WO2009061881A1

WO2009061881A1 - Spirodihydrobenzofurans as modulators of chemokine receptors

Info

Publication number: WO2009061881A1
Application number: PCT/US2008/082579
Authority: WO
Inventors: Brian W. Budzik; Pamela A. Haile; Terry Vincent Hughes; Clark A. Sehon; Gren Z. Wang
Original assignee: Glaxo Group Limited
Priority date: 2007-11-07
Filing date: 2008-11-06
Publication date: 2009-05-14

Abstract

The present invention relates to a compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein R1 -R4, R8, R9, Y, m, n, and p are defined. Compounds and compositions of the present invention are useful, for example, for the treatment of atherosclerosis.

Description

SPIRODIHYDROBENZOFURANS AS MODULATORS OF CHEMOKINE

RECEPTORS

The present invention relates to a class of spirodihydrobenzofurans that are modulators of chemokine receptors, particularly as CCR2 antagonists and their methods of use.

CCR2 is a chemokine receptor that is expressed on a cell surface of monocytes and some other blood leukocytes. CCR2 binds to the monocyte chemotactic protein MCP-I, and other CC chemokines, which are produced at sites of inflammation and infection. Recruitment of monocytes to inflammatory sites by MCP-1/CCR2 interactions has been implicated in driving the pathogenesis of a number of diseases including multiple inflammatory disorders including rheumatoid arthritis, atherosclerosis, multiple sclerosis, bronchiolitis obliterans syndrome, asthma, allergic rhinitis, eczema, atopic dermatitis, kidney disease, alveolitis, nephritis, liver cirrhosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, Alzheimer's disease, stroke, acute nerve injury, HIV infection, AIDS, autoimmune diseases, cancer, sepsis, retinosis, inflammatory bowel disease, transplant arteriosclerosis, idiopathic pulmonary fibrosis, psoriasis, HIV-associated dementia, lupus, erthematosis, hepatitis, pancreatitis, Crohn's disease, and diabetes.

Accordingly, it would be an advance in the art to discover a class of compounds that bind to CCR2, thereby preventing or minimizing the formation of the undesirable MCPl -mediated recruitment of monocytes to inflammatory sites.

Summary of the Invention

In a first aspect of the invention, there is provided a compound of the following formula:

or a pharmaceutically acceptable salt thereof;

where each R¹ is independently halo, CF₃, Ci-C₄-alkyl, Ci-C₄-alkoxy, OCF₃, cyano, Ci-C₆-alkyl-C(O)-NH-, Ci-C₆-alkyl-NH-C(O)-, -CH₂-NR⁵R⁶ , -CH₂-O-R⁷, COOH, Ci-C₄-S(O)₁, or heteroaryl;

R² and R³ are each independently H, OH, COOH, HO-Ci-C₄-alkyl, Ci-C₄-alkyl, CN, CF₃, halo, OCF₃, benzyloxy, halo, or d-C₄-alkoxy;

each R⁴ is independently halo, CF₃, Ci-C₄-alkyl, Ci-C₄-alkoxy, OCF₃, heteroaryl, or CN;

R⁵ and R⁶ are each independently H, Ci-C₄-alkyl, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group;

R' is H, Ci-Ce-alkyl, -CH₂-phenyl-(R 1^l0^u\)_s, or phenyl-(R , l^l(^uk)_s;

R⁸ is H, OH, F, Cl, CN, CF₃, Ci_C₆-alkyl, hydroxy-Ci-C₆-alkyl, or Ci_C₆-alkoxy;

each R⁹ is independently halo, CF₃, Ci-C₄-alkyl, Ci-C₄-alkoxy, OCF₃, benzyloxy, OH, or CN;

each R¹⁰ is independently OH, F, Cl, CN, CF₃, Ci_C₆-alkyl, hydroxy-Ci-C₆-alkyl, or Ci-Cβ-alkoxy;

n is 0, 1, or 2;

m is 0, 1, 2, or 3;

p is 0, 1, or 2;

r is 0, 1, or 2; and

s is 0, 1, 2, or 3.

Detailed Description of the Invention

In a first aspect, the present invention relates to a compound of the following Formula I:

or a pharmaceutically acceptable salt thereof, wherein R^-R⁴, R⁸, R⁹, Y, n, m, and p are as previously defined.

In another aspect of the present invention, R¹ is CH₃, CN, or Cl and n is 0 or 1.

In another aspect, the present invention is a compound represented by the following Formula II:

II or a pharmaceutically acceptable salt thereof, wherein R² is H and R³ is H, OH or methyl.

In another aspect, the present invention is a compound represented by either of the following formulae Ilia or IHb:

Ilia

or

nib

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is a compound or a pharmaceutically acceptable salt thereof, which compound is any of the following compounds:

(IS)- 1 - { 1 -[(2E)-3-(3,5-difiuorophenyl)-2-propenoyl]-4-piperidinyl} -2-(6-methyl- 1 'H- spiro[ 1 -benzofuran-3 ,4'-piperidin]- 1 '-yl)ethanol;

(lS)-l-{l-[(2E)-3-(3,5-difiuorophenyl)-2-propenoyl]-4-piperidinyl}-2-[(3S,3^>R)-3',6- dimethyl- 1 Η-spiro[ 1 -benzofuran-3 ,4'-piperidin]- 1 '-yljethanol; ( 1 S)-2-(6-chloπ>- 1 Η-spiro[ 1 -benzoflιran-3 ,4'-piperidin]- 1 ^?-yl)- 1 - { 1 -[(2E)-3-(3 ,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol;

( 1 S)- 1 - { 1 -[(2E)-3-(3 ,5-difluorophenyl)-2-propenoyl]-4-piperidinyl} -2-( 1 Η-spiro[ 1 - benzofuran-3,4'-piperidin]-r-yl)ethanol;

(3R,3'R)-6-chloro-r-((2S)-2-{l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyl} -2-hydroxyethyl)spiro [ 1 -benzofuran-3 ,4'-piperidin] -3 '-ol;

(3S,3'S)-6-chloro-r-((2S)-2-{l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyl} -2-hydroxyethyl)spiro [ 1 -benzofuran-3 ,4'-piperidin] -3 '-ol;

(lS)-l-{l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-[(3R,3'R)-3^>,6- dimethyl- 1 Η-spiro[ 1 -benzofuran-3 ,4'-piperidin]- 1 '-yljethanol;

(15)-2-[(3_lS,3^>5)-6-chloro-3^>-methyl- 1 'H-spiro[ 1 -benzofuran-3,4'-piperidin]-l '-yl]- 1 - {l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol;

(15)-2-[(3i?,3'i?)-6-chloro-3'-methyl- 1 'H-spiro[ 1 -benzofuran-3,4'-piperidin]-l '-yl]- 1 - {l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol;

(3£,3\S)-6-chloro- 1 '-((2R)-2- { 1 -[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-hydroxy- 4-piperidinyl}-2-hydroxyethyl)spiro[l-benzofuran-3,4'-piperidin]-3'-ol;

(3_lS,3^>5)-l^>-((25)-2-{l-[(2E)-3-(3,5-difiuorophenyl)-2-propenoyl]-4-piperidinyl}-2- hydroxyethyl)-3 '-methylspiro [ 1 -benzofuran-3 ,4'-piperidine] -6-carbonitrile; and

(3i?,3'i?)-l^>-((25)-2-{l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2- hydroxy ethyl)-3 '-methylspiro [ 1 -benzofuran-3 ,4'-piperidine] -6-carbonitrile .

As used herein, Ci-Cβ-alkyl and Ci-C₄-alkyl refer to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, t-butyl, and 1,1-dimethylpropyl.

Examples of Ci-C4-alkoxy include methoxy, ethoxy, n-propoxy, prop-2-oxy, n- butoxy, but-2-oxy, 2-methylprop-l-oxy, and 2-methylprop-2-oxy. R⁵ and R⁶, together with the nitrogen atom to which they are attached, may form a 5- or 6-membered heterocycloalkyl group, examples of which include pyrrolidinyl, morpholino, thiomorpholino, dihydropyridazinyl, piperidinyl, and piperazinyl groups.

As used herein, heteroaryl refers to a 5- or 6-membered aromatic group that contains one or more heteroatoms selected from N, S, and O. The heteroaryl ring may be optionally substituted with up to two substituents including Ci-C4-alkyl, halo, C₁-C₄- alkoxy, CN, CF₃, and OCF₃.

As used herein, "halo" refers to fluoro, chloro, or bromo.

As used herein, the term "a compound" or "the compound" refers to one or more compounds of the present invention. Compounds of the present invention may exist in solid or liquid form. In the solid state, they may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word "or" in the context of "a compound or a pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

Compounds of the present invention can form pharmaceutically acceptable salts by reaction with a suitable acid or base. Suitable acids include inorganic and organic acids; examples of suitable inorganic acids include hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids; examples of suitable organic acids include tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, methanesulfonic, ethanesulfonic, stearic, benzenesulfonic, bromobenzenesulfonic, and/?- toluenesulfonic acids. Suitable bases include NaH, potassium-t-butoxide, NaOH, KOH, Na₂CO₃, and K₂CO₃.

Compounds of the present invention may exist in stereoisomeric forms. More particularly, compounds of the present invention contain a hydroxy ethylene linker between piperidinyl groups that may be prepared as a racemic mixture or as individual enantiomers. The enantiomers may be resolved using a suitable agent such as (S,S)-Co(Salen) or (R,R)-Co(Salen). Accordingly, the individual stereoisomers and mixtures of these are included within the scope of the present invention.

In a further aspect, the invention provides a method of treating a disease comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.

While it is possible that a compound of the present invention may be administered as the pure chemical, it is generally preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, in a further aspect, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.

Compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating, and compressing, or dissolving the ingredients as appropriate to the desired preparation.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may contain conventional excipients including binding agents, fillers, lubricants, disintegrants, and wetting agents such as those well known in the art. The tablets may be coated according to methods well known in the art.

Affinity for CCR2 Receptor

Compounds of the present invention have been found to exhibit affinity for chemokine receptors, in particular the CCR2 receptor. Such affinity is typically calculated from the IC50 as the concentration of a compound necessary to inhibit 50% of the stimulated response from the receptor in an appropriate assay, and is reported as a "K₁" value calculated by the following equation: κ _ IC₅₀

¹ 1 + L / K_D where L = radioligand and K_D = affinity of radioligand for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

In the context of the present invention pKi (corresponding to the antilogarithm of Ki) is used instead of Ki. CCR-2 [³⁵Sl GTPgS SPA binding assay

Membrane preparation

CHO cells expressing the human CCR-2 receptor were grown in DMEM F 12 media supplemented with 10% foetal calf serum, 2 mM L-glutamine, G418 at 37⁰C 5% CO₂. Confluent cells were harvested using Hanks buffered salt solution (HBSS, Ca²⁺, Mg²⁺ free) containing 0.6mM EDTA. The resulting cell suspension was centrifuged at 300 g at 4 ⁰C for 10 min, cell pellet resuspended in 100 mL HBSS+EDTA and respun at 30Og for 5 min. The resulting cell pellet was resuspended in 50 mM HEPES containing 100 mM leupeptin, 25 μg/mL bacitracin, 1 mM EDTA, 1 mM PMSF and 2 μM pepstain A, at pH 7.4. The suspension was homogenised using an ice cold blender and centrifuged at 500 g for 20 min. The supernatant is withdrawn and spun at 48000 g for 30 min. This cell pellet is resuspended in the above buffer minus the pepstatin A and PMSF and stored in aliquots at -70 ⁰C.

Assay

For the assay, membranes were thawed and re-suspended in assay buffer (20 mM

HEPES, 10 mM MgCl₂, 100 mM NaCl, pH 7.4, containing 1 mg/mL saponin, 10 mM GDP) to give a final concentration of 5 μg/well. The membranes were pre-coupled with LEADseeker SPA beads (0.25mg/well) for 30 min at room temperature while mixing. Assay plates containing 0.5 μL of various test compounds (30 μM-30 pM) in 100% DMSO as 11 point, four fold dilutions across a 384 well plate were used in the assay which have been prepared on a Biomek FX. The plate also contained 16 wells of DMSO and 16 wells of a high concentration of a standard antagonist to produce high and low controls in the experiment. To this 15 μL of bead and membrane mix were added with, 15 μL [³⁵S] GTPgS (0.2 nM final assay concentration) and 15 μL of an ECgo (40 nM) of MCP-I . This concentration of MCP-I had been pre-determined from agonist curves run against this receptor. All additions were made using a multidrop. Plates were then sealed and centrifuged for 5 min at 300 rpm before they were left to incubate at room temperature for 3 hours. After this time they were read on a Viewlux imaging system. For data handling the high and low controls wells were used to normalize the data, which was then fitted using a 4 parameter kit in Excel. The assay described above is believed to have an effective limit of detection of a pKi in the region of 5.0-5.5. Accordingly, a compound exhibiting a pKi value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity. Using this assay, all of the exemplified compounds gave a of pKi > 6.

Schemes

The following schemes illustrate how compounds of the present invention can be prepared. Specific solvents and reaction conditions referred to are also illustrative and not intended to be limiting. Compounds for which synthetic details are not provided are either commercially available or are readily prepared by one skilled in the art using available starting materials.

Scheme 1

Scheme 2

Scheme 3

Z is a suitable leaving group such as -OSO₂-CH₃ or Cl.

Scheme 4

I) Pd(OAc)₂

Bu₄NCI

HCOONa

Na₂CO₃

2) deprotect

Scheme 5

In this scheme, DIAD is diisopropyl azodicarboxylate and AIBN is 2,2" -azo bis- isobutyronitrile.

Scheme 6

VinylMgBr Epoxidation

Nucleophilic Ring Opening

Deprotection

Coupling

Scheme 7

cat OsO₄, NMO

Scheme 8

In this scheme, S-Phos is l-dicyclohexylphosphino-l^β'-dimethoxy-lj '-biphenyl.

Scheme 9

1 ) Pd(OAc)₂

The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Intermediate 1 : [4-(2-Fluoro-4-methylphenyl)-4-piperidinyl]methanol

A: 1,1-Dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-l-piperidinecarboxylate

Sodium hydride (60% dispersion in oil, 6.3 g, 158 mmol) and DMSO (960 mL) were added to a 1-L round bottom flask, followed by portionwise addition of (4-chloro-2- fluorophenyl)acetonitrile (6.9 g, 41 mmol). This mixture was stirred for 1 h at ambient temperature, whereupon a solution of 1 , 1 -dimethylethyl bis(2- chloroethyl)carbamate (11.1 g, 46 mmol, 1.1 equiv) in dry DMSO (20 mL) was added dropwise. The mixture was then stirred at ambient temperature for an additional 3 h. The reaction mixture was then poured into dichloromethane (DCM 400 mL) and water (750 mL) and shaken, then filtered through a bed of Celite. The organic layer was separated, washed with water (I x 200 mL), dried with sodium sulfate, and evaporated to obtain the crude product as a dark red oil. The product was purified by normal phase slice gel chromatography (0%-25% ethyl acetate in hexanes over 15 CV with 330 g column) to afford the desired product (5.3 g, 38%) as a yellow oil. B: 4-(4-Chloro-2-fluorophenyl)-4-piperidinecarboxylic acid

A mixture of 1,1-dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-l- piperidinecarboxylate (5.3 g, 15.7 mmol) in excess concentrated hydrochloric acid, was heated to reflux. Glacial acetic acid was added portionwise to the refluxing mixture until a homogenous yellow solution was obtained. The solution was refluxed for 48 h, then concentrated in vacuo. The crude product was used without further purification for the next step.

C : [4-(4-Chloro-2-fluorophenyl)-4-piperidinyl]methanol

A solution of 4-(4-chloro-2-fluorophenyl)-4-piperidinecarboxylic acid and BH3 in THF (1 M, 6 equiv.) was prepared and refluxed for 1-2 h. The reaction was allowed to cool, whereupon MeOH was slowly added to quench the reaction. The resulting mixture was concentrated in vacuo. A 1 : 1 v/v solution of 6 N HChMeOH (—100 mL total) was then added, and the mixture was refluxed for 1 h. MeOH was removed, and DCM then 6N NaOH added to adjust the pH of the aqueous layer to 14. The DCM layer was separated and the aqueous layer extracted with DCM (x 3). The organic layers were combined, dried over sodium sulfate, followed by removal of solvent in vacuo to afford [4-(4-chloro-2-fluorophenyl)-4-piperidinyl]methanol, which was used directly in the next step without further purification. Intermediate 2: [4-(2-Fluorophenyl)-4-piperidinyl]methanol

A: [4-(2-Fluorophenyl)-4-piperidinyl]methanol

A mixture of [4-(2-fluorophenyl)-4-piperidinyl]methanol and LAH (1 M in THF, 3 equiv.) was heated at reflux for 2 h. The reaction was allowed to cool, followed by the addition of excess sodium sulfate decahydrate. The resulting mixture was filtered and the filtrate concentrated in vacuo to afford the product, which was used directly in the next step without further purification.

Intermediate 3: [(3R,4S)-4-(2-Fluoro-4-methylphenyl)-3-methyl-4- piperidinyljmethanol

A: 1,1 -Dimethylethyl (3R,4S)-4-cyano-4-(2-fluoro-4-methylphenyl)-3-methyl- 1 - piperidinecarboxylate (cis)

Lithium hexamethyldisilazide (LiHMDS) in THF (1 M, 110 mL) was added dropwise to a chilled mixture (-78 ⁰C) of 2-fluoro-4-methyl phenylacetonitrile (7.34 g, 49 mmol) in dry THF (100 mL). Upon completion of the addition, the solution was stirred at -78 ⁰C for 30 minutes, whereupon a solution of (li?)-2-({[(l,l- dimethylethyl)oxy]carbonyl} {2-[(methylsulfonyl)oxy]ethyl}amino)-l-methylethyl methanesulfonate (10.26 g, 28 mmol) dissolved in THF (75 rnL) was added dropwise. The solution temperature was allowed to rise to ambient temperature overnight. Excess DCM and water were added to the mixture. The DCM layer was separated and dried over sodium sulfate; the solvent was removed in vacuo to afford the crude product (10.46 g) as an orange oil. LCMS indicated a ratio of cis to trans of 71 :29 by UV area. The mixture was purified on a 330 g ISCO silica column, eluting 5 to 10% EtO Ac/Hex. The trans isomer eluted first, with impurities, followed by the cis isomer. 1.62 g (4.9 mmol) of the pure cis isomer was obtained.

B: (3R,4S)-4-(2-Fluoro-4-methylphenyl)-3-methyl-4-piperidinecarboxylic acid

Glacial acetic acid was added portionwise to a refluxing mixture of 1,1-dimethylethyl (3R,4S)-4-cyano-4-(2-fluoro-4-methylphenyl)-3-methyl- 1 - piperidinecarboxylate in excess concentrated hydrochloric acid until a homogenous yellow solution was obtained. The solution was refluxed for 48 h, then concentrated in vacuo to yield the crude product.

C: [(3R,4S)-4-(2-Fluoro-4-methylphenyl)-3-methyl-4-piperidinyl]methanol

A mixture of (3R,4S)-4-(2-fluoro-4-methylphenyl)-3-methyl-4-piperidinecarboxylic acid and BH3 (1 M in THF, 6 equiv.) was heated at reflux for 1-2 h. The reaction was allowed to cool, then excess MeOH added portionwise to quench the reaction. The resulting mixture was concentrated in vacuo. A solution of 1 : 1 6 N HChMeOH (-100 mL total) was then added to the concentrate and the resulting mixture was heated at reflux for 1 h. MeOH was removed, then DCM then 6 N NaOH added to provide an aqueous phase having a pH of 14. The DCM layer was separated and the aqueous extracted with DCM (x 3). The DCM layers were combined, dried over sodium sulfate and concentrated in vacuo to afford [4-(4-chloro-2-fluorophenyl)-4- piperidinyljmethanol, which was used directly in the next step without further purification.

Intermediate 4: l-[(2£)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-(2S-oxiranyl)piperidine

A: {l-[(2E)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol

DCM

4-Piperidinemethanol (17.7 g, 1.0 eq.), 3,5-difluorocinnamic acid (28.3 g, 1.0 eq.) and benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 78.2 g, 1.15 eq.) were dissolved in dichloromethane (DCM, 700 mL). Triethylamine (TEA, 46.6 g, 3.0 eq.) was added and the resulting solution was stirred at room temperature overnight. LCMS showed 100% conversion. The reaction mixture was concentrated and purified via silica gel column eluting with 0-75% ethyl acetate in hexanes to afford the product as a white solid (35 g, 81%). MS (ES) m/e 282 [M+H]+. B: l-[(2£)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde

DMSO

A 2-L round bottom flask was charged with DCM (900 mL) and oxalylchloride (25.36 g, 0.20 mole, 1.3 eq.) and cooled to -78 ⁰C. Dimethylsulfoxide (DMSO, 31.22 g, 0.40 mole, 2.6 eq.) was added dropwise and the mixture was stirred at -78 ⁰C for 10 min. Then, {1- [(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol (43.2 g, 0.15 mole, 1.0 eq, dissolved in 100 mL of DCM and a few mL DMSO) was added slowly. After stirring for another 30 min at -78 ⁰C, TEA (93.14 g, 0.92 mole, 6.0 eq.) was added slowly. The suspension was then stirred at -78 ⁰C for 30 min, then warmed to room temperature over 2 h. The mixture was diluted with 300 mL DCM and washed with 2 x 200 mL 2M HCl, 1 x 100 mL saturated NaHCOs, and then dried over MgSO₄, and concentrated to afford 1- [(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde (35.4 g, 82%) as a brown oil. The material was used in the next step without further purification. MS (ES) m/e 280 [M+H]+. ¹HNMR (CDCl₃) δ(ppm): 9.72 (s, IH), 7.56 (d, IH), 7.04 (m, 2H), 6.90 (d, IH), 6.82 (m, IH), 4.40 (m, IH), 4.00 (m, IH), 3.36 (m, IH), 3.22 (m, IH), 2.56- 2.64 (m, IH), 2.02 (m, 2H), 1.67 (m, 2H).

C: l-[(2£)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine

DMSO

An oven dried 500-mL flask was charged with (CH₃)₃SOI (46.14 g, 210 mmol, 1.3 eq) and 250 mL dry DMSO. NaH (95%, 5.30 g, 210 mmol, 1.3 eq) was added in around 10 batches and solution was then cooled to 0 ⁰C. The resulting mixture was stirred at 0 ⁰C for 30 min. The aldehyde (45 g, 161 mmol, 1.0 eq) in 150 mL dry DMSO solution was added dropwise and the resulting solution was stirred at 0 ⁰C for 30 min. LCMS showed completed reaction. The reaction was then quenched with 800 mL water and poured into 1200 mL diethyl ether. The organic layer was separated and washed with 2 x 150 mL water and dried over MgSO₄ and concentrated. Crude LCMS showed >90% purity for the desired product in 58% yield as a light yellow oil which solidified to a yellow solid overnight. MS (ES) m/e 294 [M+H]+. ¹HNMR (CDCl₃) δ(ppm): 7.56 (d, IH), 7.04 (dd, 2H), 6.91 (d, IH), 6.80 (m, IH), 4.74 (m, IH), 4.11 (m, IH), 3.05 (m, IH), 2.77 (s, 2H), 2.61 (m, IH), 1.95 (m, IH), 1.70-1.80 (m, IH), 1.30-1.60 (m, 4H).

D: l-[(2£)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-(2S-oxiranyl)piperidine

(S,S)-Co-salen catalyst (206 mg) ((S,S)-(+)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-l,2- cyclohexanediamino cobalt (H)) was dissolved in toluene (2 mL) in an open air flask. Glacial acetic acid (39 uL) was added and the reaction stirred at room temperature for 1 h. The reaction was then concentrated to a brown solid, which was placed under high vacuum overnight. l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine (2 g) was dissolved in THF (2 mL). The catalyst was dissolved in THF (0.5 mL) and added to the solution of epoxide in an open air flask. The mixture was cooled to 0 ⁰C and H2O (69 uL) was added dropwise over 5 min. The reaction was warmed to room temperature and allowed to stir for 16 h. The reaction was then concentrated and purified by flash chromatography on a 120 g silica gel column (0 to 70% EtOAc/hexanes over 60 min.) to yield a yellow oil (805 mg, 40% yield). MS (ES) m/e 294 [M+H]+ ¹H NMR (400 MHz, DMSO-^₆) d ppm 7.55 (d, J = 16 Hz, IH), 7.03 (m, 2H), 6.91 (m, IH), 6.81 (m, IH), 4.74 (m, IH), 4.13 (m, IH), 3.15 (m, IH), 2.79 (m, 4H), 1.90 (m, IH), 1.47 (m, 4H). A sample of l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-(2S-oxiranyl)piperidine from the above reaction was checked on a Chiralpac AD column with a 100% methanol mobile phase (0.9 mL/min) and found to have a retention time of 8.3 min, when compared to a racemic mixture (retention time 8.1 and 8.3 min) and found to be 99% ee.

Example 1 : (15)-l-{l-[(2E)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinyl}-2- (6-methyl- 1 'H-spiro[ 1 -benzofuran-3 ,4'-piperidin] - 1 '-yl)ethanol

A: 1,1 -Dimethylethyl 4-cyano-4-(2-fluoro-4-methylphenyl)- 1 -piperidinecarboxylate

(2-Fluoro-4-methylphenyl)acetonitrile (11.49 g, 77 mmol) was gradually added to a suspension of sodium hydride (11.70 g, 293 mmol) and DMSO (200 mL) in a 1-L round-bottomed flask fitted with a mechanical overhead stirrer. The reaction was stirred for about 5 hours, after which time the mixture was cooled in an ice bath. A mixture of 1,1 -dimethylethyl bis(2-chloroethyl)carbamate (20.38 g, 84 mmol) in 30 mL of DMSO was then added, and the resulting solution was allowed to warm to ambient temperature and stir overnight. Water was added slowly, and the organics were extracted with DCM (3 x 300 mL). The combined DCM extracts were washed with water (2 x 400 mL) then dried over sodium sulfate and concentrated. The product was purified on a 330 g silica gel column, eluting with 70-100% hexanes in DCM. The product was obtained as a yellow oil (8.2g, 33%). MS (ES) m/e 219.1

[M+H]+.

B: 4-(2-Fluoro-4-methylphenyl)-4-piperidinecarboxylic acid

Concentrated hydrochloric acid (300 mL, 3653 mmol) and glacial acetic acid (13.23 mL, 231 mmol) were added to a 1-L round-bottomed flask containing 1,1- dimethylethyl 4-cyano-4-(2-fluoro-4-methylphenyl)-l -piperidinecarboxylate (26.76 g, 84 mmol).. The resulting mixture was heated to reflux and allowed to stir for 48 hours. The mixture was then concentrated in vacuo at 70 ⁰C to a white powder. The resulting solid was used for the next reaction without further purification. MS (ES) m/e 238.1 [M+H]+.

C: [4-(2-Fluoro-4-methylphenyl)-4-piperidinyl]methanol

A solution of crude 4-(2-fluoro-4-methylphenyl)-4-piperidinecarboxylic acid (4.51 g, 19 mmol) and IM borane/THF complex (114 mL, 114 mmol) was heated to reflux for 2 h. The mixture was allowed to cool and methanol was added slowly until no bubbling was observed. The resulting solution was concentrated to a white pasty residue, to which was added a mixture of 6N HCl (80 mL, 480 mmol) and MeOH (80 mL, 1977 mmol). This solution was heated to reflux for one h. MeOH was removed and the mixture was cooled in an ice bath. DCM was added followed by slow addition of 6N NaOH (75 mL, 450 mmol) until the pH of the aqueous phase was 14. The resulting mixture was separated and the aqueous layer extracted with DCM (3 x 300 mL). The combined DCM extracts were dried over sodium sulfate and concentrated to a tan solid (4.2 g, 100%). MS (ES) m/e 224.1 [M+H]+.

D : 1 , 1 -Dimethylethyl 4-(2-fluoro-4-methylphenyl)-4-(hydroxymethyl)- 1 - piperidinecarboxylate

BOC-Anhydride (4.03 g, 18.5 mmol) was added to a stirred suspension/solution of [4-(2-fluoro-4-methylphenyl)-4-piperidinyl]methanol (4.03 g, 18.05 mmol) in MeOH (100 mL). After 30 minutes, an additional amount of BOC-anydride (0.7 g, 3.2 mmol) was added and the reaction was allowed to stir overnight. The mixture was concentrated to an oily reside, which was purified on a 120-g silica gel column, eluting with 0-40% ethyl acetate in hexane. The product was obtained as a white solid (4.6 g, 79%). MS (ES) m/e 346.2 [M+Na]+.

E : 1 , 1 -Dimethylethyl 6-methyl- 1 'H-spiro[ 1 -benzofuran-3 ,4'-piperidine] - 1 '-carboxylate

To a 15-mL microwave vial was added potassium t-butoxide (216 mg, 1.8 mmol) followed by a solution of 1,1 -dimethylethyl 4-(2-fluoro-4-methylphenyl)-4- (hydroxymethyl)-l-piperidinecarboxylate (500 mg, 1.546 mmol) in 5 mL of TΗF. The resulting mixture was microwaved at 100 ⁰C for 1 min. An additional amount of potassium t-butoxide (204 mg, 1.7 mmol) was added and the mixture was once again microwaved at 100 ⁰C for 1 min. The reaction was microwaved further at 120 ⁰C for 1 minute. The mixture was diluted with water and extracted with DCM (x 3). The combined organic layers were dried over MgSO₄ and concentrated to a clear oil. The product (0.38 g, 82%) was used without further purification for the next reaction. MS

(ES) m/e 326.2 [M+Η]+.

F : 6-Methylspiro[ 1 -benzofuran-3 ,4'-piperidine]

1 , 1 -Dimethylethyl 6-methyl- 1 Η-spiro[ 1 -benzofuran-3 ,4'-piperidine] - 1 '-carboxylate (383.8 mg, 1.265 mmol) and trifluoroacetic acid (TFA, 1 mL, 12.98 mmol) in DCM (5 mL) were added to a 100-mL round-bottomed flask to give a colorless solution. After stirring for 5 min, LCMS indicated reaction about 80% complete. After stirring an additional 15 min LCMS showed that the reaction was complete. The mixture was concentrated and the concentrate treated with saturated sodium bicarbonate and extracted with DCM (x 3). The combined DCM extracts were dried over MgSO₄ and concentrated to a white solid. MS (ES) m/e 204.1 [M+H]⁺.

G: (15)-l-{l-[(2E)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-(6-methyl- 1 'H-spiro[ 1 -benzofuran-3 ,4'-piperidin] - 1 '-yl)ethanol

1 , 1 -Dimethylethyl 6-methyl- 1 Η-spiro[ 1 -benzofuran-3 ,4'-piperidine] - 1 '-carboxylate (126 mg, 0.415 mmol) and l-[(2E)-3-(3,5-difiuorophenyl)-2-propenoyl]-4-[(2S)-2- oxiranyljpiperidine (122 mg, 0.415 mmol) in ethanol (2.52 mL) were added to a microwave reaction vial to give a yellow suspension. The mixture was microwaved at 170 ⁰C for a total of 64 min to obtain a mixture of 57% product and 23% epoxide. The reaction mixture was diluted with 15% TΗF in EtOAc and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified on a silica gel column, eluting with 0-7% MeOH in DCM. The desired fractions were combined and concentrated. The residue was further purified further by ΗPLC, 20-60% acetonitrile in water. The desired fractions were poured into a mixture of NaOH and DCM. The DCM layer was separated, dried over NaSO₄ and filtered. The filtrate was slowly concentrated under nitrogen gas stream while gradually adding hexane to precipitate the free base as a white powder (89 mg, 43%). MS (ES) m/e 497.3 [M+Η]+. IH NMR (400 MHz, CDCl₃) δ ppm 1.20 - 2.22 (m, 11 H) 2.33 (s, 3 H) 2.57 - 3.31 (m, 5 H) 3.82 (br. s., 1 H) 3.99 - 4.49 (m, 4 H) 4.77 (br. s., 1 H) 5.17 (br. s., 1 H) 6.64 - 6.85 (m, 2 H) 6.90 (d, J=15.56 Hz, 1 H) 7.04 (d, J=6.27 Hz, 2 H) 7.18 (d, J=7.78 Hz, 1 H) 7.55 (d, J=15.31 Hz, 1 H).

Example 2: (3i?,3'i?)-6-chloro-r-((25)-2-{l-[(2_JE)-3-(3,5-difluorophenyl)-2- propenoyl]-4-piperidinyl}-2-hydroxyethyl)spiro[l-benzofuran-3,4'-piperidin]-3'-ol

A: 4- { [(2-bromo-4-chlorophenyl)oxy]methyl} - 1 -(phenylmethyl)- 1 ,2,3,6- tetrahydropyridine

Triphenylphosphine (6.9 g, 26.3 mmol) was dissolved in THF (175 niL) and the solution cooled to 0 ⁰C in an ice bath under nitrogen. Diisopropyl azodicarboxylate (5.3 g, 26.2 mmol) was then added dropwise and the mixture stirred at 0 ⁰C for 20 minutes, during which a white ppt was seen to form. 2-Bromo-5-chlorophenol (4.4 g, 21 mmol) was then added as a solid followed by [1 -(phenylmethyl)- 1,2,3, 6- tetrahydro-4-pyridinyl]methanol (4.3 g, 21 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was evaporated to a residue after 16 hours and then purified by FCC on the ISCO (0% to 25% EtOAc/Hex). Fractions containing product were concentrated to give a colorless oil (6.14g, 74%). MS (ES) m/e 393.8 [M+H]+.

B: phenylmethyl 4-{[(2-bromo-4-chlorophenyl)oxy]methyl}-3,6-dihydro-l(2H)- pyridinecarboxylate

The benzyl amine (6.14g, 15.6 mmol) was dissolved in DCM (150 mL) and benzyl chloroformate (5.3 g, 31 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and chromatographed (ISCO, 0% to 25% EtO Ac/Hex) and then concentrated to give an orange oil (5.05g,

74%). MS (ES) m/e 459.7 [M+Na]+.

C : phenylmethyl 6-chloro-2',3 '-dihydro- 1 'H-spiro[ 1 -benzofuran-3 ,4'-pyridine] - 1 '- carboxylate

Phenylmethyl 6-chloro-2',3'-dihydro- 1 'H-spiro[ 1 -benzofuran-3 ,4'-pyridine]- 1 '- carboxylate (5.05 g, 11.6 mmol), silver carbonate (6.4 g, 23 mmol), palladium acetate (0.26 g 1.2 mmol), and Ph₃P (1.2 g, 4.6 mmol) were loaded into a sealed tube with stirbar. TΗF (45 mL) was added. The reaction was then heated to 120 ⁰C overnight. LCMS showed complete reaction after 16 hours. The reaction was filtered over a small plug of silica gel to remove silver and palladium salts. The filtrate was concentraed and chromatographed via ISCO (0% to 25% EtOAc/Ηex). Fractions were concentrated to a colorless oil (1.44 g, 35%). MS (ES) m/e 278.9 [M+Na]⁺.

D: phenylmethyl (3i?,3'i?)-6-chloro-3'-hydroxy-l'H-spiro[l-benzofuran-3,4'- piperidine]-l'-carboxylate and phenylmethyl βS^'^-ό-chloro-S'-hydroxy-rH- spiro[ 1 -benzofuran-3 ,4'-piperidine]- 1 '-carboxylate

The enecarbamate (3.9 g, 11.0 mmol) was dissolved in THF (59 mL) and borane-tetrahyrofuran (16 mL and a IM solution in THF) was added at -78 ⁰C. The reaction was allowed to slowly warm to r.t. over five hours. Water (15 mL) was then added followed by sodium perborate tetrahydrate (8.4 g, 55 mmol). The mixture was then stirred overnight. The mixture was diluted with DCM and the layers separated. The mixture was concentrated to give a 5:1 transxis mixture. A chiral prep HPLC was run using (OD-H column (20x250 mm) 10/20/70 methanol/isopropanol/hexane w/0.1% DEA @ 10 mL/min, Runtime -35 min). The sample was dissolved methanol (55 mg/mL) and then filtered. The peaks were checked by analytical chiral column using (OD-H column (4.6x250 mm) 10/20/70 methanol/isopropanol/hexane w/0.1% DEA @ 1.2 mL/min). Each trans enantiomer (1.0 g each) was collected and had a purity of >99% ee. MS (ES) m/e 396.8 [M+Na]⁺. Each enantiomer was carried forward separately.

E: (3i?,37?)-6-chlorospiro[l-benzofuran-3,4'-piperidin]-3'-ol

The carbamate (150 mg, 0.39 mmol) was added to a reaction flask followed by ethanol (3 mL), water (1 mL), and lithium hydroxide (28 mg, 1.2 mmol). The reaction was brought to reflux overnight. The crude reaction mixture was filtered through a tosic acid solid phase extraction cartridge, washing with methanol, and 15 eluting with 2N NH₃/Me0H. The product was concentrated. MS (ES) m/e 240.0 [M+H]+.

F: (3i?,3'i?)-6-chloro-r-((25)-2-{l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyl}-2-hydroxyethyl)spiro[l-benzofuran-3,4'-piperidin]-3'-ol

0

The spirobenzofuran (32 mg, 0.13 mmol), epoxide (39 mg, 0.13 mmol), and ethanol (1.4 mL) were mixed in a microwave vial and heated to 160 ⁰C for 10 minutes in the microwave reactor. The reaction was concentrated and injected onto a Waters prep HPLC for purification to provide (50 mg, 57%) of the desired product. MS (ES) m/e 5 533.2 [M+H]+ ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.21 (m, 2H), 1.64 (m, 2H), 1.82 (m, IH), 2.03 (m, 2H), 3.26-2.46 (m, 5H), 3.41 (m, IH), 3.49 (m, IH), 3.75 (m, 2H), 4.14 (m, IH), 4.41 (m, 2H), 4.55 (m, IH), 4.71 (m, IH), 5.61 (m, IH), 5.69 (m, IH), 6.88 (m, IH), 6.96 (m, IH), 7.07 (m, IH), 7.26 (m, IH), 7.45 (m, 2H), 7.57 (m, 2H).

Table 1 illustrates additional examples and the schemes generally used to prepare them. Examples 7 and 8 are stereoisomers of each other; the actual configuration of each compound is resolvable, for example, by way of vibrational circular dichroism. The actual configurations of compounds 3 and 10 are similarly resolvable.

Table 1

Claims

PU62714

CLAIMS:

A compound of the following formula:

or a pharmaceutically acceptable salt thereof;

where each R¹ is independently halo, CF₃, C|-C₄-alkyl, Ci-Cψ-alkoxy, OCF3, cyano, C ₁ -C₆-alky 1-C(O)-NH-, C_rC₆-alkyl-NH-C(O)-, -CH₂-NR⁵R⁶ , -CH₂-O-R⁷, COOH, Ci-C₄-S(O)_r> or heteroaryl;

R² and R³ are each independently H, OH, COOH, HO-Q-C₄-alkyl, C|-C₄-alkyl, CN, CF₃, OCF3, benzyloxy, halo, or Ci-C₄-aIkoxy;

each R⁴ is independently halo, CF₃, C|-C₄-alkyl, Ci-C₄-alkoxy, OCF₃, benzyloxy, heteroaryl, or CN;

R⁷ is H, Ci-Cβ-alkyl, -CH₂-phenyl-(R¹⁰)_s, or phenyl-(R¹⁰)_s;

R⁸ is H, OH, F, Cl, CN, CF₃, Ci.Ce-alkyl, hydroxy-C]-C₆-alkyl, or Ci.C₆-alkoxy;

each R⁹ is independently halo, CF₃, Ci-C₄-alkyl, Ci-C₄-alkoxy, OCF₃, benzyloxy, OH, or

CN;

each R¹⁰ is independently OH, F, CI, CN, CF₃, C|.C₆-alkyl, hydroxy-d-C₆-alkyl, or Ci-Cβ-alkoxy; PU62714

n is 0, 1, or 2;

m is 0, 1, 2, or 3;

p is 0, 1, or 2;

r is 0, 1 , or 2; and

s is O, 1, 2, or 3.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is CH₃, CN, or Cl and n is 0 or 1 and

3. The compound of Claim 2 which is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein R² is H and R³ is H, OH or methyl. PU62714

4. The compound of Claim 3 which is represented by either of the following formulae:

or

or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 1 which is (15)-l-{ l-[(2£)-3-(3,5-difluorophenyl)-2- propenoyl]-4-piperidinyl}-2-(6-methyI-rH-spiro[l-benzofuran-3,4'-piperidin]-l'- yl)ethanol, or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 1 which is (l S)-l-{ l-[(2E)-3-(3,5-difluorophenyl)-2- propenoyl]-4-piperidinyl}-2-[(3S,3'R)-3',6-dimethyl-lΗ-spiro[l-benzofuran-3,4'- piperidin]-l'-yl]ethanol, or a pharmaceutically acceptable salt thereof,

7. The compound of Claim 1 which is (l S)-2-(6-chloro-l'Η-spiro[l-benzofuran-3,4'- piperidin]-l'-yl)-l-{ l-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol, or a pharmaceutically acceptable salt thereof.

8. The compound of Claim 1 which is (l S)-l-{ l -[(2E)-3-(3,5-difluorophenyl)-2- propenoyl]-4-piperidinyl}-2-(rH-spiro[l -benzofuran-3,4'-piperidin]-r-yl)ethanol, or a pharmaceutically acceptable salt thereof. PU62714

9. The compound of Claim 1 which is (3R,3^lR)-6-chloro-l¹-((2S)-2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl} -2 -hydroxy ethyl)spiro[l -benzofuran-3,4'- piperidin]-3'-ol, or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 which is (3S,3'S)-6-chloro-l'-((2S)-2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)spiro[l-benzofuran-3,4'- piperidin]-3'-ol, or a pharmaceutically acceptable salt thereof.

1 1. The compound of Claim 1 which is ( 1 S)-I-( I -[(2E)-3-(3,5-difluorophenyi)-2- propenoyl]-4-piperidinyl}-2-[(3R,3'R)-3',6-dimethyI-l 'H-spiro[l-benzofuran-3,4'- piperidin]-l'-yl]ethanol, or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 1 which is (15)-2-[(35',3'5)-6-chloro-3'-methyl-rH-spiro[l- benzofuran-3,4'-piperidin]-r-yl]-l-{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyl}ethanol, or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 1 which is (15}-2-[(3R,3'Λ)-6-chloro-3'-methyl-l'H-spiro[l- benzofuran-3,4'-piperidin]-r-yl]-l -{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyljethanol, or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 1 which is (3S,3W)-6-chloro-l '-((2i?)-2-{ l -[(2£)-3-(3,5- difluorophenyl)-2-propenoyl]-4-hydroxy-4-piperidinyI}-2-hydroxyethyl)spiro[l- benzofuran-3,4'-piperidin]-3'-ol, or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 1 which is (3S,3'S)-V-((2S)-2-{ l-[(2£)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-3'-methylspiro[l- benzofuran-3,4'-piperidine]-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 which is (3Λ,3'Λ)-r-((25)-2-{l-[(2£)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-3'-methylspiro[l- benzofuran-3,4'-piperidine]-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

17. A composition that comprises a) the compound of any of Claims 1 to 16 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient. PU62714

18. A method of treating a disease comprising administering the compound of any of Claims 1 to 16 or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, or diabetes.