMR spectrum is represented by the following symbols: 'q' (quartet), 'dq' (double quartet),'t' (triplet), 'dt' (double triplet),'d' (doublet), 'dd' (double doublet),'s' (singlet), 'bs' (broad singlet), and'm' (multiplet). After the sample is contacted with one drop D ₂The NH and OH signals were identified after mixing of O.

Melting points were recorded on a B ü chi B-545 melting point tester.

All reactions involving moisture-sensitive compounds or conditions were carried out under an anhydrous nitrogen atmosphere.

The reaction was monitored by elution with the indicated eluent by Thin Layer Chromatography (TLC) on silica-coated plastic thin plates (Merck pre-coated silica gel 60F 254). By ultraviolet light (254 nm) or I₂The spots are displayed.

Liquid chromatography-Mass Spectrometry (LC-MS)

The system A comprises: column: AcquisytUPLCBEHC181.7 μm, 50X 2.1mm, packed with 1.7 μm particles. The column was in a hot state at 45 ℃ in a column furnace.

And (3) detection: diode array between 210 and 260nm

A ═ contains 0.1% CH₃99.9% water of COOH

B ═ 0.1% CH₃99.9% CH of COOH₃CN

And a system B: column: waters SunfireC18, 30X 4.6mm, packed with 2.5 μm particles. The column was in a hot state at 23 ℃ in a column furnace.

And (3) detection: UV/VIS meter, wavelength set to 254nm + at 70 ℃ and 1.7 bar N₂An evaporative light scattering detector operating under pressure.

99.9% water with 0.1% HCOOH

B ═ 99.9% CH containing 0.1% HCOOH₃CN

Reported retention time (R)_t) For system B, the peak in the Total Ion Current (TIC) chromatogram shows [ M + H ] within 0.5amu accuracy of the exact MW calculated ]+ has a mass in the chromatogram of Evaporative Light Scattering (ELS)>Relative area% (purity) correlation peak of 85%.

Synthesis overview

Suitable syntheses of the claimed spiro-piperidine moiety-containing compounds and intermediates follow the routes described below; see flow diagram 1.

Scheme 1

The synthesis starts with the appropriately substituted 2-bromophenol. Suitably substituted 2-bromophenols are commercially available or can be obtained from other commercially available 2-bromophenols. Compounds of type 1 can be converted to 3 by reaction with (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methanol in the presence of triphenylphosphine and a suitable azo reagent such as diisopropylazodicarboxylate in a solvent such as tetrahydrofuran or dichloromethane. Subsequent conversion of 3 to 4 is via Bu₃SnH mediated process in the presence of AIBN and in a solvent such as benzene or toluene under reflux conditions and or microwave conditions. Methoxy substituted derivatives (compounds)The deprotection of the compound 4) can be carried out with HBr in acetic acid under reflux to obtain 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol and or the corresponding-5-ol analogue (5). The subsequent O-alkylation can be carried out in a solvent such as dimethyl sulfoxide (DMSO), acetone, methanol, or acetonitrile in the presence of a base such as potassium hydroxide or potassium carbonate at a temperature between 0 ℃ and 60 ℃ with a suitable alkylating agent such as 1-bromooctane or benzyl bromide. In (for example) 1 '-benzyl-6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ](6) Removal of the N-benzyl group in (A) can be carried out by reaction with ACE-Cl in a solvent such as 1, 2-dichloroethane, followed by reaction of the intermediate carbamate with methanol.

The spiro-piperidine (7) obtained can be reacted with (meth) acrylic acid esters in a solvent such as acetonitrile, methanol or N, N-dimethylformamide at a temperature between room temperature and 85 ℃ with the final addition of some base such as triethylamine or 1, 8-diazabicyclo [5.4.0] undec-7-ene in a so-called Michael-addition to give the corresponding tert-butyl spiro-piperidine propionate (8) and tert-butyl spiro-piperidine-2-methylpropionate (9). Spiro-piperidines can also be reacted with suitable alkylating agents such as tert-butyl bromoacetate (tert-butylbromoacetate) or tert-butyl 4-bromobutyrate in the presence of a base such as potassium carbonate or cesium carbonate in a solvent such as acetonitrile and/or tetrahydrofuran at room temperature to give compounds of types 10 and 11. Compounds of type 12 can be obtained by reductive amination with 3-oxocyclobutane-1-carboxylate in a solvent such as dichloroethane or THF in the presence of sodium triacetoxyborohydride.

Compounds 7-12 may depend on the group R₁Is converted into the final compound (I) by basic or acidic hydrolysis of the ester. For example, tert-butyl esters may be in a solvent such as CH ₂Cl₂Or 1, 4-bisIn an alkane, at room temperature, with an acid such as trifluoroacetic acid or hydrogen chloride. As other examples, these esters may be in a solvent such as ethanol, THF, and/or water, at a temperature between room temperature and 70 deg.C, with a base such as sodium hydroxideOr lithium hydroxide treatment.

As another example, the removal of these two benzyl groups from 1 '-benzyl-6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] (4) (scheme 2) can be carried out by hydrogenation in a solvent such as ethanol and a catalyst such as palladium hydroxide. The resulting spiro-piperidine (13) may be reacted with (meth) acrylate to give tert-butyl 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate 14A) and tert-butyl 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropanoate (14B). Those compounds can be denatured in the following manner: compounds of types 8 and 9 are obtained by reaction with a suitable alkylating agent such as alkyl bromide or alkyl chloride in the presence of a base such as potassium carbonate or cesium carbonate in a solvent such as acetonitrile and/or tetrahydrofuran at room temperature. Alternatively, 14A/B can be converted to types 8 and 9 by reaction with a suitable alcohol in the presence of triphenylphosphine, and a suitable azo reagent such as diisopropylazodicarboxylate, in a solvent such as tetrahydrofuran or dichloro-methane. Furthermore, 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 ' -piperidin ] -1 ' -yl } propanoate can be converted into tert-butyl 3- {6- (6-phenoxy) -2H-spiro [ 1-benzofuran-3, 4 ' -piperidin ] -1 ' -yl } propanoate (compound of type 15) at 100 ℃ preferably overnight using bromobenzene and a mixture of palladium (II) acetate, tripotassium phosphate monohydrate, 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl and phenylboronic acid.

In another example, the corresponding 3- {6- [ (trifluoromethane) -sulfonyloxy group can be obtained, for example, from compound 14A using trifluoromethanesulfonamide and a base such as triethylamine in a solvent such as chloroform]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (16) using (R) -1- [ (1S) in the presence of potassium thioacetate_p) -2- (dicyclohexylphosphino) -ferrocenyl]Ethyl di-tert-butyl-phosphine, (CyPF-tert-butyl) and tris- (diphenylmethylene-acetone) -dipalladium (0) convertible to 3- [6- (acetylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (20, scheme 3) (van den hoogenband a. tetrahedron letters2010, 51, 6877). This is done in a solvent such as toluene at elevated temperatureThe process is carried out as follows. The derivative (20) with the S-acetyl protecting group can be hydrolyzed, for example, by in situ treatment with sodium hydroxide in ethanol, followed by benzyl halide, e.g., 1, 3-dichloro-2- (chloromethyl) -4-methoxybenzene to give 3- (6- { [2, 6-dichloro-3-methoxy) -phenyl]Methylsulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoate (21, scheme 3), which can be hydrolyzed to give compounds of formula (I). Alternatively, a compound of type 21, whose basic amine is protected in its hydrochloride salt form, can be converted to the corresponding sulfone (sulfon) analog (22) using potassium peroxymonosulfate in a solvent such as water at room temperature. Compounds of type 16 (scheme 2) are prepared using hexane-N-butanetin in a solvent such as 1, 4-di The alkane can be converted to its stannyl derivative (17) in the presence of lithium chloride and tetrakis (triphenylphosphine) -palladium (0) at higher temperatures. The 3- [6- (tributylstannyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate convertible to 3- { 6-iodo-2H-spiro [ 1-benzofuran-3, 4' -piperidine using N-iodo-succinimide in a solvent such as THF, preferably at low temperatures]-1' -yl } propionic acid tert-butyl ester (18). With N-bromosuccinimide, the bromo-analog can be prepared accordingly (19, scheme 3). In another example, a compound of type 23 can be obtained with stannyl analog 17 and a suitable acid chloride in a solvent such as dichloroethane at an elevated temperature.

Flow chart 2

Flow chart 3

3- { 6-iodo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (18) can be used for copper (I) iodide catalyzed reaction with, for example, 2-methyl-benzene-1-thiol in a solvent such as 1, 2-dimethoxyethane and in the presence of potassium carbonate at higher temperatures to give compound type 26 (scheme 2), which can be oxidized (to an example of type 27, scheme 3) using conditions to convert compound type 21 to type 22. 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]Tert-butyl (19) -1' -yl } propanoate is a suitable precursor for the Suzuki reaction. In a particular example, 2- [ (E) -2- (2, 6-dichlorophenyl) -vinyl]Potassium trifluoroborate, cesium carbonate, and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloride dichloromethane complex were reacted in a mixture of toluene and water at reflux overnight to give 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl chloride as an example of Compound type 24]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (scheme 3). In another example, a compound of type 24 can be obtained from a compound of type 16 (scheme 2) using tributyl (vinyl) tin hydride in a solvent such as 1, 4-bisIt is converted to its vinyl derivative in the presence of lithium chloride and tetrakis (triphenylphosphine) -palladium (0) at higher temperatures in an alkane. The 3- {6- (vinyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) propionate, convertible to a compound of type 24 (KarimiB, Synthesis, 2010, 1399) with a suitably substituted phenylboronic acid in a solvent such as N, N-dimethylformamide at elevated temperature. In another embodiment of the invention, a compound of type 28 (scheme 3), can be prepared from 3- { - {6- [ (trifluoro-methane) sulfonyloxy ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (compound 16) and appropriately substituted phenylacetylene derivatives are obtained in a solvent such as dimethyl sulfoxide with a base such as tripotassium phosphate monohydrate in the presence of palladium (II) acetate and triphenylphosphine at elevated temperature.

Using the description of the example of the conversion of compound 19 to compound type 24, tert-butyl 4- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -propionate (as an example of compound type 25) was obtained from 19 and the potassium salt of [2- (2, 6-dichlorophenyl) -cyclopropyl ] -trifluoroborate.

In another embodiment of the present invention, a compound of type 35 (scheme 4), can be obtained as follows: 1- (benzyloxy) -4-bromo-2, 3-difluorobenzene (29) and 4-pyridinemethanol (30) are reacted in a solvent such as NMP at 100 ℃ for 0.5 hour (Stephane GTetrahydro letters2009, 50, 3776), followed by quaternization with benzyl bromide (quaternization) and reduction of the intermediate pyridin-1-ium bromide with sodium borohydride to give compound 32. Cyclization in solvents such as benzene or toluene (Bu)₃SnH, in the presence of AIBN), may be performed under reflux conditions and or microwave conditions. In 1 '-benzyl-6- (benzyloxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ](33) The removal of the two benzyl groups in (a) can be carried out by hydrogenation in a solvent such as ethanol and a catalyst such as palladium hydroxide. Compound 34 can be converted to compound type 35 as described previously, followed by hydrolysis to give compound of formula (I).

Flow chart 4

Using this method (tetrahedron letters2009), suitable (protected) fluorinated benzene derivatives can be converted into compounds of types 38 and 41.

6-bromo-2H [ 1-benzofuran-3, 4' -piperidine ] (46, scheme 5), can be prepared in a similar manner. Removal of the N-benzyl group can be carried out by reaction with ACE-Cl in a solvent such as 1, 2-dichloroethane, followed by reaction of the intermediate carbamate with methanol. The conversion of compound 46 to compound types 47, 48 and 49 is carried out in a manner analogous to that described in schemes 1 and 2.

Alternatively, compound 45 is treated with n-butyllithium in a solvent such as tetrahydrofuran or diethyl ether at-75 ℃ followed by quenching with the appropriate isocyanate to give the corresponding amide which can be debenzylated with ACE-Cl and converted to a compound of type 50. Hydrolysis will yield the compound of formula (I).

Flow chart 5

The amides of compound type 51 (scheme 5) can be prepared with suitable substituted benzamides such as 2, 6-dichlorobenzamide and 3- { - {6- [ (trifluoromethane) sulfonyloxy ] -2H-spiro [ 1-benzofuran-3, 4 ' -piperidin ] -1 ' -yl ] -propionic acid tert-butyl ester (compound 16) in a solvent such as tert-butanol and a base such as tripotassium phosphate in the presence of tris- (dibenzylideneacetone) -dipalladium (0) and 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4 ', 6 ' -tri-i-propylbiphenyl at elevated temperatures. Hydrolysis will yield the compound of formula (I).

As another example, compound 13 (scheme 2) can be protected under nitrogen with a suitable protecting group (p.g.m.wuts, t.w.greenprotective group organic synthesis, 4 th edition, john wiley & Sons, 2006) such as t-Butyloxycarbonyl (BOC) by reaction with di-t-butyl heavy carbonate in a solvent such as acetonitrile at room temperature (compound 52, scheme 6). The phenol group can then be reacted with a suitable alkylating agent in a solvent such as acetonitrile, in the presence of a base such as potassium carbonate, at room temperature, or by using mitsunobu conditions and a suitable alcohol. The tert-Butoxycarbonyl (BOC) group can then be removed by treatment with an acid such as hydrogen chloride in a solvent such as ethanol at a temperature between room temperature and 60 ℃ to give (in an alternative manner) the spiro-piperidine of type 7 already mentioned.

Compounds of type 7 may also be modified with 2, 2-difluoro-propionate groups (54) under nitrogen by the following sequence of steps (cheguillaume a., lacriox s., Marchand-brynaertj. tetrahedron letters2003, 44, 2375): first with 1H-benzotriazole-1-methanol in a solvent such as ethanol at a temperature of about 50 ℃; and then reacted with a zinc reagent prepared from zinc dust, trimethylsilylchloride and bromodifluoroacetate in a solvent such as tetrahydrofuran at a temperature of about 70 c.

A compound of formula (I) wherein R3 ═ CH₂)₂OPO₃H₂Can be synthesized as shown in scheme 6. Thus, compound 7 is reacted with 2- (2-chloroethoxy) tetrahydro-2H-pyran in the presence of a base such as potassium carbonate, and sodium iodide in a solvent such as DMF at a temperature of about 100 ℃. tetrahydro-2H-pyran will be removed (in compound 55) by treatment with an acid such as p-toluenesulfonic acid in a solvent such as methanol at room temperature. The alcohol formed (compound 56) is then reacted in the presence of tetrazole in a solvent such as THF, CH₂Cl₂And CH₃Treatment with a phosphoramidite reagent such as di-tert-butyl N, N-diisopropyl-phosphoramidite at room temperature in a mixture of CN followed by oxidation with an oxidizing agent such as hydrogen peroxide or tert-butyl hydroperoxide in the same solvent at room temperature affords compounds of type 57. Hydrolysis of phosphate esters in solvents such as CH₂Cl₂Neutralization is carried out at room temperature by treatment with an acid such as TFA.

Flow chart 6

In another embodiment of the invention, a compound of type 64 (scheme 7), can be obtained as follows: 4- (benzyloxy) -1-bromo-2-fluoro-benzene and 3-pyridinemethanol (59) are reacted in a solvent such as NMP at 100 ℃ for 0.5 hour, followed by quaternization with benzyl bromide (quaternization) and reduction of the intermediate pyridin-1-ium bromide with sodium borohydride to give 1-benzyl-5- [5- (benzyloxy) -2-bromophenoxymethyl ] -1,2,3, 6-tetrahydropyridine. The compound can be converted to benzyl 5- [ 5-benzyloxy) -2-bromophenoxymethyl ] -1,2,3, 6-tetrahydropyridine-1-carboxylate (61) at room temperature using a base such as potassium bicarbonate in dichloromethane in the presence of benzylchloroformate. The cyclisation of compound 61 can be carried out preferentially at 140 ℃ in a solvent such as NMP and in the presence of silver carbonate and Herrmann-bellellactacle (lauren r. tetrahedron, 2008, 64, 4468). The removal of these two protecting groups and the reduction of the double bond in 6- (benzyloxy) -2 ', 6' -dihydro-1 'H, 2H-spiro [ 1-benzofuran-3, 3' -pyridine ] (62) can be carried out by hydrogenation using a catalyst such as palladium hydroxide in a solvent mixture such as methanol and ethyl acetate. Compound 63 can be converted to compounds of type 64 and analogs of other structures (e.g., analogs of compound types 24 and 28) as described previously. Hydrolysis will yield the compound of formula (I).

Flow chart 7

In another example of the invention, a compound of type 69 (scheme 8) can be obtained as follows: (1-benzyl-2, 5-dihydro-1H-pyrrol-3-yl) methanol (US2010-0069351) and 4- (benzyloxy) -1-bromo-2-fluorobenzene are reacted in a solvent such as NMP at 100 ℃ for 30 minutes to give 1-benzyl-3- [ 5-benzyloxy-benzene]-2-bromophenoxy-methyl]-2, 5-dihydro-1H-pyrrole (66). Cyclization in solvents such as benzene or toluene (Bu)₃SnH, in the presence of AIBN), may be carried out under microwave conditions (preferably at 200 ℃). The removal of both protecting groups can be carried out by ammonium formate in a solvent such as methanol with a catalyst such as palladium hydroxide. Compound 68 can be converted to compounds of type 69 (and the like) as described previously, followed by hydrolysis to give compounds of formula (I).

Flow chart 8

In another example of the invention, a compound of type 75 (scheme 9) can be prepared as follows: the amino alcohol 71 can be prepared by reacting 5- (benzyloxy) -2, 3-dihydro-1H-inden-1-one (70) and trimethylsilyl cyanide in the presence of a Lewis acid such as zinc iodide at room temperature in a neat environment. The intermediate cyanohydrin is then reduced with a reducing agent such as lithium aluminium hydride in a solvent such as tetrahydrofuran. The amino alcohol (71) can be reacted with activated chloroacetic acid or bromoacetic acid in a solvent such as dichloromethane with a base such as triethylamine followed by cyclization in a solvent such as 2-propanol with a base such as potassium hydroxide to give 5- (benzyloxy) -2, 3-dihydrospiro [ indene-1, 2 '-morpholin ] -5' -one (72). The product can be reduced with a reducing agent such as borane in a solvent such as tetrahydrofuran at a temperature between 0 ℃ and room temperature to give 5- (benzyloxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine ] (73). The product can be hydrogenated in a solvent such as MeOH with a catalyst such as palladium hydroxide to provide compound 74. Compound 74 can be converted to compounds of type 75 (and analogs) as described previously, followed by hydrolysis to provide compounds of formula (I).

Flow chart 9

In another example of the invention, a compound of type 82 (scheme 10) can be prepared as follows: 6-methoxy-2, 3-dihydro-1H-inden-1-one (76) and sodium borohydride are reacted in a solvent such as MeOH at room temperature followed by dehydration in a solvent such as toluene in the presence of hydroquinone using an acidic catalyst such as p-toluenesulfonic acid hydrate. The product is as follows: 5-methoxy-1H-indene (77) may be treated with lithium bis (trimethylsilyl) amide (LiHMDS) in a solvent such as tetrahydrofuran (0 ℃). The intermediate may be reacted with a suitable alkylating agent, for example tert-butyl N, N-bis (2-chloroethyl) carbamate, in a solvent such as tetrahydrofuran or diethyl ether, preferably between 0 ℃ and room temperature. This product (78) can be hydrogenated in a solvent such as MeOH and a catalyst such as palladium hydroxide to give compound 79, which can be reacted with sodium ethanethiol in a solvent such as N, N-dimethylformamide at 130 ℃ for 60 hours. Deprotection can be carried out using, for example, 4N HCl in a solvent such as bisIn an alkane to obtain 2, 3-dihydro-spiro [ indene-1, 4' -piperidine]-HCl salt (81) of 5-alcohol, which may be as followsConversion to compounds of type 82 (and the like) was as previously described. Hydrolysis will yield the compound of formula (I).

Flow chart 10

Specific Synthesis

(1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methanol. 4-hydroxymethyl-pyridine (20g, 183mmol, 1.0eq) was dissolved in DMF (80mL), benzyl bromide (24.2 mL; 202mmol) was added and the solution was stirred at 100 ℃ for 2 h. The solution was cooled to room temperature and diluted with EtOH (300mL) and NaBH ₄(8.7 g; 230mmol) are worked up in portions and stirred at reflux for 3 hours. The solution was allowed to cool to room temperature and concentrated to a large extent. The residue was taken up in EtOAc and water and the organic phase was dried (Na)₂SO₄) Filtered and concentrated to give 35g of crude oil. This material was eluted through a short plug (10cm) of silica with EtOAc to afford the product (23.9 g; 64%) which was isolated as an oil.¹HNMR(300MHz,CDCl₃)ppm7.39-7.2(m,5H),5.69-5.63(m,1H),4.03(s,2H),3.58(s,2H),3.0(m,2H),2.6(t,J=6Hz,2H),2.21-2.11(m,2H)。

1-benzyl-4- ((2-bromo-5-methoxyphenoxy) methyl) -1,2,3, 6-tetrahydro-pyridine. (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methanol (20.7 g; 102mmol) was dissolved in THF (150mL) and 2-bromo-5-methoxyphenol (20.7 g; 102mmol) was added, followed by PPh₃(29.4 g; 112 mmol). The solution was cooled on ice and added dropwise with twoIsopropylazodicarboxylate (22.2 mL; 112mmol), held at T<10 ℃ (2 hours time) and stirred at room temperature overnight. The mixture was concentrated and the residue was stirred in heptane (200-300mL) for 20 min. The precipitate was filtered off and washed with heptane. The filtrate was concentrated in vacuo to give 36g of a yellow oil. Heptane (150mL) was added and the mixture was stirred for 5 minutes and allowed to stand for 2 minutes (oil out), the heptane phase was decanted from the oil and concentrated to give the product (25 g; 63%) which was isolated as a yellow oil. ¹HNMR(300MHz,CDCl₃) ppm7.42-7.2(m,6H),6.48(d, J =2Hz,1H),6.39(dd, J =9 and 2Hz,1H),5.85-5.8(m,1H),4.44(s,2H),3.78(s,3H),3.6(s,2H)3.07-3.01(m,2H),2.64(t, J =6Hz,2H),2.31-2.23(m, 2H).

1-benzyl-4- ((2-bromo-4-methoxyphenoxy) methyl) -1,2,3, 6-tetrahydro-pyridine. (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methanol (18.9 g; 93mmol) was dissolved in THF (150mL) and 2-bromo-4-methoxyphenol (18.9 g; 93mmol) was added, followed by PPh₃(26.8g, 102 mmol). The solution was cooled on ice and diisopropylazodicarboxylates (20.3mL, 102mmol) were added dropwise, maintaining the T<10 ℃ (2 hours time) and stirred at room temperature for 2 days. The mixture was concentrated. The residue was taken up in EtOAc and saturated NaHCO₃Absorb and dry the organic phase (Na)₂SO₄) Filtered and concentrated to give 50g of crude oil. The material was stirred in heptane (200-300mL) for 20 minutes. The precipitate was filtered off and washed with heptane. The filtrate was concentrated to give 29g of a yellow oil. This material was purified over short packing (10cm) of silica eluting with heptane/EtOAc 6/1 to give the product (18.5 g; 51%) which was isolated as a yellow oil.¹HNMR(300MHz,CDCl₃)ppm7.38-7.2(m,5H),7.12(d,J=2Hz,1H),6.83(m,2H),5.78(m,1H),4.42(s,2H),3.76(s,3H),3.59(s,2H)3.02(m,2H),2.63(t,J=6Hz,2H),2.33-2.23(m,2H)。

1 '-benzyl-6-methoxy-2H-spiro [ benzofuran-3, 4' -piperidine]A hydrochloride salt. 1-benzyl-4- ((2-bromo-5-methoxyphenoxy) methyl) -1,2,3, 6-tetrahydro-pyridine (25 g; 64.4mmol) was dissolved in benzene (500mL) and the solution was purged with nitrogen for 30 min. Adding Bu ₃After SnH (24.97 g; 85.8mmol) AIBN (0.6g) was added and the solution was stirred at reflux overnight. The reaction mixture was concentrated and washed with EtOAc and saturated NaHCO₃And (4) absorbing. The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give 46g of crude oil. 5-6N HCl in i-PrOH (40mL) was diluted with i-PrOH (200mL) and added to the oil and stirred for 1 hour. The precipitate was filtered off and washed with TBME and dried in vacuo to give the product (15.1 g; 68%) which was isolated as a white solid.¹HNMR(freebase,300MHz,CDCl₃) ppm7.38-7.22(m,5H),7.03(d, J =9Hz,1H),6.43(dd, J =9 and 2Hz,1H),6.39(d, J =2Hz,1H),4.37(s,2H),3.77(s,3H),3.53(s,2H),2.94-2.83(m,2H),2.1-1.88(m,4H),1.74-1.67(m, 2H).

1 '-benzyl-5-methoxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]. 1-benzyl-4- ((2-bromo-4-methoxyphenoxy) methyl) -1,2,3, 6-tetrahydro-pyridine (20 g; 51.5mmol) was dissolved in benzene (400mL) and the solution was purged with nitrogen for 30 min. Adding Bu₃After SnH (23.6 mL; 87mmol) AIBN (0.5g) was added and the solution was stirred at reflux overnight. The reaction mixture was concentrated and washed with EtOAc and saturated NaHCO₃And (4) absorbing. The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give 40g of crude oil. This material was purified over a short packing (10cm) of silica eluting with heptane/EtOAc 4/1 to give the product (16.2 g; 91%) which was isolated as a pale yellow solid. ¹HNMR(300MHz,CDCl₃)ppm7.38-7.22(m,5H),6.74-6.63(m,3H),4.37(s,2H),3.77(s,3H),3.53(s,2H),2.93-2.84(m,2H),2.1-1.88(m,4H),1.76-1.67(m,2H)。

1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alcohols. 1 '-benzyl-6-methoxy-2H-spiro [ benzofuran-3, 4' -piperidine]The hydrochloride salt (15 g; 0.58mmol) was suspended in HOAc (160mL) and 48% HBr (20mL) was added and the solution was stirred at reflux for 24 h. The mixture was concentrated and the residue was taken up in EtOAc and saturated NaHCO₃And (4) absorbing. The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give the product (14 g).¹HNMR(300MHz,CDCl₃)ppm7.38-7.23(m,5H),6.94(d,J=8Hz,1H),6.37-6.26(m,2H),4.36(s,2H),3.55(s,2H),2.94-2.85(m,2H),2.11-1.88(m,4H),1.75-1.65(m,2H)。

1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-5-alcohol hydrobromide. 1 '-benzyl-5-methoxy-2H-spiro [ benzofuran-3, 4' -piperidine](16.2 g; 46.8mmol) was suspended in HOAc (160mL) and 48% HBr (20mL) was added and the solution was stirred at reflux for 20 h. The mixture was allowed to cool and partially concentrated. The precipitate was collected by filtration and dried in vacuo to give the product (14.7 g; 84%).¹HNMR(300MHz,CD₃OD)ppm7.6-7.46(m,5H),6.64-6.57(m,3H),4.43(s,2H),4.35(s,2H),3.48(s,2H),3.21-3.04(m,2H),2.23-2.08(m,2H),2.02-1.92(m,2H)。

1 '-benzyl-5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine].1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-5-alcohol hydrobromide salt (170 mg; 0)58mmol) was dissolved in MeOH (3mL) and NaOH (48 mg; 1.2mmol) and the solution was stirred for 5 minutes. 1-bromohexane (0.1 mL; 0.7mmol) was added and the solution was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was taken up in EtOAc and H ₂O was absorbed and the organic phase was dried (Na)₂SO₄) Filtered and concentrated to give 160mg of oil. This material was purified by column chromatography eluting with heptane/EtOAc 4/1 to give the product (102 mg; 60%) which was isolated as an oil.¹H-NMR(300MHz,CDCl₃)ppm7.38-7.22(m,5H),6.74-6.66(m,3H),4.36(s,2H),3.87(t,J=7Hz,2H),3.55(s,2H),2.95-2.85(m,2H),2.11-1.9(m,4H),1.8-1.68(m,2H),1.5-1.4(m,2H),1.4-1.22(m,6H),0.89(t,J=7.5Hz,3H)。

The following compounds were obtained in a similar manner:

1 '-benzyl-5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ].

1 '-benzyl-5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ].

Starting in an analogous manner with 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidin ] -6-ol) the following compounds are obtained:

1 '-benzyl-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ].

1 '-benzyl-6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ].

1 '-benzyl-6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ].

5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]A hydrochloride salt. 1 '-benzyl-5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine](2.7 g; 7.1mmol) was dissolved in 1,2-DCE (20mL) and the solution was stirred at 0 ℃. 1-chloroethyl chloroformate (3.07 mL; 28.4 mm) was added dropwiseol) and the mixture is stirred at 0 ℃ for 10 minutes and at reflux for 6 h. The solution was cooled to room temperature overnight and diluted with DCM and washed with brine. The organic phase was dried (Na) ₂SO₄) Filtered and concentrated thoroughly to give a crude oil.

The oil was dissolved in MeOH (20mL) and stirred at reflux for 1.5 hours. The mixture was concentrated to a large extent and treated with TBME. The resulting oil mass and solution were decanted off and the oil was dried in vacuo to give 0.5g of product. The decanted solution was concentrated and the residue was suspended in a small amount of MeOH. 1N HCl in i-PrOH (20mL) was added and the solution was stirred for 30 min. The mixture was concentrated to 1/2 volumes, and the precipitate was filtered off and dried in vacuo to give a further 1.2 g. The resulting fractions were combined to give the product (1.7 g; 74%) which was obtained as a white solid.¹HNMR(300MHz,CDCl₃)ppm9.78(s,2H),6.81-6.66(m,3H),4.36(s,2H),3.9(t,J=7Hz,2H),3.62-3.49(m,2H),3.14-2.93(m,2H),2.43-2.27(m,2H),2.07-1.95(m,2H),1.81-1.7(m,2H),1.51-1.3(m,6H),0.9(t,J=7.5Hz,3H)。

The following compounds were obtained in a similar manner:

5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride.

5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride.

6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride.

6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride.

6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride.

Tert-butyl 2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

Reacting 6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]The hydrochloride salt (700 mg; 2.15mmol) is suspended in CH ₃CN (15mL), and tert-butyl chloroacetate (0.37 mL; 2.58mmol) followed by K₂CO₃(714 mg; 4.3mmol) and the solution is stirred at 55 ℃ overnight. The solution was cooled to room temperature and concentrated. The residue was taken up in EtOAc and H₂And (4) absorbing the O. The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give the product (850 mg; 98%).¹HNMR(300MHz,CDCl₃)ppm7.0(d,J=9Hz,1H),6.42(dd,J=9Hz,2Hz,1H),6.37(d,J=2Hz,1H),4.37(s,2H),3.9(t,J=7.5Hz,2H),3.17(s,2H),2,99-2.9(m,2H),2.34-2.2(m,2H),2.09-1.95(m,2H),1.8-1.65(m,4H),1.48(s,9H),1.34-1.26(m,6H),0.9(t,J=7.5Hz,3H)。

The following compounds were obtained in a similar manner:

tert-butyl 2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetic acid tert-butyl ester.

Tert-butyl 2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

Tert-butyl 2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

Tert-butyl 2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

3- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester.

Reacting 6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]The hydrochloride salt (600 mg; 1.84mmol) was suspended in THF (8mL) and propylene was addedTert-butyl ester (0.32 mL; 2.2mmol) and Et was added₃N (0.36 mL; 2.58 mmol). The solution was stirred at 70 ℃ overnight. The solution was cooled to room temperature and poured into EtOAc and saturated NaHCO ₃In (1). The organic phase was dried (Na)₂SO₄) Filtered and concentrated to give the product (770 mg; 100%) obtained in oily form.¹HNMR(300MHz,CDCl₃)ppm7.19(m,1H),6.73-6.66(m,2H),4.34(s,2H),3.87(t,J=7.5Hz,2H),2,94-2.84(m,2H),2.69(t,J=7.5Hz,2H),2.44(t,J=7.5Hz,2H),2.16-1.87(m,4H),1.8-1.64(m,4H),1.46(s,9H),1.52-1.29(m,6H),0.9(t,J=7.5Hz,3H)。

The following compounds were obtained in a similar manner:

tert-butyl 2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

4- (6- (heptyloxy) -2H-spiro [ benzofuran-3, 4' -piperidine)]-1' -yl) butyric acid tert-butyl ester. Reacting 6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]The hydrochloride salt (700 mg; 2.06mmol) is suspended in CH₃CN (15mL), and tert-butyl 4-bromobutyrate (551 mg; 2.47mmol) was added followed by K₂CO₃(684 mg; 4.12mmol) and KI (342 mg; 2.47mmol), and the solution was stirred at 75 ℃ overnight. The solution was cooled to room temperature and concentrated. The residue was taken up in EtOAc and H₂And (4) absorbing the O. The organic phase was dried (Na)₂SO₄) Filtration and concentration gave the product (890mg, 97%). ¹HNMR(300MHz,CDCl₃)ppm6.96(d,J=9Hz,1H),6.42(dd,J=9Hz,2Hz,1H),6.37(d,J=2Hz,1H),4.36(s,2H),3.9(t,J=7.5Hz,2H),2,95-2.85(m,2H),2.4-2.3(m,2H),2.24(t,J=8Hz,2H),2.12-1.87(m,4H),1.87-1.63(m,6H),1.45(s,9H),1.5-1.22(m,8H),0.89(t,J=7.5Hz,3H)。

The following compounds were obtained in a similar manner:

tert-butyl 2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyrate.

2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid tert-butyl ester.

Tert-butyl 2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyrate.

Tert-butyl 2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyrate.

Tert-butyl 2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyrate.

Compound 1.2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride. 2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid tert-butyl ester (850 mg; 2.1mmol) in 4N in twoIn HCl in an alkane (10mL) was stirred overnight. The precipitate was filtered off and washed with TBME. The solid was dried in vacuo to give the product (590 mg; 73%).¹HNMR(300MHz,CD₃OD) ppm7.04(s,1H),6.48-6.44(dd, J =8 and 2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),4.11(s,2H),3.91(t, J =6.5Hz,2H),3.75-3.6(m,2H) 3.4-3.1(bs,4H),2.22(s,2H),2.03-1.94(m,2H),1.79-1.68(m,2H),1.51-1.32(m,6H),0.92(t, J =7Hz, 3H). DSC peak at 250 deg.C

The following compounds were obtained in a similar manner:

Compound 2.2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) propionic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.07(s,1H),6.48-6.44(dd, J =8Hz and 2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.92(t, J =6.5Hz,2H),3.67-3.56(m,2H),3.47(t, J =7Hz,2H),3.3-3.1(bs,2H),2.85(t, J =7Hz,2H),2.22-2.08(m,2H),2.04-1.93(m,2H),1.79-1.66(m,2H),1.51-1.3(m,6H),0.92(t, J =7Hz, 3H). DSC peak at 245.4 deg.C

Compound 3.2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.04(s,1H),6.48-6.44(dd, J =8Hz,2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.91(t, J =6.5Hz,2H),3.69-3.53(m,2H),3.27-3.18(m,2H),3.1(s,2H),2.49(t, J =7Hz,2H),2.14-1.96(m,6H),1.76-1.7(m,2H),1.48-1.32(m,6H),0.92(t, J =7Hz, 3H). DSC peak at 232.6 deg.C

Compound 4.2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.03(s,1H),6.48-6.44(dd, J =8Hz,2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),4.14(s,2H),3.91(t, J =6.5Hz,2H),3.76-3.6(m,2H),3.4-3.1(bs,2H),2.22(t,2H),2.03-1.94(m,2H),1.79-1.68(m,2H),1.52-1.27(m,8H),0.9(t, J =7Hz, 3H). The DSC peak is at 251.6 ℃.

Compound 5.2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine) ]-1' -yl) propionic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.07(s,1H),6.48-6.44(dd, J =8Hz,2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.92(t, J =6.5Hz,2H),3.67-3.56(m,2H),3.46(t, J =7Hz,2H),3.3-3.1(m,2H),2.85(t, J =7Hz,2H),2.22-2.07(m,2H),2.04-1.93(m,2H),1.78-1.66(m,2H),1.52-1.28(m,8H),0.91(t, J =7Hz, 3H). DSC peak at 240.2 deg.C

Compound 6.2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.04(s,1H),6.48-6.44(dd, J =8Hz,2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.91(t, J =6.5Hz,2H),3.68-3.55(m,2H),3.27-3.18(m,2H),3.1(s,2H),2.49(t, J =7Hz,2H),2.22-1.94(m,6H),1.8-1.68(m,2H),1.51-1.32(m,8H),0.91(t, J =7Hz, 3H). DSC peak at 229.1 deg.C

Compound 7.2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.03(s,1H),6.48-6.44(dd, J =8 and 2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),4.14(s,2H),3.91(t, J =6.5Hz,2H),3.76-3.6(m,2H),3.4-3.1(bs,2H),2.22(t, J =7Hz,2H),2.03-1.94(m,2H),1.79-1.67(m,2H),1.51-1.26(m,10H),0.9(t, J =7Hz, 3H). DSC peak at 247.6 deg.C

Compound 8.2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) propionic acid hydrochloride. ¹HNMR(300MHz,CD₃OD) ppm7.07(s,1H),6.48-6.44(dd, J =8 and 2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.92(t, J =6.5Hz,2H),3.67-3.56(m,2H),3.46(t, J =7Hz,2H),3.3-3.1(m,2H),2.85(t, J =7Hz,2H),2.22-2.07(m,2H),2.04-1.93(m,2H),1.78-1.66(m,2H),1.51-1.28(m,10H),0.91(t, J =7Hz 3H). DSC peak at 235.9 deg.C

Compound 9.2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm7.04(s,1H),6.48-6.44(dd, J =8 and 2Hz,1H),6.37(d, J =2Hz,1H),4.47(s,2H),3.91(t, J =6.5Hz,2H),3.69-3.54(m,2H),3.27-3.18(m,2H),3.1(s,2H),2.49(t, J =7Hz,2H),2.21-1.94(m,6H),1.79-1.68(m,2H),1.51-1.27(m,10H),0.9(t, J =7Hz, 3H). DSC peak at 232 deg.C

Compound 10.2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),4.14(s,2H),3.91(t,J=6.5Hz,2H),3.78-3.63(m,2H),3.3-3.1(m,2H),2.33-2.18(m,2H),2.07-1.96(m,2H),1.8-1.67(m,2H),1.53-1.42(m,2H),1.42-1.3(m,4H),0.92(t,J=7Hz,3H)。

Compound 11.2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) propionic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),3.91(t,J=6.5Hz,2H),3.68-3.58(m,2H),3.48(t,J=7Hz,2H),3.3-3.09(m,2H),2.89(t,J=7Hz,2H),2.28-2.14(m,2H),2.07-1.95(m,2H),1.8-1.67(m,2H),1.53-1.27(m,6H),0.92(t,J=7Hz,3H)

Compound 12.2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm6.82-6.67(m,3H),4.47(s,2H),3.92(t, J =6.5Hz,2H),3.7-3.58(m,2H),3.25(m,2H),3.1(m,2H),2.5(t,7Hz,2H),2.28-1.92(m,6H),1.8-1.68(m,2H),1.53-1.4(m,2H),1.42-1.27(m,6H),0.92(t, J =7Hz, 3H). DSC peak at 235.4 deg.C

Compound 13.2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),4.14(s,2H),3.91(t,J=6.5Hz2H),3.75-3.63(m,2H),3.3-3.12(m,2H),2.33-2.18(m,2H),2.07-1.96(m,2H),1.8-1.67(m,2H),1.53-1.27(m,8H),0.92(t,J=7Hz,3H)。

Compound 14.2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) propionic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),3.91(t,J=6.5Hz,2H),3.68-3.58(m,2H),3.47(t,J=7Hz,2H),3.3-3.1(m,2H),2.87(t,J=7Hz,2H),2.25-2.14(m,2H),2.07-1.96(m,2H),1.8-1.67(m,2H),1.53-1.27(m,10H),0.92(t,J=7Hz,3H)。

Compound 15.2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) pm6.82-6.67(m,3H),4.47(s,2H),3.91(t, J =6.5Hz,2H),3.68-3.57(m,2H),3.4-3.06(m,4H),2.5(t, J =7Hz,2H),2.25-1.94(m,6H),1.79-1.68(m,2H),1.51-1.27(m,10H),0.92(t, J =7Hz, 3H). DSC peak at 240 deg.C

Compound 16.2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) acetic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),4.14(s,2H),3.91(t,J=6.5Hz,2H),3.75-3.62(m,2H),3.3-3.12(m,2H),2.32-2.18(m,2H),2.07-1.95(m,2H),1.8-1.67(m,2H),1.54-1.27(m,10H),0.9(t,J=7Hz,3H)。

Compound 17.2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) propionic acid hydrochloride.¹HNMR(300MHz,CD₃OD)ppm6.82-6.67(m,3H),4.47(s,2H),3.91(t,J=6.5Hz,2H),3.68-3.58(m,2H),3.47(t,J=7Hz,2H),3.3-3.1(m,2H),2.87(t,J=7Hz,2H),2.26-2.14(m,2H),2.07-1.96(m,2H),1.8-1.67(m,2H),1.53-1.27(m,10H),0.92(t,J=7Hz,3H)。

Compound 18.2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -yl) butanoic acid hydrochloride.¹HNMR(300MHz,CD₃OD) ppm6.82-6.67(m,3H),4.47(s,2H),3.91(t, J =6.5Hz,2H),3.7-3.57(m,2H),3.36-3.03(m,4H),2.49(t, J =7Hz,2H),2.26-1.96(m,6H),1.79-1.68(m,2H),1.53-1.27(m,12H),0.92(t, J =7Hz, 3H). DSC peak at 241.1 deg.C

2H-spiro [ 1-benzofuran-3, 4' -piperidine]-5-alcohols. To 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]To a mixture of-5-alcohol hydrobromide (6g, 15.9mmol) in 120ml MeOH was added 0.6g palladium hydroxide. Subjecting the mixture to hydrogenation with H₂And treated overnight at normal pressure. The crude reaction mixture was concentrated until about 20mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. The product was concentrated to give 2.6g (80%) of a white solid.¹H-NMR(400MHz,DMSO-d₆) ppm8.8(s,1H),6.57-6.51(m,2H),6.47(dd, J =8 and 2Hz,1H),4.29(s,2H),2.9-2.84(m,2H),2.55-2.47(m,2H),1.68-1.59(m,2H),1.54-1.47(m,2H)。

2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alcohols. To 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture of-6-ol (2g, 5.3mmol) in 60mL MeOH (5 mL of 4N HCl in MeOH) was added 0.2g of palladium hydroxide. Subjecting the mixture to hydrogenation with H₂The treatment was carried out at atmospheric pressure for 48 hours. The crude reaction mixture was concentrated until about 20mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. The product was concentrated to yield 950mg (90%) of a white solid.¹HNMR(400MHz,DMSO-d₆)ppm9.3(bs,1H),6.91(d,J=8Hz,1H),6.50(d,J=2Hz,1H),4.31(s,2H),2.9-2.84(m,2H),2.54-2.45(m,2H),1.68-1.59(m,2H),1.52-1.44(m,2H)。

3- { 5-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. 2H-spiro [ 1-benzofuran-3, 4' -piperidine]A mixture of-5-ol (3.85 g; 18.76mmol), tert-butyl acrylate (3.28 mL; 22.51mmol) and N, N-diisopropylamine in MeOH (175mL) was heated at reflux overnight. After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, concentrated in vacuo, and purified by column chromatography (SiO)₂，Et₂O: hexane 1:1 followed by Et₂O) to give the product (4g), Rt1.02min (system B), [ M + H]⁺334.2

Tert-butyl 3- (5- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate to a solution (10mL) of tert-butyl 3- { 5-hydroxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate (0.51 g; 1.53mmol) in THF was added 2- (trifluoromethyl) benzyl alcohol (0.3 mL; 2.29mmol) followed by DIAD (0.43 mL;

2.2mmol) and triphenylphosphine (0.58 g; 2.2 mmol). The resulting mixture was stirred at room temperature for 3 days. Subsequently, the reaction mixture was concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O：

Hexane 2: 1) purification gave the product (0.38 g). Rt1.42min (System B), [ M + H]⁺492.2

The following compounds were obtained in a similar manner:

3- [5- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. Rt1.49min (System B), [ M + H]⁺430.3

3- (5- { [3- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.48min (System B), [ M + H]⁺492.1

3- {5- [ (2, 6-dichlorophenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.45min (System B), [ M + H]⁺492.1

3- {5- [ (3, 5-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.50min (System B), [ M + H]⁺492.1

Tert-butyl 3- {5- [ (2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {5- [ (2-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {5- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.53min (System B), [ M + H]⁺528.0

3- {5- [ (2-chloro-6-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.50min (System B), [ M + H]⁺472.1

Compound 19.3- (5- { [2- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Reacting 3- (5- { [2- (trifluoromethyl) phenyl]-methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (0.21 g; 0.43mmol) of (E) -1' -yl } propanoate was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (3.2 mL; 12.82mmol) and stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr ₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.17 g).¹HNMR(400MHz,DMSO/TFA-d₆) ppm9.5(bs,1H),7.75(d, J =8.2Hz,2H),7.68(t, J =8.2Hz,1H),7.53(t, J =7.7Hz,1H),6.69-6.82(M,3H),5.15(s,2H),4.42(bs,2H),3.45-3.60(M,2H),3.29-3.41(M,2H),2.98-3.18(M,2H),2.78(t, J =7.4Hz,2H),2.02-2.18(M,2H),1.80-1.91(M,2H), rt1.36min (system B), [ M + H, 2H ], 2H, r, c]⁺436.1

The following compounds were obtained in a similar manner:

compound 20.3- [5- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.40min (System B), [ M + H]⁺374.2

Compound 21.3- (5- { [3- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.77min (System B), [ M + H]⁺436.1

Compound 22.3- {5- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.49min (System B), [ M + H]⁺436.2

Compound 23.3- {5- [ (3, 5-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺436.0

Compound 24.3- {5- [ (2, 6-difluorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.27min (System B), [ M + H [ ]]⁺404.1

Compound 25.3- {5- [ (2-chlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.33min (System B), [ M + H]⁺402.1

Compound 26.3- {5- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride

¹HNMR(400MHz,DMSO-d₆) ppm12.63(bs,1H),10.36(bs,1H),7.79(s,2H),6.98(dd, J =8 and 2Hz,1H),6.76(dd, J =8 and 2Hz,2H),5.14(s,2H),4.46(brs,2H),3.24-3.56(m,4H),2.99-3.17(m,2H),2.87(t, J =8Hz,2H,)2.12-2.29(m,2H),1.84-1.94(m, 2H).

Rt1.47min (System B), [ M + H]⁺472.0

Compound 27.3- {5- [ (2-chloro-6-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.77min (System B), [ M + H]⁺416.1

3- {5- [ (trifluoromethane) sulfonyloxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To 3- { 5-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine at-10 deg.C]A solution of tert-butyl (1' -yl) propionate (333 mg; 1.0mmol) in 15mL of dichloromethane and pyridine (90 mg; 1.1eq) was added dropwise to a solution of trifluoromethanesulfonic anhydride (310 mg; 1.1eq) dissolved in 5mL of dichloromethane. The resulting reaction mixture was allowed to warm to room temperature and stirred overnight. By adding 5% NH ₄The reaction was stopped with an aqueous solution of Cl. The resulting mixture was extracted with dichloromethane. The organic layer was dried (Na)₂SO₄) Filtration and concentration in vacuo afforded the product (390mg) which was used directly in the next step. Rt1.34min (System B), [ M + H]⁺466.1

3- [5- (anilino) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To the degassed 3- {5- [ (trifluoromethane) sulfonyloxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]To a solution of tert-butyl propionate (380 mg; 0.82mmol) in toluene (20mL) were added aniline (91.23 mg; 0.98mmol), cesium carbonate (372mg, 1.14mmol), palladium (II) acetate (9mg, 0.04mmol), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylphenylboronic acid (39 mg; 0.08mmol), and 5mg of phenylboronic acid. The resulting mixture was heated at 100 ℃ overnight. After cooling to room temperature, 5% NaHCO was added₃Aqueous solution, and the product was extracted with EtOAc. The combined organic layers were dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂dichloromethane/MeOH 95: 5) purification gave the product (270mg), which was used directly in the next step.

Compound 28.3- [5- (anilino) -2H-spiro [ 1-benzofuran-3, 4' -piperazinesPyridine (I)]-1' -yl]Propionic acid hydrochloride. 3- [5- (anilino) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]Tert-butyl propionate (0.27 g; 0.66mmol) was dissolved in 1, 4-bisIn a solution of 4M HCl in an alkane (10mL, 40mmol) and stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.2 g). Rt1.21min (System B), [ M + H]⁺353.1

3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. 2H-spiro [ 1-benzofuran-3, 4' -piperidine]A mixture of-6-ol (5.09 g; 18.76mmol), tert-butyl acrylate (4 mL; 27.28mmol) and N, N-diisopropylamine (5.31mL, 31mmol) in MeOH (100mL) was heated at reflux overnight. After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtration and concentration in vacuo afforded the product (7.54 g).¹HNMR(400MHz,CDCl₃-d) ppm6.92(d, J =7.9Hz,1H),6.28-6.35(M,2H),5.40(bs,1H),4.35(s,2H),2.85-2.93(M,2H),2.70(t, J =7.4Hz,2H),2.45(t, J =7.4Hz,2H),2.02-2.12(M,2H),1.86-1.97(M,2H),1.67-1.75(M,2H),1.46(s,9H) rt0.97min (system B), [ M + H ] rt0.97min (system B)]⁺334.2

3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propionic acid tert-butyl ester. To (2, 6-dichlorophenyl) methanol (0.79 g; 4.45 mmol) and 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (1 g, 2.97 mmol) in dichloromethane (60mL) triphenylphosphine (1.95 g; 7.42mmol) was added and after 30 min DIAD (1.46 mL; 7.42mmol) was added. Subsequently, the resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Dichloromethane/acetone 95: 5) purification gave crude product (2 g). The product was dissolved in Et₂O (60mL) and 4mL of 1 MHCl/ethanol were added. The white solid formed is isolated by filtration and Et₂O and EtOAc washes in 5% NaHCO₃The aqueous solution was partitioned with dichloromethane. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the product (1.10g, 75%).¹HNMR (400MHz, CHLOROFORM-d) ppm7.36(d, J =8Hz,2H,)7.23(d, J =8Hz,1H),7.03(d, J =8Hz,1H),6.56(dd, J =8 and 2Hz,1H),6.51(d, J =2Hz,1H),5.22(s,2H),4.37(s,2H),2.85-2.92(m,2H),2.70(t, J =8Hz,2H),2.45(dt, J =8 and 2Hz,2H),2.03-2.11(m,2H),1.89-1.98(m,2H),1.69-1.77(m,2H),1.46(s, 9H). Rt1.45min (System B), [ M + H]⁺492.1。

The following compounds were obtained in a similar manner:

Tert-butyl 3- {6- [ (4-phenylpentyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (3-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

3- [6- (Oxopropyl-2 ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (2, 5-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [3- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2, 3-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2-chloro-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (2, 4-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ 2-chloro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (cyclohex-3-en-1-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

3- {6- [ (3, 5-dichloropyridin-4-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (3, 5-dichloro-pyridin-4-yl) -methanol was prepared as follows: to a solution of 3, 5-dichloro-4-pyridinecarboxaldehyde (4.68 mL; 26.59mmol) in MeOH (50mL) at 0 deg.C was added NaBH in small portions₄(1.01g, 26.59 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. The layers were separated and the organic layer was dried (Na)₂SO₄) Filtration and concentration in vacuo afforded the product as an amorphous solid (4.04g, 85%).

3- {6- [ (2, 4-dichloropyridin-3-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2, 4-dichloro-pyridin-3-yl) -methanol was prepared as follows: to 2, 4-dichloropyridine (3.00 mL; 27) at-78 deg.C 8mmol) in THF (25mL) was added dropwise a solution of LDA (15.3 mL; 2.00mol/l in THF/heptane/ethylbenzene; 30.6 mmol). The resulting mixture was stirred at-78 ℃ for 1 h. Subsequently, a solution of ethyl chloroformate (3.2 mL; 33.33mmol) in THF (5mL) was added dropwise at-78 deg.C, and the mixture was stirred at the same temperature for an additional 1 h. To the resulting mixture was added dropwise 5% NaHCO at-78 deg.C₃An aqueous solution. The mixture was allowed to warm to rt and extracted with EtOAc. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:3) to give ethyl 2, 4-dichloro-nicotinate (2.45 g). To a solution of ethyl 2, 4-dichloro-nicotinate (2.35 g; 10.68mmol) in THF (50mL) was added dropwise diisobutylammonium hydride (32.0 mL; 1.00mol/l in THF, 32.0mmol) at 4 ℃. After 15 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight. Subsequently, the resulting mixture was concentrated in vacuo and concentrated in 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue is purified by column chromatography (Et)₂O: Hexane 1:1) to give (2, 4-dichloropyridin-3-yl) methanol (0.40 g).

Tert-butyl 3- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (2, 6-dichloro-4-iodophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2, 6-dichloro-4-iodophenyl) methanol was prepared as follows: to a solution of 3, 5-dichlorobenzene (2.72 g; 9.97mmol) in THF (25mL) at-78 deg.C was added lithium diisopropylamide (5.48 mL; 2.00 mol/l; 10.98 mmol). The resulting mixture was stirred for 4.5 hours, followed by dropwise addition of a solution of N, N-dimethylformamide (1.16mL, 14.95mmol) in THF (5mL) at-78 ℃. The resulting reaction mixture was stirred at-40 ℃ for 2 hours. Subsequently, 5% NH was added at-20 deg.C₄The reaction was stopped with an aqueous solution of Cl. Et used for the resulting mixture₂And (4) extracting. The combined organic layers were dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (Si)O₂，Et₂O: hexane 1:3) purification gave 2, 6-dichloro-4-benzaldehyde (0.7g, 23%). To a solution of 2, 6-dichloro-4-benzaldehyde (450mg, 1.27mmol) in MeOH (15mL) at 0 deg.C was added NaBH in small portions₄(72.14 mg; 1.91 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO ₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/acetone 95: 5) to give (2, 6-dichloro-4-iodophenyl) methanol (0.42g), which was used as is.

Tert-butyl 3- {6- [ (2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [2- (2, 6-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [2- (2-fluorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (2-chloro-5-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2-chloro-5-methylphenyl) methanol was prepared as follows: to a solution of 2-chloro-5-methylbenzoic acid (2.05 g; 12.2mmol) in THF (20mL) was added borane-THF complex (1M, 24.03 mL; 24.3mmol) dropwise and then stirred at 60 ℃ for 2 h. 1MHCl (30mL) was added to the reaction mixture at 0 deg.C, and the resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na) ₂SO₄) Filtration and concentration in vacuo afforded the product (1.8g, 95%) which was used directly in the next step.

3- {6- [ (2-chloro-5-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2-chloro-5-ethylphenyl) methanol was prepared as follows: to the direction ofNitrogen purged solution of ethyl 5-bromo-2-chlorobenzoate (4.26mL, 25.05mmol) in THF (100mL) was added lithium chloride (2.12g, 50.09mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (0.82g, 1 mmol). Subsequently, the mixture was cooled to-78 ℃ and a solution of diethyl zinc (37.57 mL; 1 mol/l; 37.57mmol) in heptane was added dropwise. The reaction mixture was allowed to return to room temperature overnight. The resulting reaction mixture was cooled to-10 ℃ and quenched with 300mLEt₂And (4) diluting with oxygen. Subsequently, 1MHCl solution (150mL) was carefully added. The organic layer was separated and dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 5: 95) purification yielded ethyl 2-chloro-5-ethylbenzoate (4.61g, 86%). To a solution of ethyl 2-chloro 5-ethyl-benzoate (1g, 4.70mmol) in THF (25mL) cooled to-5 deg.C, purged with nitrogen, was added diisobutylammonium hydride in toluene (14.11 mL; 14.11 mmol). The reaction mixture was allowed to come back to room temperature and stirred overnight. The resulting reaction mixture was cooled to-10 ℃ and 5% NaHCO was added ₃Aqueous solution (10 mL). The organic layer was separated and dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:3₂O: Hexane 1:1) to give (2-chloro-6-ethylphenyl) methanol (0.59g, 75%) which was used as such.

3- {6- [ (2-chloro-5-propylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2-chloro-5-propylphenyl) methanol was prepared as follows: to a nitrogen purged solution of ethyl 5-bromo-2-chlorobenzoate (2g, 7.59mmol) in THF (14mL) was added 0.5M lithium chloride and [1, 1' -bis (diphenylphosphino) ferrocene ] in THF (30mL)]Palladium (II) dichloride (0.22g, 0.3 mmol). Subsequently, the mixture was cooled to-78 ℃ and a solution of N-propylzinc bromide (30.36 mL; 0.5 mol/l; 15.18mmol) was added dropwise. The reaction mixture was allowed to return to room temperature overnight. The resulting reaction mixture was cooled to-10 ℃ and quenched with 300mLEt₂And (4) diluting with oxygen. Subsequently, 1MHCl solution (150mL) was carefully added. The organic layer was separated and dried (Na)₂SO₄) Filtering, and filteringConcentrating in air. The residue is purified by column chromatography (SiO)₂，Et₂O, hexane 5: 95 Et later₂O: Hexane 1:0) to give ethyl 2-chloro-5-propylbenzoate (1.1g, 63%). To a solution of ethyl 2-chloro-5-propyl-benzoate (1.12g, 4.94mmol) in THF (28mL) cooled to-5 deg.C under nitrogen purge was added diisobutylammonium hydride in toluene (14.82 mL; 14.82 mmol). The reaction mixture was allowed to come back to room temperature and stirred overnight. The resulting reaction mixture was cooled to-10 ℃ and 5% NaHCO was added ₃Aqueous solution (10 mL). The organic layer was separated and dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:3₂O: Hexane 1:1) to give (2-chloro-6-propylphenyl) methanol (0.76g, 83%) which was used as it was.

Tert-butyl 3- {6- [3- (2-fluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [3- (2-chlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

3- {6- [ (5, 7-difluoro-2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired 5, 7-difluoro-2, 3-dihydro-1H-inden-1-ol is prepared as follows: to a solution of 5, 7-difluoro-1-indanone (1.20g, 7.14mmol) in EtOH (50mL) at 0 deg.C was added NaBH in small portions₄(283.5 mg; 7.49 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The product is as follows: 5, 7-difluoro-2, 3-dihydro-1H-inden-1-ol (1.2 g; 99%) was used as received.

3- {6- [ (5, 7-dichloro-2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester. The desired 5, 7-chloro-2, 3-dihydro-1H-inden-1-ol is prepared from 5, 7-dichloro-1-indanone using the conditions described for 5, 7-difluoro-2, 3-dihydro-1H-inden-1-ol.

3- {6- [ (1R) - (2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

3- {6- [ (1S) - (2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

3- [6- (3-Phenylpropoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Tert-butyl 3- {6- [2- (2, 4-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [2- (2-chlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

3- (6- { [2, 6-dichloro-4- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The desired [2, 6-dichloro-4- (trifluoromethyl) phenyl group]Methanol was prepared as follows: to a solution of 1, 3-dichloro-5- (trifluoromethyl) benzene (4.73 g; 22mmol) in THF (40mL) at-78 deg.C was added N-butyllithium (8 mL; 2.50 mol/l; 20 mmol). The resulting mixture was stirred for 15 minutes and added to dry ice in THF. Acidifying the reaction mixture to _pH =3 (with 5 mhz cl solution) and extracted with EtOAc. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂dichloromethane/MeOH 8: 2) purification gave 2, 6-dichloro-4- (trifluoro-methyl) benzoic acid (1.2 g). To this solution of 2, 6-dichloro-4- (trifluoromethyl) -benzoic acid (1.7 g; 6.56mmol) in THF (20mL) was added borane-THF complex (1M, 13.13 mL; 13.3mmol) dropwise followed by stirring at 60 ℃ overnight. To the reaction mixture was added 1M HCl (30mL) at 0 deg.C, and the resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtering, and vacuum filteringAnd (5) concentrating. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:3₂O, hexane 1:1) to obtain [2, 6-dichloro-4- (trifluoromethyl) phenyl]Methanol (1.3 g; 80%) was used directly in the next step.

3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The desired (2, 6-dichloro-4-methylphenyl) -methanol was prepared as follows: to a solution of ethyl 1-bromo-3, 5-dichlorobenzene (2.5g, 11.07mmol) in THF (14mL) under nitrogen purge was added 0.5M lithium chloride and [1, 1' -bis (diphenyl-phosphino) -ferrocene in THF (44.27 mL; 22.13mmol) ]Palladium (II) dichloride (0.32g, 0.44 mmol). Subsequently, the mixture was cooled to-78 ℃ and a solution of methyl zinc bromide (30.36 mL; 0.5 mol/l; 15.18mmol) in THF was added dropwise. The reaction mixture was allowed to return to room temperature and then heated overnight (at 60 ℃). The resulting reaction mixture was cooled to-10 ℃ and quenched with 300mLEt₂And (4) diluting with oxygen. Subsequently, 1MHCl solution (150mL) was carefully added. The organic layer was separated and dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Hexane followed by dichloromethane/hexane 1:9) to give 1, 3-dichloro-5-toluene (1.0 g; 56%) was reacted with n-butyllithium in THF, then added to dry ice (as described for 1, 3-dichloro-5- (trifluoromethyl) benzene). The product of this reaction, 2, 6-dichloro-4-methylbenzoic acid, was reduced with borane-THF complex (as described for 2, 6-dichloro-4- (trifluoromethyl) benzoic acid) to give (2, 6-dichloro-4-methylphenyl) methanol in 71% yield over two steps and used directly.

Tert-butyl 3- {6- [ (5-bromo-2-chlorophenylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2-chloro-5-phenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate. To a mixture of degassed tert-butyl 3- {6- [ (5-bromo-2-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate (100 mg; 0.56mmol) in 3mL1, 2-dimethoxyethane and sodium bicarbonate (1.5mL) was added phenylboronic acid (80 mg;

0.67mmol) and tetrakis (triphenylphosphine) palladium (0) (6 mg; 0.06 mmol). The resulting mixture was heated at reflux overnight. After cooling to room temperature, the resulting mixture was washed with EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂1:1 after O: hexane 1: 3) to give the product (180 mg; 60%).

3- {6- [ (2-chloro-5-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To degassed 3- {6- [ (5-bromo-2-chlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) propionate (0.28 g; 0.52mmol) in 9mL of toluene and 3mL of H₂To the mixture in O were added successively potassium cyclopropyltrifluoroborate (0.9 g; 0.63mmol), cesium carbonate (0.51 g; 1.56mmol) and 1 ', 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (20 mg; 0.03 mmol). The resulting mixture was heated overnight (90 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (0.23 g; 88%).

3- [6- ({ 2-chloro-5- [ 2-phenylcyclopropyl)]Phenyl } methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To degassed 3- {6- [ (5-bromo-2-chlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) propionate (0.3 g; 0.56mmol) in 9mL of toluene and 3mLH₂To the mixture in O, potassium trifluoro (2-phenylcyclopropyl) borate (0.9 g; 0.63mmol), cesium carbonate (0.55 g; 1.68mmol) and 1 ', 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (20 mg; 0.03mmol) were added in this order. The resulting mixture was heated overnight (90 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (0.23 g; 71%). The desired potassium trifluoro (2-phenylcyclopropyl) borate is prepared from trans-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) styrene using Simmons-Smith conditions (J.org.chem,2004,69,327 and J.am.chem.Soc,2009,131,6516) to give 4,4,5, 5-tetramethyl-2- (2-phenylcyclopropyl) -1,3, 2-dioxaborolan which is converted to potassium trifluoro (2-phenylcyclopropyl) borate using conditions similar to those described for the synthesis of potassium p-butyltrifluoroborate (see also: J.org.chem,2004,69, 357)

Tert-butyl 3- {6- [ (2-chloro-6-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- (6- { [ (2E) -3- (4-chlorophenyl) prop-2-en-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2E) -3- (4-chlorophenyl) prop-2-en-1-ol (j.o.c., 2006, 71, 1969-76) is prepared as follows: to a solution of ethyl (2E) -3- (4-chlorophenyl) prop-2-enoate (3.32 g; 16.88mmol) in dichloromethane (60mL), cooled to-78 deg.C, purged with nitrogen, was added dropwise diisobutyl-aluminum hydride (49 mL; 49mmol) in medium toluene over 30 minutes. The reaction mixture was returned to 0 ℃ (over 1 hour). MeOH (15mL) was added dropwise to maintain a steady state of gas evolution. The resulting reaction mixture was stirred at room temperature for another 30 minutes, followed by addition of saturated aqueous sodium potassium tartrate solution. The organic layer was separated and the aqueous phase was extracted 2 times with dichloromethane. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (2.5 g; 87.8%), used directly.

Tert-butyl 3- {6- [ (3-phenyl) prop-2-yn-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

3- [6- (2, 3-dihydro-1-benzofuran-3-yloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. The desired 2, 3-dihydro-1-benzofuran-3-The alcohol was prepared as follows: to a solution of 3-coumaranone (2.82g, 21mmol) in EtOH (50mL) at 0 deg.C was added NaBH in small portions₄(2.39 g; 63 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The product is as follows: 2, 3-dihydro-1-benzofuran-3-ol (2.59g, 90%) was used as received.

Tert-butyl 3- (6- { [ (2E) -3- (2, 6-dichlorophenyl) prop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate. The desired (2E) -3- (2, 6-dichlorophenyl) prop-2-en-1-ol was prepared as described for the preparation of (2E) -3- (4-chlorophenyl) prop-2-en-1-ol (in 91% yield).

Tert-butyl 3- (6- {3- [2- (trifluoromethyl) phenyl ] propoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 3- (6- { [ (2E) -3-phenylprop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoate.

Tert-butyl 3- {6- [3- (2, 3-difluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (7-chloro-2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- {6- [3- (2-chloro-6-fluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [3- (2, 6-dichlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [3- (4-chlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

Tert-butyl 3- (6- { [ (3-4-chlorophenyl) prop-2-yn-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 3- (6- { [ (2E) -3- (2-fluorophenyl) prop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate. The desired (2E) -3- (2-fluorophenyl) prop-2-en-1-ol was prepared as described for the preparation of (2E) -3- (4-chlorophenyl) prop-2-en-1-ol (in 66% yield).

3- {6- [ (4-Bromothiophen-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (4-bromothien-2-yl) methanol was prepared as follows: to a solution of 4-bromo-thiophenecarboxaldehyde (2.5 g; 13.09 mmol) in EtOH (50mL) at 0 deg.C was added NaBH in small portions ₄(0.74 g; 19.63 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. The layers were separated and the organic layer was dried (Na)₂SO₄) Filtration and concentration in vacuo afforded the product (2.12g, 83%) which was used as received.

3- {6- [ (4-Butylthiophen-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. N-butyl boronic acid was converted to its potassium butyltrifluoroborate salt using the protocol in org.biomol.chem., 2005, 941. A mixture of n-butylboronic acid, water (10mL) and potassium bifluoride (4.6 g; 58.9mmol) in THF (40mL) was stirred at room temperature for 4 hours. Subsequently, the solvent was removed in vacuo, and the residue was treated with toluene and concentrated in vacuo. The following steps were repeated three times to remove all water. The resulting solid was treated with hot acetone (20mL) and the acetone was decanted. This procedure was repeated once more with 20mL of acetone. The combined acetone layers were concentrated in vacuo and the residue was taken up in Et₂And (4) O treatment. The precipitate formed was collected by filtration and dried in vacuo to give potassium butyltrifluoroborate (1.4g, 87%) for use as received.

To the degassed 3- {6- [ (4-bromothiophen-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -Yl } propionic acid tert-butyl esterTo a mixture of the ester (100 mg; 0.2mmol) in 20mL of toluene were added potassium butyltrifluoroborate (35.2 mg; 0.22mmol), palladium (II) acetate (2.2 mg; 0.01mmol), tripotassium phosphate monohydrate (158.5 mg; 0.69mmol), and 2-dicyclohexylphosphino-2 ', 6' -diisopropyloxy-1 ', 1' -biphenyl (9.2 mg; 0.02mmol) in that order. The resulting mixture was heated at reflux overnight (borosilicate glass bottle). After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (65 mg; 68%).

3- {6- [ (4-Cyclopropylmethylphenylsulfanyl-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To the degassed 3- {6- [ (4-bromothiophen-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture of tert-butyl (350 mg; 0.69mmol) of-1 ' -yl } propanoate in 20mL of toluene were added potassium cyclopropyltrifluoroborate (112 mg; 0.76mmol), palladium (II) acetate (7.8 mg; 0.03mmol), tripotassium phosphate monohydrate powder (554.7 mg; 2.41mmol) and 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1 ', 1 ' -biphenyl (32 mg; 0.07mmol) in that order. The resulting mixture was heated at reflux overnight (borosilicate glass bottle). After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (230 mg; 74%).

3- (6- { [4- (2-fluorophenyl) thiophen-2-yl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To the degassed 3- {6- [ (4-bromothiophen-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture of tert-butyl (1 ' -yl) propionate (100 mg; 0.2mmol) in 20mL of toluene were added 2-fluoro-phenylboronic acid (30.2 mg; 0.22mmol), palladium (II) acetate (2.2 mg; 0.01mmol), tripotassium phosphate monohydrate (158.5 mg; 069mmol) and dicyclohexylphosphino-2 ', 6 ' -diIsopropoxy-1 ', 1' -biphenyl (9.2 mg; 0.02 mmol). The resulting mixture was heated at reflux overnight (borosilicate glass bottle). After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 2: 1) to give the product (98 mg; 95%).

The following compounds were obtained in a similar manner:

tert-butyl 3- {6- [ (4-phenylthiophen-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (4-bromo-3-methylphenylsulfanyl-2 yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (4-bromo-3-methylphenylsulfanyl-2-yl) methanol was prepared as follows: to a solution of 4-bromo-3-methylthiobenzoic acid (2 g; 0.95mmol) in THF (20mL) at 0 deg.C was added borane-THF complex (1M, 18.19 mL; 18.19mmol) dropwise. Subsequently, the reaction mixture was stirred at 60 ℃ for 1 hour. To the reaction mixture was added 1MHCl (30mL) at 0 deg.C, and the resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the product (2.2 g; 100%), used directly.

The intermediate is as follows: tert-butyl 3- {6- [ (4-bromo-3-methylphenylsulfanyl-2 yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate was used to synthesize the following 2 compounds:

3- {6- [ (3-methyl-4-phenylthiophen-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To the degassed 3- {6- [ (4-bromo-3-methylphenylsulfanyl-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]To a mixture of tert-butyl-1' -yl } propanoate (200 mg; 0.38mmol) in 10mL of toluene was added phenylboronic acid (56 mg; 0.46mmol), palladium (II) acetate (4.3 mg;0.02mmol), tripotassium phosphate monohydrate (308.5 mg; 1.34mmol) and 2-dicyclohexylphosphino-2 ', 6' -diisopropyloxy-1 ', 1' -biphenyl (15.7 mg; 0.04 mmol). The resulting mixture was heated at reflux overnight (borosilicate glass bottle). After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 2: 1) to give the product (200 mg; 100%).

3- {6- [ (4-butyl-3-methylphenylsulfanyl-2 yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To the degassed 3- {6- [ (4-bromo-3-methylphenylsulfanyl-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture of tert-butyl (1 ' -yl) propionate (200 mg; 0.38mmol) in 10mL of toluene were added potassium butyltrifluoroborate (68.6 mg; 0.42mmol), palladium (II) acetate (4.3 mg; 0.02mmol), tripotassium phosphate monohydrate (308.5 mg; 1.34mmol) and 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1 ', 1 ' -biphenyl (15.7 mg; 0.04mmol) in that order. The resulting mixture was heated at reflux overnight (borosilicate glass bottle). After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (126 mg; 65%).

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2, 6-dichloro-3-ethylphenyl) -methanol was prepared as follows: to a mixture of 2 ', 4' -dichloroacetophenone (4.85 g; 25.66mmol) suspended in diethylene glycol (20mL) was added potassium hydroxide (2.37 g; 35.92mmol) and hydrazine hydrate (2.93 mL). The resulting mixture was heated at 100 ℃ (1 hour) followed by overnight (at 200 ℃). After cooling to room temperature, the mixture was taken up in Et₂O and H₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtering, and filteringConcentrating in air. The residue is purified by column chromatography (SiO)₂Hexane) to give the product 2, 4-dichloro-1-ethylbenzene (2.24 g; 50%). To a solution of 2,2,6, 6-tetramethylpiperidine (2.36 mL; 14mmol) in THF (40mL) at-78 deg.C was added n-butyllithium (5.61 mL; 2.50 mol/l; 14 mmol). The reaction mixture was stirred for 90 minutes, bringing the temperature to 0 ℃. Subsequently, a solution of 2, 4-dichloro-1-ethylbenzene (2.23 g; 12.74mmol) in THF (5mL) was added at-78 deg.C. The resulting mixture was stirred for 2.5 hours. Subsequently, a solution of N, N-dimethylformamide (1.48 mL; 19.11mmol) was added dropwise and the resulting reaction mixture was stirred for 30 minutes. Subsequently, saturated NaH was added at-50 deg.C ₄The reaction was stopped with an aqueous solution of Cl. Et used for the resulting mixture₂And (4) extracting. The combined organic layers were dried (Na)₂SO₄) Filtered and concentrated in vacuo to give 2, 6-dichloro-3-ethylbenzaldehyde, which was redissolved in MeOH (100 mL). Subsequently, NaBH is added in small portions at 0 ℃ in small portions₄(1.45 g; 38.22 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂,Et₂Et after O: Hexane 1:7₂O: Hexane 1:1) purification to give the product: (2, 6-dichloro-3-ethylphenyl) methanol (2.11 g; 80%).

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (4-butyl-2, 6-dichlorophenyl) -methanol was prepared as follows: to a degassed solution of 1-bromo-3, 5-dichlorobenzene (4.42 g; 19.57mmol) in 90mL of toluene and 30mLH₂To the mixture in O were added potassium butyltrifluoroborate (4.01 g; 24.45mmol), cesium carbonate (19.13 g; 58.7mmol) and 1 ', 1' -bis (diphenylphosphino) ferrocene palladium (II) -dichloride dichloromethane complex (0.8 g; 0.98mmol) in that order. The resulting mixture was heated for 48 hours (90 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and washed with H ₂And O washing.The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give 1-butyl-3, 5-dichlorobenzene (3.39 g; 85%). The product was converted to (4-butyl-2, 6-dichlorophenyl) methanol by the sequence described for the conversion of 2, 4-dichloro-1-ethylbenzene to (2, 6-dichloro-3-ethylphenyl) methanol (total yield: 71%).

3- {6- [ (2, 6-dichloro-4-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2, 6-dichloro-4-cyclopropylphenyl) methanol was prepared as follows: to a solution of 2,2,6, 6-tetramethylpiperidine (2.36 mL; 14mmol) in THF (40mL) at-78 deg.C was added n-butyllithium (5.61 mL; 2.50 mol/l; 14 mmol). The reaction mixture was stirred for 90 minutes, bringing the temperature to 0 ℃. Subsequently, a solution of 3, 5-dichlorobenzene (6.82 g; 25mmol) in THF (10mL) was added at-78 deg.C. The resulting mixture was stirred for 2.5 hours. Subsequently, a solution of N, N-dimethylformamide (2.9 mL; 37.5mmol) was added dropwise and the resulting reaction mixture was stirred for 30 minutes. Adding saturated NaH at-50 deg.C₄The reaction was stopped with an aqueous solution of Cl. Et used for the resulting mixture₂And (4) extracting. The combined organic layers were dried (Na) ₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Dichloromethane, dichloromethane: hexane 1:1) purification gave the product: 2, 6-dichloro-4-iodo-benzaldehyde (5.11g, 64). Subsequently, 2.7 g; 8.52mmol of the aldehyde were redissolved in MeOH (100mL) and NaBH was added in small portions at 0 ℃₄(0.45 g; 12.79 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Dichloromethane, dichloromethane: acetone 95: 5) purification gives the product: (2, 6-dichloro-4-iodophenyl) methanol (2.2 g; 81%). To degassed (2, 6-dichloro-4-iodophenyl) methanol (303 mg; 1mmol) in 9mL of toluene and 3mLH₂In the mixture in the presence of oxygen in the solvent,potassium butyltrifluoroborate (117 mg; 1.2mmol), cesium carbonate (977 mg; 3mmol) and 1 ', 1' -bis (diphenylphosphino) -ferrocene palladium (II) dichloride dichloromethane complex (0.037 g; 0.05mmol) were added successively. The resulting mixture was heated for 72 hours (90 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and washed with H ₂And O washing. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Dichloromethane, dichloromethane: acetone 95: 5) purification yielded (2, 6-dichloro-4-cyclopropylphenyl) methanol (130 mg; 59%).

3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2-chloro-6-ethylphenyl) methanol was prepared as follows: to a solution of 2-chloro-6-ethylbenzaldehyde (1.8g, 10.67mmol) prepared according to US2007/197621 (see also WO2007/85556 and US6380387) in MeOH (50mL) at 0 deg.C was added NaBH in small portions in portions₄(1.21 g; 32.02 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:7₂O: Hexane 3:1) to give (2-chloro-6-ethylphenyl) methanol (1.2g, 66%).

3- (6- { [ 2-chloro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The desired [ 2-chloro-6- (propan-2-yl) phenyl group ]Methanol from NaBH₄Reduction of 2-chloro-6- (propan-2-yl) benzaldehyde in MeOH was obtained, prepared in a similar manner to 2-chloro-6-ethylbenzaldehyde.

3- {6- [ (2-chloro-6-cyclopropyl) phenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The required (2-chloro-6-cyclopropylphenyl) methanol is prepared from NaBH₄Reduction of 2-chloro-6-cyclopropylbenzaldehyde in MeOH, according toPrepared in a similar manner to 2-chloro-6-ethylbenzaldehyde.

3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The required [ 2-chloro-6- (2-methylpropyl) phenyl) methanol is prepared from NaBH₄Reduction of 2-chloro-6- (2-methylpropyl) benzaldehyde in MeOH was obtained, prepared in a similar manner to 2-chloro-6-ethylbenzaldehyde.

3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The required (2, 6-dichloro-3-methoxy-phenyl) methanol was obtained in the following manner: 2, 4-dichlorophenol (4.8 g; 29.45mmol), potassium carbonate (5.09 g; 36.8mmol) and methyl iodide in acetone (75mL) were heated at reflux for 3.5 hours. After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up in Et ₂O and H₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give 2, 4-dichloro-1-methoxybenzene (4.88 g; 93%). To a solution of 2,2,6, 6-tetramethylpiperidine (3.73 mL; 9.32mmol) in THF (50mL) at-78 deg.C was added n-butyllithium (5.61 mL; 2.50 mol/l; 14 mmol). The reaction mixture was stirred for 90 minutes, bringing the temperature to 0 ℃. Subsequently, a solution of 2, 4-dichloro-1-methoxybenzene (1.5 g; 8.47mmol) in THF (5mL) was added at-78 ℃. The resulting mixture was stirred for 2.5 hours. Subsequently, a solution of N, N-dimethylformamide (0.99 mL; 12.71mmol) was added dropwise and the resulting reaction mixture was stirred for 30 minutes. Adding saturated NaH at-50 deg.C₄The reaction was stopped with an aqueous solution of Cl. Et used for the resulting mixture₂And (4) extracting. The combined organic layers were dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The crude 2, 6-dichloro-3-methoxybenzaldehyde was dissolved in MeOH (50mL) and NaBH was added in small portions at 0 deg.C₄(0.96 g; 25.4 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et ₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂1: 1) purification to give the product: (2, 6-dichloro-3-methoxyphenyl) methanol (1.35; 77%).

3- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The desired [ 2-chloro-6- (trifluoro-methoxy) phenyl group]Methanol was sequentially treated with LiTMP/N, N-dimethylformamide followed by NaBH₄the/MeOH was obtained from 1-chloro-3- (trifluoromethoxy) benzene in 71% overall yield (analogous to (2, 6-dichloro-3-methoxyphenyl) methanol)).

3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester. The desired [ 2-fluoro-6- (propan-2-yl) -phenyl ] methanol was obtained in a similar sequence to that described for compound 273.

Tert-butyl 3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate. The desired (2-cyclopropyl-6-fluorophenyl) -methanol was obtained as described for compound 273.

Tert-butyl 3- {6- [ (2-ethyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate. The desired (2-ethyl-6-fluorophenyl) -methanol was obtained in analogy to the sequence described for compound 273.

3- (6- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (4-chloro-2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [1- (2, 6-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (2, 6-diethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired (2, 6-diethylphenyl) methaneThe alcohol was prepared as follows: (E) -butyl [ (2, 6-difluorophenyl) methylidene prepared according to US2007/197621 (see also WO2007/85556 and US6380387) to cooled (0 ℃) in THF (35mL)]To a solution of amine (1.97 g; 9.99mmol) was added ethyl magnesium bromide (3M, 7.32 mL; 21.97mmol) dropwise. Subsequently, the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 3mLH₂O, and the resulting mixture was washed with EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: Hexane 1:7) to give (E) -butyl [ (2, 6-diethylphenyl) -methylidene]Amine (1.18 g; 54%). The product (1.70 g; 7.82mmol) was dissolved in 20mLH ₂O and sulfuric acid (5 mL; 93.90mmol) and heated at reflux for 2 hours. After cooling to room temperature, the resulting mixture was washed with EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:7₂O: Hexane 1:7) to give (2, 6-diethylbenzaldehyde (1.27g, 95%).

The product was washed with NaBH in MeOH (50mL) at 0 deg.C₄(0.71 g; 18.8 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂1: 1O hexane) to give (2, 6-diethylphenyl) -methanol (0.68 g; 55%).

Tert-butyl 3- (6- { [2- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

3- (6- { [ 2-Ethyl-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester. The desired (2-ethyl-6- (trifluorophenyl) -methanol was obtained as described for compound 273 (starting from 2-fluoro-6- (trifluoromethyl) benzaldehyde).

3- (6- { [ 2-chloro-6- (difluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester. The desired (2-chloro-6-difluoromethoxy-phenyl) methanol was prepared as follows: to 2-chloro-6-hydroxy-benzaldehyde (1.00 g; 6.39mmol) and KOH (7.17 g; 127.7mmol) in CH at-15 deg.C₃To a solution of CN (20mL) and water (20mL) was added bromodifluoromethyl diethyl phosphate (1.25 mL; 7.03 mmol). After 30 minutes the mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. Then treated with 1MHCl aqueous solution and Et₂And (4) extracting. The combined organic layers were dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O/Hexane 1:3) to give 2-chloro-6-difluoromethoxy-benzaldehyde (0.68 g).

To a solution of 2-chloro-6-difluoromethoxy-benzaldehyde (0.65 g; 3.15mmol) in MeOH (10mL) at-15 deg.C was added NaBH₄(357.13 mg; 9.44 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 30 minutes. Subsequently, water (5mL) was added and the volatiles were removed in vacuo. The residue is taken up in Et₂O and 5% NaHCO₃The aqueous solution was partitioned. The layers were separated and the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give (2-chloro-6-difluoromethoxy-phenyl) -methanol (0.52g) which was used as received.

Tert-butyl 3- {6- [ (2-fluoro-6-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Compound 29.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {6- [ (2, 6-dichloro-phenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -ylTert-butyl propionate (1.10g, 2.23mmol) was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at 50 ℃ overnight. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate collected by filtration and dried under reduced pressure overnight to give the product (1.0g, 89%).¹HNMR(400MHz,DMSO-d₆) ppm12.9(bs,1H),10.5(bs,1H),7.54-7.58(M,2H),7.44-7.50(M,1H),7.04-6.95(M,1H),6.56-6.62(M,2H),5.18(s,2H),4.48(bs,2H),3.42-3.56(M,2H),3.24-3.41(M,2H),2.96-3.18(M,2H),2.86(t, J =8.0Hz,2H),2.10-2.30(M,2H),1.80-1.91(M,2H), Rt1.57min (System B), [ M + H =8.0Hz, [ 2H ], [ 2.]⁺436.0

The following compounds were obtained in a similar manner:

compound 30.3- {6- [ (4-phenylpentyl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.46min (System B), [ M + H]⁺424.1

Compound 31.3- {6- [ (3-chlorophenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.20(bs,1H)11.30(bs,1H)7.37-7.51(m,4H),6.94-7.08(m,1H),6.50-6.58(m,2H),5.09(s,2H),4.46(s,2H),3.24-3.49(m,4H),2.97-3.13(m,2H),2.87(t,J=7.8Hz,2H),2.13-2.26(m,2H),1.79-1.89(m,2H)。

Compound 32.3- [6- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺374.2

Compound 33.3- [6- (Oxopropyl-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.13min (System B), [ M ]+H]⁺376.2

Compound 34.3- {6- [ (2, 5-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.40min (System B), [ M + H]⁺436.1

Compound 35.3- (6- { [3- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO/TFA-d₆) ppm10.0(bs,1H),7.69-7.78(M,2H),7.56-7.66(M,2H),7.00(d, J =8.4Hz,1H),6.49-6.58(M,2H),5.15(s,2H),4.50(bs,2H),3.45-3.60(M,2H),3.29-3.41(M,2H),2.95-3.18(M,2H),2.86(t, J =7.4Hz,2H),2.18-2.33(M,2H),1.85-1.94(M,2H), Rt1.38min (System B), [ M + H [ ], [ M + H ], [ 2H ], (M,2H) ], and (B)]⁺436.1

Compound 36.3- (6- { [2- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.37min (System B), [ M + H]⁺436.1

Compound 37.3- {6- [ (2, 3-dichlorophenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.40min (System B), [ M + H]⁺436.0

Compound 38.3- {6- [ (2-chloro-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO/TFA-d₆) ppm9.80(bs,1H),7.40-7.48(M,1H),7.34(d, J =8.9Hz,1H),7.20(t, J =.8.9Hz,1H),7.01(d, J =8 Hz,1H),6.52-6.58(M,2H),5.15(s,2H),4.51(bs,1H),3.35-3.63(M,4H),3.06-3.20(M,2H),2.84(t, J =7.5Hz,2H),2.18-2.28(M,2H),1.85-1.93(M,2H). rt1.31min (system B), [ M + H ] H]⁺420.1

Compound 39.3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -propionic acid hydrochloride.

Rt1.57min (System B), [ M + H]⁺368.1

Compound 40.3- {6- [ (2, 4-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺436.1

Compound 41.3- (6- { [ 2-chloro-6- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.37min (System B), [ M + H]⁺470.1

Compound 42.3- [6- (cyclohex-3-en-1-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.38min (System B), [ M + H]⁺372.2

Compound 43.3- {6- [ (3, 5-dichloropyridin-4-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.23min (System B), [ M + H]⁺437.0

Compound 44.3- {6- [ (2, 4-dichloropyridin-3-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.19min (System B), [ M + H]⁺437.0

Compound 45.3- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.64(bs,1H),10.09(bs,1H),7.78(s,2H),7.02(bs,1H),6.54-6.59(M,2H),5.13(s,2H),4.46(s,2H),3.21-3.50(M,4H),2.92-3.11(M,2H),2.80(t, J =8Hz,2H),2.04-2.15(M,2H),1.81-1.89(M,2H), Rt1.45min (System B), [ M + H ], (s,2H) ], 1.78 (s,2H),7.02(bs,1H), 2.4-6.59 (M,2H),5.13(s]⁺471.9

Compound 46.3- {6- [ (2, 6-dichloro-4-iodophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.82(bs,1H),10.18(bs,1H),7.98(s,2H),7.00(bs,1H),6.55-6.60(M,2H),5.12(s,2H),4.47(bs,2H),3.26-3.51(M,4H),3.10-3.19(M,2H),2.83(t, J =8Hz,2H),2.08-2.19(M,2H),1.82-1.90(M,2H), Rt1.47min (System B), [ M + H ]]⁺561.8。

Compound 47.3- {6- [ (2, 6-difluorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.28min (System B), [ M + H ]⁺404.0。

Compound 48.3- {6- [2- (2, 6-dichlorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs, H),10.70(B,1H),7.49(d, J =8.1Hz,2H),7.28-7.39(M,1H),6.88-7.08(M,1H),6.41-6.51(M,2H),4.41-4.49(M,2H),4.08-4.18(M,2H),3.25-3.48(M,6H),3.06(bs,2H),2.82-2.92(M,2H),2.1-2.3(M,2H)1.78-1.83(M,2H), Rt1.41min (System B), [ M + H ], [ M]⁺450.0

Compound 49.3- {6- [2- (2-fluorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.32min (System B), [ M + H]⁺400.0

Compound 50.3- {6- [ (2-chloro-5-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.40min (System B), [ M + H]⁺416.1

Compound 51.3- {6- [ (2-chloro-5-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs.,1H)10.55(bs,1H),7.43(d, J =2.2Hz,1H),7.40(d, J =8.2Hz,1H),7.24(dd, J =8.2 and 2.2Hz,1H)6.94-7.03(M,1H),6.51-6.61(M,2H),5.06(s,2H),4.47(bs.,2H),3.22-3.55(M,4H),2.95-3.15(M,2H),2.86(t, J =7.6Hz,2H),2.61(q, J =7.6Hz,2H),2.10-2.30(M,2H),1.79-1.91(M,2H),1.16(t, J =7.6Hz,3H) rt1.45min (system B), [ M + H ″,2H, or a combination thereof ]⁺430.1。

Compound 52.3- {6- [ (2-chloro-5-propylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.52min (System B), [ M + H]⁺444.1

Compound 53.3- {6- [3- (2-fluorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(600MHz,DMSO-d₆)ppm12.80(bs,1H),10.70(bs,1H),7.27-7.32(m,1H),7.20-7.27(m,1H),7.09-7.15(m,2H),6.88-6.98(m,1H),6.44(d,J=7.6Hz,1H),6.38(d,J=2.2Hz,1H),4.45(bs.,2H),3.91(t,J=6.2Hz,2H),3.19-3.52(m,H),3.01(m,2H),2.85(t,J=7.7Hz,2H),2.74(t,J=7.6Hz,2H),2.14-2.28(m,2H),1.91-1.99(m,2H),1.73-1.88(m,2H)。

Compound 54.3- {6- [3- (2-chlorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.44min (System B), [ M + H]⁺430.1

Compound 55.3- [6- (3-Phenylpropoxy)]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.45min (System B), [ M + H]⁺396.2

Compound 56.3- {6- [2- (2, 4-dichlorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.47min (System B), [ M + H]⁺450.0

Compound 57.3- {6- [2- (2-chlorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acidA hydrochloride salt.

Rt1.39min (System B), [ M + H]⁺416.0

Compound 58.3- (6- { [2, 6-dichloro-4- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride. Rt1.49min (System B), [ M + H]⁺504.0

Compound 59.3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.64(bs,1H),9.90(bs,1H),7.42(s,2H),7.01(bs,1H),6.56-6.61(M,2H),5.14(s,2H),4.49(brs,2H),3.31-3.53(M,4H),3.01-3.11(M,2H),2.81-2.87(M,2H),2.35(s,3H),2.09-2.19(M,2H),1.84-1.92(M,2H), Rt1.43min (System B), [ M + H ] Rt1.43min (System B)]⁺450.0

Compound 60.3- {6- [ (5-bromo-2-chlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.52min (System B), [ M + H]⁺480.0

Compound 61.3- {6- [ (2-chloro-6-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺416.1

Compound 62.3- (6- {3- [2- (trifluoromethyl) phenyl]Propoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride.

Rt1.48min (System B), [ M + H]⁺464.1

Compound 63.3- {6- [3- (2, 3-difluorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺432.1

Compound 64.3- {6- [3- (2-chloro-6-fluorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺432.1

Compound 65.3- {6- [3- (2, 6-dichlorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride

¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs.,1H),10.70(bs.,1H),7.46(d, J =8.3Hz,2H),7.27(dd, J =8.3 and 7.6Hz,1H),6.95(d, J =8.0Hz,1H),6.46(dd, J =8.0 and 2.0Hz,1H),6.40(d, J =2.0Hz,1H),4.47(bs.,2H),3.99(t, J =6.1Hz,2H),3.46(M,2H),3.29(M,2H),2.98-3.10(M,4H),2.87(t, J = 7Hz,2H),2.15-2.30(M,2H),1.90-1.99(M,2H),1.78-1.88(M,2H), 1.49min (rt + M,2H), 1H + M,2H)]⁺464.0。

Compound 66.3- {6- [3- (4-chlorophenyl) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.46min (System B), [ M + H]⁺430.1

Compound 67.3- {6- [ (2-chloro-5-phenylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.90min (System B), [ M + H]⁺478.0

Compound 68.3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.80(bs.,1H),10.30(bs.,1H),7.50(d,J=8.1Hz,1H),7.45(d,J=8.1Hz,1H)6.95-7.07(m,1H),6.58-6.62(m,2H),5.19(s,2H),4.48(bs,2H),3.20-3.52(m,4H),2.95-3.20(m,2H),2.85(t,J=7.7Hz,2H)2.75(q,J=7.6Hz,2H),2.10-2.28(m,2H),1.80-1.90(m,2H),1.18(t,J=7.6Hz,3H)。

Compound 69.3- {6- [ (4-butyl-2, 6-dichlorophenyl)) Methoxy radical]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.55(bs,1H),10.27(bs,1H),7.37(s,2H),6.95(bs,1H),6.51-6.58(M,2H),5.09(s,2H),4.44(bs,2H),3.22-3.50(M,4H),2.94-3.18(M,2H),2.81(t, J =8 and 2Hz,2H),2.57(t, J =8Hz,2H),2.07-2.19(M,2H),1.78-1.86(M,2H),1.48-1.56(M,2H),1.21-1.30(M,2H),0.84-0.89(t, J =8Hz,3H), 1.92min (system B), [ M + H ], [ rt + H ], [ M, 1H ], (M,2H) ] ]⁺492.0

Compound 70.3- {6- [ (2, 6-dichloro-4-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.55(bs,1H),10.09(bs,1H),7.27(s,2H),7.00(brs,1H),6.55-6.60(M,2H),5.11(s,2H),4.49(bs,2H),3.26-3.52(M,4H),2.97-3.12(M,2H),2.84(t, J =8Hz,2H),2.08-2.22(M,2H),1.97-2.02(M,1H),1.83-1.91(M,2H),0.99-1.06(M,2H),0.78-0.82(M,2H), Rt1.65min (System B), [ M + H]⁺476.0。

Compound 71.3- {6- [ (2-chloro-5-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.68min (System B), [ M + H]⁺442.1

Compound 72.3- [6- ({ 2-chloro-5- [ 2-phenylcyclopropyl)]Phenyl } methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.

Rt1.72min (System B), [ M + H]⁺518.0

Compound 73.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) Ppm12.80(bs,1H),10.30(bs,1H),7.35-7.37(M,2H),7.26-7.30(M,1H),6.95-7.40(M,1H),6.56-6.63(M,2H),5.10(s,2H),4.49(bs,2H)3.24-3.54(M,4H),2.96-3.14(M,2H),2.87(t, J =8.2Hz,2H),2.71(q, J =7,6Hz,2H),2.18-2.33(M,2H),1.80-1.90(M,2H),1.17(t, J =7.6Hz,3H), rt1.40min (system B), [ M + H ], 10.1H, 1H, 2H, 2.1, 2H, 2.1.17 (t, J =7.6Hz,3H) ]⁺430.0

Compound 74.3- (6- { [ 2-chloro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),10.90(bs,1H),7.33-7.41(M,3H),6.94-7.04(M,1H),6.56-6.63(M,2H),5.15(s,2H),4.49(bs,2H),3.24-3.54(M,4H),3.14-3.22(M,1H),2.95-3.14(M,2H),2.88(t, J =8.0Hz,2H),2.14-2.33(M,2H),1.80-1.90(M,2H),1.19(d, J =6.7Hz,6H). Rt1.40min (System B), [ M + H]⁺430.0。

Compound 75.3- {6- [ (2-chloro-6-cyclopropyl) phenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.10(bs,1H),7.29-7.37(M,2H),6.94-7.09(M,2H),6.56-6.62(M,2H),5.26(s,2H),4.49(bs,2H),3.42-3.56(M,2H),3.24-3.41(M,2H),2.96-3.18(M,2H),2.84(t, J =7.7Hz,2H), 2.00-2.23(M,3H),1.80-1.91(M,2H),0.88-0.96(M,2H),0.73-0.65(M,2H), Rt1.43min (System B), [ M + H ]]⁺442.0

Compound 76.3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.35min (System B), [ M + H]⁺465.9

Compound No. 77.3- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride. ¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H)10.50(bs,1H)7.58-7.65(M,2H),7.46-7.51(M,1H),6.95-7.03(M,1H),6.56-6.62(M,2H),5.10(s,2H),4.49(bs,2H),3.42-3.56(M,2H),3.24-3.41(M,2H),2.96-3.18(M,2H),2.84(t, J =7.7Hz,2H),2.13-2.28(M,2H),1.83-1.91(M,2H). Rt1.41min (System B), [ M + H = 7Hz,2H]⁺486.0

Compound 78.3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.9(bs,1H),10.1(bs,1H),7.31-7.42(m,2H),7.20-7.24(m,1H),6.96-7.03(m,1H),6.56-6.62(m,2H),5.08(s,2H),4.49(bs,2H),3.45-3.56(m,2H),3.24-3.41(m,2H),2.96-3.18(m,2H),2.84(t,J=7.7Hz，2H),2.58(d,J=7.4Hz,2H),2.00-2.23(m,3H),1.80-1.91(m,2H),0.85(d,J=6.8Hz,6H)。

Compound 79.3- {6- [ (5, 7-dichloro-2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid. Mixing 3- {6- [ (5, 7-dichloro-2, 3-dihydro-benzofuran-3, 4' -piperidine)]A mixture of-1' -yl } propionate (0.27 g; 0.52mmol), aqueous 2M NaOH solution (5 mL; 10mmol) and ethanol (40mL) was stirred at 50 ℃ for 3 hours and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (10 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (209 mg; 81.8%). ¹HNMR(400MHz,CDCl₃-d) ppm7.25(s,1H), 7.19(s,1H),7.06(d, J =8.2Hz,1H),6.53(dd, J =8.2 and 2.1Hz,1H),6.47(d, J =2.1Hz,1H),5.70(d, J =5.1Hz,1H),4.40(s,2H),3.14-3.28(M,3H),2.84-2.98(M,3H),2.60(t, J =5.9Hz,2H),2.27-2.46(M,4H),2.09(t, J =11.4Hz,2H),1.89(bd, J =13.8Hz,2H), 1.47min (system B), [ M + H ], [ M + H]⁺462.0

The following compounds were obtained in a similar manner:

compound 80.3- {6- [ (5, 7-difluoro-2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.39min (System B), [ M + H]⁺430.1

Compound 81.3- {6- [ (1R) - (2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.34min (System B), [ M + H]⁺394.1

Compound 82.3- {6- [ (1S) - (2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,CDCl₃-d) ppm7.42(d, J =7.3Hz,1H),7.21-7.34(M,3H),7.05(d, J =8.2Hz,1H),6.57(dd, J =8.2 and 2.0Hz,1H),6.51(d, J =2.0Hz,1H),5.71(dd, J =6.5 and 4.4Hz,1H),4.40(s,2H),3.08-3.19(M,3H),2.87-2.97(M,1H),2.84(t, J =6.1Hz,2H),2.50-2.62(M,3H),2.30-2.46(M,2H),2.15-2.25(M,1H),2.00-2.11(M,2H),1.84-1.93(M, 34h), 2.00-2.11(M,2H),1.84-1.93(M, 34min) [ system B + H ], (r)]⁺394.1

Compound 83.3- (6- { [ (2E) -3- (4-chlorophenyl) prop-2-en-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.48min (System B), [ M + H]⁺428.0

Compound 84.3- {6- [ (3-phenyl) prop-2-yn-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.37min (System B), [ M + H]⁺392.1

Compound 85.3- [6- (2, 3-dihydro-1-benzofuran-3-yloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.

Rt1.95min (System B), [ M + H [ ]]⁺396.1

Compound 86.3- (6- { [ (2E) -3- (2, 6-dichlorophenyl) prop-2-en-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.48-7.52(m,2H),7.32(t, J =8.1Hz,1H),7.10(d, J =8.1Hz,1H),6.72-6.60(m,1H),6.53-6.46(m,2H),6.31-6.39(m,1H),4.75(dd, J =5.1 and 2.0Hz,2H),4.37(s,2H),2.87-2.95(M,2H),2.64-2.71(M,2H), 2.40-2.46(M,2H),2.12-2.22(M,2H),1.78-1.88(M,2H),1.59-1.67(M,2H), Rt1.51min (System B), [ M + H [ ]]⁺462.1

Compound 87.3- (6- { [ (2E) -3-phenylpropan-2-en-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.

Rt1.37min (System B), [ M + H]⁺394.1

Compound 88.3- {6- [ (7-chloro-2, 3-dihydro-1H-inden-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid.

Rt1.37min (System B), [ M + H]⁺428.0

Compound 89.3- (6- { [ (3- (4-chlorophenyl) prop-2-yn-1-yl)]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.

Rt1.43min (System B), [ M + H]⁺426.0

Compound 90.3- (6- { [ (2E) -3- (2-fluorophenyl) prop-2-en-1-yl]Oxygen } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.

Rt1.41min (System B), [ M + H]⁺412.1

Compound 91.3- {6- [ (4-Bromophenylthio-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.57min (System B), [ M + H]⁺452.0

Compound 92.3- {6- [ (4-Butylphenylthio-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.67min (System B), [ M + H [ ]]⁺430.1

Compound 93.3- (6- { [4- (2-fluorophenyl) thiophen-2-yl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl }Propionic acid.

Rt1.68min (System B), [ M + H]⁺468.0

Compound 94.3- {6- [ (4-Phenylthiophen-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.99min (System B), [ M + H]⁺450.0

Compound 95.3- {6- [ (4-bromo-3-methylphenylsulfanyl-2 yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) Ppm12.60(bs.,1H),7.68(s,1H),7.08-7.13(M,1H),6.45-6.51(M,2H),5.18(s,2H),4.36(s,2H),2.81-2.89(M,2H),2.61(t, J =7.2Hz,2H),2.39(t, J =7.2Hz,2H),2.17(s,3H),2.02-2.12(M,2H),1.74-1.86(M,2H),1.56-1.64(M,2H), rt1.72min (system B), [ M + H ] l ]⁺467.9

Compound 96.3- {6- [ (4-Cyclopropylmethylphenylsulfanyl-2-yl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.06-7.10(M,2H),6.91(d, J =1.2Hz,1H),6.44-6.49(M,2H),5.12(s,2H),4.35(s,2H),2.89-2.83(M,2H),2.63(t, J =7.0Hz,2H),2.40(t, J =7.0Hz,2H),2.04-2.14(M,2H),1.90(dt, J =8.4,5.0Hz,1H),1.74-1.85(M,2H),1.57-1.64(M,2H),0.82-0.89(M,2H),0.56-0.61(M,2H). rt1.69min (system B), [ M + H ], (M,2H) ]]⁺414.1。

Compound 97.3- {6- [ (3-methyl-4-phenylthiophen-2-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.69min (System B), [ M + H]⁺464.0

Compound 98.3- {6- [ (4-butyl-3-methylphenylsulfanyl-2 yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.

Rt1.82min (System B), [ M + H]⁺444.1

Compound 252.3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.37-7.46(M,1H),7.23(d, J =7.8Hz,1H),7.03-7.14(M,2H),6.47-6.54(M,2H),5.05(s,2H),4.37(s,2H),3.12-3.22(d,1H),2.82-2.91(M,2H),2.63(t, J =7.1Hz,2H),2.40(t, J =7.1Hz,2H),2.10(t, J =11.1Hz,1H),1.76-1.88(M,2H),1.62(d, J =13.1Hz,2H),1.20(d, J =6.8Hz,6H), 1.45min (system B), [ M + H ], [ rt =7.1H ], (1H), 2.1.4 (d, J = 6H), and the like ]⁺429.3

Compound 253.3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.29-7.37(M,1H),7.02-7.14(M,2H),6.85(d, J =7.8Hz,1H),6.50-6.56(M,2H),5.16(s,2H),4.37(s,2H),2.86-2.92(M,2H),2.64(t, J =7.2Hz,2H),2.41(t, J =7.2Hz,2H),2.00-2.18(M,3H),1.77-1.88(M,2H),1.62(d, J =12.6Hz,2H),0.89-0.98(M,2H),0.66-0.72(M,2H), rt1.40min (system B), [ M + H ], [ M,2H ], (system B) ]]⁺426.2

Compound 254.3- {6- [ (2-Ethyl-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.33-7.42(M,1H),7.04-7.17(M,3H),6.48-6.56(M,2H),5.02(s,2H),4.37(s,2H),2.87-2.97(M,2H),2.62-2.74(M,5H),2.45(t, J =7.2Hz,2H),2.11-2.23(M,2H),1.80-1.92(M,2H),1.64(d, J =12.4Hz,2H),1.16(t, J =7.5Hz,3H), rt1.41min (system B), [ M + H ], [ M =12.4Hz,2H ], and combinations thereof]⁺414.3

Compound 255.3- (6- { [ 2-fluoro-6- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.63-7.75(M,3H),7.12(d, J =8.0Hz,1H),6.47-6.53(M,2H),5.09(s,2H),4.37(s,2H),2.86(d, J =11.7Hz,2H),2.62(t, J =7.2Hz,2H),2.40(t, J =7.2Hz,2H),2.04-2.13(M,2H),1.77-1.86(M,2H),1.62(d, J =13.1Hz,2H) rt1.50min (system B), [ M + H ], [ 1.75 (M,2H) } ]⁺454.2

Compound 256.3- {6- [ (4-chloro-2, 6-difluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propaneAnd (4) acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.43-7.49(M,2H),7.07-7.12(M,1H),6.47(s,2H),5.01(s,2H),4.34(s,2H),2.73-2.79(M,2H),2.40-2.47(M,2H),1.85-1.98(M,4H),1.74-1.84(M,2H),1.51-1.58(M,2H), Rt1.36min (System B), [ M + H ], [ 1.]⁺439.2

Compound 257.3- {6- [1- (2, 6-dichlorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) 7.45(d, J =8.1Hz,2H),7.28-7.34(M,1H),7.02(d, J =8.1Hz,1H),6.29(dd, J =8.1,2.1Hz,1H),6.21(d, J =2.1Hz,1H),5.93(q, J =6.6Hz,1H),4.30(s,2H),2.81(d, J =11.9Hz,2H),2.57(t, J =7.2Hz,2H),2.37(t, J =7.2Hz,2H),2.02(t, J =11.2Hz,2H),1.69-1.78(M,2H),1.67(d, J =6.6Hz,3H),1.55(d, J =11.9, 2H), 1.41min (M,2H), 1.55 (rt, 11.41h) (+ M, 41h) ("B + H")]⁺450.1

Compound 258.3- {6- [ (2, 6-diethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) 7.22-7.27(M,1H),7.07-7.15(M,3H),6.49-6.55(M,2H),4.96(s,2H),4.37(s,2H),2.85(d, J =11.7Hz,2H),2.56-2.69(M,6H),2.36(t, J =7.0Hz,2H),2.01-2.10(M,2H),1.77-1.86(M,2H),1.62(d, J =12.9Hz,2H),1.14(t, J =7.5Hz,6H), rt1.47min (system B), [ M + H ], [ M, H ], (M, H) } ]⁺424.2

Compound 259.3- (6- { [2- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) Ppm7.30-7.40(M,3H),7.15-7.22(M,1H),7.08(d, J =8.0Hz,1H),6.47-6.54(M,2H),5.04(s,2H),4.39(s,2H),3.10-3.19(M,1H),3.02(d, J =11.9Hz,2H),2.81(t, J =7.0Hz,2H),2.54(t, J =7.0Hz,2H),2.32-2.43(M,2H),1.89-2.00(M,2H),1.68(d, J =13.3Hz,2H),1.16-1.22(M,6H). rt1.45min (system B), [ M + H ], (1H) ]]⁺410.7

Compound 260.3- (6- { [ 2-Ethyl-6- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆).ppm7.61-7.67(m,2H),7.53-7.60(m,1H),7.12(d,J=7.8Hz,1H),6.48-6.55(M,2H),5.04(s,2H),4.35(s,2H),2.79(d, J =11.2Hz,2H),2.73(q, J =7.5Hz,2H),2.45-2.5(M,2H),2.05(t, J =7.6Hz,2H),1.87-1.97(M,2H),1.77-1.86(M,2H),1.58(d, J =12.1Hz,2H),1.17-1.23(M,3H), 1.47min (system B), [ M + H rt, 3H) ], 1.47min (system B), [ M + H ], and]⁺464.2

compound 261.3- (6- { [ 2-chloro-6- (difluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆)ppm7.43-7.56(m,2H),7.27-7.32(m,1H),7.06-7.13(m,1H),6.49-6.57(m,2H),5.06(s,2H),4.40(s,2H),3.04(d,J=11.7Hz,2H),2.83(t,J=7.1Hz,2H),2.56(t,J=7.1Hz,2H),2.40(m,3H),1.89-2.02(m,2H),1.69(d,J=13.5Hz,2H)。

Compound 262.3- {6- [ (2-fluoro-6-methoxyphenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.37-7.47(M,1H),7.09(d, J =7.9Hz,1H),6.93(d, J =8.4Hz,1H),6.85(t, J =8.8Hz,1H),6.42-6.52(M,2H),4.95(s,2H),4.35(s,2H),3.83(s,3H),2.86(d, J =11.7Hz,2H),2.61(t, J =7.1Hz, 2H),2.38(t, J =7.1Hz, 2H),2.08(t, J =11.2Hz,2H)1.81(dt, J =12.8,3.5Hz,2H),1.61(d, J =12.8Hz,2H) 1.27min (system B), [ M + H ], [ rt + H ] (system B), [ rt + 1H ], [ 2H ], (system H) ] ]⁺416.7

3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methyl-propionic acid tert-butyl ester. To 2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a solution of-6-ol (565 mg; 2.76mmol) in N, N-dimethylformamide (5.00mL) were added tert-butyl methacrylate (0.9 mL; 5.52mmol) and DBU (1.24 mL; 8.28 mmol). The resulting mixture was heated in a sealed flask at 140 ℃ overnight. After cooling to room temperature the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) purification to give the product(0.45g，47%)。¹HNMR(400MHz,CDCl₃-d) ppm6.91(d, J =8.0Hz,1H),6.29-6.36(M,2H)5.80(bs,1H),4.34(s,2H),2.88-2.96(M,1H),2.75-2.84(M,1H),2.51-2.66(M,2H),2.26-2.35(M,1H),1.96-2.10(M,2H),1.83-1.93(M,2H),1.65-1.69(M,2H),1.48(s,9H),1.11(d, J =8.5Hz,3H) rt1.13min (system B), [ M + H ] M]⁺348.1

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester. To a solution of (2, 6-dichloro-3-ethylphenyl) methanol (324 mg; 1.58mmol) and tert-butyl 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionate (0.44g, 1.27mmol) in dichloromethane (20mL) was added triphenylphosphine (415 mg; 1.58mmol) and after 30 minutes DIAD (0.31 mL; 1.58mmol) was added. Subsequently, the resulting mixture was stirred at room temperature overnight and concentrated in vacuo.

Subsequently, the reaction mixture was washed with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) purification gave the product (670mg, 98%). Rt1.62min (System B), [ M + H]⁺534.0。

The following compounds were obtained in a similar manner:

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

Tert-butyl 2-methyl-3- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) -2-methylpropionic acid tert-butyl ester.

3- (6- { [ 2-chloro-6- (2-trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- {6- [ (2-Ethyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester. The desired [ 2-ethyl-6-fluorophenyl ] -methanol was obtained in analogy to the sequence described for compound 273.

3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) -2-methylpropionic acid tert-butyl ester.

2-methyl-3- (6- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) -2-methylpropionic acid tert-butyl ester.

Compound 99.3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride. 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropionic acid tert-butyl ester (0.62g, 1.16mmol) was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.44g, 66%).¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.00(bs,1H),7,50(d, J =8.4Hz,1H),7.44(d, J =8.4Hz,1H), 6.96-7.04(M,1H),6.56-6.62(M,2H),5.19(s,2H),4.48(bs,2H),3.30-3.55(M,4H),2.94-3.18(M,3H),2.75(q, J =7.4Hz, 2H),2.17-2.37(M,2H),1.80-1.91(M,2H),1.24(d, J =7.0Hz,3H),1.18(t, J =7.4Hz, 3H), 1.60min (system B), [ M + H ], [ rt =7.0Hz,3H) ], 1.60min (system B), [ M + H ], [ c ], [ 2H ], (M,2H]⁺478.0

The following compounds were obtained in a similar manner:

compound 100.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),9.80(bs,1H),7.54-7.58(M,2H)7.46(dd, J =8.1 and 6.2Hz,1H)7.10(bs,1H),6.58-6.62(M,2H),5.17(s,2H),4.48(bs,2H),3.44-3.53(M,4H)2.95-3.20(M,3H),2.10-2.29(M,2H),1.80-1.91(M,2H),1.24(d, J =7.8Hz,3H) rt1.42min (system B), [ M + H [, ], [ M, H ], [ 2H ], (M,2H) ], and ]⁺450.0

Compound 101.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.0(bs,1H),7.32-7.39(M,2H),7.25-7.29(M,1H),6.96-7.04(M,1H),6.56-6.62(M,2H),5.10(s,2H),4.48(bs, 2H),3.30-3.54(M,4H),2.95-3.17(M,3H),2.71(q, J =7.4Hz, 2H),2.17-2.37(M,2H),1.80-1.91(M,2H),1.24(d, J =7.0Hz,3H),1.16(t, J =7.4Hz, 3H), rt1.49min (system B), [ M + H ], 10.0(bs,1H),7.32-7.39(M,2H), 7.30-3.7.54 (M,4H), 2H),2.1]⁺444.0。

Compound 102.2-methyl-3- {6- [ (2,4, 6-trichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.10(bs,1H),7.80(s,2H),6.96-7.06(M,1H),6.56-6.62(M,2H),5.14(s,2H),4.48(bs,2H),2.98-3.55(M,7H),2.20-2.37(M,2H),1.80-1.91(M,2H),1.24(d, J =7Hz,3H), Rt1.55min (System B), [ M + H =7Hz,3H ], [ Rt1.55min (System B), [ M + H ], []⁺485.9

Compound 103.3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.

Rt1.50min (System B), [ M + H]⁺463.9

Compound 104.3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.10(bs,1H),7.52(d, J =9,1Hz,1,1H),7.25(d, J =9,1Hz, 1H),6.95-7.09(M,1H),6.56-6.62(M,2H),5.17(s,2H),4.48(bs,2H),3.90(s,3H),3.35-3.54(M,3H),2.94-3.19(M,4H),2.14-2.32(M,2H),1.80-1.90(M,2H),1.24(t, J =7.0Hz,3H), rt1.41min (system B), [ M + H ] rt1.41min (system B) ]⁺480.0。

Compound 105.3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.90(bs,1H),9.80(bs,1H),7.41(s,2H),6.95-7.05(M,1H),6.56-6.62(M,2H),5.12(s,2H),4.48(bs,2H),3.35-3.54(M,3H),2.98-3.19(M,4H),2.62(t, J =7.7Hz,2H),2.12-2.31(M,2H),1.80-1.90(M,2H),1.50-1.62(M,2H),1.20-1.35(M,5H),0.90(t, J =7.6Hz, 3H) Rt1.76min (System B), [ M + H =7.6Hz, 3H) ("Rt1.76min (System B)," [ M + H "")]⁺506.0

Compound 106.3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),9.90(bs,1H),7.31-7.39(M,2H),7.25-7.20(M,1H)6.97-7.06(M,1H),6.56-6.62(M,2H),5.08(s,2H),4.47(bs,2H),3.24-3.58(M,3H),2.88-3.18(M,4H),2.58(d, J =7.6Hz,2H),2.11-2.38(M,2H),1.80-1.91(M,3H),1.25(d, J =7.6Hz, 3H),0.85(d, J =7.6Hz, 6H), rt1.60min (system B), [ M + H ], 9.90(bs,1H),7.31-7.39(M,2H), 7.25-3H), 6.6H, 3H, rt1.60min (system B), [ M + H ]]⁺472.1

Compound 107.3- (6- { [ 2-chloro-6- (2-trifluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.9(bs,1H),9.8(bs,1H),7.58-7.65(m,2H),7.47-7.52(m,1H),7.06-6.97(m,1H),6.56-6.62(m,2H),5.10(s,2H),4.47(bs,2H),3.28-3.54(m,4H),2.95-3.18(m,3H),2.11-2.25(m,2H),1.80-1.91(m,2H),1.22(d,J=7.6Hz，3H)。

Compound 108.3- {6- [ (2-chloro-5-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.

Rt1.54min (System B), [ M + H ]⁺444.1。

Compound 263.3- {6- [ (2-Ethyl-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride. Desired [ 2-ethyl-6-fluorophenyl group]Methanol was obtained in a similar order as described for compound 273.¹HNMR(400MHz,DMSO-d₆)ppm12.88(br.s.,1H),10.29(br.s.,1H),7.34-7.42(m,1H),6.98-7.16(m,3H),6.53-6.60(m,2H),5.04(s,2H),4.47(br.s.,2H),3.29-3.54(m,4H),2.95-3.22(m,3H),2.70(q,J=7.5Hz,2H),2.24-2.38(m,2H),1.80-1.89(M,2H),1.26(d, J =7.1Hz,3H),1.17(t, J =7.5Hz,3H) rt1.44min (system B), [ M + H ]]⁺428.8。

Compound 264.3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.92(br.s.,1H),10.07(br.s.,1H),7.30-7.37(M,1H),6.95-7.09(M,2H),6.86(d, J =7.8Hz,1H), 6.55-6.62(M,2H),5.17(s,2H),4.47(br.s.,2H),3.39-3.49(M,4H),2.98-3.18(M,3H),2.18-2.34(M,2H),2.00-2.09(M,1H),1.78-1.88(M,2H),1.25(d, J =7.1Hz,3H),0.90-0.98(M,2H),0.64-0.73(M,2H), 1.42min (rt + M + H system [ system H ], (rt 1H) ] [ system H ], (rt + M,2H) ]]⁺440.7。

Compound 265.3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.91(br.s.,1H),10.03(br.s.,1H),7.38-7.46(M,1H),7.24(d, J =7.8Hz,1H),6.97-7.10(M,2H),6.53-6.60(M,2H),5.06(s,2H),4.47(br.s.,2H),3.31-3.48(M,4H),2.96-3.23(M,4H),2.18-2.35(M,2H),1.80-1.91(M,2H),1.24(d, J =7.1Hz,3H),1.20(d, J =6.8Hz,6H), rt1.49min (system B), [ M + H ], [ M + H ]⁺442.7。

Compound 266.2-methyl-3- (6- { [2- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.91(br.s.,1H),10.23(br.s.,1H),7.80(d, J =7.8Hz,1H),7.69-7.76(M,2H),7.56-7.62(M,1H),7.00(br.s.,1H),6.54(d, J =8.1Hz,1H),6.49(d, J =2.0Hz,1H),5.19(s,2H),4.47(br.s.,2H),3.31-3.54(M,4H),2.96-3.17(M,3H),2.21-2.40(M,2H),1.77-1.89(M,2H),1.25(d, J =7.1Hz,3H), 1.43min (system B), [ rt + M ], [ H ], [ 1.43min (system B ], [ 1H ], []⁺450.6。

Compound 109.3- {6- [ (2-chloro-6-ring)Propylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid 2,2, 2-trifluoroacetic acid. 3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } -2-methylpropionate (350 mg; 0.68mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL; 25.9mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.15g, 35.8%).¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),9.50(bs,1H),7.29-7.37(M,2H),7.01-7.20(M,2H),6.56-6.62(M,2H),5.26(s,2H),4.47(bs,2H),3.24-3.54(M,3H),2.88-3.18(M,4H),2.01-2.18(M,3H),1.80-1.91(M,2H),1.20(d, J =7.6Hz,3H),0.88-0.96(M,2H),0.73-0.65(M,2H). Rt1.50min (System B), [ M + H = 7.3H ]⁺456.0。

2- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid tert-butyl ester. To 2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol (1.05 g; 5.12mmol) in CH₃To a solution of CN (15mL) and N-ethyldiisopropylamine (2.19mL) was added tert-butyl bromoacetate (0.79 mL; 5.37 mmol). The resulting mixture was heated at 65 ℃ overnight.

After cooling to room temperature, the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O) purification gave the product (1.45g, 88.7%).¹HNMR(400MHz,CDCl₃-d) ppm6.94(d, J =7.9Hz,1H),6.34(dd,7.9 and 2.2Hz,1H),6.31(d, J =2.2Hz,1H),5.05-5.28(M,1H),4.36(s,2H),3.17(s,2H),2.92-3.01(M,2H),2.22-2.32(M,2H),1.97-2.07(M,2H),1.62-1.74(M,2H),1.48(s,9H), rt0.95min (system B), [ M + H ] r]⁺320.1。

2- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid tert-butyl ester. To (2,4, 6-trichloro-phenyl) methanol (248 mg; 1.17mmol) and 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } acetate (300mg, 0.94mmol) in dichloromethane (20mL) triphenylphosphine (308 mg; 1.17mmol) was added and after 30 min DIAD (0.23 mL; 1.17mmol) was added. Subsequently, the resulting mixture was stirred at room temperature overnight and concentrated in vacuo. Subsequently, the reaction mixture was washed with 5% NaHCO ₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) purification gave the product (410mg, 85%). Rt1.63min (System B), [ M + H]⁺514.0。

The following compounds were obtained in a similar manner:

tert-butyl 2- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

Tert-butyl 2- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetate.

Tert-butyl 2- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Tert-butyl 2- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

Compound 110.2- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride. 2- {6- [ (2,4, 6-trichloro-phenyl) methoxy-]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) acetate (0.41g, 0.8mmol) in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.29g, 70%).¹HNMR(400MHz,DMSO-d₆) ppm13.90(bs,1H),10.30(bs,1H),7.79(s,2H),7.03-7.19(M,1H),6.56-6.62(M,2H),5.15(s,2H),4.47(bs,2H)4.17(bs,2H),3.46-3.56(M,2H),3.15-3.28(M,2H),2.13-2.28(M,2H),1.83-1.91(M,2H), Rt1.73min (System B), [ M + H ] RtH]⁺457.9

The following compounds were obtained in a similar manner:

compound 111.2- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm13.9(bs,1H)10.90(bs,1H)7.34-7.39(M,2H),7.25-7.31(M,1H),7.17-7.20(M,1H),6.56-6.62(M,2H),5.10(s,2H),4.47(bs,2H),4.17(bs,2H),3.46-3.58(M,2H),3.15-3.28(M,2H),2.71(q, J =7.4Hz,2H),2.13-2.28(M,2H),1.83-1.91(M,2H),1.16(t, J =7.4Hz,3H). Rt1.65min (System B), [ M + H [ ], [ M,2H ] ], and ]⁺416.0

Compound 112.2- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm13.80(bs,1H),10.40(bs,1H),7.28-7.38(M,2H),7.08-7.23(M,1H)7.04(dd, J =7.0 and 2.0Hz, 1H),6.56-6.62(M,2H),5.27(s,2H),4.47(bs,2H)4.13(bs,2H),3.06-3.56(M,4H),2.13-2.28(M,2H),2.00-2.10(M,1H),1.83-1.91(M,2H),0.95-0.87(M,2H),0.73-0.65(M,2H), Rt1.67min (System B), [ M + H ] 0]⁺428.0。

Compound 113.2- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.

Rt1.99min (System B), [ M + H]⁺478.0

Compound 114.2- {6- [ (2-chloro-5-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.

Rt1.71min (System B), [ M + H]⁺416.1

Compound 115.2- (6- { [ 2-chloro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm14.0(bs,1H),10.30(bs,1H),7.31-7.42(M,3H),7.18-7.05(M,1H),6.56-6.62(M,2H),5.15(s,2H),4.45(bs,2H),4.15(bs,2H),3.45-3.56(M,2H),3.12-3.27(M,3H),2.15-2.27(M,2H),1.80-1.91(M,2H),1.20(d, J =7.2Hz,6H) Rt1.72min (System B), [ M + H ], [ 7.2Hz,6H ] Rt1.72min (System B) ]⁺430.1

Compound 116.2- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm13.9(bs,1H),10.40(bs,1H),7.50(d, J =8.4Hz,1H),7.45(d, J =8.4Hz,1H),7.19-7.03(M,1H),6.56-6.62(M,2H),5.20(s,2H),4.47(bs,2H),4.17(bs,2H),3.08-3.56(M,4H),2,75(q, J =7.2Hz,2H),2.13-2.28(M,2H),1.83-1.91(M,2H),1.18(t, J =7.2Hz,3H), rt1.75min (system B), [ M + H, [ M, J =7.2Hz,3H) ].rt 1.75min (system B), [ M + H]⁺450.1

Compound 117.2- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) acetic acid hydrochloride. Rt1.64min (System B), [ M + H]⁺472.0。

Compound 118.2- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm14.10(bs,1H),10.10(bs,1H),7.54-7.60(M,2H),7.46(dd, J =8.1 and 6.2Hz,1H)7.08(bs,1H),6.58-6.62(M,2H),5.18(s,2H),4.48(bs,2H),4.18(bs,2H),3.48-3.55(M,2H),3.15-3.30(M,2H),2.13-2.30(M,2H),1.82-1.92(M,2H), Rt2.02min (System B), [ M + H ] and]⁺422.0

compound 267.2- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm13.90(br.s.,1H),10.20(br.s.,1H),7.52(d, J =9.0Hz,1H),7.26(d, J =9.0Hz,1H),6.55-6.62(M,2H),5.17(s,2H),4.47(br.s.,1H),4.17(br.s.,1H),3.90(s,3H),3.12-3.60(M,6H),2.10-2.32(M,2H),1.82-1.93(M,2H), 1.53min (system rt), [ M + H ] rt ]⁺452.1

4- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid tert-butyl ester. To 2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol (2 g; 9.74mmol) in CH₃To a solution in CN (50mL) was added potassium carbonate (4.04 g; 29.23mmol) followed by tert-butyl 4-bromobutyrate (2.39 g; 10.72mmol) (asTetrahedron, 1992, 48(42), 9277). The resulting mixture was heated at 65 ℃ overnight.

After cooling to room temperature, the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O) purification gave the product (2.95g, 75%).

¹HNMR(400MHz,CDCl₃-d) ppm6.93(d, J =8.0Hz,1H),6.33(dd, J =8.0,2.1Hz,1H),6.30(d, J =2.1Hz,1H),5.80(bs,1H),4.35(s,2H),2.89-2.94(M,2H),2.35-2.41(M,2H),2.26(t, J =7.4Hz,2H),1.89-2.07(M,4H),1.77-1.86(M,2H),1.67-1.74(M,2H),1.45(s,9H), rt1.08min (system B), [ M + H ], [ M, 9H ], (system B)]⁺348.1

4- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid tert-butyl ester. To (2,4, 6-trichlorophenyl) methanol (164.5 mg; 0.78mmol) and 4- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } butanoate (250mg, 0.62mmol) in dichloromethane (20mL) triphenylphosphine (204 mg; 0.78mmol) was added and after 30 min DIAD (0.15 mL; 0.78mmol) was added. Subsequently, the resulting mixture was stirred at room temperature overnight and concentrated in vacuo. Subsequently, the reaction mixture was washed with 5% NaHCO ₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: hexane 1:2) to give the product (174mg, 52%). Rt1.59min (System B), [ M + H]⁺542.0。

The following compounds were obtained in a similar manner:

4- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid tert-butyl ester.

4- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid tert-butyl ester.

4- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid tert-butyl ester.

4- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid tert-butyl ester.

4- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid tert-butyl ester.

4- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butanoic acid tert-butyl ester.

4- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) } butyric acid tert-butyl ester.

4- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyric acid tert-butyl ester.

Tert-butyl 4- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyrate.

Compound 119.4- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride. 4- {6- [ (2,4, 6-trichlorophenyl) methoxy-]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -Yl } butyric acid tert-butyl ester (172mg, 0.32mmol) dissolved in 1, 4-bis4MH in an alkane (10 mL; 4 mol/l; 40mmol)Cl solution and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (144mg, 82%).¹HNMR(400MHz,DMSO-d₆) ppm14.10(bs,1H),10.30(bs,1H),7.54(d, J =8.0Hz,2H),7.33(t, J =8.0Hz,1H),7.00-7.25(M,5H),4.50(s,2H),4.19(bs,2H),3.50-3.58(M,2H),3.19-3.31(M,2H),2.20-2.31(M,2H),1.87-1.95(M,2H), 1.Rt1.46min (System B), [ M + H ]]⁺485.9。

The following compounds were obtained in a similar manner:

compound 120.4- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.20(bs,1H),10.30(bs,1H),7.34-7.38(M,2H),7.25-7.31(M,1H),7.00(d, J =8.1Hz,1H),6.55-6.62(M,2H),5.10(s,2H),4.50(s,2H),3.49(M,2H),2.95-3.12(M,4H),2.71(q, J =7.5Hz,2H),2.37(t, J =7.2Hz,2H),2.20-2.30(M,2H),1.81-2.00(M,4H),1.16(t, J =7.5Hz,3H), rt1.38min (system B), [ M + H ], (M,1H) ] ]⁺444.0。

Compound 268.1' - (3-carboxypropyl) -6- [ (2-chloro-6-ethylphenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1 '-onium-1' -alkoxide. 4- {6- [ (2-chloro-6-ethyl-phenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butyric acid hydrochloride (210 mg; 0.38mmol) was passed through a p-toluenesulfonic acid solid phase extraction cartridge using bisAlkane wash and 2NNH₃MeOH elution. The product was concentrated and dissolved in DCM (10 mL). m-CPBA (95 mg; 0.38mmol) was then added and the resulting mixture was stirred at room temperature overnight. The residue (after evaporation of the solvent) was purified by column chromatography (Inertsil ODS-3(25X5), H₂O：CH₃CN 4: 6 to pure CH₃CN) to give the product (40 mg; 22%).¹HNMR(400MHz,DMSO-d₆)ppm7.56-7.65(m,1H)7.48(m,1H)7.28(d,J=5.1Hz,1H)7.16(d,J=8.2Hz,1H)6.51-6.63(m,2H)5.10(s,2H)4.48(s,2H)3.63(s,2H)3.35-3.56(M,4H)2.71(q, J =7.5Hz,2H)2.36-2.56(M,4H)1.97-2.09(M,2H)1.71(d, J =13.8Hz,2H)1.16(t, J =7.5Hz,3H) rt1.41min (system B), [ M + H ] 3.35-3.56(M,4H)2.71(q, J =7.5Hz,2H)]⁺460.6。

Compound 121.4- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.30(bs,1H),10.30(bs,1H), 7.29-7.37(M,2H),7.04(dd, J =7.0,2.0Hz,1H),7.00(M,1H),6.56-6.64(M,2H),5.27(s,2H)4.49(bs,2H),3.48(M,2H),3.04(M,4H),2.37(t, J =7.1Hz,2H),2.20-2.30(M,2H),2.06(dt, J =8.4,5.3Hz,1H),1.90-2.00(M,2H),1.80-1.90(M,2H),0.89-0.96(M,2H),0.66-0.73(M,2H), 1.43min (rt + H) [ system (M,2H) ] [ system + H ], [ system H ], (rt, B, 1H) ] ]⁺456.0。

Compound 122.4- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride. Rt1.57min (System B), [ M + H]⁺478.0。

Compound 123.4- {6- [ (2-chloro-5-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.30(bs,1H),10.40(bs,1H),7.38-7.44(M,2H),7.24(dd, J =8.2,2.2Hz,1H),6.96-7.02(M,1H),6.51-6.60(M,2H),5.06(s,2H),4.48(bs,2H),3.42-3.52(M,2H),2.95-3.12(M,4H),2.61(q, J =7.6Hz,2H),2.36(t, J =7.2Hz,2H),2.22-2.30(M,2H),1.79-2.00(M,4H),1.17(t, J =7.6Hz,3H), 1.45min (system B), [ M + H ], [ rt + H ], [ 1H ], [ rt, 3H ], (system B, B]⁺444.0。

Compound 124.4- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.

Rt1.34min (System B), [ M + H]⁺480.0

And (c) a compound 125.4- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.

Rt1.62min (System)B），[M+H]⁺506.0

Compound 126.4- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.30(bs,1H),10.45(bs,1H),7.57-7.66(M,2H),7.48(dt, J =7.6,1.6Hz,1H),7.00(d, J =8.0Hz,1H),6.53-6.62(M,2H),5.10(s,2H),4.50(s,2H),3.43-3.52(M,2H),2.96-3.11(M,4H),2.37(t, J =7.1Hz,2H),2.21-2.32(M,2H),1.95(quin, J =7.6Hz,2H),1.81-1.89(M,2H), rt1.41min (system B), [ M + H ], (M,2H) ]⁺500.0。

Compound 127.4- (6- { [ 2-chloro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.30(bs,1H),10.60(bs,1H),7.33-7.41(m,3H),6.99(d,J=7.4Hz,1H),6.55-6.63(m,2H),5.15(s,2H),4.49(bs,2H),3.44-3.52(m,2H),3.14-3.22(m,1H),2.95-3.11(m,4H),2.23-2.40(m,4H),1.96(quin,J=7.6Hz,2H),1.81-1.88(m,2H),1.20(d,J=6.8Hz,6H)。

Compound 128.4- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.10(bs,1H),10.50(bs,1H),7.54-7.58(M,2H),7.45-7.51(M,1H),6.97-7.12(M,1H),6.56-6.62(M,2H),5.21(s,2H),4.48(bs,2H),3.38-3.54(M,2H),2.94-3.35(M,4H),2.38(t, J =7.5Hz, 2H),2.20-2.37(M,2H),1.94-2.03(M,2H),1.82-1.93(M,2H), Rt1.37min (System B), [ M + H]⁺450.0。

7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alcohols. 2H-spiro [ 1-benzofuran-3, 4' -piperidine]A mixture of-6-ol (0.78 g; 5.24mmol), sodium triacetoxyborohydride (2.22 g; 10.48mmol) and benzaldehyde (0.76 mL; 7.49mmol) in 1, 2-dichloroethane (25mL) was stirred at room temperatureOvernight. Subsequently, the reaction mixture was diluted with dichloromethane and diluted with 5% NaHCO₃And (4) extracting with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, concentrated in vacuo, and chromatographed (SiO)₂，Et₂O/hexane 1:1) purification to give 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol (1.03 g; 93.1%). Rt1.00min (System B), [ M + H ]⁺296.1. To a suspension of NaH (60% in oil) (179 mg; 4.47mmol) in 5mL THF at 0 deg.C was added dropwise 1 '-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine dissolved in 5mL THF]-6-ol (660 mg; 2.23 mmol). The resulting mixture was stirred (15 min) at 15 ℃ and cooled down again. Chloromethyl methyl ether (0.24 mL; 3.35mmol) dissolved in 5mL of HF was then added dropwise and the resulting mixture was stirred overnight. Adding H to the reaction mixture₂O and Et₂And O. The aqueous layer was separated with Et₂The O is extracted once more. The organic layer was dried (Na)₂SO₄) Filtered, concentrated in vacuo, and chromatographed (SiO)₂，Et₂O/hexane 1:1) to give 1 '-benzyl-6- (methoxymethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine (0.54 g; 71.2%). Rt1.1695in (System B), [ M + H]⁺340.1.¹HNMR(400MHz,CDCl₃-d)ppm7.23-7.36(m,5H),7.02(d,J=8.2Hz,1H),6.51-6.57(m,2H),5.12(s,2H),4.36(s,2H),3.53(s,2H),3.46(s,3H),2.85-2.91(m,2H),1.91-2.07(m,H),1.67-1.73(m,2H)。

To 1 '-benzyl-6- (methoxymethyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine (0.6 g; 1.77mmol) in Et at 0 deg.C₂To the solution in O (25mL) was added n-butyllithium (1.56 mL; 2.50 mol/l; 3.89 mmol). The reaction mixture was refluxed for 90 minutes. Subsequently, the mixture was cooled to 0 ℃ and 1, 2-dibromotetrachloroethane (1.27 g; 3.89mmol) was added. The resulting mixture was stirred for 15 min and washed with EtOAc and H₂And (4) diluting with oxygen. The layers were separated and the aqueous layer was extracted once more with EtOAc. The organic layer was dried (Na) ₂SO₄) Filtered, concentrated in vacuo, and chromatographed (SiO)₂，Et₂O/hexane 1:1) to give 1 '-benzyl-7-bromo-6- (methoxymethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine (0.36 g; 49.2%).¹HNMR(400MHz,CDCl₃-d)ppm7.24-7.36(m,5H,)6.97(d,J=8.2Hz,1H),6.67(d,J=8.2Hz,1H),5.21(s,2H),4.48(s,2H),3.50-3.55(m,5H),2.85-2.92(m,2H),1.89-2.07(m,4H),1.70-1.77(m,2H)。

1 '- -benzyl-7-bromo-6- (methoxymethyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine (0.33 g; 0.81mmol) purged with nitrogen was in 9mL of anhydrous 1, 4-bisTo the mixture in the alkane were added potassium carbonate (336 mg; 2.43mmol), trimethylboroxine (0.11 mL; 0.81mmol) and tetrakis (triphenylphosphine) palladium (0) (93 mg; 0.08mmol) in that order. The resulting mixture was heated at 115 ℃ for 28 hours (in a borosilicate glass bottle). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂1: 1O to hexane) to give 1 '-benzyl-6- (methoxymethyloxy) -7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine (0.25 g; 87%).¹HNMR(400MHz,CDCl₃-d) ppm7.24-7.36(M,5H),6.89(d, J =8.2Hz,1H),6.60(d, J =8.2Hz,1H),5.15(s,2H),4.36(s,2H),3.53(s,2H),3.48(s,3H),2.85-2.91(M,2H),2.10(s,3H),1.90-2.08(M,4H),1.67-1.73(M,2H), rt1.25min (system B), [ M + H ] rt 1.2H]⁺354.1. The compound was dissolved in 1M HCl solution in EtOH and stirred at 50 ℃ for 90 minutes. Subsequently, the solvent was removed in vacuo and the residue was taken up in iPr ₂And (4) O treatment. The precipitate was collected by filtration and dried overnight to give 1 '-benzyl-7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]6-alkoxide (220 mg; 97%) Rt1.07min (System B), [ M + H]⁺310.1

To 1 '-benzyl-7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture of-6-alkoxide (0.22 g; 0.64mmol) in 10mL of MeOH was added palladium hydroxide (44mg;0.06 mmol). The mixture was treated with H2 for 72 hours. The crude reaction mixture was concentrated until about 5mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alkoxide (137 mg; 98%)¹HNMR(400MHz,CDCl₃-d) ppm6.81(d, J =8.0Hz,1H),6.32(d, J =8.0Hz,1H),4.41(s,2H),3.11(dt, J =12.7,3.6Hz,2H),2.64-2.73(M,2H),2.11(s,3H),1.78-1.87(M,2H),1.66-1.73(M,2H). rt0.88min (system B), [ M + H [, [ M + H ], 1H ], (M,2H) ]]⁺220.1

Conversion of 7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine ] -6-ol to:

compound 129.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-7-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride in a manner analogous to that described for compound 29.¹HNMR(400MHz,DMSO-d₆) ppm12.60(bs.,1H),10.70(bs.,1H),7.54-7.60(M,2H),7.44-7.50(M,1H),6.90(bs.,1H),6.75(d, J =8.2Hz,1H),5.19(s,2H)4.46(bs.,2H),3.40-3.52(M,2H),3.24-3.39(M,2H),2.98-3.14(M,2H),2.87(t, J =7.5Hz,2H),2.14-2.28(M,2H),1.91(s,3H),1.88(br.s.,2H), rt1.41min (system B), [ M + H ]⁺450.0

7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alcohols. 4-Pyridylcarbinol (1.7 g; 15.62mmol) was dissolved in 1-methyl-2-pyrrolidone (50mL) and sodium hydride (60% in mineral oil; 0.62 g; 15.62mmol) was added. The mixture was stirred at room temperature for 30 minutes. Subsequently, 1- (benzyloxy) -4-bromo-2, 3-difluorobenzene (4.45 g; 14.88mmol) dissolved in 1-methyl-2-pyrrolidone (30mL) was added and the reaction mixture was heated to 100 ℃. TLC showed complete conversion within 15 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO₃And (4) washing with an aqueous solution. Subjecting the organic layer to H₂O washing several times, drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O hexane 2:1 to pure Et₂O) purification to obtain 4- [3- (benzyloxy)6-bromo-2-fluorophenoxymethyl radical]Pyridine (4.81 g; 83%),¹HNMR(400MHz,CDCl₃-d) ppm8.62-8.66(m,2H),7.32-7.48(m,7H), 7.21(dd, J =9.0,2.4Hz,1H),6.69(dd, J =9.0,8.0Hz,1H),5.17(s,2H),5.13(s,2H), dissolved in acetone (72 mL). To the reaction mixture was added benzyl bromide (1.85 mL; 15.45mmol) and stirred at 40 ℃ overnight. Subsequently, the mixture was concentrated in vacuo to give 1-benzyl-4- [3- (benzyloxy) -6-bromo-2-fluorophenoxymethyl group ]Pyridin-1-ium bromide (7.55 g; 99%) was dissolved in MeOH (100 mL). To the cooled (-10 ℃ C.) reaction mixture was added sodium borohydride (1.16 g; 30.71 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 hours. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂1: 1) purification to give the product: 1-benzyl-4- [3- (benzyloxy) -6-bromo-2-fluorophenoxymethyl]1,2,3, 6-tetrahydropyridine (3.73 g; 63%).¹HNMR(400MHz,CDCl₃-d) ppm7.23-7.44(M,10H),7.16(dd, J =9.0,2.3Hz, H),6.63(dd, J =9.0,7.9Hz,1H),5.78-5.82(M,1H),5.11(s,2H),4.51(s,2H),3.60(s,2H),3.00-3.04(M,2H),2.64(t, J =5.7Hz,2H),2.36-2.42(M,2H) rt1.48min (system B), [ M + H ] rt]⁺483.9。

To strongly degassed 1-benzyl-4- [3- (benzyloxy) -6-bromo-2-fluorophenoxymethyl]To a mixture of 1,2,3, 6-tetrahydropyridine (3.73 g; 7.73mmol) in 45mL of benzene were added, in order, 2' -azo (2-methylpropanenitrile) (0.05 g; 0.31mmol) and tri-n-butyltin hydride (3.13 mL; 11.60 mmol). The reaction mixture was heated under microwave conditions (using silicon carbide) at 175 ℃ for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo, during which the product precipitated. The precipitate was collected by filtration and chromatographed (SiO) ₂，Et₂O: Hexane 2:1) to give the product: 1 '-benzyl-6- (benzyloxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine](2.34g；72%)，¹HNMR(400MHz,CDCl₃-d)ppm7.24-7.46(m,10H),6.75(dd,J=8.2,1.4Hz,1H),6.51(dd, J =8.2,6.9Hz,1H),5.10(s,2H),4.46(s,2H),3.53(s,2H),2.84-2.92(m,2H),1.88-2.07(m,4H),1.69-1.75(m,2H), dissolved in MeOH (50 mL). Subsequently, ammonium formate (1.44 g; 22.8mmol) and palladium hydroxide (0.04 g; 0.29mmol) were added. The reaction mixture was stirred overnight (at 60 ℃). The crude reaction mixture was concentrated until about 5mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol (1.23; 96%)¹HNMR(400MHz,DMSO-d₆) ppm6.73(dd, J =8.1,1.2Hz,1H),6.39-6.44(M,1H),4.45(s,2H),2.87(dt, J =12.6,3.5Hz,2H),2.44-2.55(M,2H),1.59-1.70(M,2H),1.48-1.57(M,2H) rt0.40min (system B), [ M + H: [ M, H ], [ 2H ], (M,2H) ]]⁺224.1

In a similar manner and as described for compound 29, 7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Conversion of-6-ol to 3- { 7-fluoro-6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]The acid is tert-butyl propionate, and the acid is,¹HNMR(400MHz,CDCl₃-d) ppm6.70(dd, J =8.1,1.2Hz,1H),6.47(dd, J =8.1,7.3Hz,1H),4.45(s,2H),2.91(d, J =12.0Hz,2H),2.71(t, J =7.2Hz,2H),2.46(t, J =7.2Hz,2H),2.03-2.12(m,2H),1.89-1.98(m,2H),1.70-1.77(m,2H),1.45(s,9H), followed by mitsunobuchhemistry under mitsuny conditions and acidic hydrolysis to give the following compounds:

Compound 130.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs,1H),10.50(bs,1H),7.56-7.61(M,2H),7.46-7.52(M,1H),6.81-6.94(M,2H),5.26(s,2H),4.60(bs,2H),3.43-3.53(M,2H),3.25-3.37(M,2H),3.00-3.11(M,2H),2.86(t, J =7.5Hz,2H),2.13-2.29(M,2H),1.89-2.96(M,2H), 1.37min (System B), [ M + H =7 Hz,2H]⁺454.0

Compound 131.3- {6- [ (2, 6-dichloro) -6-4-methylphenyl) methoxy]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) Ppm12.50(bs,1H),10.90(bs,1H),7.42(s,2H),6.85-6.93(M,2H),5.21(s,2H),4.59(s,2H),3.41-3.52(M,2H),3.37-3.26(M,2H),3.00-3.15(M,2H),2.86(t, J =7.6Hz,2H),2.34(s,3H),2.16-2.29(M,2H),1.88-1.96(M,2H), rt1.44min (system B), [ M + H ] 1.96(M,2H) (]⁺468.1

Compound 132.3- { 7-fluoro-6- [ (2,4, 6-trichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs.,1H),10.40(bs.,1H),7.81(s,2H),6.85-6.93(M,2H),5.23(s,2H),4.60(bs.,2H),3.40-3.55(M,2H),3.25-3.37(M,2H),2.96-3.15(M,2H),2.85(t, J =7.3Hz,2H),2.12-2.25(M,2H),1.88-1.97(M,2H), rt1.44min (system B), [ M + H ] rt1.44min (system B) ]⁺490.0。

Compound 133.3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),10.50(bs.,1H),7.54(d, J =9.0Hz,1H),7.28(d, J =9.0Hz,1H),6.84-6.94(M,2H),5.25(s,2H),4.60(bs,2H),3.90(s,3H),3.41-3.54(M,2H),3.25-3.35(M,2H),2.97-3.16(M,2H),2.86(t, J =7.6Hz,2H),2.13-2.28(M,2H),1.94(M,2H). rt1.36min (system B), [ M + H ] (H) ("M, 2H"), "c]⁺484.1

Compound 134.3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),10.70(bs,1H),7.43(s,2H),6.81-6.93(M,2H),5.21(s,2H),4.60(bs, H),3.42-3.54(M,2H),3.26-3.35(M,2H),2.98-3.12, (M,2H),2.87(t, J =7.6Hz,2H),2.62(t, J =7.6Hz,2H),2.18-2.30(M,2H),1.92(d, J =13.7Hz,2H),1.51-1.62(M,2H),1.24-1.35(M,2H),0.90(t, J =7.4Hz,3H), 1.67min (system B), [ M + H = 7H ], 3H ], 1.67min (system B), [ M + H ], [ rt]⁺Rt0.97min (System B), [ M + H]⁺448.0

Compound 135.3- {6- [ (2-chloro-5-ethylbenzene)Yl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Compound 136.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),11.80(bs,1H),7.35-7.40(M,2H),7.29-7.32(M,1H),6.82-6.96(M,2H),5.19(s,2H),4.60(bs,2H),3.43-3.54(M,2H),3.24-3.34(M,2H),2.98-3.12(M,2H),2.87(t, J =7.6Hz,2H),2.73(q, J =7.8Hz,2H),2.15-2.30(M,2H),1.88-1.97(M,2H),1.17(t, J =7.8Hz,3H), rt1.47min (system B), [ M + H ], 1H, [ M + 1H ], 1.80(bs,1H),7.35-7.40(M,2H), 7.6 (bs,2H), 3.6H), 5.6 (M,2]⁺448.1

Compound 137.3- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl]Methoxy radical]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.44min (System B), [ M + H]⁺504.0。

Compound 269.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.70(br.s.,1H),10.60(br.s.,1H),7.35-7.41(M,2H),7.27-7.33(M,1H),6.80-6.97(M,2H),5.19(s,2H)4.60(br.s.,2H),3.25-3.55(M,4H),3.00-3.12(M,2H),2.87(t, J =7.5Hz,2H),2.73(q, J =7.5Hz,2H),2.18-2.30(M,2H),1.88-1.97(M,2H),1.17(t, J =7.5Hz,3H), rt1.47min (system B), [ M + H]⁺448.1。

Compound 270.3- {6- [ (2-chloro-6-fluorophenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid. 3- {6- [ (2-chloro-6-fluorophenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]A mixture of tert-butyl (178 mg; 0.36mmol) of-1' -yl } propanoate, aqueous 2M NaOH (5 mL; 10mmol) and ethanol (40mL) was stirred at 50 ℃ for 3 hours and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (10 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic phase isLayer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (142 mg; 85.5%).¹HNMR(400MHz,DMSO-d₆) ppm7.49-7.56(M,1H),7.43(d, J =8.0Hz,1H),7.33(t, J =8.8Hz,1H),7.00(d, J =8.0Hz,1H),6.80(t, J =7.6Hz,1H),5.16(d, J =1.4Hz,2H),4.48(s,2H),2.86(d, J =11.7Hz,2H),2.61(t, J =7.0Hz,2H),2.41(t, J =7.0Hz,2H),2.06(t, J =11.7Hz,2H),1.78-1.88(M,2H)1.67(d, J =12.5Hz,2H). 1.min (system B), [ M + H ], [ 34m + H ], [ 34]⁺438.1。

The following compounds were obtained in a similar manner:

compound 271.3- {6- [ (2-chloro-6- (propan-2-yl) phenyl)]Methoxy } -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.35-7.45(M,3H),7.01(d, J =8.5Hz,1H),6.84(t, J =7.4Hz,1H),5.22(s,2H),4.48(s,2H),3.16-3.25(M,1H),2.84-2.89(M,2H),2.61(t, J =7.0Hz,2H),2.40(t, J =7.0Hz,2H),2.02-2.11(M,2H),1.80-1.89(M,2H),1.67(d, J =12.9Hz,2H),1.20(d, J =6.8Hz,6H), 1.49min (system B), [ M + H ], [ 1.]⁺462.2。

Compound 272.3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.30-7.38(M,2H),7.06(dd, J =6.9,1.9Hz,1H),7.01(d, J =8.0Hz,1H),6.86(t, J =7.3Hz,1H),5.34(s,2H),4.49(s,2H),2.87-2.94(M,2H),2.65(t, J =7.0Hz,2H),2.42(t, J =7.0Hz,2H),2.04-2.16(M,3H),1.80-1.90(M,2H),1.68(d, J =12.8Hz,2H),0.89-0.96(M,2H),0.66-0.72(M,2H), rt1.44min (system B), [ M + H ], [ rt 2H ], [ rt]⁺460.2。

Compound 273.3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy group]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆)ppm7.31-7.38(m,1H),7.07(t,J=9.1Hz,1H),6.99(d,J=8.2Hz,1H),6.80-6.90(m,2H),5.25(s,2H),4.48(s,2H),2.87(d,J=12.1Hz,2H),2.62(t,J=7.2Hz,2H),2.40(t, J =7.2Hz,2H),2.03-2.12(M,3H),1.78-1.89(M,2H),1.66(d, J =12.6Hz,2H),0.90-0.98(M,2H),0.66-0.72(M,2H). rt1.42min (system B), [ M + H ])]⁺444.2。

The desired (2-cyclopropyl-6-fluorophenyl) methanol was prepared as follows: to a cooled (0 ℃ C.) solution of (E) -butyl [ (2, 6-difluorophenyl) methylene ] in THF (100mL)]An amine (4.45 g; 22.56mmol), prepared according to US2007/197621 (see also WO2007/85556 and US6380387), was added dropwise to a solution of cyclopropyl magnesium bromide (0.5M, 51.9 mL; 25.95 mmol). Subsequently, the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 3mLH ₂O, and the resulting mixture was washed with EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give (E) -butyl [ (2-cyclopropyl-6-fluorophenyl) methylidene]Amine (5.07 g; 100%) dissolved in 24mLH₂O and sulfuric acid (8mL) and heated at reflux for 2 hours. After the mixture is cooled to the room temperature,

the resulting mixture was purified in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂Et after O: Hexane 1:7₂O: Hexane 1:7) to give (2-cyclopropyl-6-fluorobenzaldehyde (2.37g, 66%).¹HNMR(400MHz,CDCl₃-d) ppm10.64(s,1H),7.39-7.45(m,1H),6.92-6.99(m,1H),6.83(d, J =7.9Hz,1H),2.81-2.90(m,1H),1.04-1.11(m,2H),0.70-0.77(m,2H). to (2-cyclopropyl-6-fluorobenzaldehyde (2.37 g; 14.44mmol) in MeOH (50mL) at 0 deg.C, NaBH is added in small portions₄(1.21 g; 32.02 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for one hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO) ₂，Et₂Et after O: Hexane 1:7₂O: hexane 1:3) to give (2-cyclopropyl-6-fluorophenyl)Methanol (2.02g, 84%).¹HNMR(400MHz,CDCl₃-d)ppm7.13-7.22(m,1H)6.86-6.94(m,1H)6.79(d,J=7.8Hz,1H)4.95(d,J=3.9Hz,2H)2.15(m,1H)1.74(t,J=5.5Hz,1H)0.97-1.04(m,2H)0.68-0.75(m,2H)。

Compound 274.3- (7-fluoro-6 { [ 2-fluoro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.43(M,1H),7.25(d, J =7.9Hz,1H),7.08(t, J =9.0Hz,1H),7.00(d, J =7.5Hz,1H),6.82(t, J =7.5Hz,1H),5.13(d, J =1.1Hz,2H),4.48(s,2H),3.14-3.24(M,1H),2.87(d, J =11.9Hz,2H),2.61(t, J =7.0Hz,2H),2.40(t, J =7.0Hz,2H),2.07(t, J =11.4Hz,2H),1.78-1.88(M,2H),1.66(d, J =12.7Hz,2H),1.20(d, J =6.8, 6H, 461H) [ rt + M,2H ], 1.465H (rt, B + M,2H), 1.4Hz,2H), 1.4H, 2H, 1.8 (rt, 1H, 4H), 1H, 2]⁺446.3。

Compound 275.3- [ 7-fluoro-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid. To 3- { 7-fluoro-6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid tert-butyl ester, CH₃CN (10mL), 1-bromohexane (0.123 mL; 0.88mmol) was added, followed by K₂CO₃(400 mg; 2.92mmol) and the solution is stirred at 75 ℃ overnight. The solution was cooled to room temperature and concentrated. The residue was taken up in EtOAc and H₂And (4) absorbing the O. The organic phase was dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give 3- { 7-fluoro-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]Tert-butyl propionate (100 mg; 100%) was dissolved in 2M NaOH aqueous solution (2 mL; 4mmol) and ethanol (10 mL). The reaction mixture was stirred at 50 ℃ for 3 hours and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (4 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (150 mg; 67.1%)。¹HNMR(400MHz,DMSO-d₆) ppm6.93(d, J =8.3Hz,1H),6.57-6.62(M,1H),4.46(s,2H),3.97(t, J =6.5Hz,2H),2.85(d, J =11.9Hz,2H),2.60(t, J =7.2Hz,2H),2.39(t, J =7.2Hz,2H),2.06(t, J =11.3Hz,2H),1.76-1.86(M,2H),1.61-1.73(M,4H),1.35-1.44(M,2H),1.25-1.33(M,4H),0.84-0.90(M,3H), rt1.45min (system B), [ M + H ] 1H]⁺380.3。

The following compounds were obtained in a similar manner:

compound 276.3- [ 7-fluoro-6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.93(d, J =8.3Hz,1H),6.57-6.63(M,1H),4.47(s,2H),3.97(t, J =6.5Hz,2H),2.86(d, J =11.9Hz,2H),2.61(t, J =6.9Hz,2H),2.40(t, J =6.9Hz,2H),2.08(t, J =11.2Hz,2H),1.81(td, J =12.6,3.4Hz,2H),1.61-1.73(M,4H),1.20-1.43(M,8H),0.86(t, J =6.7Hz,3H), rt1.56min (system B), [ M + H ], [ M =6.7Hz,3H) ] ]⁺394.3。

Compound 277.3- [ 7-fluoro-6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.92(dd, J =8.3,1.2Hz,1H),6.55-6.63(M,1H),4.46(s,2H),3.97(t, J =6.5Hz,2H),2.85(d, J =12.0Hz,2H),2.60(t, J =7.2Hz,2H),2.39(t, J =7.2Hz,2H),2.00-2.11(M,2H),1.81(td, J =12.6,3.8Hz,2H),1.60-1.73(M,4H),1.18-1.43(M,10H),0.86(t, J =6.8Hz,3H), rt1.64min (system B), [ M + H ], (M, J =6.8Hz,3H) ]]⁺408.3。

Compound 278.3- [ 7-fluoro-6- (hex-5-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.92(dd, J =8.3,1.3Hz,1H),6.57-6.63(M,1H),5.82(ddt, J =17.2,10.2,6.6,6.6Hz,1H),4.94-5.06(M,2H),4.46(s,2H),3.99(t, J =6.6Hz,2H),2.85(d, J =12.0Hz,2H),2.61(t, J =7.1Hz,2H),2.39(t, J =7.1Hz,2H),2.02-2.12(M,4H),1.81(td, J =12.6,3.8Hz,2H),1.61-1.75(M,4H),1.44-1.54(M,2H), 1.45min (rt + M systems (M,2H), [ system H) ], (rt + M + H)]⁺378.3。

Compound 279.3- [ 7-fluoro-6- (oct-7-en-1-yloxy) -2H-spiro [ 1-benzofuranPyran-3, 4' -piperidines]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.92(dd, J =8.2,1.2Hz,1H),6.56-6.62(M,1H),5.80(ddt, J =17.1,10.3,6.7,6.7Hz,1H),4.91-5.04(M,2H),4.46(s,2H),3.97(t, J =6.6Hz,2H),2.81-2.88(M,2H),2.60(t, J =7.0Hz,2H),2.38(t, J =7.0Hz,2H),1.98-2.11(M,4H),1.76-1.86(M,2H),1.60-1.73(M,4H),1.27-1.44(M,6H), rt1.59min (system B), [ M + H ], [ rt, 1H ] (system B), [ M + H ], (system B, 2H), 2H, 1H, 2H ]⁺406.3。

Compound 280.3- [ 7-fluoro-6- (hept-6-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.92(d, J =8.2Hz,1H),6.57-6.63(M,1H),5.74-5.86(M,1H),4.92-5.05(M,2H),4.46(s,2H),3.97(t, J =6.3Hz,2H),2.85(d, J =11.9Hz,2H),2.60(t, J =7.0Hz,2H),2.39(t, J =7.0Hz,2H),2.00-2.11(M,4H),1.76-1.86(M,2H),1.61-1.74(M,4H),1.40(dt, J =6.6,3.5Hz,4H), rt1.29min (system B), [ M + H ], [ M + H]⁺392.3。

Compound 281.3- { 7-fluoro-6- [ (5,6, 6-trifluorohex-5-en-1-yl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.92(d, J =8.2Hz,1H),6.57-6.63(M,1H),5.74-5.86(M,1H),4.92-5.05(M,2H),4.46(s,2H),3.97(t, J =6.3Hz,2H),2.85(d, J =11.9Hz,2H),2.60(t, J =7.0Hz,2H),2.39(t, J =7.0Hz,2H),2.00-2.11(M,4H),1.76-1.86(M,2H),1.61-1.74(M,4H),1.40(dt, J =6.6,3.5Hz,4H), rt1.39min (system B), [ M + H ], [ M =8.2H ], 1H, 2H, 2.6, 3.5Hz,4H, and rt1.]⁺432.3。

Compound 282.3- { 7-fluoro-6- [ (4,4,5,5, 5-pentafluoropentyl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,CDCl₃-d) ppm6.79(d, J =8.2Hz,1H),6.50(dd, J =8.2,7.0Hz,1H),4.49(s,2H),4.08(t, J =5.9Hz,2H),3.16(d, J =12.0Hz,2H),2.83(t, J =6.2Hz,2H),2.58(t, J =6.2Hz,2H),2.20-2.41(M,4H),1.99-2.15(M,4H),1.85-1.94(M,2H) rt1.38min (system B), [ M + H ] l ]⁺456.2。

Compound 283.3- { 7-fluoro-6- [ (5,5,6,6, 6-pentafluorohexyl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.94(d, J =8.2Hz,1H),6.59-6.64(M,1H),4.47(s,2H),4.03(t, J =6.2Hz,2H),2.86(d, J =11.8Hz,2H),2.60(t, J =7.1Hz,2H),2.21-2.43(M,4H),2.06(t, J =11.2Hz,2H),1.76-1.87(M,4H),1.60-1.72(M,4H) 1.44min (system B), [ M + H ] rt]⁺470.2。

Compound 284.3- [ 7-fluoro-6- (4,4, 4-trifluorobutoxy)]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.95(dd, J =8.3,1.1Hz,1H),6.58-6.65(M,1H),4.48(s,2H),4.06(t, J =6.2Hz,2H),2.85(d, J =11.9Hz,2H),2.60(t, J =7.1Hz,2H),2.34-2.48(M,4H),2.05(t, J =11.0Hz,2H),1.88-1.98(M,2H),1.81(td, J =12.6,3.6Hz,2H),1.65(d, J =12.8Hz,2H) rt1.28min (system B), [ M + H [, ] H]⁺406.2

Compound 285.3- [6- (cyclohexyloxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.93(d, J =8.1Hz,1H),6.90-6.94(M,1H),4.46(s,2H),4.01(t, J =6.6Hz,2H),2.85(d, J =11.4Hz,2H),2.60(t, J =7.0Hz,2H),2.38(t, J =7.0Hz,2H),2.05(t, J =11.4Hz,2H),1.55-1.86(M,12H),1.38-1.50(M,1H),1.07-1.27(M,2H),0.87-1.00(M,2H). rt1.51min (system B), [ M + H ] M]⁺406.7

Compound 286.3- {6- [ (2-ethylhexyl) oxy group ]-7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm6.93(d, J =8.2Hz,1H),6.58-6.64(M,1H),4.46(s,2H),3.87(d, J =5.7Hz,2H),2.85(d, J =11.7Hz,2H),2.60(t, J =7.0Hz,2H),2.39(t, J =7.0Hz,2H),2.06(t, J =11.7Hz,2H),1.75-1.87(M,2H),1.59-1.71(M,3H),1.22-1.49(M,8H),0.82-0.92(M,6H), rt1.57min (system B), [ M + H (r) ("M, H)", l (r, 2H), 2.5 (r), 2.0.0.0.5H), 2.5 (M,2H), 2.5 (M,2]⁺408.7_

Compound 287.3- { 7-fluoro-6- [ (3,5, 5-trimethylhexyl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆)ppm6.93(d,J=8.2Hz,1H),6.61(t,J=7.7Hz,1H),4.46(s,2H),4.00(t,J=6.1Hz,2H),2.85(d,J=11.9Hz,2H),2.60(t,J=7.0Hz,2H),2.39(t,J=7.0Hz,2H),2.01-2.11(m,2H) 1.75-1.86(M,2H),1.60-1.74(M,3H),1.55(s,1H),1.27(dd, J =14.0,3.2Hz,1H),1.02-1.09(M,1H),0.94(d, J =6.3Hz,3H),0.87(s,9H) rt1.59min (system B), [ M + H ] r]⁺422.8

Compound 288.3- [6- (3-Cyclohexylpropoxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆)ppm6.92(d,J=8.2Hz,1H),6.59(t,J=7.7Hz,1H),4.46(s,2H),3.95(t,J=6.5Hz,2H),2.85(d,J=11.7Hz,2H),2.60(t,J=7.0Hz,2H),2.39(t,J=7.0Hz,2H),2.06(t,J=11.2Hz,2H),1.81(td,J=12.5,3.4Hz,2H),1.57-1.75(m,9H),1.05-1.32(m,6H),0.80-0.93(m,2H)。

5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ] -6-ol. 4-pyridinemethanol (7.9 g;

32.37mmol) was dissolved in 1-methyl-2-pyrrolidone (200mL) and sodium hydride (60% in mineral oil; 2.89 g; 72.37 mmol). The mixture was stirred at room temperature for 30 minutes. Subsequently, 1-bromo-2, 5-difluoro-4- (methoxy-methoxy) benzene (17.44 g; 68.92mmol) dissolved in 1-methyl-2-pyrrolidone (150mL) was added and the reaction mixture was heated to 100 ℃. TLC showed complete conversion within 15 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO ₃And (4) washing with an aqueous solution. Subjecting the organic layer to H₂O washing several times, drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O hexane 2:1 to pure Et₂O) to obtain 4- [ 2-bromo-4-fluoro-5- (methoxymethoxy) pentyloxymethyl]Pyridine (10.23 g; 29.81 mmol; 43.38%).¹NMR(400MHz,CDCl₃-d) ppm8.61-8.66(m,2H)7.39-7.43(m,2H)7.33(d, J =10.1Hz,1H)6.84(d, J =7.2Hz,1H)5.16(s,2H)5.10(s,2H)3.49(s,3H), dissolved in acetone (153 mL). To the reaction mixture was added benzyl bromide (4.46 mL; 37.26mmol) and the mixture was stirred at 40 ℃ overnight. Subsequently, the mixture was concentrated in vacuo to give 1-benzyl-4- [ 2-bromo-4-fluoro-5- (methoxymethoxy) phenoxy) -methyl) pyridin-1-ium bromide (17.29 g; 99%) was dissolved in MeOH (200 mL). To the cooled (-10 ℃ C.) reaction mixture was added sodium borohydride (2.8 g; 74.12 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 hours. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO) ₂，Et₂O) purification to give the product: 1-benzyl-4- [ 2-bromo-4-fluoro-5- (methoxymethoxy) pentyloxymethyl]1,2,3, 6-tetrahydropyridine (8.47 g; 67.8%).¹HNMR(400MHz,CDCl₃-d) ppm7.23-7.37(M,6H)6.83(d, J =7.3Hz,1H)5.80-5.83(M,1H)5.18(s,2H)4.43(s,2H)3.60(s,2H)3.51(s,3H)3.03(br.s.,2H)2.63(t, J =5.7Hz,2H)2.24-2.29(M,2H) rt1.49min (system B), [ M + H ] r]⁺438.1。

To the strongly degassed 1-benzyl-4- [ 2-bromo-4-fluoro-5- (methoxy-methoxy) pentyloxymethyl]To a mixture of 1,2,3, 6-tetrahydropyridine (5.78 g; 13.25mmol) in benzene (75mL) were added, in order, 2' -azo (2-methylpropanenitrile) (0.09 g; 0.53mmol) and tri-n-butyltin hydride (5.36 mL; 19.87 mmol; 1.5 eq). The reaction mixture (divided into 5 batches) was heated under microwave conditions (with silicon carbide) at 175 ℃ for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and purified by column chromatography (SiO)₂，Et₂O: Hexane 2: 1). The residue was dissolved in Et₂O (150mL) and washed with 25mL of 10% aqueous KF solution, dried and concentrated to give the product: 1 '-benzyl-5-fluoro-6- (methoxymethyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine](3.80g；80.26%)。¹HNMR(400MHz,CDCl₃-d) ppm7.24-7.36(M,5H)6.86(d, J =10.3Hz,1H)6.66(d, J =6.6Hz,1H)5.14-5.17(M,2H)4.35(s,2H)3.53(s,2H)3.51(s,3H)2.83-2.91(M,2H)1.98-2.07(M,2H)1.91(td, J =12.6,3.8Hz,2H)1.67-1.73(M,2H) rt1.13min (system B), [ M + H ] 3.1.1.1.3 (M,2H) rt1.13min (system B), [ M + H ]⁺358.2, which was dissolved in 1, 2-dichloroethane (20mL) at 0 ℃. Subsequently, 1-chloroethyl chloroformate is added(0.82 mL; 7.55mmol) and the reaction mixture was stirred for 1 hour (at room temperature). Methanol (20mL) was added and the reaction mixture was stirred overnight and concentrated in vacuo to give 5-fluoro-6- (methoxymethyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine](0.83g；90%)。¹HNMR(400MHz,DMSO-d₆) ppm9.20(br.s.,1H)9.00(br.s.,1H)7.02(d, J =10.3Hz,1H)6.75(d, J =6.7Hz,1H)5.19(s,2H)4.48(s,2H)3.22-3.42(M,5H)2.89-3.03(M,2H)1.99-2.10(M,2H)1.80(d, J =14.1Hz,2H) was suspended in hydrochloric acid (25mL, 1M) and 25mL ethanol. The reaction mixture was stirred at reflux for 1 hour. The residue was concentrated in vacuo to give 5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Hydrochloride of 6-ol (0.68 g).¹HNMR(400MHz,DMSO-d₆) ppm9.90(s.,1H),9.05(br.s.,1H),8.85(br.s.,1H),6.91(d, J =10.4Hz,1H),6.41(d, J =7.0Hz,1H),4.42(s,2H),3.26(d, J =13.0Hz,2H),2.87-3.02(m,2H),1.92-2.05(m,2H),1.77(d, J =14.2Hz,2H), which was filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-alcohol (0.57 g; 97%) Rt0.41min (System B), [ M + H ]⁺224.2

In a similar manner and as described for compound 29, 5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Conversion of-6-ol to 3- { 5-fluoro-6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]The acid is tert-butyl propionate, and the acid is,¹HNMR(400MHz,CDCl₃-d) ppm6.79(d, J =9.7Hz,1H),6.44(d, J =7.0Hz,1H),4.34(s,2H),2.88(d, J =12.0Hz,2H),2.69(t, J =7.3Hz,2H),2.45(t, J =7.3Hz,2H),2.02-2.10(m,2H),1.83-1.92(m,2H),1.68-1.75(m,2H),1.46(s,9H), followed by Mitsunobu chemistry and hydrolysis (as described for compound 270) to give the following compounds:

compound 289.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆)ppm7.54-7.60(m,2H),7.46-7.51(m,1H),7.17(d,J=10.7Hz,1H),6.88(d,J=6.9Hz,1H),5.23(s,2H),4.38(s,2H),2.86(d,J=11.8Hz,2H),2.60(t,J=7.1Hz,2H),2.39(t,J=7.1Hz,2H),2.06(t,J=11.8Hz,2H),1.83(td,J=12.7,3.6Hz,2H),1.62(d, J =12.7Hz,2H) rt1.36min (system B), [ M + H [ ]]⁺454.1

Compound 290.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.37(d, J =4.4Hz,2H)7.26-7.31(M,1H)7.16(d, J =10.7Hz,1H)6.89(d, J =6.9Hz,1H)5.16(s,2H)4.38(s,2H)2.85(d, J =11.7Hz,2H)2.72(q, J =7.5Hz,2H)2.59(t, J =7.0Hz,2H)2.36(t, J =7.0Hz,2H)2.04(t, J =11.7Hz,2H)1.83(td, J =12.6,3.3Hz,2H)1.61(d, J =12.6Hz,2H)1.16(t, J =7.5Hz,3H) 1.39min (rtb + M system [ + l, J =7.5Hz,3H) ([ 39min ], [ system H ], [ l [ + l, 3H ], [ l [ + l ], [ l ]]⁺448.6_

Compound 336.3- [ 5-fluoro-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid.¹HNMR(400MHz,DMSO-d₆)ppm6.78-7.03(m,1H)6.69(d,J=6.9Hz,1H)4.45(br.s.,2H)3.98(t,J=6.4Hz,2H)3.20-3.61(m,4H)2.96-3.19(m,2H)2.89(t,J=7.7Hz,H)2.23(m,2H)1.86(d,J=13.1Hz,2H)1.62-1.74(m,2H)1.21-1.46(m,6H)0.87(t,J=6.4Hz，3H)

7-chloro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ] -6-ol. This compound was synthesized in comparable or better yield as 1-bromo-3-chloro-2-fluoro-4- (methoxy-methoxy) benzene following the procedure for 5-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidin ] -6-ol (see compound 289). Some examples illustrating this approach are:

4- [ 6-bromo-2-chloro-3- (methoxymethoxy) phenoxymethyl]Pyridine (76%)¹HNMR(400MHz,CDCl₃-d)ppm8.62-8.68(m,2H),7.50(d,J=5.4Hz,2H),7.42(d,J=9.0Hz,1H),6.95(d,J=9.0Hz,1H),5.25(s,2H),5.06(s,2H),3.52(s,3H)。

1-benzyl-4- [ 6-bromo-2-chloro-3- (methoxymethoxy) phenoxymethyl]-1,2,3, 6-tetrahydropyridine (74%).¹HNMR(400MHz,CDCl₃-d)ppm7.23-7.39(m,6H),6.88(d,J=9.0Hz,1H),5.85-5.88(m,1H),5.23(s,2H),4.40(s,2H),3.62(s,2H),3.51(s,3H),3.04-3.08(m,2H),2.67(t,J=5.7Hz,2H),2.42-2.48(m,2H)

7-chloro-6- (methoxymethyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine](100%)。¹HNMR(400MHz,DMSO-d₆)ppm9.20(br.s.,1H),9.00(br.s.,1H),7.01(d,J=8.3Hz,1H),6.78(d,J=8.3Hz,1H),5.24(s,2H),4.60(s,2H),3.40(s,3H),3.28(d,J=13.1Hz,2H),2.90-3.03(m,2H),2.07(td,J=13.1,4.2Hz,2H),1.84(d,J=14.3Hz,2H)。

7-chloro-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-a 6-alcohol, which is,¹HNMR(400MHz,DMSO-d₆) ppm6.88(d, J =8.2Hz,1H)6.45(d, J =8.2Hz,1H)4.43(s,2H)2.86-2.92(M,2H)2.48-2.55(M,2H)1.66(dt, J =11.6,4.2Hz,2H)1.84(d, J =13.0Hz,2H) rt0.60min (system B), [ M + H =13.0Hz,2H)]⁺240.1。

In a similar manner and as described for compound 29, 7-chloro-2H-spiro [ 1-benzofuran-3, 4 ' -piperidin ] -6-ol was converted to tert-butyl 3- { 7-chloro-6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 ' -piperidin ] -1 ' -yl ] propionate. Subsequently, Mitsunobu chemistry and hydrolysis (as described for compound 270) were performed to give the following compounds:

Compound 291.3- { 7-chloro-6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.31-7.38(M,2H)7.17(d, J =8.2Hz,1H)7.06(dd, J =7.0,1.8Hz,1H)6.88(d, J =8.2Hz,1H)5.34(s,2H)4.48(s,2H)2.84-2.91(M,2H)2.62(t, J =7.0Hz,2H)2.40(t, J =7.0Hz,2H)2.03-2.13(M,3H)1.85(t, J =11.5Hz,2H)1.68(d, J =12.8Hz,2H)0.88-0.95(M,2H)0.67-0.73(M,2H) 1.48min (system B), [ M + rth H ], [ M + rt H ] (system B) ]]⁺476.2

Compound 292.3- (7-chloro-6- { [ 2-fluoro-6- (propan-2-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆)ppm7.36-7.43(m,1H),7.07-7.19(m,3H),6.84(d,J=8.3Hz,1H),5.12(s,2H),4.48(s,2H),2.87(d,J=11.7Hz,2H),2.72(q,J=7.5Hz,2H),2.61(t,J=7.0Hz,2H),2.40(t,J=7.0Hz,2H),2.07(tJ =11.4Hz,2H),1.79-1.89(M,2H),1.67(d, J =12.8Hz,2H),1.18(t, J =7.5Hz,3H)]⁺448.2

3- [6- (acetylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a solution of tert-butyl (1' -yl) propionate (7.9g, 23.7mmol) in 15mL of chloroform was added a solution of triethylamine (4,93 mL; 35.54mmol), 4-dimethylaminopyridine (290mg, 2.37mmol) and trifluoromethanesulfonamide (10.16g, 28.43mmol) in 5mL of chloroform. The resulting reaction mixture was heated at 60 ℃ and stirred overnight. Subsequently, the mixture was cooled to 0 ℃, water was added, followed by 5% NaHCO ₃The solution was extracted with chloroform. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- {6- [ (trifluoromethane) sulfonyloxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (9.5 g; 86%).¹HNMR(400MHz,CDCl₃-d) ppm7.11(d, J =8.2Hz,1H),6.77(dd, J =8.2 and 2.3Hz,1H),6.68(d, J =2.3Hz,1H),4.34(s,2H),2.85-2.94(m,2H),2.69(t, J =7.6Hz,2H),2.45(t, J =7.6Hz,2H),2.02-2.10(m,2H),1.86-1.97(m,2H),1.72-1.75(m,2H),1.46(s, 9H).

3- { - {6- [ (trifluoromethane) sulfonyloxy ] purged to nitrogen]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]To a solution of tert-butyl propionate (1.4g, 3.01mmol) in toluene (30mL) was added (R) -1- [ (1S)_p) -2- (dicyclohexylphosphino) ferrocenyl]Ethyl di-tri-butylphosphine (Stremchemics; Cat. No. 88733), (CyPF-t-Bu)) (83.4 mg; 0.15mmol) was added, followed by tris- (dibenzylideneacetone) -dipalladium (0) (68.85 mg; 0.08 mmol). The mixture was stirred for 5 minutes. Subsequently, potassium thioacetate (0.69 g; 6.02mmol) was added and the resulting mixture was heated at 110 ℃ for 24 hours. Subsequently, the reaction is mixedThe mixture was cooled and Et ₂O dilution and filtration. The remaining organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane to acetone 9:1) to give 3- {6- [ (acetylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (0.95 g; 80%).¹HNMR(400MHz,CDCl₃-d) ppm7.14(d, J =8Hz,1H),6.93(dd, J =8 and 2Hz,1H),6.84(d, J =2Hz,1H),4.39(s,2H),2.86-2.94(M,2H),2.69(t, J =8Hz,2H),2.44(t, J =8Hz,2H),2.40(s,3H),2.02-2.11(M,2H),1.90-1.99(M,2H),1.72-1.79(M,2H),1.46(s,9H), 1.53min (system B), [ M + H rtti (r), 1.5H (system B) ]]⁺538.0

3- (6- { [ (2, 6-dichloro-3-methoxy) phenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. A solution of NaOH (22 mg; 0.55mmol) in 5EtOH (5mL) was added to 3- [6- (acetyl-sulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine) dissolved in EtOH (5mL) with cooling in an ice bath]-1' -yl]Tert-butyl propionate (0.18 g; 0.46mmol) and stirring continued for 30 minutes during which time LCMS showed complete removal of the protecting group S-acetyl. To the reaction mixture was added 1, 3-dichloro-2- (chloromethyl) -4-methoxybenzene (160 mg; 0.53mmol) dissolved in EtOH (2mL) and stirred at 0 ℃ for a further 20 minutes. Subsequently, the reaction mixture was diluted with EtOAc and washed with brine. The remaining organic layer was dried (Na) ₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- (6- { [2, 6-dichloro-3-methoxy) phenyl]Methylsulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-220 mg of 1' -yl } propanoate; 80 percent.

The required 1, 3-dichloro-2- (chloromethyl) -4-methoxybenzene was obtained (75%) from (2, 6-dichloro-3-methoxyphenyl) methanol (already described) using thionyl chloride in benzene (14 eq).

The following compounds were obtained in a similar manner. The corresponding benzylic chloride was obtained from the aforementioned benzylic alcohol:

tert-butyl 3- (6- { [ (4-butyl-2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ (2-chloro-6-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

3- (6- { [ (2-chloro-6-cyclopropylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid tert-butyl ester

Tert-butyl 3- (6- { [ (2, 6-dichloro-3-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ (2,4, 6-trichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ (2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ (2-chlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- (6- { [ (2-methylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (Benzylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- (6- { [ (2-cyclopropyl-6-fluorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- [6- ({ [ 2-fluoro-6- (propan-2-yl) phenyl ] methyl } sulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoate.

Compound 138.3- (6- { [ (2, 6-dichloro-3-methoxy) phenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Reacting 3- (6- { [ (2, 6-dichloro-3-methoxy) phenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (190mg, 0.35mmol) of (E) -1' -yl } propanoate in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr ₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (144mg, 82%). Rt1.45min (System B), [ M + H]⁺482.0

The following compounds were obtained in a similar manner:

compound 139.3- (6- { [ (4-butyl-2, 6-dichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.75min (System B), [ M + H]⁺508.0

Compound 140.3- (6- { [ (2-chloro-6-ethylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.73(bs,1H),10.27(bs,1H),7.19-7.35(m,3H),7.06(bs,1H),6.94(d,J=8Hz,1H),6.88(s,1H),4.50(bs,2H)m4.31(s,2H),3.27-3.54(m,4H),2.99-3.15(m,2H),2.85(t,J=8Hz,2H),2.66-2.74(m,2H),2.12-2.26(m,2H),1.84-1.94(m,2H),1.18(t,J=8Hz,3H)。

Compound 141.3- (6- { [ (2-chloro-6-cyclopropylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.82(bs,1H),9.91(bs,1H),7.36(d,J=8Hz,1H),7.28(t,J=8Hz,1H),7.13(bs,1H),7.03(t,J=8Hz,2H),6.96(d,J=2Hz,1H),4.56(bs,4H),3.37-3.59(M,4H),3.19-3.25(M,2H),2.88(t, J =8Hz,2H),2.17-2.23(M,2H),2.09-2.13(M,1H),1.92-1.99(M,2H),0.96-1.12(M,2H),0.64-0.80(M,2H) rt1.52min (system B), [ M + H ] l]⁺458.0。

Compound 142.3- (6- { [ (2, 6-dichloro-3-ethylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.57min (System B), [ M + H]⁺480.0

Compound 143.3- (6- { [ (2,4, 6-trichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. ¹HNMR(400MHz,DMSO-d₆) ppm12.82(bs,1H),10.09(bs,1H),7.71(s,2H),7.05(bs,1H),6.94(d, J =8Hz,1H),6.88(d, J =2Hz,1H),4.50(bs,2H),4.34(s,2H),3.26-3.54(M,4H),2.99-3.12(M,2H),2.83(t, J =8Hz,2H),2.10-2.22(M,2H),1.85-1.92(M,2H), rt1.55min (system B), [ M + H =8Hz,2H), [ M + H ] rt1.55min (system B), [ M + H ], []⁺487.9

Compound 144.3- (6- { [ (2, 6-dichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.55(bs,1H),10.18(bs,1H),7.50(d, J =8Hz,2H),7.35(t, J =8Hz,1H),7.06(bs,1H),6.95(bd, J =8Hz,1H),6.89(s,1H),4.50(bs,2H),4.39(s,2H),3.27-3.54(M,4H),2.99-3.12(M,2H),2.84(t, J =8Hz,2H),2.09-2.24(M,2H),1.85-1.92(M,2H), rt1.44min (system B), [ M + H ], [ M,2H ]]⁺451.9

Compound 145.3- (6- { [ (2-chlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.82(bs,1H),10.00(bs,1H),7.41-7.48(M,2H),7.25-7.33(M,2H),7.03(bs,1H),6.88(d, J =8Hz,1H),6.84(s,1H),4.47(bs,2H),4.28(s,2H),3.18-3.55(M,4H),2.97-3.12(M,2H),2.83(t, J =8Hz,2H),2.06-2.21(M,2H),1.81-1.91(M,2H), Rt2.31min (System B), [ M + H ] (M,2H)]⁺418.0。

Compound 146.3- (6- { [ (2-methylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid hydrochloride.

Rt1.72min (System B), [ M + H]⁺398.1

Compound 147.3- [6- (benzylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm………

Rt1.35min (System B), [ M + H]⁺384.1

Compound 293.3- (6- { [ (2-cyclopropyl-6-fluorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.73(brs,1H),10.27(brs,1H),7.20-7.25(M,1H),6.97-7.06(M,2H),6.93(d, J =8Hz,1H),6.88(s,1H),6.80(d, J =8Hz,1H),4.49(brs,2H),4.35(s,2H),3.25-3.53(M,4H),3.01-3.13(M,2H),2.83(t, J =8Hz,2H),2.11-2.22(M,2H),2.01-2.08(M,1H),1.87(d, J =8Hz,2H),0.91-0.98(M,2H),0.64-0.68(M,2H), 1.47min (rt + H) [ system (M,2H) ], [ system H ], [ system 1.]⁺442.2。

Compound 294.3- [6- ({ [ 2-fluoro-6- (propan-2-yl) phenyl]Methyl } sulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm7.27-7.46(M,1H),6.93-7.14(M,5H),4.50(brs,2H),4.22(brs,2H),3.32-3.53(M,4H),3.12-3.17(M,2H),2.81-2.86(M,3H),2.13-2.18(M,2H),1.85-1.91(M,2H),1.16(d, J =8Hz,6H), rt1.48min (system B), [ M + H =8Hz,6H ], [ rt1.48min (system B) ], and]⁺444.3。

mixing 3- { 7-fluoro-6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Conversion of tert-butyl (E) -1 '-yl } -propionate to 3- [6- (acetylsulfanyl) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]The acid is tert-butyl propionate, and the acid is,¹HNMR(400MHz,CDCl₃-d) ppm6.86-6.94(m,3H),4.50(s,2H),2.88-2.94(m,2H),2.67-2.72(t, J =8Hz,2H),2.44(t, J =8Hz,5H),2.01-2.10(m,2H),1.91-1.99(m,2H),1.78-1.82(m,2H),1.46(s,9H) and converted to the following compounds (in an analogous manner and as described for compound 138):

compound 295.3- (6- { [ (2, 6-dichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.64(brs,1H),9.82(brs,1H),7.47(d, J =8Hz,2H),7.31-7.36(M,1H),6.95-6.99(M,1H),6.88-6.91(M,1H),4.64(brs,2H),4.33(s,2H),3.31-3.52(M,4H),3.03-3.12(M,2H),2.82(t, J =8Hz,2H),2.11-2.19(M,2H),1.92-1.98(M,2H), rt1.49min (system B), [ M + H ], [ M, H = 2H ], (system B)]⁺470.1。

Compound 296.3- (6- { [ (2-chloro-6-ethylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.64(brs,1H),9.90(brs,1H),7.18-7.32(M,3H),7.00-7.05(M,1H),6.87-6.94(M,1H),4.63(brs,2H),4.27(s,2H),3.25-3.54(M,4H),2.96-3.13(M,2H),2.83(t, J =8Hz,2H),2.63-2.72(M,2H),2.11-2.20(M,2H),1.89-2,00(M,2H),1.15(t, J =8Hz,3H), rt.1.67min (system B), [ M + H ] l]⁺464.1。

Compound 297.3- [ 7-fluoro-6- (pentylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]Propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.63(brs,1H),10.27(brs,1H),6.94-6.99(M,2H),6.89-6.92(M,1H),4.63(brs,2H),3.26-3.54(M,4H),2.91(t, J =8Hz,2H),2.85(t, J =8Hz,2H),2.14-2.25(M,2H),1.89-1.97(M,2H),1.50-1.59(M,2H),1.23-1.40(M,6H),0.91(t, J =8Hz,3H), rt1.43min (system B), [ M + H ], [ M + H [, [ 1H ], [ 2H ], (M,2H) ]]⁺382.7。

The following compound, starting from 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methyl-propionic acid tert-butyl ester, was obtained according to the procedure described for compound 138.

The corresponding benzylic chlorides were obtained from the benzylic alcohols already described:

compound 148.2-methyl-3- (6- { [ (2,4, 6-trichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm13.00(bs,1H),9.64(bs,1H),7.82(s,2H),7.06(d, J =8Hz,1H),7.18(bs,1H),7.01(d, J =2Hz,1H),4.61(bs,2H),4.46(s,2H),3.41-3.65(M,4H),3.16-3.27(M,2H),3.07-3.14(M,1H),2.25-2.39(M,2H),1.95-2.05(M,2H),1.35(d, J =8Hz,3H), rt1.65min (system B), [ M + H ], [ M + H]⁺502.0。

Compound 149.3- (6- { [ (2, 6-dichloro-3-methoxyphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.91(bs,1H),9.82(bs,1H),7.45(d,J=8Hz,1H),7.14(d,J=8Hz,1H),7.05(bs,1H),6.95(d,J=8Hz,1H),6.89(d,J=2Hz,1H),4.49(bs,2H),4.37(s,2H),3.86(s,3H),3.42-3.55(m,3H),2.98(m,4H),2.18-2.29(m,2H),1.83-1.91(m,2H),1.24(d,J=8Hz,3H)。

Compound 150.3- (6- { [ (2, 6-dichloro-4-methylphenyl) methyl ]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride. Rt1.55min (System B), [ M + H]⁺487.9

Compound 151.3- (6- { [ (2-chloro-6-ethylphenyl) methyl]Sulfanyl } -2H-spiro- [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.57min (System B), [ M + H]⁺460.1

Compound 152.3- [6- ({ [ 2-chloro-6- (propan-2-yl) phenyl]Methyl } sulfanyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.82(bs,1H),9.82(bs,1H),7.27-7.33(m,3H),7.01-7.09(bs,1H),6.94(d,J=8Hz,1H),6.88(s,1H),4.49(bs,2H),4.34(s,2H),3.31-3.52(m,4H),2.99-3.21(m,4H),2.19-2.33(m,2H),1.82-1.92(m,2H),1.24(d,J=8Hz,3H),1.16(d,J=8Hz,6H)。

Compound 153.3- (6- { [ (2, 6-dichlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.82(bs,1H),9.82(bs,1H),7.49(d,J=8Hz,2H),7.38(t,J=8Hz,1H),7.06(bs,1H),6.95(d,J=8Hz,1H),6.88(s,1H),4.49(bs,2H),4.38(s,2H),3.30-3.53(m,4H),2.98-3.17(m,3H),2.18-2.35(m,2H),1.82-1.93(m,2H),1.24(d,J=8Hz,3H)。

Compound 298.3- (6- { [ (2-chloro-6-cyclopropylphenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.87(brs,1H),9.80(brs,1H),7.31(d, J =4Hz,1H),7.23(t, J =4Hz,1H),7.04(brs,1H),6.98(t, J =4Hz,2H),6.90(s,1H),4.46(s,4H),3.30-3.55(M,4H),3.00-3.15(M,3H),2.20-2.30(M,2H),2.02-2.10(M,1H),1.84-1.91(M,2H),1.23(d, J =4Hz,3H),0.91-0.95(M,2H),0.66-0.70(M,2H), 1.58min (system B), [ M + H ], [ 1H ], (M,1H) ], 6.]⁺472.1

Compound 154.3- (6- { [ (2-chlorophenyl) methane]Sulfonyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid hydrochloride. Coupling 3- (6- { [ (2-chlorophenyl) methyl]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (237mg, 0.50mmol) of (E) -1' -yl } propanoate in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 5 minutes. Subsequently, the solvent was removed in vacuo and the residue was taken up in iPr₂And O treatment, and collecting precipitates through filtration. To this HCl salt dissolved in MeOH (7.50mL) at 0 deg.C was added H₂Potassium peroxymonosulfate (922 mg; 1.50mmol) in O (7.50mL) and the reaction mixture was stirred for 2 hours. Subsequently, the reaction mixture was diluted with dichloromethane and diluted with 5% NaHCO₃Aqueous solution and brine. The remaining organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- (6- { [ (2-chlorophenyl) methane]Sulfonyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (220 mg; 72.5%) was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (150mg, 70%). ¹HNMR(400MHz,DMSO-d₆) ppm12.55(bs,1H),10.27(bs,1H),7.24-7.44(M,6H),7.08(s,1H), 4.74(s,2H),4.59(brs,2H),3.24-3.54(M,4H),3.01-3.14(M,2H),2.81-2.89(t, J =8Hz,2H),2.15-2.28(M,2H),1.89-1.96(M,2H), Rt1.36min (System B), [ M + H ]]⁺450.0

The following compounds were obtained in a similar manner:

compound 299.3- (6- { [ (2, 6-dichlorophenyl) methane]Sulfonyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.64(brs,1H),10.27(brs,1H),7.52(d, J =8Hz,2H),7.40-7.45(M,2H),7.32-7.39(M,2H),4.87(s,2H),4.63(s,2H),3.26-3.56(M,4H),3.01-3.16(M,2H),2.84(t, J =8Hz,2H),2.17-2.28(M,2H),1.91-1.99(M,2H) rt1.24min (system B), [ M + H ] r]⁺484.1

Compound 300.3- (6- { [ (2, 6-dichlorophenyl) methane]Sulfinyl } -2H-Spiro [ 1-benzofuran-3, 4' -piperidines]-1' -yl } propanoic acid hydrochloride. To 3- (6- { [ (2, 6-dichlorophenyl) -methyl in MeOH (7.50mL) at 0 deg.C]Sulfanyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -propionic acid tert-butyl ester hydrochloride (210mg, 0.41mmol) was added in H₂Potassium peroxymonosulfate (254 mg; 0.41mmol) in O (7.50mL) and the reaction mixture was stirred for 2 hours. Subsequently, the reaction mixture was diluted with EtOAc and diluted with 5% NaHCO ₃Aqueous solution and brine. The remaining organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane to acetone 95: 5) to obtain 3- (6- { [ (2, 6-dichlorophenyl) methane]Sulfinyl } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (130mg) was dissolved in aqueous 2M NaOH (1 mL; 2mmol) and ethanol (10 mL). The reaction mixture was stirred at 60 ℃ for 3 hours and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (2 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washed and dried in vacuo to give the product (100 mg; 70%).¹HNMR(400MHz,DMSO-d₆) ppm7.57(d, J =8Hz,2H),7.44-7.49(M,2H),7.03-7.09(M,2H),4.56(d, J =12Hz,3H),4.39(d, J =12Hz,1H),2.92-3.01(M,2H),2.71(t, J =8Hz,2H),2.48(t, J =8Hz,2H),2.15-2.23(M,2H),1.89-1.99(M,2H),1.71-1.79(M,2H) rt1.35min (system B), [ M + H ] r]⁺468.1

3- { 6-iodo-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

3- { - {6- [ (trifluoromethane) sulfonyloxy ] purged to nitrogen]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1′-radical]Tert-butyl propionate (5g, 10.74mmol) and hexa-N-butylstannylene (12.46 g; 21.48mmol) in 1, 4-bisTo a solution in alkane (25mL) was added lithium chloride (2.28 g; 53.7mmol) and tetrakis (triphenylphosphine) palladium (0). The mixture was stirred at 108 ℃ for 72 hours. Subsequently, the reaction mixture was cooled and Et₂Diluted with O and used in H₂KF solution in O (5mol/l) was extracted. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:3) to give 3- [6- (tributylstannyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (4.29 g; 66%).¹HNMR(400MHz,CDCl₃-d) ppm7.11(d, J =8.2Hz,1H),6.96(d, J =8.2Hz,1H),6.91(s,1H),4.34(s,2H),2.85-2.94(m,2H),2.69(t, J =7.8Hz,2H), 2.45(t, J =7.8Hz,2H),2.02-2.12(m,2H),1.93-2.01(m,2H),1.72-1.77(m,2H),1.47-1.68(m,6H),1.46(s,9H),1.26-1.39(m,6H),0.99-1.04(m,6H),0.89(t, J =7.2Hz,9H), THF (50mL) of a 3- [ 3- (tributyl-2H) -benzofuran [ 1H, 3-c-methyl-3-ethyl-2-methyl-piperidine ] furan-4-methyl-2H)]-1' -yl]To a solution of tert-butyl propionate (3 g; 4.95mmol) was added N-iodosuccinimide (1.67 g; 7.42mmol) (in portions). The resulting reaction mixture was stirred for 75 minutes (at 0 ℃). Subsequently, the reaction mixture was washed with EtOAc and Na ₂S₂O₃And (6) diluting. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- { 6-iodo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1.55 g: 70%) 1' -yl } propanoate. Rt1.32min (System B), [ M + H]⁺444.0

3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester was prepared in an analogous manner from 3- [6- (tributylstannyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoate using N-bromosuccinimide (57%).

3- {6- [ (2-methylphenyl) sulfanyl group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Purging 3- { 6-iodo-2H-spiro [ 1-benzofuran-3, 4' -piperidine with nitrogen]Tert-butyl-1' -yl } propanoate (0.2g, 0.43mmol) in 1, 2-dimethoxyethane (5mL) was added 2-toluene-1-thiol (0.05 mL; 0.43mmol) and potassium carbonate (118 mg; 0.86mmol), and finally copper (I) iodide (9 mg; 0.045 mmol). The mixture was stirred at 93 ℃ for 24 hours. Additional 2-toluene-1-thiol (0.01mL) and copper (I) iodide (10mg) were added and the reaction mixture was stirred for an additional 4 hours. Subsequently, the reaction mixture was cooled, diluted with EtOAc and taken up in saturated NH ₄Cl solution and brine extraction. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- {6- [ (2-methylphenyl) sulfanyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) propionate (0.14 g; 74%). Rt1.47min (System B), [ M + H]⁺444.1

The following compounds were obtained in a similar manner:

tert-butyl 3- {6- [ (2, 6-dichlorophenyl) sulfanyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2-methylbenzene) sulfonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate. This compound was prepared from tert-butyl 3- {6- [ (2-methylphenyl) sulfanyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate using the procedure for compound 154.

3- {6- [ (2, 6-dichlorobenzene) sulfonyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To a solution of 3- [6- (tributylstannyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine in THF (15ml) at-78 deg.C]-1' -yl]To a solution of tert-butyl propionate (450 mg; 0.74mmol) was added n-butyllithium (0.45 mL; 2.50 mol/l; 1.11 mmol). The reaction mixture was stirred for 30 minutes. Subsequently, a solution of 2, 6-dichlorobenzene-1-sulfonyl fluoride (0.2 g; 0.87mmol) in THF (7mL) was added at-78 deg.C. The resulting mixture was stirred and allowed to warm to room temperature overnight. By adding saturated NaH ₄The reaction was stopped with an aqueous solution of Cl. Mixing the obtained mixtureWith Et₂O extraction and 10mLKF (10% in H)₂O in). The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give the product (75 mg; 19%) Rt1.35min (System B), [ M + H]⁺525.9

The following compounds were obtained in a similar manner:

3- [6- (phenylsulfonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoic acid tert-butyl ester.

Compound 155.3- {6- [ (2-methylphenyl) sulfanyl group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {6- [ (2-methylphenyl) sulfanyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (120mg, 0.25mmol) of (E) -1' -yl } propanoate in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (90mg, 82%).¹HNMR(400MHz,DMSO-d₆) ppm12.73(bs,1H),10.27(bs,1H),7.18-7.38(M,4H),7.08(bs,1H),6.74(d, J =8Hz,1H),6.55(s,1H),4.48(bs,2H),3.23-3.55(M,4H),2.95-3.15(M,2H),2.80-2.88(M,2H),2.32(s,3H),2.08-2.23(M,2H),1.84-1.93(M,2H), Rt1.40min (System B), [ M + H ] M ]⁺384.1

The following compounds were obtained in a similar manner:

compound 156.3- {6- [ (2, 6-dichlorophenyl) sulfanyl group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.73(bs,1H),10.18(bs,1H),7.70(d, J =8Hz,2H),7.56(t, J =8Hz,1H),7.04(bs,1H),6.59(dd, J =8 and 2Hz,1H),6.44(s,1H),4.47(bs,2H),3.25-3.53(m,4H),2.96-3.11(m,2H),2.82(t, J =8Hz,2H),2.06-2.18(m,2H),1.83-1.92(m,2H), Rt1.39min (System B),[M+H]⁺437.9。

compound 157.3- {6- [ (2-Methylbenzene) sulfonyl group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.21min (System B), [ M + H]⁺416.0

Compound 158.3- {6- [ (2, 6-dichlorophenyl) sulfanyl group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.63min (System B), [ M + H]⁺469.9

Compound 159.3- [6- (phenylsulfonyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.40min (System B), [ M + H]⁺384.1

Tert-butyl 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

To a solution of (bromomethyl) triphenylphosphonium bromide (23.92 g; 54.85mmol) in THF (150mL) at-78 deg.C was added a suspension of potassium tert-butoxide (6.16 g; 54.85mmol) in THF (50mL), (adv. Synth. Catal., 2006, 348, 851). The reaction mixture was stirred for 2 hours. Subsequently, a solution of 2, 6-dichlorobenzaldehyde (8 g; 45.71mmol) in THF (50mL) was added dropwise at-78 ℃. The resulting mixture was stirred and allowed to warm to room temperature overnight. By adding saturated NaH ₄The reaction was stopped with an aqueous solution of Cl. The resulting mixture was washed with Et₂O extracted and washed with brine. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Hexane) to give 2- [ (E) -2-bromovinyl group]-1, 3-dichlorobenzene (7.22 g; 62%).¹HNMR(400MHz,CDCl₃-d)ppm7.32(d,J=8.0Hz,2H),7.12-7.20(m,2H),6.97(d,J=14.2Hz,1H)

2- [ (E) -2-bromovinyl) purged with nitrogen]-1, 3-dichlorobenzene (7.22 g; 28.66mmol) in 1, 4-bisTo a mixture in an alkane (200mL) were added, in order, bis (pinacolato) diboron (8.01 g; 31.52mmol), potassium acetate (8.44 g; 85.97mmol), 1 ' -bis (diphenyl-phosphino) -ferrocenepalladium (II) dichloride dichloromethane complex (0.7 g; 0.86mmol) and (additional) 1 ', 1 ' -bis (diphenylphosphino) -ferrocene (0.48 g; 0.86 mmol). The resulting mixture was heated overnight (85 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and washed with H₂And O washing. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O hexane 1:7) to give 2- [ (E) -2- (2, 6-dichloro-phenyl) ethenyl]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (dioxaborolan) (6.24 g; 72%).¹HNMR(400MHz,CDCl₃-d) ppm7.39(d, J =18.8Hz,1H),7.31(d, J =8.0Hz,2H),7.11(d, J =8.0Hz,1H),6.24(d, J =18.8Hz, H),1.33(s,12H) to 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl ]To a mixture of-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (2.5 g; 8.36mmol) in MeOH (60mL) and water (15mL) was added potassium difluorohydride (4.57 g; 58.3mmol) and the mixture was stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo, and the residue was treated with toluene and concentrated in vacuo. The following steps were repeated three times to remove all water. The resulting solid was treated with hot acetonitrile (20mL) and the acetonitrile was decanted off. This step was repeated 3 times. The combined acetonitrile layers were concentrated in vacuo and the residue was taken up in Et₂And (4) O treatment. The precipitate formed was collected by filtration and dried in vacuo to give 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl]Potassium trifluoroborate (2.31g, 99%).¹HNMR(400MHz,DMSO-d₆)ppm7.39(d,J=8.0Hz,2H),7.16(t,J=8.0Hz,1H),6.42(d,J=18.6Hz,1H),6.08-6.17(m,1H)。

To degassed 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester (1.26 g;3.18mmol) and 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl]To a mixture of potassium trifluoroborate (1.06g, 3.82mmol) in toluene (45mL) and water (15mL) was added cesium carbonate (3.54 g; 10.87mmol) and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloride dichloromethane complex (0.13 g; 0.16mmol) in that order. The resulting mixture was heated overnight (100 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO ₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: Hexane 1:1 followed by 2:1) to give 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1.04 g; 67%) 1' -yl propionate.¹HNMR(400MHz,CDCl₃-d) ppm7.34(d, J =8.0Hz,2H),7.01-7.15(M,6H),4.40(s,2H),2.88-2.94(M,2H),2.67-2.74(M,2H),2.42-2.48(M,2H),2.04-2.13(M,2H),1.92-2.20(M,2H),1.72-1.88(M,2H),1.47(s,9H), rt1.58min (system B), [ M + H ], (s,9H) ], 1.5H]⁺488.1

The following compounds were obtained in a similar manner. The aldehydes are commercially available and or have been described previously:

3- {6- [ (E) -2- (2-chlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

3- {6- [ (E) -2-Phenylvinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (E) -2- (4-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (E) -2- (2, 6-dichloro-3-ethylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

3- {6- [ (E) -2- (2, 6-dichloro-4-cyclopropylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

3- {6- [ (E) -2- (4-butyl-2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid tert-butyl ester.

3- {6- [ (1Z) -3,3, 3-trifluoro-2-phenylprop-1-en-1-yl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. The desired trifluoro [ (1Z) -3,3, 3-trifluoro-2-phenylprop-1-en-1-yl group]The potassium borate was prepared as follows: conversion of 2,2, 2-trifluoro-1-phenyleth-1-one to [ (1E) -1-bromo-3, 3, 3-trifluoroprop-1-en-2-yl]Benzene and [ (1Z) -1-bromo-3, 3, 3-trifluoroprop-1-en-2-yl]Benzene (4:1) to resemble 2- [ (E) -2-bromovinyl]-1, 3-dichlorobenzene. Converting the mixture into trifluoro [ (1E and Z) -3,3, 3-trifluoro-2-phenylprop-1-en-1-yl)]Mixture of potassium borate and 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate was reacted to give a mixture, which was purified (HPLC) to give the title compound.¹HNMR(400MHz,CDCl₃-d) ppm7.37-7.43(m,3H),7.27-7.31(m,2H),7.12-7.15(m,1H),6.93(d, J =7.8Hz,1H),6.62(dd, J =7.8,1.2Hz,1H),6.33(d, J =1.2Hz,1H),4.28(s,2H),2.82-2.89(m,2H),2.67(t, J =7.4Hz,2H),2.42(t, J =7.4Hz,2H),1.97-2.07(m,2H),1.83-1.92(m,2H),1.63-1.69(m,2H),1.45(s,9H) HPLC conditions are: ChiralpakAD20um, 60 ml/min. Eluens heptane EtOH (8: 2).

Compound 160.3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1.04g, 2.13mmol) of (E) -1' -yl } propanoate was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate collected by filtration and dried under reduced pressure overnight to give the product (0.93g, 89.4%).¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs,1H),10.30(bs,1H),7.53(d, J =8.1Hz,2H),7.30-7.35(M,1H),6.99-7.25(M,5H),4.51(s,2H),3.41-3.55(M,2H),3.30-3.39(M,2H),3.01-3.19(M,2H),2.85(t, J =7.5Hz,2H),2.13-2.25(M,2H),1.86-1.95(M,2H) Rt1.49min (System B), [ M + H ] (M,2H) } Rt1.49min (System B)]⁺432.1

The following compounds were obtained in a similar manner.

Compound 161.3- {6- [ (E) -2- (2-chlorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.42min (System B), [ M + H]⁺398.0

Compound 162.3- {6- [ (E) -2-Phenylethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.64(bs,1H),10.55(bs,1H),7.59(d,J=8Hz,2H),7.38(t,J=8Hz,2H),7.27(t,J=8Hz,1H),7.22(s,2H),7.10-7.17(m,3H),4.50(bs,2H),3.28-3.52(m,4H),3.01-3.18(m,2H),2.86(t,J=8Hz,2H),2.16-2.28(m,2H),1.87-1.95(m,2H)。

Compound 163.3- {6- [ (E) -2- (4-fluorophenyl) ethenyl ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.70(bs,1H),10.10(bs,1H),7.63(dd,J=8.6,5.5Hz,2H),7.04-7.28(m,7H),4.49(bs,2H),3.42-3.54(m,2H),3.30-3.38(m,2H),3.01-3.15(m,2H),2.83(t,J=7.6Hz,2H),2.12-2.22(m,2H),1.86-1.94(m,2H)。

Compound 164.3- {6- [ (E) -2- (2, 6-dichloro-3-ethylphenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.54min (System B), [ M + H]⁺460.0

Compound 165.3- {6- [ (E) -2- (2, 6-dichloro-4-cyclopropylphenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.56min（System B), [ M + H]⁺472.0

Compound 166.3- {6- [ (E) -2- (4-butyl-2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.70min (System B), [ M + H]⁺488.0

Compound 167.3- {6- [ (1Z) -3,3, 3-trifluoro-2-phenylprop-1-en-1-yl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) Ppm12.70(bs.,1H),9.60(bs.,1H),7.41-7.52(M,5H),7.30(s,1H),7.15-7.25(M,1H),7.01(d, J =7.7Hz,1H),6.90(s,1H),4.53(s,2H),3.48-3.56(M,2H),3.30-3.41(M,2H),3.02-3.20(M,2H),2.80(t, J =7.4Hz,3H),2.06-2.17(M,2H),1.94(bd, J =14.1Hz,2H), rt1.55min (system B), [ M + H ] rt1.55 (system B)]⁺432.0

3- {6- [ (E) -2- (2-chloro-5-ethylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

To a solution of methyltriphenylphosphonium bromide (5.77 g; 16.15mmol) in THF (25 mL) at-78 ℃ was added a suspension of potassium tert-butoxide (1.81 g; 16.15mmol) in THF (50mL) (adv. synth. cat., 2006, 348, 851). The reaction mixture was stirred for 1.5 hours. Subsequently, a solution of 2-chloro-5-ethylbenzaldehyde (2.27 g; 13.45mmol) (from 2-chloro-5-ethylbenzaldehyde already described by oxidation of manganese dioxide (69%) in acetonitrile) in THF (30mL) is added dropwise at-78 deg.C, the resulting mixture is stirred and allowed to warm to room temperature overnight, by addition of saturated NaH ₄The reaction was stopped with an aqueous solution of Cl. The resulting mixture was washed with Et₂O extracted and washed with brine. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Hexane) to obtainThe product, 1-chloro-2-vinyl-4-ethylbenzene (2.11 g; 94%).

To a degassed mixture of 1-chloro-2-vinyl-4-ethylbenzene (2.1 g; 12.6mmol) in dichloromethane (50mL) was added successively vinyl boronic acid pinacol ester (1.94 mL; 11.46mmol) and a second generation Hoveyda-Grubbs catalyst (0.36 g; 0.57mmol) (Tetrahedron, (65), 2009, 3130). The resulting mixture was heated overnight (40 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc and H₂And O washing. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Hexane) to give 2- [ (E) -2- (2-chloro-5-ethylphenyl) vinyl group]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (2.32 g; 69%) which is used directly for conversion into 3- {6- [ (E) -2- (2-chloro-5-ethylphenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate, using a similar description to that for the precursor of compound 160.

The following compounds were obtained in a similar manner.

Tert-butyl 3- {6- [ (E) -2- (2, 5-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (E) -2- (3-methylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (E) -2- (2-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Compound 168.3- {6- [ (E) -2- (2-chloro-5-ethylphenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1.04g, 2.13mmol) of (E) -1' -yl } propanoate in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate collected by filtration and dried under reduced pressure overnight to give the product (0.93g, 89.4%). Rt1.53min (System B), [ M + H]⁺426.0。

The following compounds were obtained in a similar manner.

Compound 169.3- {6- [ (E) -2- (2, 5-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.20(bs,1H),7.94(d, J =3.0Hz,1H),7,52(d, J =8,1Hz,1H),7.27-7.46(M,3H),7,09-7.23(M,3H),4.52(bs,2H),3.46-3.56(M,2H),3.26-3.35(M,2H),3.00-3.14(M,2H),2.86(t, J =7.7Hz,2H),2.16-2.30(M,2H),1.85-1.95(M,2H), rt1.50min (system B), [ M + H ] H ]⁺432.0。

Compound 170.3- {6- [ (E) -2- (3-methylphenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.37min (System B), [ M + H]⁺378.1

Compound 171.3- {6- [ (E) -2- (2-fluorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.50(bs,1H),7.78(t, J =7.7Hz,1H),7.01-7.40(M,8H),4.50(br.s.,2H),3.42-3.56(M,2H),3.26-3.39(M,2H),3.00-3.14(M,2H),2.87(t, J =7.7Hz,2H),2.16-2.32(M,2H),1.83-1.95(M,2H), 1.34min (system B), [ M + H ] rt, [ M]⁺382.1。

Compound 301.3- {6- [ (E) -2- (2-chloro-6-fluorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- { - {6- [ (trifluoromethane) sulfonyloxy ] purged to nitrogen]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (600mg, 1.29mmol) and tributyl- (vinyl) tin hydride (0.37 mL; 1.29mmol) in 1, 4-bisLithium chloride (164 mg; 3.87mmol) was added to a solution in an alkane (25mL), followed by tetrakis (triphenylphosphine) palladium (0) (149 mg; 0.13mmol) (tetrahedron letters, 48(2007), 323-326). The mixture was stirred in a preheated oil bath (110 ℃ C.) for 70 minutes. Subsequently, the reaction mixture was cooled and Et ₂O dilution and filtration. The organic layer was washed with 5% aqueous KF solution and dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give 3- {6- (vinyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine)]Tert-butyl-1' -yl } propanoate (330 mg; 74.5%).¹HNMR(400MHz,CDCl₃-d) ppm7.07(d, J =8Hz,1H),6.91(dd, J =8 and 2Hz,1H),6.87(d, J =2Hz,1H),6.66(dd, J =10 and 10Hz,1H),5.68(d, J =18Hz,1H),5.19(d, J =10Hz,1H),4.36(s,2H),2.86-2.93(m,2H),2.69(t, J =8Hz,2H),2.45(t, J =8Hz,2H),2.03-2.11(m,2H),1.91-1.99(m,2H),1.69-1.76(m,2H),1.46(s, 9H). As for Oxidative heck cross-coupling (Synthesis (2010), 1399-1427), 3- {6- (vinyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine)]-1' -Yl } propionic acid tert-butyl ester (100 mg; 0.29mmol), palladium acetate (10 mg; 0.04mmol), BIAN (bis (aryl) acenaphthodiimine) (J.Org.chemistry published form (2011) (24 mg; 0.06mmol) and 2-chloro-6-fluorophenylboronic acid (76 mg; 0.44mmol) were dissolved in 5mLN, N-dimethylformamide the reaction mixture (open vessel) was stirred overnight (90 ℃ C.) additional palladium acetate (5mg), BIAN (bis (aryl) acenaphthodiimine) (12mg) and 2-chloro-6-fluorophenylboronic acid (50mg) were added and the reaction mixture was stirred for an additional 24 hours (90 ℃ C.) then the reaction mixture was cooled, diluted with EtOAc and diluted with 5% NaHCO ₃Washing with an aqueous solution and drying (Na)₂SO₄) Filtering, and purifying inConcentrating in vacuum. The residue was purified by column chromatography (SiO)₂Dichloromethane acetone 9:1) to give 3- {6- [ (E) -2- (2-chloro-6-fluorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (70 mg; 43.3%). Rt1.50min (System B), [ M + H]⁺472.2, conversion to 3- {6- [ (E) -2- (2-chloro-6-fluorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -propionic acid hydrochloride (69%) (as described for compound 168).¹HNMR(400MHz,DMSO-d₆) ppm12.73(brs,1H),10.91(brs,1H),7.10-7.41(M,8H),4.51(brs,2H),3.29-3.52(M,4H),3.02-3.13(M,2H),2.83(t, J =8Hz,2H),2.12-2.22(M,2H),1.87-1.95(M,2H), Rt1.42min (System B), [ M + H [ ], [ M + H ] ], 2H ] ], and]⁺416.2_

compound 302.3- {6- [ (E) -2- (2-cyclopropyl-6-fluorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {6- [ (E) -2- (2-bromo-6-fluorophenyl) ethenyl using the conditions described for Compound 71(53%) (see above)]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -propionic acid tert-butyl ester (according to the synthesis of compound 301), Rt1.42min (System B), [ M + H ]]⁺518.5 with potassium cyclopropyltrifluoroborate (tetrahedron letters, 2008, 4122-4124) to give 3- {6- [ (E) -2- (2-cyclopropyl-6-fluorophenyl) vinyl ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Rt1.53min (System B), [ M + H]⁺478.7, which is converted into 3- {6- [ (E) -2- (2-cyclopropyl-6-fluorophenyl) ethenyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride (69%) (as described for compound 168).¹HNMR(400MHz,DMSO-d₆) ppm11.73(brs,1H),10.09(brs,1H),7.39(d, J =16Hz,1H),7.04-7.22(M,6H),6.91(d, J =8Hz,1H),4.52(brs,2H),3.48-3.58(M,2H),3.03-3.13(M,2H),2.85(t, J =8Hz,2H),2.09-2.25(M,5H),1.87-1.95(M,2H),0.97-1.02(M,2H),0.70-0.74(M,2H), rt1.46min (system B), [ M + H ], [ M,2H ], [ M + H ], (M,2H) ]]⁺422.7

6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]. 4-Pyridylcarbinol (17.56 g; 160.9mmol) was dissolved in 1-methyl-2-pyrrolidone (150mL) and sodium hydride (60% in mineral oil; 6.44 g; 160.9mmol) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was then added to 1, 4-dibromo-2-fluorobenzene (20.43 g; 80.47mmol) dissolved in 1-methyl-2-pyrrolidone (250 mL). The resulting reaction mixture was heated to 100 ℃. TLC showed complete conversion within 5 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO₃And (4) washing with an aqueous solution. Subjecting the organic layer to H ₂O washing several times, drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O hexane 2:1 to pure Et₂O) to give 4- (2, 5-dibromophenoxymethyl) pyridine (17.4 g; 63%) was dissolved in acetone (260 mL). To the reaction mixture was added benzyl bromide (6.37 mL; 53.26mmol) and the mixture was stirred at 40 ℃ overnight. Subsequently, the mixture was concentrated in vacuo to give 1-benzyl-4- (2, 5-dibromophenoxymethyl) pyridin-1-ium bromide (24.9 g; 95%) which was dissolved in MeOH (225 mL). To the cooled (-10 ℃ C.) reaction mixture was added sodium borohydride (4.51 g; 119.50 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 hours. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: Hexane 1:1) to give the product: 1-benzyl-4- (2, 5-dibromophenoxymethyl)]1,2,3, 6-tetrahydropyridine (19.78 g; 94%). Rt1.37min (System B), [ M + H]⁺437.8。

To strongly degassed 1-benzyl-4- (2, 5-dibromophenoxy-methyl)]To a mixture of 1,2,3, 6-tetrahydropyridine (8 g; 18.3mmol) in 75mL of benzene were added, in order, 2' -azo (2-methylpropanenitrile) (0.12 g; 0.73mmol) and tri-n-butyltin hydride (7.4 mL; 27.45 mmol). The reaction mixture was heated at 115 ℃ for 72 hours. After cooling to room temperature, the mixture was cooled With Et₂O was diluted and washed with 10% aqueous KF. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂，Et₂O: Hexane 1:1) to give the product: 1 '-benzyl-6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine](1.3g；20%)，¹HNMR(400MHz,CDCl₃-d) ppm7.24-7.35(m,5H),6.97-7.02(m,2H),6.91-6.94(m,1H),4.38(s,2H),3.53(s,2H),2.85-2.92(m,2H),1.90-2.07(m,4H),1.67-1.74(m,2H). The product is dissolved in 1, 2-dichloroethane (20mL) at 0 ℃. Subsequently, 1-chloroethyl chloroformate (0.98 mL; 9.07mmol) was added and the reaction mixture was stirred for 15 minutes. The crude reaction mixture was concentrated in vacuo. Toluene (100mL) was added and the mixture was concentrated. This last step was repeated twice. MeOH (20mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo to give 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Hydrochloride salt (1.1 g; 99%).¹HNMR(400MHz,DMSO-d₆) ppm8.80-9.15(m,2H),7.05-7.11(m,3H),4.53(s,2H),3.25-3.32(m,2H),2.92-3.03(m,2H),2.05(dt, J =13.6,4.2Hz,2H),1.78-1.85(m,2H). the product was dissolved in MeOH (5mL) and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine ](0.8 g). Rt1.05min (System B), [ M + H]⁺270.0

4- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid tert-butyl ester. To 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Hydrochloride (0.55 g; 1.81mmol) in CH₃To a suspension in CN (35mL) were added potassium carbonate (0.75 g; 5.42mmol) and potassium iodide (0.36 g; 2.17mmol), followed by tert-butyl 4-bromobutyrate (0.48 g; 2.17 mmol). The resulting mixture was heated at 65 ℃ overnight.

After cooling to room temperature, the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: Hexane 2: 1) to give the product (0.54g, 72%).¹HNMR (400MHz, CHLOROFORM-d) ppm7.00(dd, J =7.8,1.5Hz,1H),6.97(d, J =7.8Hz,1H)6.93(d, J =1.5Hz,1H),4.37(s,2H),2.88-2.94(M,2H),2.34-2.40(M,2H),2.27(t, J =7.4Hz,2H),1.89-2.03(M,4H)1.69-1.85(M,4H),1.45(s,9H) rt1.30min (system B), [ M + H ] r]⁺412.0。

2- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid tert-butyl ester. To 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Hydrochloride (0.55 g; 1.81mmol) in CH₃To a suspension of CN (35mL) and potassium carbonate (0.75 g; 5.42mol) was added tert-butylbromoacetate (0.42 g; 2.17 mmol). The resulting mixture was heated at 65 ℃ overnight.

After cooling to room temperature, the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue is purified by column chromatography (SiO)₂，Et₂O: Hexane 1:1) to give the product (0.46g, 66.7%). Rt2.59min (System B), [ M + H]⁺383.9

3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methyl-propionic acid tert-butyl ester. To a suspension of 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine ] hydrochloride (0.53 g; 1.74mmol) in N, N-dimethylformamide (7mL) was added tert-butyl methacrylate (0.57 mL; 3.48mmol) and DBU (0.78 mL; 5.22 mmol). The resulting mixture was heated in a closed flask at 140 ℃ overnight.

After cooling to room temperature the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) gave the product (436mg, 61%).

Rt1.36min (System B), [ M + H]⁺412.0。

4- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid tert-butyl ester. To degassed 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -yl) butyrate (0.26 g; 0.63mmol) and 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl ]To a mixture of potassium trifluoroborate (0.21g, 0.76mmol) in toluene (9mL) and water (3mL) were added cesium carbonate (0.71 g; 2.17mmol), and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloro-dichloromethane complex (26 mg; 0.03mmol) in that order. The resulting mixture was heated overnight (100 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂3:1 after O: Hexane 1: 1) to give 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } butanoate (257 mg; 80%). Rt1.57min (System B), [ M + H]⁺502.2

2- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid tert-butyl ester. To degassed 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid tert-butyl ester (244 mg; 0.59mmol) and 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl]To a mixture of potassium trifluoroborate (196mg, 0.76mmol) in toluene (9mL) and water (3mL) were added cesium carbonate (0.65 g; 2mmol), and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloride dichloromethane complex (24 mg; 0.03mmol) in that order. The resulting mixture was heated overnight (100 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO ₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂3:1 after O: Hexane 1: 1) to give 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } butanoate (187 mg; 67%).¹HNMR(400MHz,CHLOROFORM-d)ppm6.96-7.02(m,2H) 6.93(d, J =1.1Hz,1H),4.38(s,2H),3.17(s,2H),2.93-2.99(M,2H),2.27(dt, J =12.5 and 2.5Hz,2H),2.03(dt, J =12.5,4.0Hz,2H),1.68-1.76(M,2H),1.48(s,9H). rt1.62min (system B), [ M + H [ ], [ M + H ], [ 1.1Hz, 2H ], 2.5 (M,2H) ]]⁺474.2。

3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropionic acid tert-butyl ester. To degassed 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropionic acid tert-butyl ester (218 mg; 0.53mmol) and 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl]To a mixture of potassium trifluoroborate (178mg, 0.64mmol) in toluene (9mL) and water (3mL) were added cesium carbonate (520 mg; 1.59mmol), and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloride dichloromethane complex (22 mg; 0.03mmol) in that order. The resulting mixture was heated overnight (100 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO ₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: Hexane 1:2) to give 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methyl-propionic acid tert-butyl ester (197 mg; 31.6%). Rt1.63min (System B), [ M + H]⁺502.0。

Compound 172.4- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride. 3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -Yl } butyric acid tert-butyl ester (257mg, 0.51mmol) dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (233mg, 89.6%).¹HNMR(400MHz,DMSO-d₆)ppm12.85(bs.,1H),9.90(bs.,1H),7.54(d,J=8.1Hz,2H),7.33(t,J=8.1Hz,1H),6.99-7.18(m,5H),4.52(bs.,2H),3.41-3.55(M,2H),3.00-3.17(M,4H),2.24-2.40(M,4H),1.84-2.01(M,4H) Rt1.44min (System B), [ M + H [ ] -H]⁺446.0。

The following compounds were obtained in a similar manner.

Compound 173.2- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride. ¹HNMR(400MHz,DMSO-d₆) ppm14.10(bs.,1H),10.30(bs.,1H),7.54(d, J =8.0Hz,2H),7.33(t, J =8.0Hz,1H),7.00-7.25(M,5H),4.50(s,2H),4.19(bs.,2H),3.50-3.58(M,2H),3.19-3.31(M,2H),2.20-2.31(M,2H),1.87-1.95(M,2H), rt1.67min (system B), [ M + H) ], [ M + H ], [ 1H ], [ system B ]]⁺418.0。

Compound 174.3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.

Rt1.53min (System B), [ M + H]⁺446.0。

4- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid tert-butyl ester. The desired [2- (2, 6-dichlorophenyl) -cyclopropyl group]Potassium trifluoroborate was prepared as follows: to freshly distilled dichloromethane (10mL) was added Et2Zn (6.02 mL; 1m/l in hexane; 6.02mmol) (J.Org.chem., 69, (2), 2004, 327) at 0 ℃. To this solution (very slowly) was added trifluoroacetic acid (0.46 mL; 6.02mmol) in dichloromethane (20 mL). After the addition was complete (75 min), the reaction mixture was stirred at 0 ℃ for 30 min. Subsequently, diiodomethane (0.48 mL; 6.02mmol) dissolved in dichloromethane (10mL) was added and the resulting reaction mixture was stirred at 0 ℃ for an additional 20 minutes. To the reaction mixture was added 2- [ (E) -2- (2, 6-dichlorophenyl) vinyl group in dichloromethane (10mL) ]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.9 g; 3.01mmol)It was allowed to warm to room temperature and stirred overnight. With saturated NH₄The reaction was quenched with aqueous Cl and diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:7) to give 2- [2- (2, 6-dichloro-phenyl) cyclopropyl ] amino]Potassium-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.7 g; 74%) was dissolved in MeOH (8mL) and water (2 mL). Subsequently, potassium difluorohydride (1.19 g; 15.21mmol) was added and the reaction mixture was stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo, and the residue was treated with toluene and concentrated in vacuo. The following steps were repeated three times to remove all water. The resulting solid was treated with hot acetonitrile (20mL) and the acetonitrile was decanted off. This step was repeated 3 times. The combined acetonitrile layers were concentrated in vacuo and the residue was taken up in Et₂And (4) O treatment. The precipitate formed was collected by filtration and dried in vacuo to give [2- (2, 6-dichlorophenyl) cyclopropyl ] amine]Potassium trifluoroborate (0.41g, 64%).¹HNMR(400MHz,DMSO-d₆) ppm7.3(d, J =8.0Hz,2H),7.13(t, J =8.0Hz,1H),1.37-1.44(m,1H),0.65-0.71(m,1H),0.36-0.43(m,1H), -0.09-0.01(m,1H), 3- { 6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine ] purged to nitrogen ]Tert-butyl (1' -yl) butyrate (0.26 g; 0.63mmol) and [2- (2, 6-dichlorophenyl) cyclopropyl ]]To a mixture of potassium trifluoroborate (0.22g, 0.76mmol) in toluene (9mL) and water (3mL) was added cesium carbonate (0.71 g; 2.17mmol), and 1 ', 1' -bis (diphenyl-phosphino) -ferrocene palladium (II) dichloride dichloromethane complex (26 g; 0.03mmol) in that order (org.Lett., Vol.6, No.3, 2004, 357). The resulting mixture was heated overnight (100 ℃). After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain 4- {6- [2- (2, 6-dichlorophenyl) -cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } butanoate (268 mg; 82%). Rt1.61min (System B), [ M + H]⁺516.0。

The following compounds were obtained in a similar manner.

Tert-butyl 2- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetate.

3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid tert-butyl ester.

Tert-butyl 3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

For the following compounds, the desired potassium [2- (substituted-phenyl) cyclopropyl ] -trifluoroborate analog was obtained from the corresponding 2- [ (E) -2- (substituted-phenyl) vinyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan analog by the sequence described above;

tert-butyl 3- [6- (2-phenylcyclopropyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [2- (2-fluorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [2- (2-chlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester.¹HNMR(400MHz,CDCl₃-d) ppm7.30-7.26(m,2H)7.04-7.13(m,2H),6.79(dd, J =7.7 and 1.6Hz,1H),6.66(d, J =1.6Hz,1H),4.36(s,2H),2.87-2.94(m,2H),2.71(t, J =7.6Hz,2H),2.46(t, J =7.6Hz,2H),2.19-2.24(m,1H),1.92-2.16(m,5H),1.72-1.79(m,2H),1.54-1.61(m,1H),1.46(s,9H),1.37-1.41(m, 1H).

Tert-butyl 3- {6- [2- (2-chloro-5-ethylphenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

As an example, NMR data for a and B are given:

A：¹HNMR(400MHz,CDCl₃-d)ppm7.76(d,J=18.4Hz,1H),7.46(d,J=2.1Hz,1H),7.26(d,J=8.2Hz,1H),7.06(dd,J=8.2,2.1Hz,1H),6.17(d,J=18.4Hz,1H),2.62(q,J=7.6Hz,2H),1.32(s,12H),1.22(t,J=7.6Hz,3H)。

B：¹HNMR(400MHz,CDCl₃-d) ppm7.23(d, J =8.1Hz,1H),6.93(dd, J =8.1 and 2.0Hz,1H),6.80(d, J =2.0Hz,1H),2.55(q, J =7.6Hz,2H),2.34(dt, J =8.1 and 5.7Hz,1H)1.26(s,12H),1.15-1.23(m,4H),1.00-1.06(m,1H),0.15-0.23(m,1H)

Tert-butyl 3- {6- [2- (4-butyl-2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Compound 175.4- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride. 4- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -Yl } butyric acid tert-butyl ester (268mg, 0.52mmol) in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (239mg, 92.7%). Rt1.44min (System B), [ M + H]⁺460.0。

The following compounds were obtained in a similar manner:

compound 176.2- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } acetic acid hydrochloride.

Rt1.70min (System B), [ M + H]⁺431.9

Compound 177.3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylpropanoic acid hydrochloride.

Rt1.53min (System B), [ M + H]⁺460.0。

Compound 178.3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),10.20(bs,1H),7.45(d, J =8.1Hz,2H),7.30(t, J =8.1Hz,1,1H),6.67-7.30(M,1H),6.82(d, J =8.4Hz,1,1H),6.68(s,1H),4.47(bs,2H),3.42-3.55(M,2H),3.21-3.42(M,2H),2.95-3.14(M,2H),2.86(t, J =8,3Hz,2H),2.08-2.28(M,4H),1.82-1.95(M,2H),1.54-1.62(M,1H),1.32-1.41(M,1H), 1.45min (rt + H) [ systems + M,1H ], (rt + M)]⁺446.0。

Compound 179.3- [6- (2-phenylcyclopropyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.33min (System B), [ M + H]⁺378.2。

Compound 180.3- {6- [2- (2-fluorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs,1H),10.90(bs,1H),7.09-7.29(M,4H),6.95-7.05(M,1H),6.78(d, J =7.8Hz,1H),6.65(s,1H),4.45(bs,2H),3.38-3.56(M,2H),3.24-3.39(M,2H),2.96-3.20(M,2H),2.88(t, J =7.8Hz,2H),2.12-2.40(M,4H),1.78-1.95(M,2H),1.41-1.55(M,2H), Rt1.35min (System B), [ M + H]⁺396.0。

Compound 181.3- {6- [2- (2-chlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.50(bs,1H),7.46(d, J =4,1Hz,1H),7.40-7.44(M,1H),7.12-7.34(M,3H),6.93-7.08(M,1H),6.82(d, J =6.2Hz,1H),6,70(s,1H),4.48(bs,2H),3.42-3.56(M,2H),3.26-3.39(M,2H),3.00-3.14(M,2H),2.86(t, J =7.7Hz,2H)2.32-2.42(M,1H)2.08-2.32(M,3H)1.81-1.95(M,2H)1.49-1.56(M,1H),1.39-1.49(M,1H), 1.49-1H) 1.49(M,1H) 1H (M,1H) 1H + 1H (rt + 1H) system ]⁺412.0。

Compound 182.3- {6- [2- (2-chloro-5-ethylphenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs.,1H),10.70(bs.,1H),7.31(d, J =8.1Hz,1H),7.06(dd, J =8.1,2.0Hz,1H),6.95-7.10(m,2H),6.79(dd, J =8.1 and 1.2Hz,1H),6.67(d, J =1.2Hz,1H),4.47(bs.,2H),3.43-3.52(m,2H),3.25-3.30(m,2H),2.99-3.11(m,2H),2.88(t, J =7.6Hz,2H),2.58(q, J =7.6Hz,2H),2.34(dt, J =8.8 and 5.4, 1H),2.20-2.30(m = 2H), 2.8.8 =8 and 5.4, 1H), 2.20-2.6 Hz,2H, 2.82 (m =8, 1H), 1H, 8.8, 1H), 1H, 5.6 Hz, 8H, 5H, 8H, 1H, 8, 5, 1H, 5H, 8, 5H, 1H, 5H, 8, 1H, 5H, 1H, [ M + H ]]⁺440.1。

Compound 183.3- {6- [2- (4-butyl-2, 6-dichlorophenyl) cyclopropyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.77min (System B), [ M + H]⁺502.0。

Compound 303.3- [6- (2-phenylethynyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride. To the degassed 3- { - {6- [ (trifluoro-methane) sulfonyloxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]To a mixture of tert-butyl propionate (235mg, 0.5mmol) and phenylacetylene (0.08 mL; 0.76mmol) in dimethyl sulfoxide (5mL) was added tripotassium phosphate monohydrate (128 mg; 0.61 mmol). Palladium (II) acetate (6 mg; 0.03mmol) and triphenylphosphine (26.5 mg; 0.1mmol) were subsequently added. The resulting mixture was heated in an oil bath for 1 hour (80 ℃). After cooling to rt, the mixture was diluted with EtOAc. The reaction mixture was washed with EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: MeOH 95: 5 to 9:1) to give 3- [6- (2-phenylethynyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (C)190 mg; 90%). Rt1.44min (System B), [ M + H]⁺418.3. This product (170 mg; 0.41mmol) was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and heated in an oil bath for 1.5 hours (50 ℃). Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (120mg, 70%).¹HNMR(400MHz,DMSO-d₆) ppm12.55(brs,1H),10.18(brs,1H),7.39-7.45(M,2H),7.28-7.33(M,3H),7.02(s,2H),6.87(s,1H),4.42(s,2H),3.14-3.44(M,4H),2.89-3.01(M,2H),2.73(t, J =8Hz,2H),2.05-2.17(M,2H),1.75-1.84(M,2H), Rt1.37min (System B), [ M + H ], [ RtH ] (System B)]⁺363.2。

The following compounds were obtained in a similar manner:

compound 304.3- {6- [2- - (2-chlorophenyl) ethynyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm7.52-7.56(M,1H),7.40-7.44(M,1H),7.22-7.26(M,2H),7.07-7.14(M,2H),6.97(s,1H),4.39(s,2H),2.88-2.95(M,2H),2.70(t, J =8Hz,2H),2.45(t, J =8Hz,2H),2.03-2.12(M,2H),1.91-2.01(M,2H),1.71-1.78(M,2H),1.46(s,9H), rt1.39min (system B), [ M + H [, [ M, H ] ], or ]⁺396.2。

3- { 6-benzyl-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

To a degassed mixture of B-benzyl-9-BBN (279.3 mg; 1.32mmol) (0.5m/l in THF (15mL) was added tripotassium phosphate monohydrate (420 mg; 1.98mmol) and the reaction mixture was stirred for 15 min, followed by addition of 3- { - {6- [ (trifluoromethane) sulfonyloxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (307mg, 0.66mmol), palladium (II) acetate (6 mg; 0.03mmol) and 2-dicyclohexylphosphino-2 ', 6' -dimethoxy-1 ', 1' -biphenyl (22 mg; 0.05 mmol). The resulting mixture was heated at reflux for 1 hour. After cooling to rt, the mixture was diluted with EtOAc. The reaction mixture was washed with EtOAc and 5%NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: MeOH95:1) to give the product (200 mg; 74.4%) Rt1.40min (System B), [ M + H%]⁺408.2。

3- [6- (2-phenylethyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To a degassed solution of potassium phenethyltrifluoroborate (209 mg; 0.99mmol) in toluene (15mL) and H₂To the mixture in O (1.5mL) was added tripotassium phosphate monohydrate (630 mg; 3mmol), and the resulting reaction mixture was stirred for 15 minutes. Followed by the addition of 3- { - {6- [ (trifluoro-methane) sulfonyloxy ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (307mg, 0.66mmol), palladium (II) acetate (7 mg; 0.03mmol) and 2-dicyclohexylphosphino-2 ', 6' -diisopropoxy-1 ', 1' -biphenyl (30 mg; 0.07 mmol). The resulting mixture was heated in a preheated oil bath for 1 hour (100 ℃). After cooling to rt, the mixture was diluted with EtOAc. The reaction mixture was washed with EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂Dichloromethane: MeOH 95: 5) the product was obtained (190 mg; 68.4%). Rt1.43min (System B), [ M + H]⁺422.2。

3- {6- [ (2- (2, dichlorophenyl) ethyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To degassing [2- (2, 6-dichlorophenyl) ethyl]To a solution of potassium trifluoroborate (0.3 g; 1.07mmol) in toluene (10mL) and water (1mL) was added tripotassium phosphate (0.68 g; 3.2mmol) and the reaction mixture was stirred for 10 minutes. Followed by the addition of 3- { - {6- [ (trifluoromethane) sulfonyloxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (382mg, 0.82mmol), palladium (II) acetate (7.3 mg; 0.03mmol), and 2-dicyclohexylphosphino-2 ', 6' -diisopropoxy-1 ', 1' -biphenyl (30 mg; 0.07 mmol). The resulting mixture was heated at reflux overnight. After cooling to room temperature, the resulting mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO ₃Partitioning between aqueous solutions. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give the product (0.21 g; 52.1%). Rt1.52min (System B), [ M + H]⁺490.0

The desired [2- (2, 6-dichlorophenyl) ethyl group]Potassium trifluoroborate was prepared as follows: to a solution of 2, 6-dichlorostyrene (1.58 mL; 11.6mmol) in THF (15mL) were added chloro (1, 5-cyclooctadiene) iridium (I) dimer (38.8 mg; 0.06mmol), 1, 2-bis (diphenylphosphino) ethane (46.1 mg; 0.12mmol) and pinacolborane (11.6 mL; 1M in THF; 11.6 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo and purified by column chromatography (SiO)₂，Et₂O: Hexane 1: 3). The resulting product was treated with MeOH (56mL), water (14mL), and potassium difluorohydride (3.43 g; 43.9mmol) and stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo, and the residue was treated with toluene and concentrated in vacuo. The following steps were repeated three times to remove all water. Subjecting the obtained solid to CH₃CN treatment and heating at 50 ℃. The precipitate was removed by filtration and washed with CH₃And (5) CN washing. To merge CH₃The CN layer was concentrated in vacuo and the residue was taken up in Et ₂And (4) O treatment. The precipitate formed was collected by filtration and dried in vacuo to give [2- (2, 6-dichlorophenyl) ethyl ] ethyl]Potassium trifluoroborate (1.12g) was used as received.

3- {6- [ (2- (2-fluorophenyl) ethyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. To 3- {6- [ (E) - (2- (2-fluorophenyl) ethenyl) in 10 mM MyLEOH]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (compound 171) (80 mg; 0.18mmol) palladium hydroxide (3 mg; 0.02mmol) was added. Subjecting the mixture to hydrogenation with H₂And (4) treating overnight. The crude reaction mixture was filtered through Celite to give the product (80 mg; 99%). Rt1.39min (System B), [ M + H]⁺440.1。

3- [6- (pentyloxymethyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To the degassed trifluoro (pentyloxymethyl)]Potassium borane (0.3 g; 1.07mmol) (O)To a solution of rg.lett., 2008, vol.10, No.11, 2135 in toluene (20mL) and water (2mL) was added tripotassium phosphate (0.64 g; 3mmol) and the reaction mixture stirred for 10 minutes. Followed by the addition of 3- { - {6- [ (trifluoromethane) sulfonyloxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (325mg, 0.7mmol), palladium (II) acetate (15.6 mg; 0.07mmol), and 2-dicyclohexylphosphino-2 ', 6' -diisopropoxy-1 ', 1' -biphenyl (65 mg; 0.14 mmol). The resulting mixture was heated at reflux for 70 hours. After cooling to room temperature, the mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9:1) to give the product (0.25 g; 84.1%). Rt1.29min (System B), [ M + H]⁺424.4。

3- [6- (anilino) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate. To a solution of degassed aniline (84 mg: 0.9mmol) in toluene (15mL) were added cesium carbonate (342 mg; 1.05mmol), 3- { - {6- [ (trifluoromethane) sulfonyloxy { (III) } and]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate (350mg, 0.75mmol), palladium (II) acetate (8.44 mg; 0.04mmol), phenylboronic acid (4.5 mg; 0.04mmol) and 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl (35 mg; 0.08 mmol). The resulting mixture was heated at 100 ℃ overnight. After cooling to room temperature, the mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane to acetone 97: 3) the product was obtained (0.27 g; 87.9%). Rt1.33min (System B), [ M + H]⁺409.2。

Compound 184.3- { 6-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl } propanoic acid hydrochloride. Mixing 3- { 6-benzyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (180mg, 0.44mmol) of (E) -1' -yl } propanoate dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (120mg, 66.5%). Rt1.29min (System B), [ M + H]⁺352.2。

The following compounds were obtained in a similar manner:

compound 185.3- [6- (2-phenylethyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]The hydrochloride of the propionic acid is obtained,

rt1.37min (System B), [ M + H]⁺366.2。

Compound 186.3- {6- [ (2- (2, dichlorophenyl) ethyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride,

rt1.36min (System B), [ M + H]⁺384.1。

Compound 187.3- {6- [ (2- (2-fluorophenyl) ethyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride,¹HNMR(400MHz,DMSO-d₆) ppm12.90(bs,1H),10.20(bs,1H), 7.42-7.48(M,2H),7.27-7.32(M,1H),7.04(bs,1H),6.82(d, J =6.2Hz,1H),6,69(s,1H),4.48(bs,2H),3.42-3.56(M,2H),3.26-3.39(M,2H),3.00-3.14(M,4H),2.86(t, J =7.7Hz,2H),2.68-2.75(M,2H),2.16-2.30(M,2H),1.85-1.95(M,2H), Rt1.42min (System B), [ M + H [, 2H ] ], 2H ]⁺433.9。

Compound 188.3- [6- (pentyloxymethyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]The hydrochloride of the propionic acid is obtained,¹HNMR(400MHz,DMSO-d₆) ppm12.64(bs,1H),10.18(bs,1H),7.29(t, J =8Hz,2H),7.12(bs,1H),6.88-7.03(M,5H),5.05(s,2H),4.49(s,2H),3.27-3.54(M,4H),3.00-3.16(M,2H),2.84(t, J =8Hz,2H),2.12-2.27(M,2H),1.85-1.94(M,2H) Rt1.32min (System B), [ M + H ], [ Rt1.32min (System B) ], and]⁺368.2

compound 189.3-[6- (anilino) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]The hydrochloride of the propionic acid is obtained,

rt1.24min (System B), [ M + H]⁺353.2

Compound 190.6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]A hydrochloride salt. 2H-spiro [ 1-benzofuran-3, 4' -piperidine]A mixture of-6-ol (2.6 g; 12.7mmol) and di-tert-butyl heavy carbonate (3.04 g; 13.9mmol) in dichloro-methane (50mL) was stirred at room temperature overnight. Subsequently, the resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO)₂，Et₂O; hexane) to give 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (1' -carboxylate) (2.5 g; 81%). Rt1.89min (System B), [ M + H]⁺306.1. To (2, 6-dichlorophenyl) methanol (0.24 g; 1.38mmol) and 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a solution of tert-butyl (0.28g, 0.92mmol) of-1' -carboxylate in dichloromethane (10mL) was added triphenylphosphine (0.36 g; 1.38mmol) and after 30 min DIAD (0.27 mL; 1.38 mmol). Subsequently, the resulting mixture was stirred at room temperature overnight, diluted with dichloromethane, and 5% NaHCO ₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (430mg;100%) 1' -carboxylate.

3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -carboxylate (3.68g, 7.92mmol) was dissolved in 1M HCl solution in EtOH (30mL) and stirred at 50 ℃ for 2 h. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, collecting the precipitate by filtration and drying under reduced pressure overnight to give 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Hydrochloride salt (1.89g, 59%).¹HNMR(400MHz,DMSO-d₆) ppm7.55-7.58 (m,2H)7.46(dd, J =8.1 and 6.2Hz,1H)7.05(d, J =8.1Hz,1H)6.57-6.61(m,2H),5.18(s,2H),4.49(bs,2H),3.23-3.32(m,2H),2.91-3.03(m,2H),1,98-2.10(m,2H),1.77-1.82(m, 2H).

Compound 191.6- [ (2, 6-dichlorophenyl) methoxy group]-1 '-methyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](220 mg; 0.55mmol) and N-ethyldiisopropylamine (0.19 mL; 1.10mmol) in MeOH (20mL), formaldehyde (0.08 mL; 1.1 mmol; 37% in H) was added ₂O) and sodium triacetoxyborohydride (232 mg; 1.1 mmol). Subsequently, the resulting mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with EtOAc, 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue is purified by column chromatography (SiO)₂MeOH) to give the product (160 mg; 67.5%). Rt1.36min (System B), [ M + H]⁺378.0。

Compound 192.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid hydrochloride. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](0.6 g; 1.5mmol) to a mixture in dichloroethane (12mL) was added tert-butyl acetoacetate (1 mL; 6mmol), sodium triacetoxyborohydride (232 mg; 1.1mmol) and one drop of acetic acid. Subsequently, the resulting mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with EtOAc, 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:3) to give 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } butanoate (0.76 g; 72.5%). Rt1.70min (System B), [ M + H ]⁺506.0 for use in 1, 4-bis4MH in alkanesIt was hydrolyzed in Cl solution to yield the product (90%).¹HNMR(400MHz,DMSO-d₆) ppm12.80(bs,1H),10.70(bs,1H),7.55-7.59(M,2H),7.46(dd, J =8.1 and 6.2Hz,1,1H)7.05(bs,1H),6.55-6.62(M,2H),5.18(s,2H),4.52(bs,2H),3.62-3.72(M,1H),3.30-3.48(M,2H),2.98-3.20(M,3H),2.52-2.63(M,1H)2.30-2.48(M,2H), 1.80-1.90(M,2H)1.33(d, J =7.8Hz,3H), rt1.70min (system B), [ M + H ], 1H, 1.4H, 2H, and B]⁺450.0。

Compound 193.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2, 2-difluoropropionic acid. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](1 g; 2.5mmol) in EtOH (10mL) 1H-benzotriazole-1-methanol (0.37 g; 2.5mmol) was added and the reaction mixture was heated at 50 ℃ for 20 min. After cooling to room temperature, the solvent was removed in vacuo to give 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1H-benzotriazole; can be used directly.

To a suspension of zinc powder (0.33 g; 4.99mmol) in anhydrous THF (10mL) were added chlorotrimethylsilane (0.32 mL; 2.5mmol) and ethylbromodifluoroacetate (0.48 mL; 3.74mmol), and the mixture was heated under reflux for 10 minutes and then cooled to room temperature. To the resulting mixture was added dropwise 6- [ (2, 6-dichlorophenyl) -methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1H-benzotriazole in THF (5 mL). After the addition was complete, the resulting mixture was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was filtered through Kieselguhr and the filter cake was washed with ethanol. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } -2, 2-difluoropropionate (0.21 g; 16.8%). Rt2.61min (System B), [ M + H]⁺500.0, which was dissolved in EtOH (15 mL). Sodium hydroxide (3.0 mL; 2 mol/l; 6 mmol; 14.3eq) was added and the reaction mixture was stirred at 50 ℃ for 3 hours, then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (6 mL; 1mol/l), after which it was concentrated in vacuo. The residue was taken up with saturated brine and dichloromethaneAnd (6) processing. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (100 mg; 50.4%).¹HNMR(400MHz,DMSO-d₆) ppm7.56-7.59(M,2H),7.47(dd, J =8.1 and 6.2Hz,1H),7.12(d, J =8.0Hz, 1H),6.58-6.62(M,2H),5.17(s,2H),4.45(bs,2H),3.87(t, J =15.1Hz,2H),3.35-3.42(M,2H),3.03-3.18(M,2H)2.08-2.19(M,2H),1.79-1.85(M,2H) Rt1.77min (System B), [ M + H ] 7.47(dd, J =8.1 and 6.2Hz,1H),7.12(d, J =15.1Hz,2H), 3.3.35-3.42 (M,2H),3 ]⁺472.0。

Compound 194.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2, 2-methylpropanoic acid. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture (0.42 g; 1.05mmol) in dichloroethane (10mL) was added tert-butyl 2, 2-dimethyl-3-oxopropanoate (0.35 g; 2.1mmol), sodium triacetoxyborohydride (0.6 g; 3mmol), and the resulting mixture was stirred at room temperature for 72 hours. Subsequently, the mixture was diluted with EtOAc, 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1:1) to give 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -Yl-tert-butyl 2, 2-Methylpropanoate (0.54 g). Rt1.70min (System B), [ M + H]⁺506.0, which was suspended in THF (11 mL). Lithium hydroxide (82 mg; 3.39mmol) was added to the suspension and the mixture was stirred at 50 ℃ for 48 hours. To the mixture (at room temperature) was added 3mL of 1MHCl, 50mLH₂O and 25mL of phosphate buffer solution (_pH7) In that respect The mixture was washed with dichloromethane (3 times). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give the product (490 mg; 93%). ¹HNMR(400MHz,CDCl₃-d) ppm7.36-7.39(m,2H)7.25(dd, J =8.1 and 6.2Hz,1H),7.08(d, J =8.3Hz,1H),6.60(dd, J =8.2 and 2.3Hz, 1H)6.53(d, J =2.2Hz,1H),5.23(s,2H),4.39(s,2H),3.08-3.18(m,2H),2.45-2.62(m,4H),2.01-2.11(m,2H),1.80-1.88(m, 2H)) 1.27(s,6H). Rt1.64min (System B), [ M + H]⁺464.0。

Compound 305.4- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -3-methylbutyric acid. Reacting 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](0.45g；1.12mmol)、K₂CO₃(0.47 g; 3.37mmol), methyl 4-chloro-3-methylbutyrate, and potassium iodide (0.22 g; 1.35mmol) in CH₃The mixture in CN (20mL) was refluxed for 72 hours. After cooling to room temperature the reaction mixture was quenched with 5% NaHCO₃Aqueous solution and Et₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain 4- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -3-methyl-butyric acid tert-butyl ester (0.16 g; 30%). Rt1.36min (System B), [ M + H]⁺478.6。

A mixture of this product (150 mg; 0.31mmol), aqueous 2M NaOH (2 mL; 4mmol) and ethanol (10mL) was stirred at 50 ℃ for 3h and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (4 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na) ₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O is washed and dried in vacuum to obtain 4- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -3-methyl-butyric acid (50 mg; 32.6%).¹HNMR(400MHz,DMSO-d₆) ppm7.53-7.58(M,2H),7.43-7.50(M,1H),7.12(d, J =8.1Hz,1H),6.51-6.57(M,2H),5.16(s,2H),4.37(s,2H),2.76-2.92(M,2H),2.37(dd, J =15.1,6.0Hz,1H),2.18-2.24(M,2H),2.07-2.17(M,2H),1.98-2.06(M,2H),1.78-1.89(M,2H),1.62(d, J =12.9Hz,2H),0.89(d, J =6.4Hz,3H), rt1.39min (system B), [ M + H =12.9Hz,2H ], (system B), [ M + H ], (1H), 2H), 5.6.6.5.0.4 Hz,3H, 2H]⁺464.6。

Compound 306.4- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } pentanoic acid. To 6- [ (2, 6-dichlorophenyl) -methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](0.63 g; 1.57mmol) in dichloroethane (12mL) was added ethyl levulinate (0.67 mL; 4.72mmol), sodium triacetoxyborohydride (0.93 g; 4.4mmol) and a few drops of acetic acid. The resulting mixture was stirred at room temperature for 72 hours. Subsequently, the mixture was diluted with EtOAc, 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO) ₂，Et₂1: 1O: hexane) to obtain ethyl 4- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } pentanoate (0.14 g; 18.8%). Rt1.40min (System B), [ M + H]⁺492.6, which was hydrolyzed to the acid as described for compound 305 (100mg; 70%).¹HNMR(400MHz,DMSO-d₆) ppm7.54-7.59(M,2H),7.44-7.50(M,1H),7.07(d, J =8.1Hz,1H),6.53-6.60(M,2H),5.17(s,2H),4.41-4.48(M,2H),2.97-3.10(M,2H),2.72-2.82(M,1H),2.58-2.69(M,1H),2.25-2.41(M,2H),1.91-2.13(M,4H),1.75(d, J =12.9Hz,2H),1.52-1.63(M,1H),1.12(d, J =6.4Hz,3H), rt1.35min (system B), [ M + H ], [ M + H =12.9Hz,2H ], 2H, 1.52-1.63(M,1H),1.12(d, J =6.4Hz,3H), rt1.35min (]⁺464.6。

Compound 195.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } ethan-1-ol hydrochloride. Reacting 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](1.61 g; 4.02mmol), 2- (2-chloroethoxy) tetrahydro-2H-pyran (0.71 ml; 4.82mmol), K₂CO₃A mixture of (1.67 g; 12.05mmol) and NaI (0.12 g; 0.8mmol) in DMF215mL) was heated to 100 ℃ overnight. After cooling to room temperature the reaction mixture was quenched with 5% NaHCO₃Aqueous solution and Et₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO) ₂，Et₂O) to obtain 6- [ (2, 6-dichlorophenyl) methoxy]-1 '- [2- (oxapropan-3-yloxy) ethyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine](1 g; 50%) it was dissolved in MeOH (20 mL). To the reaction mixture was added p-toluenesulfonic acid oneHydrate (0.39 g; 2mmol) and the resulting mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was washed with 5% NaHCO₃Partitioned between aqueous and EtOAc. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂MeOH) to give the product (0.46g), which was converted to the HCl salt by concentration in vacuo after treatment with 1m HCl in EtOH (70 mg; 7.7%).¹HNMR(400MHz,DMSO-d₆)ppm9.70(bs.,1H),7.54-7.80(m,2H),7.44-7.50(m,1H),7.0(d,J=7.9Hz,1H),6.55-6.62(m,2H),5.37(m,1H),5.17(s,2H),4.50(s,2H),3.74-3.82(m,2H),3.49-3.57(m,2H),3.14-3.20(m,2H),3.00-3.12(m,2H),2.13-2.27(m,2H),1.81-1.89(m,2H)。

Compound 196.(2- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } ethoxy) phosphonic acid. To 3- {6- [ (2, 6-dichlorophenyl) methoxy group at room temperature]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a solution of-1' -yl } ethan-1-ol (0.36 g; 0.88mmol) in N, N-dimethylformamide (3mL) was added tetrazole in CH₃CN (7.84 mL; 0.45 mmol). The resulting mixture was stirred for 30 minutes, then di-tert-butyl-N, N-diisopropylphosphoramidite (0.56 mL; 1.76mmol) was added and stirred, and the reaction mixture was stirred for 1.5 hours. Subsequently, the mixture was cooled to 0 ℃ and a solution of tert-butyl hydroperoxide in nonane (0.24 mL; -5.5 mol/l, 1.32mmol) was added. After this time the mixture was stirred at room temperature for a further 30 min. By adding 5% NaHCO ₃The reaction was quenched with aqueous EtOAc and extracted with EtOAc. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂EtOAc followed by MeOH) afforded (2- {6- [ (2, 6-dichlorophenyl) methoxy)]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Di-tert-butyl-1' -yl } ethyl) phosphonate (0.30 g; 62.5%). Rt2.03min (System B), [ M + H]⁺544.0, dissolved in hydrochloric acid (5 mL; medium 4 mol/l; 20 mmol). The reaction was stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.23g, 81)%)。¹HNMR(400MHz,DMSO-d₆) ppm11.30(bs,1H),7.55-7.59(M,2H),7.46(dd, J =8.1 and 6.2Hz,1H),7.10(bs,1H),6.55-6.62(M,2H),5.18(s,2H),4.48(bs,2H),4.18-4.24(M,2H),3.30-3.48(M,2H),3.44-3.53(M,2H),3.35-3.43(M,2H),3.09-3.2(M,2H),2.13-2.24(M,2H),1.84-1.91(M,2H), Rt2.03min (System B), [ M + H]⁺487.9。

Compound 197.6- [ (2, 6-dichlorophenyl) methoxy group]-1 '- [2- (1H-1,2,3, 4-tetrazol-5-yl) ethyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture (0.51 g; 1.27mmol) in MeOH (10mL) was added N-ethyldiisopropylamine (0.27 mL; 1.59mmol) and acrylonitrile (0.11 mL; 2.8mmol), and the resulting mixture was stirred at 80 deg.C for 4 hours (in a closed borosilicate glass bottle). Subsequently, the mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO) ₂，Et₂O) to obtain 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionitrile (0.31 g; 58%). Rt1.80min (System B), [ M + H]⁺417.0, dissolved in toluene (10 mL). Azidotrimethyltin (0.39 g; 1.8mmol) was then added and the reaction mixture was heated at 100 ℃ for 72 hours. Subsequently, the mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO)₂EtOAc: MeOH9:1, then MeOH) gave the product (0.09 g; 29.3%). Rt1.54min (System B), [ M + H]⁺460.0。

Compound 198.(3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propyl) phosphonic acid. Reacting 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine](0.59 g; 1.47mmol), diethyl (3-bromopropyl) phosphonate (0.34 mL; 1.77mmol), NaI (0.04 g; 0.29mmol) and K₂CO₃(0.61 g; 4.42mmol) in CH₃The mixture in CN (10mL) was heated at reflux for 2 hours. After cooling to room temperature the mixture was washed with 5% NaHCO₃Aqueous solution and Et₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. Passing the residue through a columnChromatographic purification (SiO)₂EtOAc: MeOH90:10) to yield diethyl (3- {6- [ (2, 6-dichlorophenyl) methoxy) ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propyl) phosphonate (0.8 g; 85., 1%). Rt1.62min (System B), [ M + H]⁺542.0, diethyl (3- {6- [ (2, 6-dichlorophenyl) methoxy)]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propyl) phosphonate (0.68 g; 1.25mmol) in CH₂Cl₂To the solution in (15mL) was added bromotrimethylsilane (1.32 mL; 10mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated in vacuo, redissolved in MeOH (10mL) and stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and treated with iPr₂And O. The precipitate was collected by filtration and dried in vacuo to give the product (0.65 g; 86.8%).¹HNMR(400MHz,DMSO-d₆) ppm9.10-11.10(M,2H),7.54-7.59(M,2H),7.46(dd, J =8.1 and 6.2Hz,1H),7.10(bs,1H),6.55-6.62(M,2H),5.18(s,2H),4.52(bs,2H),3.40-3.58(M,2H),3.12-3.24(M,2H),2.97-3.12(M,2H),2.02-2.13(M,2H),1.83-1.97(M,4H),1.59-1.70(M,2H), Rt1.61min (System B), [ M + H [ ], [ M ], 2H ], []⁺485.9。

Compound 199.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -3-oxopropanoic acid. To 6- [ (2, 6-dichlorophenyl) methoxy group at 0 DEG C]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a suspension of (0.62 g; 1.55mmol) and N-ethyldiisopropylamine (0.79 mL; 4.64mmol) in dichloromethane (15mL) was added ethylmalonyl chloride (0.3 mL; 2.32mmol) dropwise. The resulting mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was washed with 5% NaHCO ₃The aqueous solution was partitioned with dichloromethane. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain ethyl 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -3-oxopropanoate (0.46 g; 62.1%). Rt2.44min (System B), [ M + H]⁺478.0, dissolved in EtOH (15mL) and sodium hydroxide (3 mL; 2 mol/l; 6mmol) and the mixture stirred at 50 ℃ overnight. Cooling to room temperature and adding the resulting mixtureLoaded onto a PE-AX column [ ISOLUTE (BiotageAB); 0.58mmol/g, 10g]The above. CH for column₃CN washing, then removing the required compound from CH₃Elution with 20v/v% TFA in CN. The fractions containing the compound were concentrated in vacuo to afford the product (60 mg; 14.8%). Rt2.62min (System B), [ M + H]⁺450.0。

Compound 307.2-methyl-4- {6- [ (2,4, 6-trichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butanoic acid. 2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-ol (1.06 g; 5.16mmol), N-ethyldiisopropylamine (2.65 mL; 15.49mmol), potassium iodide (0.86 g; 5.16mmol) and methyl 4-chloro-2-methylbutyrate in CH₃The mixture in CN (50mL) was refluxed for 72 hours. After cooling to room temperature the reaction mixture was quenched with 5% NaHCO ₃Aqueous solution and Et₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to give 4- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } -2-methylbutyrate (0.82 g; 50%).¹HNMR(400MHz,CDCl₃-d) ppm6.93(d, J =8.3Hz,1H),6.28-6.36(m,2H),4.35(s,2H),3.69(s,3H),2.88-2.94(m,2H),2.47-2.55(m,1H),2.32-2.41(m,2H),1.86-2.06(m,5H),1.57-1.75(m,3H),1.18(d, J =7.6Hz,3H) to (2,4, 6-trichlorophenyl) methanol (0.24 g; 1.13mmol) and 4- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } -2-methylbutyrate (0.29g, 0.91mmol) in dichloromethane (20mL) triphenylphosphine (0.3 g; 1.13mmol) was added and after 30 min DIAD (0.22 mL; 1.13mmol) was added. Subsequently, the resulting mixture was stirred at room temperature overnight, diluted with dichloromethane, and 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO)₂，Et₂O: Hexane 1: 1) to give 2-methyl-4- {6- [ (2,4, 6-trichlorophenyl)Methoxy radical]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } butyric acid tert-butyl ester acid (butanoateacid) (280 mg; 60%). Rt1.51min (System B), [ M + H ]⁺514.1。

A mixture of this product (270 mg; 0.53mmol), aqueous 2M NaOH (2 mL; 4mmol) and ethanol (10mL) was stirred at 50 ℃ for 3h and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (4 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (160 mg; 60%).¹HNMR(400MHz,DMSO-d₆) ppm7.79(s,2H),7.11(d, J =8.0Hz,1H),6.49-6.55(M,2H),5.13(s,2H),4.36(s,2H),2.80-2.88(M,2H),2.31-2.42(M,3H),1.96-2.10(M,2H),1.72-1.87(M,3H),1.61(d, J =12.4Hz,2H),1.45-1.55(M,1H),1.07(d, J =7.0Hz,3H) rt1.49min (system B), [ M + H [ ]]⁺500.1。

The following compounds were obtained in a similar manner:

compound 308.4- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylbutyric acid.¹HNMR(400MHz,DMSO-d₆) ppm7.54-7.59(M, J =7.6Hz,2H),7.44-7.50(M,1H),6.92-7.18(M,1H),6.56-6.62(M,2H),5.17(s,2H),4.47(s,2H),3.25-3.54(M,3H),2.91-3.19(M,3H),2.42-2.49(M,1H),2.12-2.29(M,2H),1.94-2.09(M,1H),1.75-1.91(M,3H),1.13(d, J =8.5Hz,3H), rt.1.34min (system B), [ M + H, 3H) ("rt 1.1H") ]⁺464.1。

Compound 309.4- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylbutyric acid.¹HNMR(400MHz,DMSO-d₆)ppm7.33-7.38(m,2H),7.24-7.30(m,1H),7.11(d,J=7.5Hz,1H),6.50-6.57(m,2H),5.09(s,2H),4.38(s,2H),2.88-2.99(m,2H),2.71(q,J=8.1Hz,2H),2.36-2.44(m,1H),2.15-2.23(m,1H),1.74-1.93(m,3H)1.65(d, J =12.9Hz,2H),1.49-1.60(M,1H),1.16(t, J =8.1Hz,3H),1.09(d, J =7.1Hz,3H), rt1.39min (system B), [ M + H]⁺458.2。

Compound 310.4- {6- [ (2-chloro-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } -2-methylbutyric acid.¹HNMR(400MHz,DMSO-d₆) ppm7.47-7.54(M,1H),7.39-7.45(d, J =8.4Hz,1H),7.28-7.35(t,1H),7.11(d, J =7.8Hz,1H),6.48-6.56(M,2H),5.08(d, J =1.6Hz,2H),4.36(s,2H),2.79-2.89(M,2H),2.31-2.43(M,3H),1.96-2.10(M,2H),1.72-1.88(M,3H),1.61(d, J =12.7Hz,2H),1.45-1.54(M,1H),1.07(d, J =7.6Hz,3H), rt1.31min (system B), [ M + H ], [ rt + H ], [ 1H ], (r, 3H) ], 1.]⁺448.2。

3- { 5-bromo-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -yl } propionic acid tert-butyl ester. To a solution of 2,2,6, 6-tetramethylpiperidine (16.1 mL; 95.5mmol) in tetrahydrofuran (370mL (-78 deg.C) was added n-butyllithium (38.19mL, 2.5mol/l in hexane, 95.5 mmol). The reaction mixture was stirred for 90 minutes, bringing the temperature to 0 ℃. Subsequently (at-70 ℃ C.) 2-fluoropyridine (8.2 mL; 95.5mmol) in THF (10mL) was added dropwise. During the addition, the temperature of the reaction mixture was kept below-60 ℃. The reaction mixture was stirred at-70 ℃ for one hour, after which iodine (29 g; 114.6mmol) in tetrahydrofuran (50mL) was added dropwise. The resulting reaction mixture was stirred at-70 ℃ for 2 hours. The reaction mixture was warmed to 0 ℃ and saturated NH was added ₄Aqueous Cl solution, then Et₂And O, stopping the reaction. The organic phase is separated off and extracted with sodium bisulfite solution, followed by NaHCO₃And (4) extracting with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane 5: 95) to give 2-fluoro-3-iodopyridine (15.59 g; 73%).¹H-NMR(CDCl₃400MHz) ppm8.21-8.13(m,2H),7.01-6.95(m,1H) Rt1.55minSystem B), [ M + H]⁺224.0。

To a stirred solution of (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methanol (WO2007/057775) (11.73 g; 57.7mmol) in N, N-dimethylformamide (114mL) was added a dispersion of sodium hydride in mineral oil (2.32g) (portionwise). The reaction mixture was allowed to stand at room temperature for 1 hour and added to 2-fluoro-3-iodopyridine (11.39 g; 51mmol) dissolved in N, N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 5% sodium bicarbonate solution and extracted with ether. The organic layer was washed with water (3 times) and brine. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂1:1 of O and hexane) to obtain 2- [ (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methoxy]3-iodopyridine (17.5 g; 84.31%). ¹H-NMR(CDCl₃400MHz) ppm: 8.07(d, J =5.8Hz,1H),8.00(d, J =3.0Hz,1H),7.36-7.23(M,5H),6.63(t, J =4.8Hz,1H),5.87-5.80(M,1H),4.76(s,2H),3.07-3.00(s,2H),3.03(s,2H),2.64(t, J =5.8Hz,2H),2.32-2.24(M,2H), rt1.19min (system B), [ M + H ], 1H, and so on]⁺407.1。

To strongly degassed 2- [ (1-benzyl-1, 2,3, 6-tetrahydropyridin-4-yl) methoxy]To a solution of 3-iodopyridine (3.5 g; 8.62mmol) in toluene (500mL) were added 2, 2' -azo (2-methylpropanenitrile) (0.28 g; 1.72mmol) and tri-n-butyltin hydride (6.95 mL; 28.85mmol) in that order. The reaction mixture was heated at 110 ℃ for 24 hours. After cooling to room temperature, the mixture was taken up in Et₂O was diluted and washed with 10% aqueous KF. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain 1' -benzyl-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines](2.42g；70%)。¹H-NMR(CDCl₃400MHz) ppm: 8.01(d, J =3.5Hz,1H),7.42(d, J =5.5Hz,1H),7.35-7.25(M,5H),6.81(t, J =5.3Hz,1H),4.39(s,2H),3.54(s,2H),2.91-2.83(M,2H),2.13-2.03(M,2H),2.01-1.91(M,2H),1.80-1.71(M,2H) rt0.89min (system B), [ M + H, 1H), rt0.89min (system B), and so on]⁺281.1。

A solution of N, N-dimethylcholamine (1.64 mL; 16.26mmol) in THF (10mL) was cooled to-5 deg.C, after which N-butyllithium (13mL, 2.5M in hexanes; 32.52mmol) was added dropwise (chem. Rev., 1993, 93, 2317). The resulting yellow mixture was stirred at 0 ℃ for 30 minutes. Subsequently, the reaction mixture was cooled to-78 ℃ and 1' -benzyl-2H-spiro [ furo [2,3-b ] was added ]Pyridine-1, 4' -piperidines](1.52 g; 5.42mmol) in THF (10 mL). The resulting reaction mixture was stirred for 1 hour. Subsequently, a solution of 1, 2-dibromotetrafluoroethane (2.58 mL; 21.7mmol) in THF (40mL) was added to the reaction mixture. After addition, the reaction mixture was allowed to warm slowly and stirred at room temperature overnight. By adding saturated NaH₄Aqueous Cl solution, then Et₂O stops the reaction mixture. The organic phase is separated off and NaHCO₃And (4) extracting with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane, triethylamine 35: 60: 5) to obtain 1' -benzyl-5-bromo-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines](0.65g；33.3%)。¹H-NMR(CDCl₃400MHz) ppm: 7.36-7.25(M,6H),7.00(d, J =7.3Hz,1H),4.43(s,2H),3.55(s,2H),2.90-2.82(M,2H),1.98-1.87(M,2H),1.78-1.71(M,2H) rt1.09min (system B), [ M + H ]]⁺361.1。

To the 1' -benzyl-5-bromo-2H-spiro [ furo [2,3-b ] at 0 deg.C]Pyridine-1, 4' -piperidines](0.9 g; 2.56mmol) in 1, 2-dichloroethane (20mL) was added 1-chloroethyl chloroformate (0.3 mL; 2.74 mmol). The reaction mixture was stirred at 60 ℃ for 3 hours. The crude reaction mixture was concentrated in vacuo. Toluene (100mL) was added and the mixture was concentrated. This last step was repeated twice. MeOH (20mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo to give 5-bromo-2H-spiro [ furo [2,3-b ] ]Pyridine-1, 4' -piperidines]Hydrochloride salt (0.85 g;>100%)。¹H-NMR(DMSO-d₆400MHz) ppm: 9.17-9.03(M,1H),7.55(d, J =7.5Hz,1H),7.18(d, J =7.5Hz,1H),4.58(s,2H),3.65-3.25(M,3H),3.07-2.92(M,2H),2.15-2.03(M,2H),1.93-1.84(M,2H). rt0.85min (system B), [ M + H [, 1H ], 2.5 Hz,1H, 2H ], 3.65-3.25(M,3H),3.07-2.92(M,2H),2.15-2.]⁺269.0

To a suspension of 5-bromo-2H-spiro [ furo [2,3-b ] pyridine-1, 4' -piperidine ] hydrochloride (0.85 g; 2.78mmol) in MeOH (20mL) was added tert-butyl methacrylate (0.48 mL; 3.34mmol) and N, N-diisopropylethylamine (1 mL; 5.84 mmol). The resulting mixture was heated in a closed flask at 140 ℃ overnight.

After cooling to room temperature the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain 3- { 5-bromo-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]Tert-butyl-1' -yl } propanoate (630 mg; 57%).¹H-NMR(CDCl₃400MHz) ppm: 7.26(d, J =7.5Hz,1H),7.01(d, J =7.5Hz,1H),4.42(s,2H),2.90-2.82(M,2H),2.69(t, J =7.3Hz,2H),2.43(t, J =7.3Hz,2H),2.15-2.05(M,2H),1.95-1.85(M,2H),1.46(s,9H) rt1.15min (system B), [ M + H ] r]⁺399.0

3- {5- [ (2-chlorophenyl) methoxy-2H-spiro [ furo [2,3-b ] pyridine-1, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester.

To degassed 3- { 5-bromo-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]To a solution of tert-butyl (1 ' -yl) propionate (300mg, added 0.76mmol) and (2-chlorophenyl) methanol (215.32 mg; 1.51mmol) in toluene (2.67mL) were added cesium carbonate (0.37g, 1.13mmol), palladium (II) acetate (3.39mg, 0.02mmol), and 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl (7.26mg, 0.02 mmol). The reaction mixture was stirred at 70 ℃ overnight. After one night, palladium (II) acetate (3.39mg, 0.02mmol) and 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl (7.26 mg; 0.02mmol) were added to the reaction mixture. The resulting mixture was stirred for an additional 3 hours. After cooling to room temperature, the reaction was mixedThe material was diluted with EtOAc, filtered and washed with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane, triethylamine 50:49: 1) to give 3- {5- [ (2-chlorophenyl) -methoxy-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -yl) propionic acid tert-butyl ester (220 mg; 63%).¹H-NMR(CDCl₃400MHz) ppm: 7.54-7.52(M,1H),7.39-7.36(M,2H),7.28-7.24(M,2H),6.36(d, J =7.8Hz,1H),5.42(s,2H),4.40(s,2H),2.90-2.81(M,2H),2.68(t, J =7.5Hz,2H),2.44(t, J =7.5Hz,2H),2.15-2.05(M,2H),1.96-1.86(M,2H),1.70-1.78(M,2H),1.46(s,9H), rt1.38min (system B), [ M + H ] H ]⁺459.0。

The following compounds were obtained in a similar manner:

3- {5- [ (2, 6-dichlorophenyl) methoxy-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -yl]Tert-butyl propionate.¹H-NMR(CDCl₃400MHz) ppm: 7.21-7.37(M,4H),6.31(d, J =7.8Hz,1H),5.54(s,2H),4.42(s,2H),2.90-2.82(M,2H),2.70(t, J =7.5Hz,2H),2.44(t, J =7.5Hz,2H),2.17-2.06(M,2H),1.97-1.87(M,2H),1.79-1.69(M,2H),1.46(s,9H), rt1.40min (system B), [ M + H ] rt]⁺493.0。

Tert-butyl 3- [5- (2, 6-dimethylphenoxy) -2H-spiro [ furo [2,3-b ] pyridin-1, 4 '-piperidin ] -1' -yl ] propionate. To a solution of degassed tert-butyl 3- { 5-bromo-2H-spiro [ furo [2,3-b ] pyridine-1, 4 '-piperidin ] -1' -yl } propanoate (250 mg; 0.63mmol) in xylene (3mL) were added 2, 6-dimethylphenol (76.78 mg; 0.63mmol), potassium carbonate (173.92 mg; 1.26mmol), 1-butylimidazole (0.50 mL; 3.8mmol) and copper (I) iodide (23.97 mg; 0.13mmol) in that order. The reaction mixture was heated at 140 ℃ and stirred overnight. After the mixture is cooled to the room temperature,

the reaction mixture was diluted with EtOAc, filtered and diluted with 5% NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane, triethylamine 50:49: 1) The product was obtained (70mg, 25%).¹H-NMR(CDCl₃400MHz) ppm: 7.33(d, J =7.8Hz,1H),7.07-7.02(M,3H),6.09(d, J =7.8Hz,1H),4.38(s,2H),2.89-2.81(M,2H),2.69(t, J =7.5Hz,1H),2.43(t, J =7.5Hz,2H),2.13(s,6H),2.10-2.03(M,2H),1.95-1.85(M,2H),1.78-1.71(M,2H),1.45(s,9H), 1.35min (system B), [ M + H rtt, 1H ], (system B), [ M + H { (1H) }]⁺493.1。

Compound 200.3- {5- [ (2-chlorophenyl) methoxy-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -yl } propanoic acid hydrochloride.

3- {5- [ (2-chlorophenyl) methoxy-2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -Yl) propionic acid tert-butyl ester (200 m)_g0.44mmol) in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (170mg, 88%).¹HNMR(400MHz,DMSO-d₆) ppm12.08(bs,1H),10.9(bs,1H),7.56-7.48(M,3H),7.41-7.36(M, 2H),6.45(d,1H),5.32(s,2H),4.56-4.55(M,2H),3.5-3.4(M,2H),3.37-3.27(M,2H),3.20-3.01(M,2H),2.87(t, J =7.4Hz,2H),2.30-2.10(M,2H),1.96-1.87 (Rtm, 2H), 1.30min (System B), [ M + H ], [ M, H ]]⁺403.0

Prepared in a similar manner:

compound 201.3- {5- [ (2, 6-dichlorophenyl) methoxy-2H-spiro [ furo [2,3-b ] ]Pyridine-1, 4' -piperidines]-1' -yl) propionic acid hydrochloride.¹H-NMR(DMSO-d₆400MHz) ppm: 12.08(bs,1H),10.03(bs,1H),7.58-7.41(M,4H),6.40-6.36(M,2H),5.39(s,2H),4.59-4.53(M,2H),3.55-3.4(M,2H),3.34-3.22(M,2H),3.15-2.99(M,2H),2.85(t, J =7.3Hz,2H),2.28-2.13(M,2H),1.96-1.87(M,2H), Rt1.32min (System B), [ M + H ] 2]⁺436.9

Compound 202.3- [5- (2, 6-dimethylphenoxy) -2H-spiro [ furo [2,3-b ]]Pyridine-1, 4' -piperidines]-1' -yl]Propionic acid hydrochloride.¹H-NMR(DMSO-d₆,400MHz)ppm：

12.08(bs,1H),10.03(bs,1H),7.52(s,1H),7.15-7.04(M,3H),6.40-6.36(M,2H),4.53-4.40(M,2H),3.52-3.40(M,2H),3.39-3.25(M,2H),3.13-2.93(M,2H),2.84(t, J =7.3Hz,2H),2.20-2.08(M,2H),2.03(s,6H),1.97-1.87(M,2H), 1.24min (System B), [ M + H RtR (M,2H) } (M, 1H), [ M + H (M,2H) ] (M,2H)]⁺383.1

3- { 4-hydroxy-4- [ 4-hydroxy-2- (hydroxymethyl) phenyl } piperidin-1-yl } propanoic acid tert-butyl ester. Reacting 5- (benzyloxy) -3H-spiro [ 2-benzofuran-1, 4' -piperidine]-3-one (5g, mp138-142 ℃) prepared according to J.org.chem., 40, 10, 1975, 1427, reduced to 4- [4- (benzyloxy) -2- (hydroxymethyl) phenyl]Piperidin-4-ol (US3962259) (4.3g, mp198-202 ℃) was converted to 3- {4- [4- (benzyloxy) -2- (hydroxymethyl) -phenyl ] using the conditions described previously (N, N-diisopropylamine in MeOH before tert-butyl acrylate) ]Tert-butyl (4-hydroxypiperidin-1-yl) propionate (2.3 g). Using the following conditions (Pd (OH)₂/H₂Debenzylation of this intermediate with MeOH (overnight at room temperature) afforded the title compound (1.6g, m)_p68-70℃)。¹HNMR(400MHz,DMSO-d₆)ppm9.1(bs,1H),7.09(bd,J=8Hz,1H),6.97(bs,1H),6.54(bd,J=8Hz,1H),5.69(bs,1H),4.99(bs,1H),4.74(bs,2H),2.66-2.31(m,8H),1.92-1.73(m,4H),1.41(s,9H)。

3- {5- [ (2, 6-dichlorophenyl) methoxy group]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Tert-butyl 3- { 4-hydroxy-4- [ 4-hydroxy-2- (hydroxymethyl) phenyl } piperidin-1-yl } propanoate (0.41 g; 1.17mmol), K₂CO₃(1.61 g; 11.67mmol) and 2- (bromoethyl) -1,3A mixture of-dichlorobenzene (0.28 g; 1.17mmol) in acetone (50mL) was heated at 35 deg.C overnight. After cooling to room temperature the reaction mixture was quenched with NaHCO₃Partition between aqueous solution and DCM. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂DCM followed by EtOAc) gave 3- (4- {4- [ (2, 6-dichlorophenyl) -methoxy]-tert-butyl 2- (hydroxymethyl) phenyl } -4-hydroxypiperidin-1-yl) propionate (0.49 g; 84.8%). Rt1.32min (System B), [ M + H]⁺510.1, which was dissolved in DCM (100 mL). Triethylamine (0.54 mL; 4mmol) and methanesulfonyl chloride (0.16 mL; 2.06mmol) were added successively and the resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was washed with NaHCO₃Partition between aqueous solution and DCM. The organic layer was dried (Na) ₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂And DCM: EtOAc3:1 followed by 1: 1) gave 3- {5- [ (2, 6-dichlorophenyl) -methoxy]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]Tert-butyl (1' -yl) propionate (0.26 g; 56.1%). Rt1.45min (System B), [ M + H]⁺492.1。

The following compounds were obtained in a similar manner:

3- [5- (cyclohexylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

3- {5- [ (2-chlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- (5- { [2- (trifluoromethyl) phenyl ] methoxy } -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoate.

3- [5- (Oxopropyl-2-ylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propionic acid tert-butyl ester.

3- {5- [ (3-chlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- {5- [ (2, 3-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (5- { [3- (trifluoromethyl) phenyl ] methoxy } -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {5- [ (2, 5-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {5- [ (3, 5-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoate.

Compound 203.3- {5- [ (2, 6-dichlorophenyl) methoxy group]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {5- [ (2, 6-dichlorophenyl) methoxy]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]Tert-butyl (260mg, 0.53mmol) of (E) -1' -yl } propanoate was dissolved in 1, 4-bisIn a solution of 4MHCl in an alkane (8 mL; 4 mol/l; 32mmol) and stirred at room temperature for 72 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (220mg, 95.5%).¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs.,1H),10.40(bs,1H),7.56-7.60(M,2H),7.46-7.51(M,1H),7.00-7.18(M,3H),5.22(s,2H),5.02(s,2H),3.42-3.49(M,2H),3.30-3.39(M,2H),3.11-3.21(M,2H),2.84(t, J =7.6Hz,2H),2.21-2.31(M,2H),1.78-1.86(M,2H). Rt1.35min (System B), [ M + H ], [ M, H ] (B)]⁺436.1。

The following compounds were obtained in a similar manner:

compound 204.3- [5- (cyclohexylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.41min (System B), [ M + H]⁺374.2。

Compound 205.3- {5- [ (2-chlorophenyl) methoxy group ]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.35min (System B), [ M + H]⁺402.1。

Compound 206.3- (5- { [2- (trifluoromethyl) phenyl]Methoxy } -3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.36min (System B), [ M + H]⁺436.1。

Compound 207.3- [5- (Oxopropyl-2-ylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.17min (System B), [ M + H]⁺376.2。

The compound 208.3- {5- [ (3-chlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid hydrochloride.

Rt1.34min (System B), [ M + H]⁺402.1。

Compound 209.3- {5- [ (2, 3-dichlorophenyl) methoxy group]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride

¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs,1H),10.40(bs,1H),7.65-7.79(M,1H),7.56-7.60(M,1H),7.43(t, J =7.5Hz,1H),6.98-7.13(M,3H),5.20(s,2H),5.01(s,2H),3.43-3.51(M,2H),3.31-3.39(M,2H),3.12-3.23(M,2H),2.85(t, J =7.6Hz,2H), 2.21-2.31(M,2H),1.78-1.86(M,2H), Rt1.40min (System B), [ M + H]⁺436.1。

Compound 210.3- (5- { [3- (trifluoromethyl) phenyl]Methoxy } -3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.40min (System B), [ M + H ]⁺436.1。

Compound 211.3- {5- [ (2, 5-dichlorophenyl) methoxy group]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

Rt1.43min (System B), [ M + H]⁺436.1。

Compound 212.3- {5- [ (3, 5-dichlorophenyl) methoxy group]-3-H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.80(bs,1H),10.50(bs,1H),7.58-7.61(m,1H),7.50-7.53(m,2H),6.96-7.10(m,3H),5.13(s,2H),4.99(s,2H),3.44-3.53(m,2H),3.30-3.39(m,2H),3.11-3.22(m,2H),2.86(t,J=7.6Hz,2H),2.21-2.32(m,2H),1.76-1.85(m,2H)。

Compound 213.3- {6- [ ((2, 6-dichlorophenyl) carbamoyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride

1 '-benzyl-6-bromo-2H-spiro [ 1-benzofuran-3, 4' -piperidine]A solution (0.51 g; 0.87mmol) in tetrahydrofuran (50mL) was cooled to-78 deg.C and n-butyllithium (0.35mL, 2.5mol/l in hexanes, 0.87mmol) was added. Subsequently (at-78 ℃ C.) 1, 3-dichloro-2-isocyanatobenzene (0.18 g; 0.96mmol) in THF (10mL) is added dropwise. The reaction mixture was stirred at-70 ℃ for 30 minutes. The reaction mixture was warmed to 0 ℃ and saturated NH was added₄An aqueous solution of Cl,

Then Et was added₂And O, stopping the reaction. The organic phase is separated off and NaHCO₃And (4) extracting with an aqueous solution. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane 1: 2) to obtain 1 '-benzyl-N- (2, 6-dichlorophenyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]6-carboxamide (0.17 g; 41.8%). Rt1.22min (System B), [ M + H]⁺467.1。

To a solution of 1 '-benzyl-N- (2, 6-dichlorophenyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] -6-carboxamide (0.17 g; 0.36mmol) in 1, 2-dichloroethane (10mL) at 0 deg.C,

1-chloroethyl chloroformate (0.08 mL; 0.76mmol) and a few drops of triethylamine were added. The reaction mixture was stirred at room temperature for 3 hours. The crude reaction mixture was concentrated in vacuo. Toluene (100mL) was added and the mixture was concentrated. This last step was repeated twice. MeOH (20mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. The product is concentrated to obtain N- (2, 6-dichlorophenyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-6-carboxamide (0.14 g; 100%)

Rt1.05min (System B), [ M + H]⁺377.1, dissolve it in MeOH (10 mL). Tert-butyl acrylate (0.06 mL; 0.44mmol) and N, N-diisopropylethylamine (0.09 mL; 0.50mmol) were then added. The resulting mixture was heated in a closed flask at 140 ℃ overnight. After cooling to room temperature, the reaction mixture was quenched with 5% NaHCO₃Partitioned between aqueous and EtOAc. After separation, the organic layer was dried (Na) ₂SO₄) Filtered and concentrated. The residue was purified by column chromatography (SiO)₂，Et₂O）

To give 3- {6- [ ((2, 6-dichlorophenyl) carbamoyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (160mg, 79%). Rt1.25min (System B), [ M + H]⁺505.1, dissolving it in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the title compound (140mg, 80.9%). Rt1.09min (System B), [ M + H]⁺449.1。

Compound 311.3- {6- [ ((2, 6-dichlorobenzene) amide group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.

To degassed 2, 6-dichlorobenzamide (113 mg; 0.6mmol) and 3- { - {6- [ (trifluoromethane) sulfonyloxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]To a solution of tert-butyl propionate (232mg, 0.5mmol) in tert-butanol (7.5mL) was added tripotassium phosphate (0.16 g; 0.75 mmol). Followed by tris- (diphenylmethyleneacetone) -dipalladium (0) (9.1 mg; 0.01mmol), and 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ', 4 ', 6 ' -tri-i-propylbiphenyl (24 mg; 0.05 mmol). The resulting mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9: 1) to give the product (0.18 g; 71%).¹HNMR(400MHz,CHCl₃-d) ppm7.56(brs,1H),7.38-7.45(M,1H),7.22(d, J =2Hz,1H),6.96-7.10(M,3H),5.90(brs,1H),4.39(s,2H),2.87-2.94(M,2H),2,70(t, J =8Hz,2H),2.45(t, J =8Hz,2H),2.03-2.12(M,2H),1.90-1.99(M,2H),1.71-1.77(M,2H),1.48(s,9H), rt1.31min (system B), [ M + H ], [ M + H [, [ 1H ], [ system B ], [ 2H ], and (c]⁺505.2, dissolving it in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at 65 ℃ for 3 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (80mg, 49%).¹HNMR(400MHz,DMSO-d₆) ppm10.73(s,1H),7.46-7.62(M,3H),7.28(brs,1H),7.13-7.18(M,2H),4.49(brs,2H),3.30-3.51(M,4H),3.00-3,20(M,2H),2.81-2.87(M,2H),2.12-2.19(M,2H),1.86-1.92(M,2H), Rt1.25min (System B), [ M + H [ ], [ M + H ] ], and]⁺449.2

compound 312.3- {6- [ ((2, 6-difluorobenzene) amide group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propaneAcid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.64(brs,1H),10.82(s,1H),10.27(brs,1H),7.56-7.63(m,1H),7.04-7.29(m,5H),4.51(brs,2H),3.29-3.55(m,4H),3.05-3.12(m,2H),2.82-2.89(m,2H),2.15-2.24(m,2H),1.84-1.93(m,2H)。

3- {6- [ (2-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. Mixing Cs ₂CO₃(240 mg; 0.735mmol) and NaI (4 mg; 0.025mmol) were placed as solids in a 16X100mm glass tube reactor equipped with a magnetic stir bar. Adding 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl (81 mg; 0.245mmol) of (E) -1' -yl } propanoate in CH₃CN/THF/DMF1.5:1:1.5(0.061M) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1- (bromoethyl) -2-chlorobenzene (61.77 mg; 0.3mmol) in 0.5ml of DMF (0.6M) and the resulting mixture was warmed at 80 ℃ for 20 h. The reaction was cooled down and the solvent was removed using GenevacHT4 at 40 ℃ for 14 hours (full vacuum). The refining step included the addition of 2mL of K₂CO₃1M and 4mL of DCM/MeOH 95: after 5 stirring for 15 min. The phase separation is performed by the phase separation cartridge 1 PS. The aqueous layer was washed again with 2mL of DCM/MeOH 95: 5 extraction, the organic layers are combined and dried through phase separation cartridge 1 PS. The crude compound was obtained after removal of the solvent using GenevacHT4 at complete vacuum 40 ℃ for 14h and was used directly in the next step.

The following compounds were obtained in a similar manner:

3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (4-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (6-cyanohexyl) oxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- [6- (4-phenylbutoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionate.

3- [6- (2, 3-dihydro-1-benzofuran-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

3- [6- (2-Phenoxyethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

3- [6- (2-Phenoxypropoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

3- [6- (2-Phenoxybutoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Tert-butyl 3- {6- [3- (benzyloxy) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (2-, 3-dihydro-1, 4-benzodi)En-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Tert-butyl propionate.

3- (6- { [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester.

3- (6- { [4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid tert-butyl ester.

3- (6- { [4- (1H-pyrazol-1-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid tert-butyl ester.

Tert-butyl 3- (6- { [4- (1H-1,2, 4-triazol-1-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

3- {6- [ (2-methyl-1, 3-thiazol-4-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (1-methyl-1H-pyrazol-3-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoate.

Tert-butyl 3- [6- ({ 6-methylimidazol [1,2-a ] pyridin-2 yl } methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoate.

3- [6- (hex-5-yn-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Tert-butyl 3- {6- [ (5-oxohexyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [2- (naphthalen-2-yloxy) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- (6- {3- [ (2-propyl-1, 3-thiazol-5-yl) oxy ] propoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionate.

Tert-butyl 3- {6- [ (7-methoxyheptyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (phenylcarbamoyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [2- (benzyloxy) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (4-methanesulfonylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Compound 214.3- {6- [ (2-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propaneTrifluoroacetic acid is used as an acid. Crude 3- {6- [ (2-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate was treated with a mixture of TFA/DCM2:1 and stirred at room temperature for 2 h. Subsequently, the volatiles were removed with a nitrogen stream followed by a full vacuum using GenevacHT4 at 40 ℃ for 14 hours. The crude product was purified by preparative HPLC to give the title compound; rt =1.38 min. (System A), [ M + H]⁺Measured value: 403.21, respectively; calculated values: 402.14. preparation type LC-MS is prepared by dissolving in 600LDMSO/CH₃Crude product in CN1: 2; column ACQUITYUPLCBEHC181.7 μm (50X 2.1mm X1.7 μm) at 45 ℃. Mobile phase a = water +0.1% CH₃COOH and B = CH₃CN+0.1%CH₃COOH, 5% B to 90% B in 5 minutes. C18 flow 0.8 mL/min, detected by UV210-260 nm.

The following compounds were obtained in a similar manner:

compound 215.3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.28min]⁺Measured value: 368.23, respectively; calculated values: 368.18.

compound 216.3- {6- [ (4-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.42min]⁺Measured value:

403.21, respectively; calculated values: 402.14.

compound 217.3- {6- [ (6-cyanohexyl) oxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.18min]⁺Measured value:

387.28, respectively; calculated values: 387.22.

compound 218.3- [6- (4-Phenylbutoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.54min]⁺Measured value:

410.30, respectively; calculated values: 410.23.

compound 219.3- [6- (2, 3-dihydro-1-benzofuran-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.32min]⁺Measured value: 410.25, respectively; calculated values: 410.19.

compound 220.3- [6- (2-Phenoxyethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.38min]⁺Measured value:

398.27, respectively; calculated values: 398.19.

Compound 221.3- [6- (2-Phenoxypropoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.49min]⁺Measured value:

412.28, respectively; calculated values: 412.21.

compound 222.3- [6- (2-Phenoxybutoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.62min]⁺Measured value: 426.30, respectively; calculated values: 426.22.

compound 223.Tert-butyl 3- {6- [3- (benzyloxy) propoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a) =1.51min, [ M + H ·]⁺Measured value: 426.31, respectively; calculated values: 426.22.

compound 224.3- [6- (2-, 3-dihydro-1, 4-benzodi)En-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.44min]⁺Measured value: 426.27, respectively; calculated values: 426.19.

compound 225.3- (6- { [3- (4-tert-butylphenyl) -1,2,4-Diazol-5-yl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid trifluoroacetic acid. R_t=1.89min. (system a), [ M + H ·]⁺Measured value: 492.32, respectively; calculated values: 492.24.

compound 226.3- (6- { [4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) phenyl ]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid trifluoroacetic acid. R_t(system a) =1.33min, [ M + H ·]⁺Measured value: 450.29, respectively; calculated values: 450.20.

compound 227.3- (6- { [4- (1H-pyrazol-1-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid trifluoroacetic acid. R_t(system a) =1.33min, [ M + H ·]⁺Measured value: 434.28, respectively; calculated values: 434.20.

compound 228.3- (6- { [4- (1H-1,2, 4-triazol-1-yl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.09min · (system a)]⁺Measured value: 435.29, respectively; calculated values: 435.20.

compound 229.3- {6- [ (2-methyl-1, 3-thiazol-4-yl) methoxy ] methyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.05min]⁺Measured value: 389.21; calculated values: 389.15.

compound 230.3- {6- [ (1-methyl-1H-pyrazol-3-yl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =0.92min]⁺Measured value: 372.25, respectively; calculated values: 372.19.

compound 231.3- [6- ({ 6-methylimidazol [1,2-a ]]Pyridin-2 yl } methoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -yl]Propionic acid trifluoroacetic acid. R_t=0.77min. (system a), [ M + H ·]⁺Measured value: 421.28, respectively; calculated values: 422.20.

compound 232.3- [6- (hex-5-yn-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.3min]⁺Measured value: 358.26, respectively; calculated values: 358.20.

compound 233.3- {6- [ (5-oxohexyl) oxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.06min]⁺Measured value:

376.27, respectively; calculated values: 376.21.

compound 234.3- {6- [2- (naphthalen-2-yloxy) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.65min]⁺Measured value: 448.29, respectively; calculated values: 448.21.

compound 235.3- (6- {3- [ (2-propyl-1, 3-thiazol-5-yl) oxy]Propoxy } -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl) propionic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.48min]⁺Measured value: 461.29, respectively; calculated values: 461.21.

compound 236.3- {6- [ (7-Methoxyheptyl) oxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.49min]⁺Measured value: 406.33, respectively; calculated values: 406.25.

Compound 237.3- {6- [ (Phenylcarbamoyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.12min]⁺Measured value: 411.27, respectively; calculated values: 411.19.

compound 238.3- {6- [2- (benzyloxy) ethoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.38min]⁺Measured value: 412.28, respectively; calculated values: 412.21.

compound 239.3- {6- [ (4-Methylsulfonylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. R_t(system a), [ M + H ] =1.06min]⁺Measured value: 446.26, respectively; calculated values: 446.16.

tert-butyl 3- {6- [ (2-methylphenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (Tributylstannyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine in dichloroethane (5mL) purged with nitrogen]-1' -yl]To a solution of tert-butyl propionate (0.3 g; 0.49mmol) was added 2-methylbenzoyl chloride (0.1 mL; 0.74 mmol). The resulting reaction mixture was stirred at 70 ℃ for 72 hours. Subsequently, the reaction mixture was cooled and diluted with EtOAc and brine. Subjecting the organic layer to KFH₂O solution washing (5mol/l), drying (Na) ₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane: acetone 9: 1) to give the product (120 mg; 55.7%) Rt1.47min (System B), [ M + H%]⁺436.2。

The following compounds were obtained in a similar manner:

3- { 6-benzoyl-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid tert-butyl ester.

Tert-butyl 3- {6- [ (2-chlorophenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2E) -3-phenylprop-2-enoyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- {6- [ (2E) -3- (2-chlorophenyl) prop-2-enoyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid tert-butyl ester.

Tert-butyl 3- {6- [ (1-benzofuran-2-yl) carbonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

Tert-butyl 3- {6- [ (2-phenylcyclopropyl) carbonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoate.

3- [6- (3-phenylpropionyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid tert-butyl ester.

Compound 240.3- {6- [ (2-Methylphenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. 3- {6- [ (2-chlorophenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine ]-1' -Yl } propionic acid tert-butyl ester (100mg, 0.23mmol) in 1, 4-bisIn a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 80mmol) and stirred at room temperature for 48 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.7g, 73%). Rt1.36min (System B), [ M + H]⁺380.1。

The following compounds were obtained in a similar manner:

compound 241.3- { 6-benzoyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.45min (System B), [ M + H]⁺366.2。

Compound 242.3- {6- [ (2-chlorophenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.72(bs,1H),10.20(bs,1H),7.58-7.63(m,2H),7.46-7.52(m,2H),7.39-7.42(m,1H),7.22-7.26(m,1H),7.15(bs,1H),4.59(bs,2H),3.29-3.56(m,4H),3.04-3.13(m,2H) 2.81-2.88(M,2H),2.15-2.25(M,2H),1.92-2.01(M,2H) Rt1.55min (System B), [ M + H [ ]]⁺400.0

Compound 243.3- {6- [ (2E) -3-phenylprop-2-enoyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. 3- {6- [ (2E) -3-phenylprop-2-enoyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]Tert-butyl-1' -yl } propanoate (200mg, 0.45mmol) was dissolved in DCM (6mL), trifluoroacetic acid (2 mL; 25.96mmol) was added and stirred at room temperature overnight. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr ₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.21 g; 88.3%). Rt1.35min (System B), [ M + H]⁺392.1。

The following compounds were obtained in a similar manner:

compound 244.3- {6- [ (2E) -3- (2-chlorophenyl) prop-2-enoyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. Rt1.38min (System B), [ M + H]⁺426.0。

Compound 245.3- {6- [ (1-benzofuran-2-yl) carbonyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. Rt1.26min (System B), [ M + H]⁺406.1。

Compound 246.3- {6- [ (2-Phenylcyclopropyl) carbonyl]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid trifluoroacetic acid. Rt1.31min (System B), [ M + H]⁺406.1。

Compound 247.3- [6- (3-phenylpropionyl) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid trifluoroacetic acid. Rt1.30min (System B), [ M + H]⁺394.1

3- [6- (2, 6-Dichlorophenoxy) -2H-spiro[ 1-benzofuran-3, 4' -piperidines]-1' -yl]Tert-butyl propionate. To 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine in DMF (5mL)]To a solution of (e) -1' -yl } propanoate (250 mg; 0.75mmol) and 2, 6-dichlorofluorobenzene (123.7 mg; 075mmol) was added K₂CO₃(155 mg; 1.2 mmol). The resulting reaction mixture was stirred at 100 ℃ for 48 hours. Subsequently, the reaction mixture was cooled and diluted with EtOAc and brine. NaHCO for organic layer ₃Washing with the aqueous solution of (1), and drying (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (SiO)₂And DCM: MeOH95: 1) afforded the product (130 mg; 36.2%). Rt1.44min (System B), [ M + H]⁺478.1。

3- {6- (6-phenoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propionic acid tert-butyl ester. 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 4' -piperidine purged with nitrogen]To a solution of (237 mg; 0.71mmol) of (E) -1 '-yl } propionate in 20mL of toluene were added bromobenzene (111.6 mg; 0.71mmol), palladium (II) acetate (8 mg; 0.04mmol), tripotassium phosphate monohydrate (302 mg; 1.42mmol), 2-di-t-butylphosphino-2', 4 ', 6' -triisopropylbiphenyl (23 mg; 0.05mmol) and phenylboronic acid (4.3 mg: 0.04mmol) in that order. The resulting mixture was heated at 100 ℃ overnight. After cooling to room temperature, the mixture was concentrated in vacuo and concentrated in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂And DCM: MeOH 97: 3) the product was obtained (150 mg; 51%). Rt1.38min (System B), [ M + H]⁺410.2。

The following compounds were obtained in a similar manner:

tert-butyl 3- [6- (2, 6-dimethylphenoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionate.

Compound 248.3- [6- (2, 6-Dichlorophenoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride. 3- [6- (2, 6-dichlorophenoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid tert-butyl ester (1)20mg, 0.25mmol) in 1, 4-bisIn a solution of 4MHCl in an alkane (10 mL; 4 mol/l; 40mmol) and stirred at 50 ℃ for 2 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.1g, 86.9%).¹HNMR(400MHz,DMSO-d₆) ppm12.70(bs,1H),10.10(bs,1H),7.64(d, J =8.2Hz,2H),7.38(t, J =8.2Hz,1H),6.97-7.06(M,1H),6.24-6.33(M,2H),4.51(bs,2H),3.43-3.52(M,2H),3.26-3.37(M,2H),2.96-3.09(M,2H),2.83(t, J =7.5Hz,2H),2.07-2.18(M,2H),1.86-1.93(M,2H) rt1.33min (system B), [ M + H ] r]⁺422.0。

The following compounds were obtained in a similar manner:

compound 249.3- {6- (6-phenoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } propanoic acid hydrochloride. Rt1.27min (System B), [ M + H [ ]]⁺354.1。

Compound 250.3- [6- (2, 6-dimethylphenoxy) -2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl]Propionic acid hydrochloride. Rt1.36min (System B), [ M + H]⁺382.2

Compound 251.3- {6- [ (2, 6-dichlorophenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } cyclobutane-1-carboxylic acid hydrochloride. To 6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]To a mixture (0.5 g; 1.25mmol) in dichloroethane (30mL) was added tert-butyl 3-oxocyclobutane-1-carboxylate (276 mg; 1.62mmol), sodium triacetoxyborohydride (423 mg; 2mmol) and the resulting mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with EtOAc, 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And filtering. The residue was purified by column chromatography (SiO)₂，Et₂1: 1O Hexane) to give 3- {6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } cyclobutane-1-carboxylic acid tert-butyl ester (0.4)2g of the total weight of the mixture; 65%). Rt1.50min (System B), [ M + H]⁺518.0 for 1, 4-bisIt was hydrolyzed in 4M HCl solution in an alkane to give the product (340 mg; 80%).¹HNMR(400MHz,DMSO-d₆) ppm12.5(bs,1H),10.10(bs,1H),7.55-7.58(M,2H),7.47(dd, J =8.1 and 6.2Hz,1H),6.98-7.02(M,1H),6.56-6.62(M,2H),5.18(s,2H),4.48(bs,2H),3.57-3.62(M,1H),3.26-3.44(M,2H),2.78-2.93(M,3H),2.35-2.53(M,2H),1.78-2.18(M,4H), Rt1.33min (System B), [ M + H [ ], [ M ] ], 2.]⁺461.9。

Compound 313.2- {6- [ (2, 6-dichlorophenyl) methoxy group ]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } cyclopentane-1-carboxylic acid. 2- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]-1' -yl } cyclopentane-1-carboxylic acid ethyl ester prepared from 6- [ (2, 6-dichlorophenyl) methoxy]-2H-spiro [ 1-benzofuran-3, 4' -piperidine]And ethyl 2-oxocyclopentane-1-carboxylate (following the procedure for compound 251).¹HNMR(400MHz,CDCl₃-d) ppm7.33-7.40(m,2H),7.20-7.28(m,1H),7.00(d, J =8.2Hz,1H),6.47-6.59(m,2H),5.22(s,2H),4.31-4.42(m,2H),4.17(qd, J =7.1,1.1Hz,2H),3.23(d, J =11.1Hz,1H),3.01-3.10(m,1H),2.93(d, J =11.1Hz,1H),2.58-2.72(m,1H),1.76-2.13(m,9H),1.54-1.73(m,3H),1.29(t, J =7.0Hz,3H), the product is converted to compound 313 using the description of compound 79.¹HNMR(400MHz,DMSO-d₆) ppm7.53-7.59(M,2H)7.44-7.50(M,1H)7.15(d, J =7.9Hz,1H)6.50-6.58(M,2H)5.17(s,2H)4.41(s,2H)3.14-3.58(M,3H)3.03(d, J =11.9Hz,1H)2.85-2.95(M,2H)2.31-2.49(M,2H)2.00-2.11(M,1H)1.63-1.94(M,7H)1.47-1.62(M,2H). rt1.33min (system B), [ M + H ] 1.7.6 (M,2H) 7.15(d, 1H), 1.6 (M,2H) 1.1.1.33min (system B)]⁺476.6。

Compound 314.3- {6- [ (2-chloro-6-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl }Propionic acid hydrochloride. 3-Pyridylcarbinol (7.22 mL; 74.34mmol) was dissolved in 1-methyl-2-pyrrolidone (25mL) and sodium hydride (60% in mineral oil; 2.97 g; 74.34mmol) was added. The mixture was stirred at room temperature for 30 minutes. Subsequently, 4- (benzyloxy) -1-bromo-2-fluorobenzene (10.45 g; 37.17mmol) dissolved in 1-methyl-2-pyrrolidone (20mL) was added and the reaction mixture was heated to 100 ℃. TLC showed complete conversion within 30 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO ₃And (4) washing with an aqueous solution. Subjecting the organic layer to H₂O washing several times, drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1: 1) to give 3- [5- (benzyloxy) -2-bromophenoxymethyl]Pyridine (13.71 g; 99%),¹HNMR(400MHz,CDCl₃-d) ppm8.70(d, J =2.0Hz,1H)8.59(dd, J =4.9,2.0Hz,1H)7.81-7.87(m,1H)7.30-7.46(m,6H)6.62(d, J =2.8Hz,1H)6.52(dd, J =8.7,2.8Hz,1H)5.11(s,2H)5.03(s,2H) dissolved in acetone (200 mL). To the reaction mixture was added benzyl bromide (4.64 mL; 38.82mmol) and stirred at 40 ℃ overnight. Subsequently, the mixture was concentrated in vacuo to give 1-benzyl-3- [5- (benzyloxy) -2-bromophenoxy) methyl) pyridin-1-ium bromide (19.7 g; 98%). Mixing 14.68 g; (27.12mmol) of the product was dissolved in MeOH/THF (1: 1; 400 mL). To the cooled (-60 ℃ C.) reaction mixture was added sodium borohydride (2.57 g; 67.80 mmol). Upon completion of the addition, the mixture was allowed to warm to room temperature and stirred for an additional hour. Subsequently, the mixture was cooled to 0 ℃, water was added, and MeOH was evaporated in vacuo. To this aqueous solution was added 5% NaHCO₃Aqueous solution and Et₂And O. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO) ₂，Et₂1: 1O: hexane) to give the product: 1-benzyl-5- [5- (benzyloxy) -2-bromophenoxymethyl]1,2,3, 6-tetrahydro-pyridine (10.54 g; 83%).

¹HNMR(400MHz,CDCl₃-d)ppm7.23-7.43(m,11H),6.54(d,J=2.7Hz,1H),6.46(dd,J=8.7,2.7Hz,1H),5.88(m,1H),5.02(s,2H),4.40(s,2H),3.63(s,2H),3.09(d,J=1.9Hz,2H),2.58(t, J =5.7Hz,2H),2.18-2.25(m, 2H). To 1-benzyl-5- [5- (benzyloxy) -2-bromophenoxymethyl]To a mixture of-1, 2,3, 6-tetrahydropyridine (1.40 g; 3.01mmol) and potassium bicarbonate (0.30 g; 3.01mmol) in 10mL of dichloromethane was added benzylchloroformate (2.04 mL; 13.57 mmol). The reaction mixture was stirred at room temperature overnight. Subsequently, ice water and 5% NaHCO were added₃Aqueous solution, followed by addition of dichloromethane. After separation, the organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. The precipitate was collected by filtration and purified by column chromatography (SiO)₂，Et₂O: Hexane 1: 3) to give the product: benzyl 5- [ 5-benzyloxy) -2-bromophenoxymethyl]1,2,3, 6-tetrahydropyridine-1-carboxylate (1.33 g; 86.78%).¹HNMR(400MHz,CDCl₃-d) ppm7.30-7.43(m,11H),6.54(d, J =2.6Hz,1H),6.48(dd, J =8.7,2.6Hz,1H),5.94-5.99(m,1H),5.16(s,2H),5.03(s,2H),4.44(s,2H),4.11(br.s.,2H),3.58(t, J =5.7Hz,2H),2.16-2.28(m, 2H). To a mixture of the strongly degassed previous product (0.66 g; 1.30mmol) and silver carbonate (0.45 g; 1.62mmol) in 1-methyl-2-pyrrolidone (6mL) was added Herrmann-Bellerplaadacycle (0.06 g; 0.06mmol) (Tetrahedron, 64(2008), 4468). The reaction mixture was heated at 140 ℃ for 18 hours. After cooling to rt, the mixture was diluted with water and EtOAc. The layers were separated and the organic layer was dried (Na) ₂SO₄) Filtered and concentrated in vacuo to give benzyl 6- (benzyloxy) -2 ', 6' -dihydro-1 'H, 2H-spiro [ 1-benzofuran-3, 3' -pyridine]-1' -Carboxylic acid ester (0.50 g; 90%) dissolved in MeOH (10mL) and EtOAc (20 mL). Palladium hydroxide (20 mg; 0.12mmol) is added and the mixture is washed with H₂The treatment was carried out overnight at 50 psi. The crude reaction mixture was concentrated until about 5mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 2H-spiro [ 1-benzofuran-3, 3' -piperidine]6-ol (220 mg; 91%).¹HNMR(400MHz,DMSO-d₆)ppm9.20(br.s.,1H),6.92(d,J=8.0Hz,1H),6.11-6.26(m,2H),4.55(d,J=8.8Hz,1H),4.18(d,J=8.8Hz,1H),2.78-2.88(m,1H),2.43-2.65(m,3H),1.48-1.74(m,3H),1.23-1.39(m,1H)。

In a similar manner and as described for compound 292H-spiro [ 1-benzofuran-3, 3' -piperidine]Conversion of-6-ol to 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propionic acid tert-butyl ester (59%).¹HNMR(400MHz,CDCl₃-d) ppm6.90-6.96(d, J =9.7Hz,1H)6.28-6.34(m,2H)4.60(d, J =8.8Hz,1H)4.25(dd, J =8.8,1.2Hz,1H)2.77-2.86(m,1H)2.62-2.71(m,2H)2.55-2.61(m,1H)2.32-2.40(t, J =8.8Hz,2H)2.05-2.14(m,2H)1.46-1.75(m,4H)1.44(s,9H), after which under Mitsunobu chemistry conditions tri-butyl 3- {6- [ (2-chloro-6-ethylphenyl) methoxy group is obtained]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl]Propionate ester. This product (340 mg; 0.7mmol) was dissolved in 1, 4-bis In a solution of 4MHCl in an alkane (20 mL; 4 mol/l; 40mmol) and stirred at 50 ℃ for 2 hours. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr₂Treatment with O, the precipitate was collected by filtration and dried under reduced pressure overnight to give the product (0.25g, 72.8%).¹HNMR(400MHz,DMSO-d₆) ppm12.70(br.s.,1H),10.55(br.s.,1H),7.33-7.41(M,2H),7.25-7.32(M,1H),7.17(d, J =8.3Hz,1H),6.57-6.64(M,2H),5.11(s,2H),4.93(d, J =9.6Hz,1H),4.34(d, J =9.6Hz,1H),3.17-3.47(M,6H),2.83-2.97(M,2H),2.71(q, J =7.2Hz,2H),1.74-1.94(M,4H),1.15(t, J =7.2Hz,3H), 1.48min (system B), [ M + H ], [ rt = 7.1H ], 1.5.]⁺430.0。

The following compounds were obtained in a similar manner:

compound 315.3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.60(br.s.,1H),7.33(td, J =8.0,6.2Hz,1H),7.16(d, J =8.0Hz,1H),7.06(t, J =8.0Hz,1H),6.86(d, J =7.7Hz,1H),6.58-6.64(M,2H),5.18(d, J =1.2Hz,2H),4.99(d, J =9.9Hz,1H),4.32(d, J =9.7Hz,1H),3.15-3.52(M,6H),2.86-2.98(M,2H),1.99-2.10(M,1H),1.71-1.90(M,4H),0.89-0.98(M, 0.74H), 0.66H, 0.420.66H (rt + 420.4266H), 2H + M,1H, B, 1H, 4H, 1H, 2H, and B + 4220H]⁺426.2。

Compound 316.3- (6- { [ 2-chloro-6- (propan-2-yl) benzeneBase of]Methoxy } -2H-spiro [ 1-benzofuran-3, 3' -piperidine ]-1' -yl) propionic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.60(br.s.,1H),7.32-7.45(M,3H),7.17(d, J =8.0Hz,1H),6.56-6.65(M,2H),5.15(s,2H),4.99(d, J =9.5Hz,1H),4.33(d, J =9.5Hz,1H),3.11-3.47(M,6H),2.86-2.99(M,3H),1.74-1.93(M,5H),1.20(d, J =6.7Hz,6H), rt1.53min (system B), [ M + H ], [ M, H ], (1H) ], 1.]⁺444.0。

Compound 317.3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.20(br.s.,1H),7.28-7.37(M,2H),7.12-7.21(M,1H),7.04-7.09(M,1H),6.58-6.66(M,2H),5.28(s,2H),4.87(d, J =9.6Hz, 1H),4.34(d, J =9.6Hz,2H),3.18-3.46(M,6H),2.79-3.09(M,2H),2.01-2.11(M,1H),1.73-1.93(M,4H),0.88-0.96(M,2H),0.64-0.73(M,2H), rt1.49min (system B), [ M + H ], 1H, 10.9-6.4H, 1.4H, rt, 1.4H, etc. (system B), [ M + H, B, 2H, B]⁺442.0。

Compound 318.3- {6- [ (2-chloro-6-fluorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.40(br.s.,1H),7.48-7.56(M,1H),7.40-7.45(M,1H),7.29-7.36(M,1H),7.17(d, J =7.9Hz,1H),6.57-6.63(M,2H),5.10(s,2H),4.93(d, J =9.5Hz,1H),4.34(d, J =9.5Hz,1H),3.16-3.46(M,6H),2.84-2.95(M,2H),1.71-1.95(M,4H), rt1.35min (system B), [ M + H]⁺420.2。

Compound 319 (iii). 3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.50(br.s.,1H),7.46(dd, J =7.5Hz,2H),7.18(d, J =7.8Hz,1H),6.57-6.65(M,2H),5.20(s,2H),4.96(d, J =9.6Hz,1H),4.34(d, J =9.6Hz,1H),3.16-3.47(M,6H),2.83-2.98(M,2H),2.75(q, J =7.5Hz,2H),1.75-1.92(M,4H),1.18(t, J =7.5Hz,3H), rt1.55min (system B), [ M + H ], (1H) } 1H),10.50(br.s, 1H),7.46(dd, J =7.5Hz,2H), and (M, J = 7.6H)]⁺464.0。

Compound 320.3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy group]-2H-Spiro [ 1-benzofuran-3, 3' -piperidines]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆)ppm12.80(br.s.,1H),10.40(br.s.,1H),7.42(s,2H),7.17(d,J=7.9Hz,1H),6.57-6.64(m,2H),5.13(s,2H),4.98(d,J=9.5Hz,1H),4.33(d,J=9.5Hz,1H),3.33-3.47(m,2H),3.16-3.32(m,2H),2.82-2.99(m,2H),2.61(t,J=7.6Hz,2H),1.74-1.94(m,4H),1.56(m,2H),1.29(m,2H),0.90(t,J=7.6Hz,3H)

Rt1.72min (System B), [ M + H]⁺492.0

Compound 321.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.10(br.s.,1H),7.57(d, J =8.1Hz,2H),7.44-7.52(M,1H),7.17(d, J =8.4Hz,1H),6.58-6.65(M,2H),5.18(s,2H),4.91(d, J =9.9Hz,1H),4.34(d, J =9.9Hz,1H),3.32-3.47(M,4H),3.18-3.32(M,2H),2.82-3.00(M,2H),1.74-1.92(M,4H), 1.41min (system B), [ M + H]⁺435.9。

Compound 322.3- {6- [ (2,4, 6-trichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d₆) ppm12.80(br.s.,1H),10.30(br.s.,1H),7.80(s,2H)7.17(d, J =8.5Hz,1H),6.57-6.64(M,2H),5.15(s,2H),4.94(d, J =9.6Hz,1H),4.34(d, J =9.6Hz,1H),3.34-3.48(M,4H),3.16-3.32(M,2H),2.83-2.97(M,2H),1.74-1.94(M,4H), rt1.54min (system B), [ M + H ] ]⁺471.9。

Compound 323.3- {6- [ (3, 5-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid. Mixing 3- {6- [ (3, 5-dichlorophenyl) -methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]Tert-butyl-1' -yl } propanoate (270 mg; 0.55mmol), aqueous 2M NaOH (2 mL; 10mmol) and ethanol (10mL) were stirred at 50 ℃ for 3h and then cooled to 0 ℃. To the reaction mixture was added dropwise aqueous HCl (10 mL; 1mol/l), after which it was concentrated in vacuo. The residue was treated with saturated brine and dichloromethane. The aqueous layer was washed with dichloromethane (twice). Subsequently, the organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo, then diluted with iPr₂And (4) O treatment. The precipitate formed was collected by filtration and used with iPr₂O washes and dries in vacuo to give the product (40 mg; 15.4%).¹HNMR(400MHz,DMSO-d₆)ppm7.57(s,1H),7.48(s,2H),7.08(d,J=8.7Hz,1H),6.43-6.50(m,2H),5.07(s,2H),4.46(d,J=8.8Hz,1H),4.24(d,J=8.8Hz,1H),2.68-2.79(m,1H),2.43-2.65(m,3H),2.21(t,J=7.2Hz,2H),2.00-2.16(m,2H),1.52-1.66(m,3H),1.36-1.53(s,1H)。

The following compounds were obtained in a similar manner:

compound 324.3- {6- [ (2, 5-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.64(s,1H),7.55(d, J =1.5Hz,1H),7.45(M,1H),7.08(d, J =8.7Hz,1H),6.43-6.50(M,2H),5.07(s,2H),4.46(d, J =9.0Hz,1H),4.24(d, J =9.0Hz,1H),2.68-2.79(M,1H),2.43-2.67(M,3H),2.35(t, J =7.2Hz,2H),2.00-2.18(M,2H),1.52-1.66(M,3H),1.36-1.51(M,1H), rt1.46min (system B), [ M + H ], (M,1H) ] ]⁺436.1。

Compound 325.3- {6- [ (2-chloro-6-methylphenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm12.10(br.s.,1H),7.06-7.38(M,4H),6.47-6.54(M,2H),5.10(s,2H),4.48(d, J =8.8Hz,1H),4.25(d, J =8.8Hz,1H),2.71-2.80(M,1H),2.47-2.67(M,3H),2.30-2.44(M,5H),2.02-2.18(M,2H),1.55-1.69(M,3H),1.37-1.53(M,1H), rt1.42min (system B), [ M + H [, ], 1H]⁺416.2

Compound 326.3- (6- { [ 2-chloro-6- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm12.29(br.s.,1H),7.92(d, J =8.1Hz,1H),7.83(d, J =8.1Hz,1H),7.64-7.71(M,1H),7.09-7.13(M,1H),6.48-6.54(M,2H),5.13(s,2H),4.48(d, J =8.8Hz,1H),4.26(d, J =8.8Hz,1H),2.74-2.80(M,1H),2.52-2.66(M,3H),2.31-2.39(M,2H),2.05-2.27(M,2H),1.56-1.69(M,3H),1.40-1.51(M,1H), 1.42min (system B) [ rt + M ], [ rt + H ] (system H) [ 1H ], [ 1.]⁺416.2

Compound 327 (ii).3- {6- [1- (2, 6-dichlorophenyl) ethoxy]-2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl } propanoic acid.¹HNMR(400MHz,DMSO-d₆) ppm12.19(br.s.,1H),7.45(d, J =8.0Hz,2H),7.28-7.34(M,1H),7.00(d, J =8.0Hz,1H),6.29(dd, J =8.2,2.1Hz,1H),6.21(d, J =2.1Hz,1H),5.93(q, J =6.6Hz,1H),4.41(d, J =8.8Hz,1H),4.18(d, J =8.8Hz,1H),2.69-2.77(M,2H),2.44-2.62(M,4H),2.28-2.35(M,2H),1.99-2.09(M,3H),1.67(d, J =6.6Hz,3H), 1.48-1.48 (M,1H), 1.48H), 1.4248 (M,1H), 1.4248H, 1H + B (M,1H) ]⁺416.2

Compound 328.3- (6- { [ 2-fluoro-6- (trifluoromethyl) phenyl]Methoxy } -2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,DMSO-d₆) ppm7.62-7.77(M,3H),7.11(d, J =8.8Hz,1H),6.45-6.53(M,2H),5.09(s,2H),4.48(d, J =9.0Hz,1H),4.25(d, J =9.0Hz,1H),2.71-2.81(M,1H),2.52-2.66(M,3H),2.35(t, J =6.9Hz,2H),2.05-2.18(M,2H),1.53-1.70(M,3H),1.37-1.52(M,1H), rt1.45min (system B), [ M + H ] 2.18(M,2H),1.53-1.70(M,3H),1.37-1.52(M,1H)]⁺454.2

Compound 329.3- [6- (oct-7-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1 '-yl) propionic acid from 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 3' -piperidine]Tert-butyl-1' -yl } propanoate was prepared using the method described for compound 275.¹HNMR(400MHz,CDCl₃-d) ppm12.10(br.s.,1H),7.04(d, J =8.1Hz,1H),6.32-6.41(M,2H),5.73-5.84(M,1H),4.95(M,2H),4.46(d, J =8.8Hz,1H),4.22(d, J =8.8Hz,1H),3.88(t, J =6.5Hz,2H),2.72-2.80(M,1H),2.51-2.67(M,3H),2.31-2.40(t, J =6.9Hz,2H),1.97-2.18(M,3H),1.53-1.71(M,6H),1.26-1.50(M,7H), 1.37min (system B), [ M + rth [ (+ rt [, ] r ], [ 1H ], [ 1.]⁺388.3

The following compounds were obtained in a similar manner:

compound 330.3- [6- (hept-6-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,CDCl₃-d)ppm12.10(br.s.,1H),7.04(d,J=8.1Hz,1H),6.32-6.40(m,2H),5.80(ddt,J=17.0,103,6.7,6.7Hz,1H),4.90-5.06(M,2H),4.45(d, J =8.8Hz,1H),4.22(d, J =8.9Hz,1H),3.88(t, J =6.5Hz,2H),2.69-2.80(M,1H),2.51-2.65(M,3H),2.29-2.39(M,2H),1.98-2.16(M,4H),1.52-1.73(M,5H),1.33-1.48(M,5H) rt1.53min (system B), [ M + H ] rt1.5 min (system B) ]⁺374.3

Compound 331.3- [6- (hex-5-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3' -piperidine]-1' -yl) propionic acid.¹HNMR(400MHz,CDCl₃-d) ppm12.10(br.s.,1H),7.04(d, J =8.1Hz,1H),6.29-6.42(M,2H),5.69-5.91(M,1H),4.90-5.10(M,2H),4.45(d, J =9.4Hz,1H),4.22(d, J =9.4Hz,1H),3.84-3.94(M,2H),2.69-2.83(M,1H),2.60-2.68(s,3H),2.28-2.41(M,2H),2.00-2.18(M,3H),1.33-1.77(M,9H), rt1.53min (system B), [ M + H]⁺360.3

Compound 332.3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -pyrrolidine]-1' -yl } propanoic acid hydrochloride.

(1-benzyl-2, 5-dihydro-1H-pyrrol-3-yl) methanol (US2010/0069351) (0.47 g; 2.49mmol) was dissolved in 1-methyl-2-pyrrolidone (5mL) and sodium hydride (60% in mineral oil; 0.1 g; 2.49mmol) was added. The mixture was stirred at room temperature for 30 minutes. Subsequently, 4- (benzyloxy) -1-bromo-2-fluorobenzene (0.35 g; 1.25mmol) dissolved in 1-methyl-2-pyrrolidone (3mL) was added and the reaction mixture was heated to 100 ℃ for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO₃And (4) washing with an aqueous solution. Subjecting the organic layer to H₂O washing several times, drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO) ₂，Et₂O hexane 1:1 to pure Et₂O) to obtain 1-benzyl-3- [ 5-benzyloxy-group]-2-bromophenoxymethyl radical]-2, 5-dihydro-1H-pyrrole (0.48 g; 85%). Rt1.45min (System B), [ M + H]⁺452.5。

To strongly degassed 1-benzyl-3- [ 5-benzyloxy group]-2-bromophenoxy-methyl]To a mixture of (E) -2, 5-dihydro-1H-pyrrole (0.46 g; 7.73mmol) in 5mL of benzene were added 2, 2' -azo (2-methylpropanenitrile) (17 mg; 0.1mmol) and tri-n-butyltin hydride (0.41 mL; 1.53mmol) in that order. The reaction mixture was heated at 200 ℃ for 2 hours under microwave conditions. After cooling to room temperature, the reaction mixture was diluted with EtOAc and with 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O: hexane 1: 1) to give 1' -benzyl-6- (benzyloxy-phenyl)]-2H-spiro [ 1-benzofuran 3, 3' -pyrrolidine](0.26g；68%)。¹HNMR(400MHz,CDCl₃-d) ppm7.20-7.45(M,10H),7.10(d, J =8.2Hz,1H),6.52(dd, J =8.2,2.2Hz,1H),6.43(d, J =2.2Hz,1H),5.01(s,2H),4.51(d, J =8.8Hz,1H),4.34(d, J =8.8Hz,1H),3.68(d, J =13.1Hz,1H),3.59(d, J =13.1, 1H),2.87(dt, J =8.7,5.0Hz,1H),2.79(d, J =9.2Hz,1H),2.61(dt, J =8.9,6.9Hz,1H),2.48(d, J =9.2Hz,1H),2.20 (ddl =9, 1H), 2.95H, 1H, 13.1H, 13H, 0H, 1H), 2.95H, 0H, 1H, 0H, 2.1H, 2.9, 0H, 1H, 2.1H, 1H, 13H, 1H ]⁺372.6. A mixture of this product (260 mg; 0.7mmol), ammonium formate (0.18 g; 2.8mmol) and palladium hydroxide (5 mg; 0.03mmol) in methanol (25mL) was stirred overnight (at 60 ℃ C.). The crude reaction mixture was concentrated until about 5mL and filtered through a p-toluenesulfonic acid solid phase extraction cartridge, washed with MeOH, and washed with 2NNH₃MeOH elution. Concentrating the product to obtain 2H-spiro [ 1-benzofuran-3, 3' -pyrrolidine]6-alcohol (0.13 g; 97%).¹HNMR(400MHz,DMSO-d₆)ppm7.08(d,J=8.1Hz,1H),6.31(dd,J=8.1,2.1Hz,1H),6.21(d,J=2.1Hz,1H),4.46(d,J=9.0Hz,1H),4.32(d,J=9.0Hz,1H),3.04-3.30(m,3H),3.01(d,J=11.4Hz,1H),1.95-2.11(m,2H).。

In a similar manner and as described for compound 29, 2H-spiro [ 1-benzofuran-3, 3' -pyrrolidine]Conversion of-6-ol to 3- { 6-hydroxy-2H-spiro [ 1-benzofuran-3, 3' -pyrrolidine]-1' -yl } propionic acid tert-butyl ester.¹HNMR(400MHz,CDCl₃-d)ppm6.99(d,J=8.1Hz,1H),6.34(dd,J=8.1,2.2Hz,1H),6.28(d,J=2.2Hz,1H),4.47(d,J=8.8Hz,1H),4.30(d,J=8.8Hz,1H),2.84-2.94(m,2H),2.79(t,J=7.4Hz,2H),2.55-2.63(m,2H),2.46(t, J =7.4Hz,2H),2.10-2.21(m,1H),1.94-2.05(m,1H)1.45(s,9H), followed by Mitsunobu chemistry and acidic hydrolysis to give the product: 3- {6- [ (2, 6-dichlorophenyl) methoxy group]-2H-spiro [ 1-benzofuran-3, 3' -pyrrolidine]-1' -yl } propanoic acid hydrochloride. NMR (400MHz, DMSO-d)₆)ppm12.70(br.s.,1H),11.55(br.s.,1H),7.57(d,J=7.4Hz,2H),7.36-7.52(m,2H),6.65(dd,J=8.3,2.2Hz,1H),6.60(d,J=2.2Hz,1H),5.19(s,2H),4.23-4.81(m,2H),3.14-3.91(m,6H),2.84(t,J=7.7Hz,2H),2.10-2.40(m,2H)。

Compound 333.3- {5- [ (2, 6-dichlorophenyl) methoxy group]-2, 3-dihydrospiro [ indene-1, 2' -morpholine]-4' -yl } propanoic acid hydrochloride. 5- (benzyloxy) -2, 3-dihydro-1H-inden-1-one (13.11 g; 55.02mmol), zinc iodide (0.35 g; 1.1mmol), and trimethylsilyl cyanide (22.71 mL; 181.5mmol) were stirred at room temperature overnight. Subsequently, the excess trisilyl cyanide was removed in vacuo and the residue was dissolved in THF (250 mL). The resulting solution was added dropwise to a mixture of lithium aluminum hydride (8.56 g; 225.57mmol) in THF (200 mL). The resulting mixture was heated at reflux for 2 hours. Next, the mixture was cooled to 0 ℃ and treated with water (10mL), 2M NaOH aqueous solution (20mL) and water (10mL) in that order. After this time the mixture was heated at reflux for 15 minutes, cooled to room temperature again, filtered over celite (Kieselguhr), and concentrated in vacuo. The residue was purified by column chromatography (SiO) ₂MeOH) to give 1- (aminomethyl) -5- (benzyloxy) -2, 3-dihydro-1H-inden-1-ol (10.7 g; 72%). To 1- (aminomethyl) -5- (benzyloxy) -2, 3-dihydro-1H-inden-1-ol (10.50 g; 40mmol) and Et at 0 deg.C₃N (6.52 mL; 46.78mmol) in CH₂Cl₂Chloroacetyl chloride (3.42 mL; 42.9mmol) in CH was added dropwise to a solution in a mixture of (100mL) and MeOH (16mL)₂Cl₂(10 mL). After 1 hour at 0 ℃ the reaction mixture was quenched with 1M aqueous Cl (200 mL). After separation, the organic layer was washed with 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And concentrated to give N- { [5- (benzyloxy) -1-hydroxy-2, 3-dihydro-1H-inden-1-yl]Methyl } -2-chloroacetamide (10.5 g; 78%). The residue was dissolved in 2-propanol (100mL) and potassium tert-butoxide (3.71 g; 33mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The crude product was partitioned between EtOAc and 0.5MHCl aqueous solution. After separation, the organic layer was washed with 5% NaHCO₃Washing with an aqueous solution and drying (Na)₂SO₄) And evaporated in vacuo. The residue was purified by column chromatography (SiO)₂EtOAc: MeOH9: 1) to give 5- (benzyloxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine]-5' -ketone (5.1 g; 54.8%).¹HNMR(400MHz,CDCl₃-d)ppm7.29-7.45(m,6H),7.05(br.s.,1H),6.83-6.91(m,2H),5.06(s,2H),4.15-4.30(m,2H),3.61(dd,J=12.2,1.9Hz,1H),3.46(dd,J=12.2,2.9Hz,1H),3.05-3.15(m,1H),2.84(dt,J=16.1,6.7Hz,1H),2.30(t,J=6.7Hz,2H)。

To a solution of the aforementioned product (0.7 g; 2.26mmol) in THF (10mL) at 0 deg.C was added borane-THF complex (1M, 11.3 mL; 11.3mmol) dropwise. After 1 hour the mixture was allowed to warm to room temperature and stirred overnight. MeOH (10mL) was added to the reaction mixture at 0 ℃, and the resulting mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The residue was suspended in MeOH (10mL), 1M NaOH aqueous solution (25mL) was added and heated at reflux for 1 h. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂EtOAc: MeOH9:1 to 1: 9) to give 5- (benzyloxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine](0.47g；70.3%)。¹HNMR(400MHz,CDCl₃-d) ppm7.29-7.45(M,6H),6.82-6.88(M,2H),5.05(s,2H),3.78(dd, J =7.0,2.8Hz,2H),2.95-3.05(M,3H),2.86-2.93(M,1H),2.74-2.84(M,2H),2.48(ddd, J =13.0,8.4,4.4Hz,1H),2.23(ddd, J =13.0,8.4,7.0,1.2Hz,1H) rtti 1.19min (system B), [ M + H ] 7.45(M,6H),6.82-6.88(M,2H),5.05(s,2H), 2.86-2.93(M,1H),2.74-2.84(]⁺296.1

Reacting 5- (benzyloxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine](0.46 g; 1.56mmol) of a solventIn MeOH (20 mL). Palladium hydroxide (11 mg; 0.16mmol) is added and the mixture is washed with H₂The treatment was carried out overnight. Concentrating the reaction mixture to obtain 2, 3-dihydrospiro [ indene-1, 2' -morpholine]5-alcohol (310 mg; 97%).¹HNMR(400MHz,DMSO-d₆) ppm9.30(br.s.,1H)7.22(d, J =8.0Hz,1H)6.54-6.59(M,2H)3.56(dd, J =5.8,3.7Hz,2H)2.55-2.85(M,6H)2.41(ddd, J =13.0,8.0,4.5Hz,1H)1.91-2.00(M,1H) rt0.30min (system B), [ M + H]⁺206.1

Mixing 2, 3-dihydrospiro [ indene-1, 2' -morpholine]A mixture of-5-ol (0.3 g; 1.46mmol), tert-butyl acrylate (0.64 mL; 4.38mmol) and N, N-diisopropylamine (0.76mL, 4.46mmol) in MeOH (20mL) was heated to reflux overnight (closed borosilicate glass vial). After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up in EtOAc and 5% NaHCO ₃The aqueous solution was partitioned. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O) to obtain tert-butyl 3- { 5-hydroxy-2, 3-dihydrospiro [ indene-1, 2' -morpholine]-4' -yl } propanoate (0.32 g; 65.5%).¹HNMR(400MHz,CDCl₃-d) ppm7.46(d, J =8.1Hz,1H),6.60-6.68(M,2H),4.97(s,1H),3.69-3.81(M,2H),2.93-3.03(M,1H),2.33-2.79(M,10H),2.08-2.17(M,1H),1.46(s,9H) rt1.04min (system B), [ M + H]⁺334.1

Mixing 3- { 5-hydroxy-2, 3-dihydrospiro [ indene-1, 2' -morpholine]Tert-butyl (4' -yl) propionate (315 mg; 0.94mmol), K₂CO₃(0.39 g; 2.83mmol) and 2, 6-dichlorobenzyl bromide (250 mg; 1.04mmol) in CH₃The mixture in CN (10mL) was stirred overnight (at room temperature). The reaction mixture was washed with 5% NaHCO₃Aqueous solution and Et₂And (4) distributing among the O. The organic layer was dried (Na)₂SO₄) Filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂，Et₂O, hexane 4: 6) to obtain 3- {5- [ (2, 6-dichlorophenyl) methoxy]-2, 3-dihydrospiro [ indene-1, 2' -morpholine]Tert-butyl (4' -yl) propionate (0.387 g; 83%). Rt1.68min (System B), [ M + H]⁺492.0. dissolving it in 1, 4-bisIn a 1M HCl solution in an alkane (10mL) and stirred at 70 ℃ for 2 h. Subsequently, the solvent was removed in vacuo and the residue was taken up with iPr ₂O treatment, the precipitate was collected by filtration and dried under reduced pressure overnight to give 3- {5- [ (2, 6-dichlorophenyl) methoxy]-2, 3-dihydrospiro [ indene-1, 2' -morpholine]-4' -yl } propanoic acid hydrochloride (300mg, 83%).¹HNMR (400MHz, DMSO-d) ppm12.80(bs,1H),11.20(bs,1H),7.58(d, J =8.0Hz,2H),7.47(t, J =8.0Hz,1H),7.29(d, J =8.8Hz,1H),7.02(s,1H),6.95(d, J =8.8Hz,1H),5.22(s,2H),3.98(d, J =7.5Hz,2H),2.88-3.54(M,11H),2.08-2.18(M,1H) rt1.45min (system B), [ M + H ] M]⁺435.9。

The following compounds were obtained in a similar manner:

compound 334.3- [5- (octyloxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine]-4' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d)ppm12.80(bs,1H),11.20(bs,1H),7.23(d,J=8.8Hz,1H),6.78-6.86(m,2H),3.85-4.03(m,4H),3.24-3.50(m,4H),3.05-3.23(m,2H),2.80-3.03(m,5H),2.04-2.18(m,1H),1.62-1.75(m,2H),1.18-1.45(m,10H),0.85-0.95(m,3H)。

Compound 335.3- [5- (2, 6-Dichlorophenoxy) -2, 3-dihydrospiro [ indene-1, 2' -morpholine]-4' -yl } propanoic acid hydrochloride.¹HNMR(400MHz,DMSO-d)ppm12.80(bs,1H),10.60(bs,1H),7.66(d,J=8.0Hz,2H),7.38(t,J=8.0Hz,1H),7.32(d,J=8.8Hz,1H),6.69-6.75(m,2H),3.87-3.99(m,2H),3.05-3.53(m,8H),2.82-2.92(m,3H),2.08-2.18(m,1H)。

2, 3-dihydrospiro [ indene-1, 4' -piperidine]-5-alcohols. To a solution of 6-methoxy-2, 3-dihydro-1H-inden-1-one (25 g; 154mmol) in MeOH (400mL) was added NaBH in portions at room temperature₄(7.0 g; 185 mmol). The mixture was stirred at room temperature for 1 hour. Subsequently, water (100mL) was added followed by 2N hydrochloric acid(150 mL). The mixture was stirred at room temperature for 1.5 hours and then extracted with MTBE (2-methoxy-2-methylpropane). The combined organic layers were washed with brine and dried (NaSO) ₄) And concentrated in vacuo to give 6-methoxy-2, 3-dihydro-1H-inden-1-ol as an oil, 25g (99%).¹HNMR(300MHz,CDCl₃-d) ppm7.15(d, J =8Hz,1H),6.95(d, J =2Hz,1H),6.80(d, J =8Hz,1H),4.82-4.78(m,1H),3.80(s,3H),3.05-2.95(m,1H),2.80-2.70(m,1H),2.40-2.30(m,1H),2.15-2.05(m,1H) 6-methoxy-2, 3-dihydro-1H-inden-1-ol (18.5 g; 113mmol), p-toluenesulfonic acid hydrate (0.1 g; 0.5mmol), hydroquinone (0.1 g; 1mmol), and toluene (150mL) were heated at reflux for 1 hour. After cooling to room temperature, the mixture was diluted with MTBE (50mL), washed with saturated sodium bicarbonate, then brine, and dried (NaSO)₄) And concentrated to give 5-methoxy-1H-indene (15.5 g; purity 75%),¹HNMR(300MHz,CDCl₃-d) ppm7.43(d, J =8Hz,1H),7.06(d, J =2Hz,1H),6.92(d, J =6Hz,1H),6.85(dd, J =8,2Hz,1H),6.66(d, J =6Hz,1H),3.90(s,3H),3.42(s, 2H). To a solution of the crude 5-methoxy-1H-indene (15.0 g; 75% pure, 60mmol) in THF (50mL at 0 deg.C) was added lithium bis (trimethylsilyl) amide (LiHMDS, 1M solution in THF/ethylbenzene, 200 mL; 200 mmol). The resulting brown solution was added dropwise over 20 minutes to a solution of tert-butyl N, N-bis (2-chloroethyl) carbamate (23 g; 95mmol) in THF (100 mL). The mixture was stirred at 0 ℃ for 1 hour and then at room temperature for 1 hour. The mixture was concentrated in vacuo and purified by column chromatography (SiO) ₂EtOAc: hexane 1: 9) gave an oil, 23 g. Crystallization of pentane to obtain 5-methoxy spiro [ indene-1, 4' -piperidine]Tert-butyl (1' -carboxylate) (9.4 g; (50%).¹HNMR(300MHz,CDCl₃-d) ppm7.22(d, J =8Hz,1H),6.88(d, J =2Hz,1H),6.78(dd, J =8,2Hz,1H),6.72(s,2H),4.30-4.10(m,2H),3.80(s,3H),3.10(t, J =12Hz,2H),1.98(dt, J =12,4Hz,2H),1.50(s,9H),1.30(d, J =12Hz,2H), 5-methoxyspiro [ indene-1, 4' -piperidine ], c 1, c]A mixture of tert-butyl (3.15 g; 10mmol) of the-1' -carboxylic acid, 10% Pd/C (0.6 g; 0.6mmol) and ethanol (50mL) was hydrogenated at 5bar for 4 hours. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo to give 5-methoxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1' -Carboxylic acid tert-butyl ester (2.8 g; 88%).¹HNMR(400MHz,CDCl₃-d) ppm7.13(d, J =8Hz,1H),6.75(dd, J =8,2Hz,1H),6.70(d, J =2Hz,1H),4.15-4.05(m,2H),3.80(s,3H),2.95(t, J =12Hz,2H),2.85(t, J =7Hz,2H),2.05(t, J =7Hz,2H),1.80(dt, J =12,4Hz,2H),1.55(d, J =12Hz,2H),1.50(s,9H) to 5-methoxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine ], (ii, H) ]]To a solution of tert-butyl (1' -carboxylate) (320 mg; 1.0mmol) in N, N-dimethylformamide (15mL) was added sodium ethanethiol (360 mg; 4.0 mmol). The mixture was heated at 130 ℃ for 60 hours. The mixture was cooled to room temperature and saturated ammonium chloride solution (50mL) was added. The resulting mixture was extracted with dichloromethane. The combined extracts were washed with brine and dried (NaSO) ₄) And concentrated. The residue was purified by column chromatography (SiO)₂EtOAc: hexane 1: 2) to yield 5-hydroxy-2, 3-dihydrospiro [ indene-1, 4' -piperidine]-1' -carboxylic acid tert-butyl ester (110mg (37%).¹HNMR(300MHz,CDCl₃-d) ppm7.07(d, J =8Hz,1H),6.67(dd, J =8,2Hz,1H),6.63(d, J =2Hz,1H),4.15-4.05(m,2H),2.95(t, J =12Hz,2H),2.85(t, J =7Hz,2H),2.07(t, J =7Hz,2H),1.75(dt, J =12Hz,2H),1.55(d, J =12Hz,2H),1.52(s,9H) dissolved in bisIn 4N HCl in an alkane (4 mL). The precipitate (formed after 1 hour) was collected by filtration and taken up in Et₂Washing with O and drying to obtain 2, 3-dihydrospiro [ indene-1, 4' -piperidine]HCl salt of-5-ol (65 mg; 75%).¹HNMR(300MHz,D₂O)ppm7.20(d,J=8Hz,1H),6.82-6.78(m,2H),3.46(d,J=12Hz,2H),3.23(t,J=12Hz,2H),2.88(t,J=7Hz,2H),2.14(t,J=7Hz,2H),2.02(dt,J=12,4Hz,2H),1.78(d,J=12Hz,2H)。

The structures of compounds 1-336 according to the present invention are described in the following table.

In these structures, the structural elementsRepresents a COOH group.

5 pharmacological test & data

In vitro functional Activity at the human S1P5 receptor (agonism)

CHO-human-S1P 5-aequorin assay Euroscreen (Euroscreen, technical archive, human lysophospholipid S1P5 (Edg 8) receptor, DNA clone and CHOAequoSCreen from Brussels^TMRecombinant cell line, accession No.: ES-593-A, 9 months 2006). human-S1P 5-aequorin cells express mitochondrially targeted apophotoprotein. To reconstitute active aequorin, the cells must be loaded with coelenterazine. The intracellular calcium concentration increases after binding of the agonist to the human S1P5 receptor and binding of calcium to the apop-aequorin/coelenterazine complex results in an oxidative reaction of coelenterazine resulting in the production of apop-aequorin, Coelenterate amide, CO₂And light (lambda)_max469 nm). The fluorescence response is dependent on agonist concentration. Fluorescence was measured using a MicroBetaJet (PerkinElmer). Agonistic use of compounds pEC₅₀To indicate. Compounds were tested at 10-point semilogarithmic concentration range and 3 independent experiments were performed in single-point measurements.

In vitro functional Activity at the human S1P3 receptor (agonism)

CHO-human-S1P 3-aequorin assay (CHO/G.alpha.16/AEQ/h-S1P)₃) Established in solvay pharmaceuticals. Plasmid DNA encoding the S1P3 receptor (accession No. NM-005226 in GenBank) was purchased from UMRcDNAresourceContentre (Rolla, MO). The pcDNA3.1/hS1P3 construct carrying the mitochondrially targeted apophotoprotein and the G.alpha.16 protein was transfected into the CHOK1 cell line.

human-S1P 3-aequorin cells express mitochondrially targeted apophotoprotein. To reconstitute active aequorin, the cells must be loaded with coelenterazine. Intracellular calcium concentration increases following binding of agonist to human S1P3 receptor and binding of calcium to the apop-aequorin/coelenterazine complex results in an oxidative reaction of coelenterazine, resulting in the production of apop-aequorin, coelenterazine, coelenteramide, CO₂And light (lambda) _max469 nm). The fluorescence response is dependent on agonist concentration. Fluorescence was measured using a MicroBetaJet (PerkinElmer). Agonistic use of compounds pEC₅₀To indicate. Compounds were tested at 10-point semilogarithmic concentration range and 3 independent experiments were performed in single-point measurements.

In vitro functional Activity (agonism) at the human S1P1 receptor (method A)

CHO-K1-human-S1P 1-aequorin assay Euroscreenfast (Euroscreen, technical archive, human S1P1 (Edg 1) receptor, DNA clone and CHO-K1 AequoroSCreen from Brussels^TMRecombinant cell line, accession No.: FAST-0197L, 2 months 2010). human-S1P 1-aequorin cells express mitochondrially targeted apophotoprotein. To reconstitute the active jellyfishProtein, the cell must be loaded with coelenterazine. Intracellular calcium concentration increases following binding of agonist to human S1P1 receptor and binding of calcium to the apop-aequorin/coelenterazine complex results in an oxidative reaction of coelenterazine, resulting in the production of apop-aequorin, coelenterazine, coelenteramide, CO₂And light (lambda)_max469 nm). The fluorescence response is dependent on agonist concentration. Fluorescence was measured using a MicroBetaJet (PerkinElmer). Agonistic use of compounds pEC ₅₀To indicate. Compounds were tested at 10-point semilogarithmic concentration range and 2 independent experiments were performed in single-point measurements.

In vitro functional Activity (agonism) at the human S1P1 receptor (method B)

CHO-K1-human S1P1-c-AMP assay was performed in Brussels' Euroscreenfast (Euroscreen, human S1P1 coupled G_i/0(Edg 1) receptor, accession number: FAST-0197C, 2009, 12 months).

Recombinant CHO-K1 cells expressing human S1P1 were grown to the mid-log phase in antibiotic-free medium, isolated, centrifuged and resuspended. For agonists the test cells were mixed with the compound and Forskolin (Forskolin) and incubated at room temperature. Cells were lysed and cAMP concentrations estimated using the HTRF kit from CIS-BIOINTIONAL (accession number 62AM2 PEB) according to the manufacturer's instructions.

Agonistic effects of compounds with their EC₁₀₀The concentration is expressed as a percentage of the activity of the reference compound, and the EC is calculated₅₀And the results are expressed as pEC₅₀Reporting. Compounds were tested at 10 point semilog concentration range, in duplicate for each experiment.

Pharmacological data (receptor agonism) for selected compounds:

S1P1^A: measurement by method A

S1P1^B: measurement by method B

nd = no measurement

An in vivo treatment model; t-shaped maze

Age-related memory deficits occur in humans and rodents. Spontaneous alterations are the inherent intent of rodents to alter free choice through a series of sequential operations in T-maze. This sequential process depends on working memory and is sensitive to different pharmacological manipulations that affect the memory progression (Aginglandcheilogyafspatialmemory. Barnes C. A. neurobiol. Aging1988: 563-8; DemberWN, Fowler H. Spontaneousalternationbehavior. pseudo-hold. Bull.1958,55 (6): 412. 427; Gerlair. Anewcontutinous outpatiationstaskt-mazedetectsthoppappaldpastosystemfunctination. Asparanganesudy. BehavBrainRes199895 (1): 91-101).

For this study, male C57BL/6J mice, 2 or 12 months of age, were used for a spontaneous replacement task in T-type maze. Briefly, mice were subjected to a 1-session experiment comprising 15 trials consisting of 1 "forced choice" trial followed by 14 "free choice" trials. An animal is considered to enter one arm of the maze when all four paws are placed in that arm. Whatever the first event occurred, once the 14 free choice trials had been completed or 15 minutes had elapsed, the session was terminated and the animals were evacuated from the maze. The percent of replacement, which each mouse exhibited during 14 free choice trials, was determined and used as an index of working memory. Compound of the invention was administered orally for 21 days prior to the maze test and at T-30 minutes on the day of maze test. The compounds of the invention were found to reverse age-related cognitive decline up to 100% in 12-month old mice at a dose range of 0.01-15 mg/kg/day. Thus, the treated 12-month old mice were identical in their performance to vehicle treated 2-month old mice. (see FIG. 1)

ConclusionThe compounds of the present invention have a positive effect on age-related cognitive decline.

Claims (34)

1. Spiro-cyclic amine derivatives of formula (I) or pharmaceutically acceptable salts thereof

Wherein

R1 is selected from

The cyano group(s),

(2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkyl, each optionally substituted with CN or one or more fluorine atoms,

(3-6C) cycloalkyl, (4-6C) cycloalkenyl or (8-10C) bicyclic group, each optionally substituted with halogen or (1-4C) alkyl,

phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, (1-6C) alkyl optionally substituted with one or more fluorine atoms, (1-6C) alkoxy optionally substituted with one or more fluorine atoms, amino, (1-4C) alkylamino, and (3-6C) cycloalkyl optionally substituted with phenyl which may be substituted with (1-4) alkyl or halogen,

phenyl substituted with: phenoxy, benzyl, benzyloxy, phenethyl or monocyclic heterocycle, each optionally substituted with (1-4C) alkyl, wherein (1-4C) alkyl is optionally substituted with one or more fluorine atoms,

a monocyclic heterocycle, optionally independently substituted with: halogen, (1-6C) alkyl optionally substituted with one or more fluorine atoms, (3-6C) cycloalkyl, or phenyl optionally substituted with (1-4C) alkyl or halogen,

And

bicyclic heterocycle optionally substituted with halogen or (1-4C) alkyl, wherein (1-4C) alkyl is optionally substituted with one or more fluorine atoms;

-Y-(C_n-alkylene) -X-is a linking group, wherein,

y is linked to R1 and is selected from the group consisting of a direct bond, -O-, -CO-, -S-, -SO-, -SO₂-、-NH-、-CH＝CH-、-C(CF₃)＝CH-、-C≡C-、-CH₂-O-, -CO-NH-, -NH-CO-, and trans-cyclopropylene;

n is an integer of 0 to 10; and is

X is attached to the phenylene/pyridyl moiety and is selected from the group consisting of direct bond, -O-, -S-, -SO-, -SO₂-, -NH-, -CO-, -CH ═ CH-and trans-cyclopropylene;

r2 is H or independently selected from one or more substituents selected from halogen, (1-4C) alkoxy, and (1-4C) alkyl optionally substituted with one or more fluorine atoms;

r3 is (1-4C) alkylene-R4, wherein the alkylene may be substituted by one or more halogen atoms or by (CH)₂)₂Substituted to form a cyclopropyl group, or R3 is (3-6C) cycloalkylene-R4, or-CO-CH₂-R4, wherein R4 is-OH, -PO₃H₂、-OPO₃H₂-COOH, -COO (1-4C) alkyl or tetrazol-5-yl;

q is a direct bond;

-W-T-is selected from-CH₂-CH₂-、-CH₂-O-and-O-CH₂-；

R5 is H or independently selected from one or more halogens;

z is CH, CR2 or N; and is

A represents a morpholine ring structure or a 5-, 6-or 7-membered cyclic amine.

2. The compound of claim 1, wherein R3 is selected from- (CH) ₂)₂-OH、-CH₂-COOH、-(CH₂)₂-COOH、-(CH₂)₃-COOH、-CH₂-CHCH₃-COOH、-CH₂-C(CH₃)₂-COOH、-CHCH₃-CH₂-COOH、-CH₂-CF₂-COOH、-CO-CH₂-COOH, 1, 3-cyclobutylidene-COOH, - (CH)₂)₂-PO₃H₂、-(CH₂)₃-PO₃H₂、-(CH₂)₂-OPO₃H₂、-(CH₂)₃-OPO₃H₂、-CH₂-tetrazol-5-yl, - (CH)₂)₂-tetrazol-5-yl and- (CH)₂)₃-tetrazol-5-yl.

3. A compound according to any one of claims 1 to 2 wherein R2 is H, methyl, chloro or fluoro and Z is CH or CR 2.

4. A compound according to any one of claims 1 to 2, wherein-W-T-is selected from-CH₂-O-and-O-CH₂-; and R5 is H.

5. A compound according to any one of claims 1 to 2 wherein Y is selected fromFrom a direct bond, -O-, -CO-, -CH-, -C (CF)₃) -CH-, -C ≡ C-and trans-cyclopropylene; n is an integer of 0 to 6.

6. A compound according to any one of claims 1 to 2 wherein R1 is selected from (1-4C) alkyl, cyclohexyl, cyclohexenyl, biphenyl optionally substituted with halogen, phenyl optionally substituted with one, two or three substituents independently selected from halogen, (1-4C) alkyl, trifluoromethyl, (1-4C) alkoxy, trifluoromethoxy and cyclopropyl optionally substituted with phenyl, thienyl, pyridyl, tetrahydropyranyl, each optionally substituted with halogen, (1-4C) alkyl, cyclopropyl or phenyl optionally substituted with halogen, and indolyl, dihydrobenzofuranyl and benzodioxanyl, each optionally substituted with halogen or (1-4C) alkyl.

7. A compound according to any one of claims 1 to 2, wherein

R1 is selected from phenyl, optionally substituted with one or more substituents independently selected from halo, (1-4C) alkyl, cyclopropyl and trifluoromethyl; group-Y- (C)_n-alkylene) -X-is selected from-CH₂-O-、-CH₂-S-and-CH ═ CH-;

and-W-T-is-O-CH₂-。

8. A compound according to any one of claims 1 to 2, wherein a represents a piperidine structure.

9. The compound of any one of claims 1 to 2, having structure (II)

10. The compound of any one of claims 1 to 2, wherein R1 is 2, 6-dichlorophenyl and R3 is- (CH)₂)₂-COOH。

11. The compound of claim 1 selected from

2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetic acid,

2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) acetic acid,

2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) acetic acid,

2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetic acid,

2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (5- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) acetic acid,

2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (5- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) acetic acid,

2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- (5- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butanoic acid,

3- (5- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [5- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- (5- { [3- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid,

3- {5- [ (3, 5-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {5- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2-chloro-6-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [5- (anilino) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-phenylpentyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (3-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [6- (cyclohexylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (oxiranyl-2 ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2, 5-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid,

3- (6- { [3- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 3-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -propionic acid,

3- {6- [ (2-chloro-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -propionic acid,

3- {6- [ (2, 4-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propionic acid,

3- (6- { [ 2-chloro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin-1' -yl } propanoic acid,

3- [6- (cyclohex-3-en-1-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (3, 5-dichloropyridin-4-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 4-dichloropyridin-3-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-4-iodophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2, 6-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2-fluorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-propylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [3- (2-fluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [3- (2-chlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (3-phenylpropoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [2- (2, 4-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2-chlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [2, 6-dichloro-4- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin-1' -yl) propionic acid,

3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (5-bromo-2-chlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- {3- [2- (trifluoromethyl) phenyl ] propoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [3- (2, 3-difluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [3- (2-chloro-6-fluorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [3- (2, 6-dichlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [3- (4-chlorophenyl) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-phenylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-4-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- ({ 2-chloro-5- [ 2-phenylcyclopropyl ] phenyl } methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoic acid,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2-chloro-6-cyclopropyl) phenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (5, 7-dichloro-2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (5, 7-difluoro-2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (1R) - (2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (1S) - (2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (2E) -3- (4-chlorophenyl) prop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (3-phenyl) prop-2-yn-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (2, 3-dihydro-1-benzofuran-3-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- (6- { [ (2E) -3- (2, 6-dichlorophenyl) prop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoic acid,

3- (6- { [ (2E) -3-phenylprop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoic acid,

3- {6- [ (7-chloro-2, 3-dihydro-1H-inden-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (3- (4-chlorophenyl) prop-2-yn-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoic acid,

3- (6- { [ (2E) -3- (2-fluorophenyl) prop-2-en-1-yl ] oxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoic acid,

3- {6- [ (4-Bromophenylthio-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-butylthiophen-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [4- (2-fluorophenyl) thiophen-2-yl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-Phenylthiophen-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-bromo-3-methylphenylsulfanyl-2 yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (4-Cyclopropylmethylphenylsulfanyl-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (3-methyl-4-phenylthiophen-2-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (4-butyl-3-methylphenylsulfanyl-2 yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropanoic acid,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

2-methyl-3- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropanoic acid,

3- (6- { [ 2-chloro-6- (2-methylpropyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) -2-methylpropionic acid,

3- (6- { [ 2-chloro-6- (2-trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl) -2-methylpropionic acid,

3- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

2- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetic acid,

2- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

2- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) acetic acid,

2- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

4- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyric acid,

4- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) butyric acid,

4- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -7-methyl-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-4-methylphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- { 7-fluoro-6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-5-ethylphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-chloro-6- (trifluoromethoxy) phenyl ] methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2, 6-dichloro-3-methoxy) phenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (4-butyl-2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2-chloro-6-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2-chloro-6-cyclopropylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2, 6-dichloro-3-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2,4, 6-trichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (2-chlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (6- { [ (2-methylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (benzylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

2-methyl-3- (6- { [ (2,4, 6-trichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (2, 6-dichloro-3-methoxyphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

3- (6- { [ (2, 6-dichloro-4-methylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

3- (6- { [ (2-chloro-6-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

3- [6- ({ [ 2-chloro-6- (propan-2-yl) phenyl ] methyl } sulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- (6- { [ (2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropanoic acid,

3- (6- { [ (2-chlorophenyl) methane ] sulfonyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-methylphenyl) sulfanyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichlorophenyl) sulfanyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-methylbenzene) sulfonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichlorobenzene) sulfonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (phenylsulfonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2-chlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2-phenylvinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -propionic acid,

3- {6- [ (E) -2- (4-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2, 6-dichloro-3-ethylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2, 6-dichloro-4-cyclopropylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (4-butyl-2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (1Z) -3,3, 3-trifluoro-2-phenylprop-1-en-1-yl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2-chloro-5-ethylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2, 5-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (3-methylphenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

4- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

2- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

3- {6- [ (E) -2- (2, 6-dichlorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

4- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butanoic acid,

2- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- {6- [2- (2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (2-phenylcyclopropyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2-fluorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2-chlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (2-chloro-5-ethylphenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (4-butyl-2, 6-dichlorophenyl) cyclopropyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- { 6-benzyl-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [6- (2-phenylethyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2- (2, dichlorophenyl) ethyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2- (2-fluorophenyl) ethyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (pentyloxymethyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (anilino) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2, 2-difluoropropionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2, 2-methylpropanoic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } ethan-1-ol,

(2- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } ethoxy) phosphonic acid,

6- [ (2, 6-dichlorophenyl) methoxy ] -1'- [2- (1H-1,2,3, 4-tetrazol-5-yl) ethyl-2H-spiro [ 1-benzofuran-3, 4' -piperidine ],

(3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propyl) phosphonic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -3-oxopropanoic acid,

3- {5- [ (2-chlorophenyl) methoxy-2H-spiro [ furo [2,3-b ] pyridine-1, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {5- [ (2, 6-dichlorophenyl) methoxy-2H-spiro [ furo [2,3-b ] pyridin-1, 4 '-piperidin ] -1' -yl) propionic acid,

3- [5- (2, 6-dimethylphenoxy) -2H-spiro [ furo [2,3-b ] pyridin-1, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {5- [ (2, 6-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [5- (cyclohexylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2-chlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (5- { [2- (trifluoromethyl) phenyl ] methoxy } -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [5- (oxiranyl-2-ylmethoxy) -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (3-chlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {5- [ (2, 3-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (5- { [3- (trifluoromethyl) phenyl ] methoxy } -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (2, 5-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {5- [ (3, 5-dichlorophenyl) methoxy ] -3-H-spiro [ 2-benzofuran-1, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ ((2, 6-dichlorophenyl) carbamoyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (benzyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (4-chlorophenyl) methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (6-cyanohexyl) oxy-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (4-phenylbutoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (2, 3-dihydro-1-benzofuran-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (2-phenoxyethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (2-phenoxypropoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (2-phenoxybutoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

Tert-butyl 3- {6- [3- (benzyloxy) propoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (2-, 3-dihydro-1, 4-benzodioxin-2-ylmethoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- (6- { [3- (4-tert-butylphenyl) -1,2, 4-oxadiazol-5-yl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [4- (1H-pyrazol-1-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [4- (1H-1,2, 4-triazol-1-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2-methyl-1, 3-thiazol-4-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (1-methyl-1H-pyrazol-3-yl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [6- ({ 6-methylimidazol [1,2-a ] pyridin-2-yl } methoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoic acid,

3- [6- (hex-5-yn-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (5-oxohexyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (naphthalen-2-yloxy) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- {3- [ (2-propyl-1, 3-thiazol-5-yl) oxy ] propoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (7-methoxyheptyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (phenylcarbamoyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [2- (benzyloxy) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-methanesulfonylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-methylphenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- { 6-benzoyl-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2-chlorophenyl) carbonyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2E) -3-phenylprop-2-enoyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2E) -3- (2-chlorophenyl) prop-2-enoyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (1-benzofuran-2-yl) carbonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-phenylcyclopropyl) carbonyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (3-phenylpropionyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (2, 6-dichlorophenoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- (6-phenoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (2, 6-dimethylphenoxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } cyclobutane-1-carboxylic acid,

3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-ethyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (4-chloro-2, 6-difluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [1- (2, 6-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-diethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [2- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [ 2-ethyl-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin-1' -yl) propionic acid,

3- (6- { [ 2-chloro-6- (difluoromethoxy) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2-fluoro-6-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-ethyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylpropionic acid,

3- (6- { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) -2-methylpropionic acid,

2-methyl-3- (6- { [2- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

2- {6- [ (2, 6-dichloro-3-methoxyphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } acetic acid,

1'- (3-carboxypropyl) -6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4' -piperidine ] -1 '-onium-1' -alkoxide,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-fluorophenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6- (propan-2-yl) phenyl ] methoxy } -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (7-fluoro-6 { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propanoic acid,

3- [ 7-fluoro-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [ 7-fluoro-6- (heptyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [ 7-fluoro-6- (octyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [ 7-fluoro-6- (hex-5-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [ 7-fluoro-6- (oct-7-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [ 7-fluoro-6- (hept-6-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- { 7-fluoro-6- [ (5,6, 6-trifluorohex-5-en-1-yl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- { 7-fluoro-6- [ (4,4,5,5, 5-pentafluoropentyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- { 7-fluoro-6- [ (5,5,6,6, 6-pentafluorohexyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [ 7-fluoro-6- (4,4, 4-trifluorobutoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- [6- (cyclohexylethoxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2-ethylhexyl) oxy ] -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- { 7-fluoro-6- [ (3,5, 5-trimethylhexyl) oxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- [6- (3-cyclohexylpropoxy) -7-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -5-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -5-fluoro-2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- { 7-chloro-6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- (7-chloro-6- { [ 2-fluoro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl) propionic acid,

3- (6- { [ (2-cyclopropyl-6-fluorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [6- ({ [ 2-fluoro-6- (propan-2-yl) phenyl ] methyl } sulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propanoic acid,

3- (6- { [ (2, 6-dichlorophenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (2-chloro-6-ethylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [ 7-fluoro-6- (pentylsulfanyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- (6- { [ (2-chloro-6-cyclopropylphenyl) methyl ] sulfanyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylpropionic acid,

3- (6- { [ (2, 6-dichlorophenyl) methane ] sulfonyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ (2, 6-dichlorophenyl) methane ] sulfinyl } -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2-chloro-6-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (E) -2- (2-cyclopropyl-6-fluorophenyl) vinyl ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } propanoic acid,

3- [6- (2-phenylethynyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid,

3- {6- [2- - (2-chlorophenyl) ethynyl) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

4- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -3-methylbutyric acid,

4- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } pentanoic acid,

2-methyl-4- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } butyric acid,

4- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidine ] -1' -yl } -2-methylbutyric acid,

4- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylbutyric acid,

4- {6- [ (2-chloro-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } -2-methylbutyric acid,

3- {6- [ ((2, 6-dichlorobenzene) amido ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ ((2, 6-difluorophenyl) amido ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } propanoic acid,

2- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl } cyclopentane-1-carboxylic acid,

3- {6- [ (2-chloro-6-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-cyclopropyl-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-chloro-6- (propan-2-yl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2-chloro-6-cyclopropylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2-chloro-6-fluorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichloro-3-ethylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (4-butyl-2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidine ] -1' -yl } propionic acid,

3- {6- [ (2,4, 6-trichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- {6- [ (3, 5-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidine ] -1' -yl } propionic acid,

3- {6- [ (2, 5-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidine ] -1' -yl } propionic acid,

3- {6- [ (2-chloro-6-methylphenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-chloro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- {6- [1- (2, 6-dichlorophenyl) ethoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl } propanoic acid,

3- (6- { [ 2-fluoro-6- (trifluoromethyl) phenyl ] methoxy } -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- [6- (oct-7-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- [6- (hept-6-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- [6- (hex-5-en-1-yloxy) -2H-spiro [ 1-benzofuran-3, 3 '-piperidin ] -1' -yl) propionic acid,

3- {6- [ (2, 6-dichlorophenyl) methoxy ] -2H-spiro [ 1-benzofuran-3, 3 '-pyrrolidin ] -1' -yl } propanoic acid,

3- {5- [ (2, 6-dichlorophenyl) methoxy ] -2, 3-dihydrospiro [ indene-1, 2 '-morpholin ] -4' -yl } propanoic acid,

3- [5- (octyloxy) -2, 3-dihydrospiro [ indene-1, 2 '-morpholine ] -4' -yl } propionic acid,

3- [5- (2, 6-dichlorophenoxy) -2, 3-dihydrospiro [ indene-1, 2 '-morpholin ] -4' -yl } propanoic acid,

3- [ 5-fluoro-6- (hexyloxy) -2H-spiro [ 1-benzofuran-3, 4 '-piperidin ] -1' -yl ] propionic acid.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of the formula

18. A compound according to any one of claims 1, 2 or 11 to 17 for use in therapy.

19. A compound according to any one of claims 1, 2 or 11 to 17 for use in the treatment, alleviation or prevention of diseases and conditions in which any S1P receptor is involved, or in which modulation of the endogenous S1P signaling system by any S1P receptor is involved.

20. A compound according to claim 19 for use in the treatment, alleviation or prevention of CNS dysfunction.

21. The compound of claim 20, wherein the CNS dysfunction is a neurodegenerative disease.

22. The compound of claim 21, wherein the neurodegenerative disorder is selected from cognitive disorders, alzheimer's disease, dementia, niemann-pick disease, and cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis, and pain.

23. The compound of claim 22, wherein the cognitive disorder is age-related cognitive decline.

24. The compound of claim 22 wherein the dementia is vascular dementia.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and at least one pharmaceutically acceptable adjuvant.

26. Use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for the treatment, alleviation or prevention of diseases and disorders in which the S1P5 receptor is involved or in which modulation of the endogenous S1P signaling system by the S1P5 receptor is involved.

27. The use of claim 26, wherein the disease is CNS dysfunction.

28. The use of claim 27, wherein the CNS dysfunction is a neurodegenerative disease.

29. The use of claim 28, wherein the neurodegenerative disorder is selected from the group consisting of cognitive disorders, alzheimer's disease, dementia, niemann-pick disease, and cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis and pain.

30. The use of claim 29, wherein the cognitive disorder is age-related cognitive decline.

31. The use of claim 29, wherein the dementia is vascular dementia.

32. A compound of formula (III)

Where Br is attached at one of the positions indicated by the asterisks.

33. A compound of formula (IV)

Wherein OH is attached at one of the positions indicated by #, and wherein,

If OH is at the position represented by 1, the compound may be independently substituted at one or both positions represented by 2 with (1-4C) alkyl or halogen selected from F or Cl; and is

W-T is-O-CH₂-or-CH₂-CH₂-; and is

A represents a morpholine ring structure or a 5-, 6-or 7-membered cyclic amine;

with the proviso that the compound of the formula (IV) is notOr

34. A process for the preparation of a compound of formula (I) according to claim 1 wherein R2 is H or one or two substituents selected from fluoro, (1-4C) alkyl and (1-4C) alkoxy; -W-T-is-O-CH₂-and Z is CH or CR2, comprising an intramolecular Heck cyclization step, wherein the compound of formula (V),

wherein A' represents a 5-, 6-or 7-membered cyclic amine containing a double bond at the carbon atom indicated by the arrow, P1 is selected from-CO₂-benzyl and-CO₂A protecting group for the (1-4C) alkyl group, Bn being benzyl and the BnO-group being able to be attached in one of the positions indicated by #, in the presence of silver carbonate and a Herrmann-Beller catalyst, at elevated temperature in a suitable solvent to a compound of formula (VI),

wherein A "represents a 5-, 6-or 7-membered cyclic amine containing a double bond at one or both carbon atoms which is displaced in position relative to the carbon atom indicated by the arrow in ring A' — depending on the position of the nitrogen atom in the ring,

followed by further work-up steps to give the compounds of the formula (I).