WO2010080873A1 - Oxazoles as modulators of chemokine receptors - Google Patents

Abstract

The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein R¹-R⁷, X, Y, m, and n are as described herein. Compounds of the present invention are useful for the treatment of a variety of diseases associated with overexpression of the CCR2 receptor.

Description

OXAZOLES AS MODULATORS OF CHEMOKINE RECEPTORS

The present invention relates to a class of oxazoles 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, endometriosis, ocular indications 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

The present invention is a compound represented by the following formula (I):

or a pharmaceutically acceptable salt thereof; wherein

Y is O, or S;

R¹ is H and R² is:

or R¹ and R², together with the carbon atom to which they are attached, form:

wherein Z is N

each R³ is independently halo,

R⁴ is H or OH; each R⁵ is independently halo,

R⁶ and R⁷ are each independently H, C₁-C₆ alkyl, phenyl-(Rⁿ)_r, heteroaryl-(R¹²)_r,

or R⁶ and R⁷, together with the carbon atoms to which they are attached, form a fused benzo group; each R⁸ is independently halo, CN, Ci-Qs-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, SO₂CH₃, or COOH;

R⁹ is H or C₁-Ce-alkyl;

each R is H or, together with the carbon atoms to which they are attached form a double bond;

each R¹¹ is independently halo, CN, C₁-C₆-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, or COOH;

each R¹² is halo, CN, C₁-C₆-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, or COOH;

each R¹³ is independently H or CH₃, or together with the nitrogen atom to which they are attached, form a piperidinyl, piperazinyl, pyrrolidinyl, or morpholino ring;

m, n, and p are each independently O, 1 , or 2; and

r is O, 1, 2, or 3.

Compounds of the present invention are useful as modulators of CCR2 chemokine receptor.

Detailed Description of the Invention

The present invention is a compound represented by the following formula (I):

or a pharmaceutically acceptable salt thereof; wherein

, m, and n are as previously defined. In another aspect of the present invention is R¹ is H and R² is:

In another aspect of the present invention, the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof, where Z is O.

In another aspect, Z is NH or NCH₃;

In another aspect, Z is CR¹⁰, and each R¹⁰ is either H, or together with the carbon atoms to which they are attached, form a double bond.

In another aspect of the present invention, R³ and R⁵ are each independently CH₃, OH, or CH₂OH; m is O or 1 ; and n is O or 1 ;

R⁴ is H;

R⁶ is H, -C(O)-N(R¹³)₂, C₁-Cs-alkyl, or Cl;

R⁷ is H is phenyl-(Rⁿ)_r, CN, -C(O)-N(R¹³)₂, or pyridinyl, with the proviso that one of R⁶ and R⁷ is not H;

R¹¹ is F, Cl, CF₃, Or CH₃;

Y is O; and

r is 0, 1, or 2.

In another aspect of the present invention, the compound is represented by the following formula:

where R is CH₃ or OH; and

R⁸ is halo, CH₃, or CN.

In another aspect of the present invention, the compound is represented by the following formula:

wherein R⁶ is H, Cl, CH₃, CH₂CH₃, or -C(O)-N(R¹³)₂;

R⁸ is Cl, CH₃, or CN;

each R¹³ is independently H, or C₁-C₃-alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl group;

m is 0 or 1 ; and

r is 1 or 2.

In another aspect, R is H.

In another aspect of the present invention, the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof, where R³ is CH₃ or OH; and

R⁸ is halo, CH₃, or CN.

In another aspect of the present invention, the compound is represented by the following formula:

In another aspect, the present invention is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein R³ is OH or CH3;

R⁸ is CH₃ or Cl; each R¹¹ is independently F, Cl, CF₃, or CH₃; m is 0 or 1 ; p is 0 or 1 ; and r is 0, 1, or 2.

In another aspect, the present invention is represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein R CH₃, CN, F or Cl;

R¹¹ is F, Cl, CF₃, Or CH₃;

m is O or 1 ; and

r is 0, 1 or 2.

In another aspect, the present invention is a composition comprising the compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention is a method of treating a disease comprising administering a 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.

As used herein, C₁-Cβ-alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, ^-propyl, n- butyl, isobutyl, isopropyl, ϊ-butyl, and 1,1-dimethylpropyl.

As used herein, heteroaryl refers to a S- or 6-membered aromatic group that contains one or more heteroatoms selected from N, S, and O. Examples of heteroaryl groups include pyridinyl, furyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, and pyrimidinyl groups.

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 may exist in crystalline or non-crystalline 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 present invention includes all such solvates and forms.

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. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to the present invention 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, andp-toluenesulfonic acids. Suitable bases include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na₂CO₃, K₂CO₃, NaH, and potassium-t-butoxide.

Compounds of the present invention may exist in stereoisomeric forms. For example, compounds of the present invention contain a hydroxyethylene linker between piperidinyl groups that may be prepared as a racemic mixture or as individual enantiomers. The enantiomers of a common epoxide intermediate (see scheme 16) may be resolved using a suitable agent such as (S,S)-Co(Salen) or (R,R)-Co(Salen). Accordingly, the individual stereoisomers and mixtures thereof are included within the scope of the present invention.

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 present 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:

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 [³⁵S] 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 37°C 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 ºC 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 ºC.

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 (0.25 mg/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 EC₈₀ (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. The specific solvents and reaction conditions referred to are also illustrative and are not intended to be limiting.

where NFSi is N-fluorbenzenesulfonimide. w



where Pd(O₂CCFs)₂ is palladium(II) trifluroracetate, DMA is N,N-dimethylacetamide, and BINAP is 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl.

Scheme 14

where L is a suitable leaving group such as -OSO2-CH3 or Cl

where V0(acac)2 is vanadyl(acetylacetonate) and ^BuOOH is tert-butyl hydroperoxide

Examples

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

Intermediate 1: Phenylmethyl 4-[(2S)-2-oxiranyl]-1-piperidinecarboxylate

A: Phenylmethyl 4-(2-oxiranyl)-1-piperidinecarboxylate

Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of sodium hydride (NaH, 300 mg, 7.5 mmol) in anhydrous N,N-dimethylsulfoxide (DMSO, 10 mL) at room temperature. The resulting mixture was stirred for 1 h, whereupon a solution of phenylmethyl 4-formyl- 1 -pipCeridinecarboxylate (1.24 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then poured into cold water (100 mL), and extracted with diethyl ether (Et₂O, 2 x 100 mL). The extracts were combined, washed with water, brine, and dried over sodium sulfate (Na₂SO₄) The solvent was removed in vacuo to give the title compound (0.95 g, 73%) as a colorless oil. MS (ES) m/e 262 [M+H]+.

B: Phenylmethyl 4-[(2S)-2-oxiranyl]-1-piperidinecarboxylate

(S,S)-(+)-N,N'-Bis(3,S-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (4.4 g, 7.3 mmol) was dissolved in toluene (76 mL) in a reaction flask. Acetic acid (0.88 mL, 14.6 mmol) was added and the reaction was vigorously stirred at room temperature open to air for 1 h. The brown mixture was then concentrated and left on the high vacuum overnight (20 h). Phenylmethyl 4-(2-oxiranyl)-1-piperidinecarboxylate (76 g, 292 mmol) and the catalyst are then taken up in tetrahydrofuran (THF, 76 mL) and cooled to 0 ºC. Water (2.94 mL, 164 mmol) was added dropwise and the brown tar-like mixture was allowed to warm to room temperature and stir overnight. The mixture was then concentrated and purified on the ISCO (0% to 55% EtO Ac/Hex over 70 min). Obtained phenylmethyl 4-[(2S)-2-oxiranyl]-1-piperidinecarboxylate (30 g, 115 mmol, 39%). MS(ES) m/e 284 [M+Na]+.

Intermediate 2: (3S,4S>l-[(2S>2-Hydroxy-2-(4-piperidinyl)ethyl]-4-(7-methyl-1H- indol-3-yl)-3-piperidinol

A: 1 , 1 -Dimethylethyl 4-(7-methyl- 1H-indol-3-yl)-3 ,6-dihydro- 1 (2H)- pyridinecarboxylate

A mixture of 7-methylindole (3.0 g, 22.9 mmol), 1 , 1 -dimethylethyl 4-oxo-1- piperidinecarboxylate (5.4 g, 27.4 mmol) and potassium hydroxide (KOΗ, 3.9 g, 68.7 mmol) was dissolved in methanol (MeOH, 30 mL) and heated at 60 ºC for 5 h. The solvent was removed in vacuo and the residue was triturated with H₂O (200 mL) to obtain the product as a yellowish solid. MS (ES) m/e 313 [M+H]⁺.

B: 1 , 1 -Dimethylethyl (3R,,4R )-3,4-dihydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 - piperidinecarboxylate

Water (54 mL), K₂Fe(CN)₆ (19 g, 57.7 mol), K₂CO₃ (7.97 g, 57.7 mmol), MeSO₂NH₂ (1.83 g, 19.2 mmol), K₂OsO₄2H₂O (0.35 g, 0.96 mmol), hydroquinidine 1,4- phthalazinediyl diether ((DHQD)₂PHAL, 0.15 g, 0.19 mmol), and ϊ-butanol (ϊBuOH, 36 mL) was added to a 250-mL round bottom flask in that order. The mixture was stirred at room temperature for 5 min, whereupon 1 , 1 -dimethylethyl 4-(7-methyl-1H-indol-3-yl)- 3,6-dihydro-l(2H)-pyridinecarboxylate (6.0 g, 19.2 mmol) was slowly added. After 2 days, ethyl acetate (EtOAc, 100 mL) was added and stirred vigorously for 2 h; the mixture was filtered over a pad of celite and the solid was washed with EtOAc (3x). The filtrates were combined and washed with 2N KOΗ then brine, and concentrated in vacuo. The crude product was purified by normal phase silica gel chromatography (40 g silica gel 60, 0 to 100% EtOAc in hexane) to give a white solid (2.6 g, 7.5 mmol, 39%). MS(ES) m/e 369 [M+Na]+.

C: 1 , 1 -Dimethylethyl (3S',4S)-3-hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 - piperidinecarboxylate

To a refluxing mixture of Raney Nickel (20 g wet weight) in H₂O and ethanol (EtOH, 20 mL) was slowly added a solution of 1,1 -dimethylethyl (3R ,4R )-3,4-dihydroxy-4-(7- methyl-1H-indol-3-yl)-l -piperidinecarboxylate (1 g, 2.89 mmol) in EtOH (5 mL) via an addition funnel over a period of 30 min. The mixture was allowed to cool to room temperature before it was filtered through Celite, ensuring that the liquid level did not fall below the surface of the filter cake. A total of 1 L of EtOH was used to wash to filter cake. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 2.3 mmol, 79%) plus some of the cis isomer in an 8:1 ratio. MS (ES+) m/e 683 [2M + Na]⁺. D: 4-(7-Methyl-1H-indol-3-yl)-3-piperidinol

To a solution of 1,1-dimethylethyl (3S4S)-3-hydroxy-4-(7-methyl-1H-indol-3-yl)-1- piperidinecarboxylate (0 .9 g, 2.75 mmol) in MeOH (2 mL) was added a solution of 1 N HCl in dioxane (2 mL). The mixture was stirred at room temperature for 1O h, then diluted with EtOAc, treated with sodium bicarbonate (NaΗCOs) and recrystallized from EtOAc to obtain an enantiomerically pure compound 99+ee (0.57 g, 2.5 mmol, 91%). MS(ES) m/e 231 [M+Η]+.

E: Phenylmethyl 4-{(1S)-1-hydroxy-2-[(3S',4S)-3-hydroxy-4-(7-methyl-1H-indol-3-yl)- 1 -piperidinyl] ethyl} - 1 -piperidinecarboxylate

Intermediate 1

A mixture of (3S',4S)-4-(7-methyl-1H-indol-3-yl)-3-piperidinol (9.94 g, 43.2 mmol) and phenylmethyl 4-[(2S)-2-oxiranyl]-1-piperidinecarboxylate (11.28 g, 43.2 mmol) in EtOΗ (5 mL) was heated at 80 ºC overnight. The reaction mixture was concentrated and the concentrate was dissolved in 1 ,2-dichloroethane (10OmL) and PL-NCO MP Resin (6 g, 10OA, 3.13 mmol/g, 150-300μm) added. The heterogeneous mixture was heated at 80 ºC for 4 h. The resin was filtered off and washed with EtOAc several times. The organic washes were concentrated to obtain phenylmethyl 4-{(1S)-1-hydroxy-2-[(3S',4S)-3- hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 -piperidinyl] ethyl} - 1 -piperidinecarboxylate (21.2 g, 43.1 mmol, 100%) as a yellow solid. MS(ES) m/e 492 [M+Η]+. F: (3S,4S)- 1 -[(2S)-2-Hydroxy-2-(4-piperidinyl)ethyl]-4-(7-methyl- 1H-indol-3-yl)-3- piperidinol

To a solution of phenylmethyl 4-{(1S)-1-hydroxy-2-[(3S',4S)-3-hydroxy-4-(7-methyl-1H- indol-3-yl)-1-piperidinyl] ethyl} - 1 -piperidinecarboxylate (4.35 g, 8.85 mmol) in EtOH (15 mL) was added 10% Pd/C (1.5 g). The mixture was completely purged 5 X with nitrogen and 3X with H₂ then it was placed in a Parr hydrogenator at 50 psi for 1 day. LCMS showed complete conversion. The catalyst was filtered off and washed 3X with MeOH (500 mL total). The filtrates were combined and concentrated to obtain (3S,4S)- l-[(2S)-2-hydroxy-2-(4-piperidinyl)ethyl]-4-(7-methyl-1H-indol-3-yl)-3-piperidinol (3.2 g, 100%) as a yellow crystalline solid. MS(ES) m/e 358 [M+Η]+.

Intermediate 3: (1 S)-2-[(3R,3'R)-3',6-Dimethyl-1,2-dihydro-1'H-spiro[indole-3,4'- piperidin]- 1 '-yl]-l -(4-piperidinyl)ethanol

A: Phenylmethyl 3-methyl-4-oxo-l -piperidinecarboxylate

In a 100 mL round-bottomed flask was filled with 3-methyl-1-(phenylmethyl)-4- piperidinone (10 g, 49.2 mmol) in toluene (30 mL) to give a colorless solution. Phenylmethyl chloridocarbonate (18 mL, 53.3 mmol) in toluene (50% w/w) was added, and the reaction mixture was heated at 80 ºC for 3 h, then allowed to cool to room temperature while stirring for 16 h. The mixture was diluted with ethyl acetate (20 mL) and washed with IN HCl (10 mL), water (10ml), and brine (10 mL). The organic solution was dried over magnesium sulfate (MgSθ4), filtered, and concentrated. The crude material was purified via flash chromatography using an ISCO Companion with 12O g silica column eluting with 0-20% ethyl acetate in hexane to afford the desired product as a colorless oil (10.5 g, 82%).

B: Phenylmethyl (4)-3-methyl-4-[(methyloxy)methylidene]- 1 -piperidinecarboxylate

A 2L round-bottomed flask was charged with [(methyloxy)methyl](triphenyl) phosphonium chloride (122 g, 355 mmol) and THF (700 mL) to give a colorless suspension. The mixture was cooled to -78 ºC, and nBuLi (142 mL, 355 mmol) was added over 15 min. After stirring for 30 min at -78 ºC the cold bath was removed and the reaction mixture was allowed to warm to -5 ºC and a solution of phenylmethyl 3- methyl-4- oxo-1 -piperidinecarboxylate (54.8 g, 222 mmol) in THF (100 mL) was added drop wise over 7 min. The mixture was allowed to warm to room temperature while stirring for 16 h at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (NH4CI, 200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic solutions were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated. The crude material was dissolved in dichloromethane (DCM, 300 mL) and 100 g of silica gel was added. The product was purified via flash chromatography (SiO2) 0-15% EtOAc in Hexane to afford the desired product as colorless oil (46.25 g, 76%). MS (ES) m/e 276 [M+H]⁺.

C. (2-Bromo-3-methylphenyl)hydrazine

A 2L 3-necked flask was charged with 2-bromo-3-methylaniline (20 g, 107 mmol), cone. HCl (120 mL), and water (40 mL). The reaction was cooled to 5 ºC and a solution of sodium nitrite (NaNO₂, 8.2 g, 118 mmol) in water (125 mL) was slowly added maintaining an internal temperature <10 ºC. The reaction was stirred for 30 min and then a solution of SnCl₂-2H₂O (72 g, 321 mmol) in cone HCl (260 mL) was added while maintaining an internal temperature <10 ºC. The reaction was allowed to warm to room temperature while stirring for 16 h. The mixture was filtered and the filtrate was washed with brine (500 mL) at 0 ºC and hexanes/Et₂O (2/1 , 200 mL). The resulting solid was dried in the vacuum oven at 40 ºC. The solid was dissolved in 2N NaOH (800 mL) and DCM (800 mL). The organic layer was dried over Na₂SO₄ filtered, and concentrated to give the desired product as a white solid. MS (ES) m/e 201 M⁺.

D. Phenylmethyl 7-bromo-3',6-dimethyl-l ,2-dihydro-lΗ-spiro[indole-3,4'-piperidine]- l'-carboxylate

A flask was charged with phenylmethyl (4)-3-methyl-4-

[(methyloxy)methylidene]-l -piperidinecarboxylate (25.5 g, 89.1 mmol), (2-bromo-3- methylphenyl)hydrazine, and dichloroethane (309 mL). The solution was cooled to 0 ºC and trifluoroacetic acid (35.9 mL) was added over 15 min. The resulting solution was then warmed to 70 ºC for 1.75 h. The reaction was then cooled to room temperature and NaBH₄ (10.1 g, 267.3 mmol) was added portionwise. The reaction was stirred for 1 h then was cooled to 0 ºC and quenched with 10% NH4OH(aq) (200 mL). The organic layer was washed with brine, dried over Na₂Sθ4, filtered, and concentrated. The crude material was loaded onto silica and purified via flash chromatography using a 750 g silica cartridge eluting with 10-20% EtOAc in hexanes for 10 min then 20% for 15 min and then 30% until the material was eluted to give 25.3 g of the desired product (63%). MS (ES) m/e 429 M+ E. 3',6-Dimethyl-l ,2-dihydrospiro[indole-3,4'-piperidine]

A solution of phenylmethyl 7-bromo-3',6-dimethyl-1,2-dihydro-lΗ-spiro[indole-3,4'- piperidine]-l'-carboxylate (12.2 g, 28.4 mmol) in EtOH (140 mL) was treated with 10% Pd/C (5.7 g). The reaction was placed in a Parr shaker with 50 psi H₂ for 16 h. The mixture was then filtered through celite washing with MeOH. The solvent was removed and the crude material was loaded onto silica and purified via flash chromatography eluting with 2-10% of a solution of 2N NH₃/ MeOH in DCM to give the title compound. MS (ES) m/e 217 [M+H]⁺.

F. (3R,3'R)-3',6-Dimethyl-1,2-dihydrospiro[indole-3,4'-piperidine]

The racemic mixture of 3',6-dimethyl-1,2-dihydrospiro[indole-3,4'-piperidine] was resolved via chiral HPLC using a chiral OJ-H (250x20mm) column eluting with 15% EtOH in hexanes with 0.4% diethylamine. The injections were 350 μL of a 100 mg/mL solution in the eluting solvent.

G. Phenylmethyl 4-{(lS)-2-[(3R,3'R)-3',6-dimethyl-1,2-dihydro-lΗ-spiro[indole-3,4^>- piperidin]- 1 '-yl]-l -hydroxyethyl} - 1 -piperidinecarboxylate

A lO mL microwave vial was charged with (3R,3'R)-3',6-dimethyl-1,2- dihydrospiro[indole-3,4'-piperidine] (260 mg, 1.20 mmol) and phenylmethyl 4-[(2S)-2- oxiranyl]-l -piperidinecarboxylate (314 mg, 1.20 mmol) in DMF (2 mL) to give a colorless solution. The reaction mixture was heated via microwave irradiation to 160 ºC for 30 min then was diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na₂SO₄ filtered, and concentrated. The residue was purified via flash chromatography on a 40 g silica cartridge eluting with 0-5% MeOH in DCM over 20 min then 5% MeOH in DCM for 10 min to give the desired product as a white solid (475 mg, 83%). MS (ES) m/e 478 [M+H]⁺.

A solution of phenylmethyl 4-{(lS)-2-[(3R,3'R)-3',6-dimethyl-l,2-dihydro-l'H- spiro[indole-3,4'-piperidin]- 1 '-yl]-l -hydroxy ethyl} - 1 -piperidinecarboxylate (6.7 g, 14.1 mmol) in EtOH (71 mL) was stirred under an atmosphere OfH₂ for 16 h. The reaction was filtered through celite washing with MeOH. The solvent was removed to give the desired product as a white solid. MS (ES) m/e 344 [M+H]⁺.

Intermediate 4: 2-(6-Chloro-l,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-r-yl)-2-(4- piperidinyl)ethanol

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

(4-Chloro-2-fluorophenyl)acetonitrile (2.3 g, 13.7 mmol, 1.0 equiv) was added to a suspension of NaH (2.1 g, 52.5 mmol, 3.8 equiv) in DMSO (20 mL) at 23 ºC. The resulting yellow suspension was stirred for 10 min and the color turned red-brown. Boc-N(CH₂CH₂C1) (N, N-bis(2-chloroethyl)-t- butylcarbamate, (3.7 g, 15.3 mmol, 1.1 equiv) in DMSO (20 mL) was added to the reaction mixture (bubbling observed) and the resulting suspension was heated to 85 ºC with stirring for an additional 1.5 h. The reaction mixture was cooled to 23 ºC then poured onto a 1:1 mixture of ethyl acetate and hexanes (300 mL). The organic fraction was washed with water (100 mL) and a saturated aqueous solution of NaCl (100 mL). The organic layer was dried over anhydrous sodium sulfate. The dried solution was then filtered and the filtrate was concentrated. The residue was purified by flash silica chromatography (0-30% ethyl acetate in hexanes) to afford the bis-alkylation product 1,1- dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-1-piperidinecarboxylate (1.9 g, 5.6 mmol, 38%) as a yellow crystalline solid. MS (ES) m/e 239 [M - Boc +H]⁺.

B: 6-Chloro-1,2-dihydrospiro[indole-3,4'-piperidine]

A solution of HCl (4.0 N in dioxane, 10 mL, 40 mmol, 7.1 equiv) was added to a solution of 1,1-dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-1-piperidinecarboxylate (1.9 g, 5.6 mmol, 1 equiv) in 1,4-dioxane (25 mL) at 23 ºC. The resulting solution was warmed to 45 ºC and stirred for 1 h (white precipitation formed). The suspension was concentrated to afford 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile hydrochloride as a pale-yellow solid. Ethanol (1.6 mL, 38.1 mmol, 6.8 equiv) was slowly added to a suspension of lithium aluminium hydride (LAH, 1.15 g, 30.3 mmol, 5.4 equiv) in glyme (16 mL) at 0 ºC. The resulting suspension was heated to reflux and stirred for 5 min. A suspension of the newly prepared 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile hydrochloride in glyme (10 mL) was added in portions. The resulting brown suspension was heated at reflux for 1 h, then cooled to 0 ºC. Water (8 mL) was added slowly at 0 ºC and the resulting suspension was warmed to room temperature and stirred for 30 min. The suspension was filtered through Celite pad and the solid was rinsed with DCM (200 mL). The filtrate was dried over anhydrous potassium carbonate. The dried solution was concentrated. The residue was purified by reverse phase C18 column to afford 6-chloro-1,2-dihydrospiro[indole-3,4'- piperidine] as a white powder (1.2 g, 5.4 mmol, 96%). MS (ES) m/e 223 [M+H]+. C : 1 , 1 -Dimethylethyl 4-[ 1 -(6-chloro- 1 ,2-dihydro- 1 'H-spiro[indole-3 ,4'-piperidin]- 1 '-yl)-2- (methyloxy)-2-oxoethyl]- 1 -piperidinecarboxylate

A mixture of 6-chloro- l,2-dihydrospiro[indole-3,4'-piperidine] (1.0 g, 4.49 mmol) and 1 , 1 -dimethylethyl 4-[l-bromo-2-(methyloxy)-2-oxoethyl]-1-piperidinecarboxylate (1.5 g, 4.49 mmol) was dissolved in CH₃CN (12.5 mL) and treated with DIEA (1.56 mL, 8.98 mmol). The resulting mixture was warmed at 75 ºC for 60 h. The resulting mixture was absorbed onto SiO₂ (3g) and purified by silica gel chromatography (4Og, 10-50% THF/Hex) to afford the product as a white foam (0.982 g, 46%). MS (ES) m/e 478 [M+H]+.

D: (6-Chloro-1,2-dihydro-l'H-spiro[indole-3,4'-piperidin]-l'-yl)(l-{[(l,l- dimethylethyl)oxy]carbonyl} -4-piperidinyl)acetic acid

A solution of 1 , 1 -dimethylethyl 4-[l -(6-chloro- 1,2-dihydro- l'H-spiro[indo le-3,4'- piperidin]-l'-yl)-2-(methyloxy)-2-oxoethyl]-l -piperidinecarboxylate (0.98g, 2.05 mmol) dissolved in TΗF/MeOΗ/Η₂O (3/1/1, 12 mL) was treated with NaOH (1.2 g, 30 mmol). The resulting mixture was warmed at 65 ºC for 3 h. The mixture was then acidified with IN HCl and extracted with EtOAc, dried (Na₂SO₄), and concentrated to afford the product

(0.773g, 83%). MS (ES) m/e 464 [M+H]+. E: 1 , 1 -Dimethylethyl 4-[ 1 -(6-chloro- 1 ,2-dihydro- 1 'H-spiro [indole-3 ,4'-piperidin]- 1 ^?-yl)- 2 -hydroxy ethyl]- 1 -piperidinecarboxylate

A solution of (6-chloro- 1 ,2-dihydro- 1 'H-spiro [indole-3 ,4'-piperidin] - 1 '-yl)( 1 - { [( 1 , 1 - dimethylethyl)oxy]carbonyl}-4-piperidinyl)acetic acid (770 mg, 1.66 mmol) dissolved in TΗF (5mL) was treated with Borane-TΗF complex (BH₃-THF, IM in THF, 10 mL) and warmed at reflux for 3 h. The reaction mixture was then allowed to cool to 25 ºC then quenched with MeOH (~5 mL). The mixture was then extracted with EtOAc, dried

(Na₂SO₄), and concentrated to afford the product (0.643g, 86%). MS (ES) m/e 450 [M+H]+.

F: 2-(6-Chloro-1,2-dihydro-l'H-spiro[indole-3,4'-piperidin]-l'-yl)-2-(4-piperidinyl)ethanol

A solution of 1 , 1 -dimethylethyl 4-[ 1 -(6-chloro- 1,2-dihydro- l'H-spiro[indo le-3,4'- piperidin]-l'-yl)-2-hydroxyethyl]-l -piperidinecarboxylate (630 mg, 1.4 mmol) in DCM (1OmL) was treated with TFA (5mL) and the resulting mixture was stirred at 25 ºC for 1 h. The reaction mixture was diluted with DCM, washed with 2N NaOH and the DCM layer was dried (Na₂SO₄) and concentrated to afford the product as a clear colorless oil

(530 mg, 100%). MS (ES) m/e 350 [M+Η]+. Intermediate 5: 4-[(1R )-2-(6-Chloro-1,2-dihydro-l'H-spiro[indole-3,4'-piperidin]-1'-yl)- 1 -hy droxy ethyl] -4-piperidinol

A: Phenylmethyl 4-ethenyl-4-hydroxy-l -piped dinecarboxylate

Bromo(ethenyl)magnesium (44 mL, 44.0 mmol) was added over 20 min to a solution of phenylmethyl 4-oxo-1-piperidinecarboxylate (8 g, 34.3 mmol) in diethyl ether (150 mL) at 0 ºC with stirring under N₂. The reaction mixture was stirred at 0 ºC for 2 h then quenched with saturated NH4CI (aq, 60 mL) and allowed to warm up to room temperature. Water (100 mL) was added, and the mixture was extracted with diethyl ether (150 mL). The organic layer was washed with brine, dried with Na₂SO₄. The solvent was removed in vacuo to afford the desired product (8.96 g). MS (ES) m/e 262

[M+H]+

B. Phenylmethyl 4-hydroxy-4-(2-oxiranyl)- 1 -piperidinecarboxylate

Vanadyl(acetylacetonate) (VO(acac)₂, 0.227 g, 0.857 mmol) was added to a solution of phenylmethyl 4-ethenyl-4-hydroxy-l -piperidinecarboxylate (8.96 g, 34.3 mmol) in Toluene (120 mL) at room temperature. Tert-butyl hydroperoxide ( ^tBuOOH, 14.71 mL, 103 mmol) was added to the above solution over 5 min via syringe, and the mixture was stirred at room temperature for 64 h. The reaction was quenched with a solution of sodium sulfite (100 mL) and extracted with ether (200 mL). The organic was washed with brine and dried (Na₂SO₄. The solvent was evaporated to give the desired product

(9 g, 95%) as colorless oil. MS (ES) m/e 278 [M+H]+.

C. Phenylmethyl 4-hydroxy-4-[(2R)-2-oxiranyl]- 1 -piperidinecarboxylate

(S,S)-(+)-N,N'-Bis(3,5-di-tert-butylsalicyclidene)-1,2-cyclohexanediaminocobalt(II) (0.054 g, 0.090 mmol) was dissolved in toluene (2 mL). Acetic acid (0.052 mL, 0.901 mmol) was added and the reaction was stirred at room temperature open to the air for 1 h. The brown mixture was then concentrated and left on high vacuum for 24 h. Phenylmethyl 4-hydroxy-4-(2-oxiranyl)-l -piperidinecarboxylate (0.500 g, 1.803 mmol) and the prepared catalyst were taken up in THF (3 mL) and cooled to 0 ºC. Water (0.018 mL, 0.992 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was purified on silica gel (ISCO, 40 g column), using 30-50% EtOAc in Hexane to give product (251 mg, 50%) as a brown oil. Chiral purity analysis was performed on AD-H column (1 mL/min, 60% EtOH -

40% Hexane) and showed >99%ee. MS (ES) m/e 278 [M+H]+.

A mixture of 6-Chloro-1,2-dihydrospiro[indole-3,4'-piperidine] (115 mg, 0.516 mmol) and phenylmethyl 4-hydroxy-4-[(2R)-2-oxiranyl]-l -piperidinecarboxylate (143 mg, 0.516 mmol) ethanol (2 mL) and heated in a microwave reactor for 30 min at 120 ºC. The reaction was completed judged by LCMS. The mixture was taken to next step directly. MS (ES) m/e 500 [M+H]+.

E. 4-[(lR)-2-(6-chloro-1,2-dihydro-lΗ-spiro[indole-3,4'-piperidin]-l'-yl)-1- hydroxyethyl]-4-piperidinol

Phenylmethyl 4-[(lR)-2-(6-chloro-1,2-dihydro-l'H-spiro[indole-3,4'-piperidin]-l'-yl)-1- hydroxyethyl] -4-hydroxy- 1 -piperidinecarboxylate (258 mg, 0.516 mmol) was dissolved in EtOH (10 mL) and Pd/C (10.98 mg, 0.103 mmol) was added and the mixture was hydrogenated with H₂ balloon at room temperature for 16 h. The reaction mixture was filtered through a pad of celite, washed with EtOH, concentrated to give a pale solid

(165 mg, 87%). MS (ES) m/e 366 [M+H]+. Intermediate 6: 1 -[2 -hydroxy- 1 -(4-piperidinyl)ethyl]-4-(7-methyl- 1H-indol-3-yl)-3- piperidinol

A: 1,1 -dimethylethyl 4-[l -[3-hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 -piperidinyl]-2- (methyloxy)-2-oxoethyl]- 1 -piperidinecarboxylate

A mixture of 4-(7-methyl-1H-indol-3-yl)-3-piperidinol (0.3 g, 1.303 mmol), 1,1- dimethylethyl 4-[l-bromo-2-(methyloxy)-2-oxoethyl]-l -piperidinecarboxylate (0.438 g, 1.303 mmol) and DIEA (0.449 mL, 2.61 mmol) in acetonitrile (3 mL) was heated at 70 ºC for 2 days. The mixture was taken up in EtOAc, washed with NaΗCO₃ and brine, dried over MgSθ4 and concentrated. The residue was purified by silica gel column using gradient dilution, 10% EtOAc in hexane to 35% EtOAc in Ηexane for 60 min. Obtained the desired product, 1 , 1 -dimethylethyl 4-[ 1 -[3-hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 - piperidinyl]-2-(methyloxy)-2-oxoethyl]-l -piperidinecarboxylate (0.31 g, 49%) as a white solid. MS(ES) m/e 486 [M+Η]+.

B: (1- {[(1 ,l-dimethylethyl)oxy]carbonyl}-4-piperidinyl)[3-hydroxy-4-(7-methyl-1H- indol-3-yl)-1-piperidinyl]acetic acid

The ester, 1 , 1 -dimethylethyl 4-[ 1 -[3-hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 -piperidinyl]- 2-(methyloxy)-2-oxoethyl]-1-piperidinecarboxylate (0.32 g, 0.659 mmol) was dissolved in a mixture of TΗF (2 mL), MeOH (1 mL) and water (1 mL). The resulting solution was treated with NaOH (0.395 g, 9.9 mmol) and heated under reflux for 3h. The mixture was then concentrated to afford the desired product. MS(ES) m/e 472 [M+Η]+, MS(ES) m/e 494 [M+Na]+.

C: 1,1 -dimethylethyl 4- {2-hydroxy- 1 - [3-hydroxy-4-(7-methyl- 1H-indol-3-yl)- 1 - piperidinyljethyl} - 1 -piperidinecarboxylate

To a solution of (l-{[(l,l-dimethylethyl)oxy]carbonyl}-4-piperidinyl)[3-hydroxy-4-(7- methyl-1H-indol-3-yl)-1-piperidinyl]acetic acid (0.146 g, 0.31 mmol) in a solution of MeOH (1 mL), H₂O (1 mL), and THF (2 mL) was added Borane-THF complex (1 M, 3.1 mL). The resulting mixture was heated under reflux for 5 h. The mixture was then cooled, acidified with 2N HCl, and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 and concentrated to afford the product (0.12 g). MS(ES) m/e 358 [M+H]+.

D: 1 -[2-hydroxy- l-(4-piperidinyl)ethyl]-4-(7-methyl-1H-indol-3-yl)-3-piperidinol hydrochloride

To a solution of 1,1 -dimethylethyl 4-{2-hydroxy-1-[3-hydroxy-4-(7-methyl-1H-indol-3- yl)-1-piperidinyl]ethyl}-l -piperidinecarboxylate (0.12 g, 0.262 mmol) in MeOH (2 mL) was added IN HCl in dioxane (0.262 mmol). The mixture was stirred at room temperature for 4 h. LCMS showed a mixture of the product and the starting material. After sitting overnight in the refrigerator, the mixture was concentrated and triturated with hexane and ether to obtain the product, l-[2-hydroxy-1-(4-piperidinyl)ethyl]-4-(7- methyl-1H-indol-3-yl)-3-piperidinol hydrochloride as a sticky solid. (0.1 g). MS(ES) m/e 358 [M+Η]+.

Intermediate 7: 6-methylspiro[l-benzofuran-3,4'-piperidine]

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 h, 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 DMSO (30 mL) was then added, and the resulting solution was allowed to warm to room 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 hydrochloride

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 -piped dinecarboxylate (26.76 g, 84 mmol). The resulting mixture was heated to reflux and allowed to stir for 48 h. The mixture was then concentrated in vacuo at 70 ºC to afford the product as a white powder. 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 1 h. Methanol 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

Di-tert-butyl dicarbonate (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 min, 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 ϊ-butoxide (KtBuO, 216 mg, 1.8 mmol) followed by a solution of 1,1 -dimethylethyl 4-(2-fluoro-4-methylphenyl)-4- (hydroxymethyl)- 1 -piperidinecarboxylate (500 mg, 1.546 mmol) in TΗF (5 mL). The resulting mixture was micro waved at 100 ºC for 1 min. An additional amount of potassium ϊ-butoxide (204 mg, 1.7 mmol) was added and the mixture was once again microwaved at 100 ºC for 1 min. The reaction was micro waved further at 120 ºC for 1 min. The mixture was diluted with water and extracted with DCM (x 3). The combined organic layers were dried over MgSθ4 and concentrated to afford the product

(0.38 g, 82%) as a clear oil. MS (ES) m/e 326.2 [M+Η]+. F: 6-Methylspiro[l-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 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 afford the product as a white solid. MS (ES) m/e 204.1 [M+H]+.

Intermediate 8:

To a solution of LiΗMDS (1.0 M in TΗF, 373 mL, 373.49 mmol) was added dropwise indene (21.0 mL, 177.85 mmol) under nitrogen at 0ºC. The resulting solution was stirred for 30 min before being cannulated into a flask containing (1R))-2-({[(1,1- dimethylethyl)oxy]carbonyl} {2-[(methylsulfonyl)oxy]ethyl} amino)- 1 -methylethyl methanesulfonate (66.78 g, 177.85 mmol) as a solution in THF (220 mL) at 0 ºC. After stirring overnight, the reaction was partially concentrated and the residue partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (I x 300 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography (0-20 % ethyl acetate :hexane) and subsequent crystallization from hexanes afforded the product (12 g, 23 %) as a 34:1 transxis mixture of diastereomers.

B: (li?,3'i?)-3'-methylspiro[indene-l ,4'-piperidine]

carboxylate (1.0 g, 3.34 mmol) was dissolved in 4M HCl in dioxane (10 mL) at room temperature. Reaction was then concentrated upon completion. The resulting solid was recrystallized using DCMto afford the product (400 mg, 61 %) in 88 % ee as a white solid: MS (ES) m/e 200 [M+Η]⁺ _.

Example 1: (3S,4S)- l-((2S)-2-{l -[5-(3-Fluoro-5-methylphenyl)- 1, 3-oxazol-2-yl]-4- piperidinyl}-2-hydroxyethyl)-4-(7-methyl-1H-indol-3-yl)-3-piperidinol

A: 5-(3,5-Difluorophenyl)-1,3-oxazole

A solution of 3,5-difluorobenzaldehyde (80 g, 0.56 mmol) and p-toluenesulfonylmethyl isocyanide (109.9 g, 0.56 mmol) and K₂CO₃ (77.8 g, 0.56 mmol) in MeOH (800 mL) was heated to 70 ºC and stirred for 3 h. The mixture was cooled to room temperature and the solvent was evaporated. The resulting solid was dissolved in EtOAc/MeOH and washed with water and brine. The organic layer was dried with a drying agent, filtered and concentrated. The crude material was purified by silica gel column, to give the product, 5-(3,5-difiuorophenyl)-1,3-oxazole (65 g, 0.36 mmol, 64%).

B: 2-Chloro-5-(3,5-difluorophenyl)-1,3-oxazole

To a solution of 5-(3,5-difluorophenyl)-1,3-oxazole (40 g, 0.22 mmol) in THF (400 mL) cooled to -70 ºC, was added dropwise, a solution of 2.5 M n-butyl lithium («-BuLi, 106 mL, 0.26 mmol). After stirring for 30 min, hexachloro ethane (105 g, 0.44 mmol) was added and the mixture was allowed to slowly warm to room temperature and stir for an additional 5 h. The reaction was cooled to -20 ºC and quenched with water. The resulting mixture was extracted with EtOAc. The organic extracts were washed with water, dried and concentrated to obtain the crude product as a red solid. The crude material was purified by silica gel column to obtain the product 2-chloro-5-(3,5- difluorophenyl)-1,3-oxazole (32 g, 0.149 mmol, 68 %) as a white solid.

C: (3S,4S)- 1 -((2S)-2- { 1 -[5-(3 ,5-Difiuorophenyl)- 1 ,3-oxazol-2-yl]-4-piperidinyl} -2- hydroxyethyl)-4-(7-methyl-1H-indol-3-yl)-3-piperidinol

A mixture of (35',45)-1-[(2S)-2-hydroxy-2-(4-piperidinyl)ethyl]-4-(7-methyl-1H-indol-3- yl)-3-piperidinol (30 mg, 0.084 mmol), 2-chloro-5-(3,5-difluorophenyl)-1,3-oxazole (22 mg, 0.10 mmol), and diisopropylethylamine (DIEA, 22 mg, 0.168 mmol) in dimethylformaide (DMF, 1 mL) was subjected to microwave irradiation for 30 min at 160 ºC. The crude reaction mixture was purified by reverse phase chromatography utilizing a 30X150 Sunfϊre Prep Cl 8 column and eluting with CΗ₃CN/Η₂0 with 0.1% trifiuoroacetic acid (TFA) to obtain (3S,4S)-1-((2S)-2-{l-[5-(3,5-difluorophenyl)-1,3- oxazol-2-yl]-4-piperidinyl}-2-hydroxyethyl)-4-(7-methyl-1H-indol-3-yl)-3-piperidinol (53 mg, 0.77 mmol, 92%). MS(ES) m/e 537 [M+Η]+.

Example 2: (1S)-1-{l-[5-(3,5-Difiuorophenyl)-4-fiuoro-1,3-oxazol-2-yl]-4-piperidinyl}- 2-[(3R ,3' R)-3',6-dimethyl-1,2-dihydro-l'H-spiro[indole-3,4'-piperidin]-l'-yl]ethanol

A: 5-(3,5-Difluorophenyl)-4-fluoro-1,3-oxazole

To a solution of 5-(3,5-difluorophenyl)-1,3-oxazole (1.0 g, 3.5 mmol) in THF (20 mL) at -70 ºC was added dropwise a solution of lithium hexamethyldisilazide (LiHMDS, IM in THF, 6 mL). After 1 h, N-fluorbenzenesulfonimide (NFSi, 2.1 g, 6.6 mmol) was added and the mixture was stirred at -70 ºC for 3 h. The reaction was quenched with saturated NH4CI solution and extracted with EtOAc (40 mL). The organic layer was washed with brine (30 mL x 2), dried over Na₂SO₄ and concentrated to afford the crude product (1.5 g). The product was purified on silica gel column, eluting with 100: 1 petroleum ether in EtOAc to afford 5-(3,5-difluorophenyl)-4-fluoro-1,3-oxazole (200 mg, 18%). MS(ES) m/e 200 [M+H]+.

B: 2-Chloro-5-(3,5-difluorophenyl)-4-fluoro-l ,3-oxazole

To a solution of 5-(3,5-difluorophenyl)-4-fiuoro-1,3-oxazole (440 mg, 2.2 mmol) in THF (10 mL) cooled to -70 ºC was added dropwise, LiHMDS (IM in THF, 2.4 mL). After 1 h, hexachloro ethane (628 mg, 2.7 mmol) was added and the mixture stirred for an additional 3 h. The mixture was then quenched with saturated NH4CI (20 mL) and extracted with EtOAc (20 mL). The organic extract was washed with brine, (20 mL x 2), dried with Na2SO4 and concentrated. The concentrate was purified on silica gel column, eluting with 100: 1 petroleum ether in EtOAc to afford 2-chloro-5-(3,5-difluorophenyl)-4- fluoro-1,3-oxazole (158 mg, 31%) as a yellow solid.

C: (1S)-1-{l-[5-(3,5-Difiuorophenyl)-4-fiuoro-1,3-oxazol-2-yl]-4-piperidinyl}-2-[(3'R )- 3',6-dimethyl-1,2-dihydro-rH-spiro[indole-3,4'-piperidin]-r-yl]ethanol

In a conical microwave tube was combined 2-chloro-5-(3,5-difluorophenyl)-4-fluoro-1,3- oxazole (50 mg, 0.214 mmol), (lS)-2-[(3'R)-3',6-dimethyl-1,2-dihydro-lΗ-spiro[indole- 3,4'-piperidin]-l'-yl]-1-(4-piperidinyl)ethanol (73.5 mg, 0.214 mmol), and DIEA (0.037 mL, 0.214 mmol) in DMF (1.0 mL). The tube was sealed and placed in a microwave for 5 min at 160 ºC. The crude mixture was purified by HPLC (Gemini, 30X100) using aqueous ammonium hydroxide (NH4OH , pH 10) in acetonitrile as eluent. Obtained ( 1 S)- 1 - { 1 - [5-(3 ,5 -difluorophenyl)-4-fluoro- 1 ,3 -oxazol-2-yl] -4-piperidinyl} -2- [(37?)-3',6-dimethyl- 1 ,2-dihydro- 1 'H-spiro[indole-3,4'-piperidin]- 1 '-yl]ethanol (10 mg, 9%). MS(ES) m/e 541 [M+Η]+.

Example 3: 5-(3,5-Difluorophenyl)-2-(4- {(1S)2-[(3R ,3'R)-3',6-dimethyl-l ,2-dihydro- 1 'H-spiro[indole-3,4'-piperidin]- 1 '-yl]-l -hydroxyethyl} - 1 -piperidinyl)- 1 ,3-oxazole-4- carboxamide

A: 3,5-Difluorobenzoyl chloride

To a solution of 3,5-difluorobenzoic acid (10 g, 63.2 mmol) in DCM (20 mL) was added thionyl chloride (SOCl₂, 10 mL). The mixture was heated to 80 ºC for 18 h. The solution was concentrated to afford 3,5-difluorobenzoyl chloride (10 g, 90%).

B: Ethyl 5-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylate

To a solution of ethyl isocyanoacetate (3.23 g, 28.3 mmol) and triethylamine (Et₃N, 8.6 g, 84.9 mmol) in THF (20 mL) was added a solution of 3,5-difluorobenzoyl chloride (5 g, 28.3 mmol) in THF dropwise. After stirring at room temperature for 48 h, the mixture was diluted with water and extracted with EtAOc (50 mL x 2), dried over Na₂Sθ4 and concentrated to afford the crude product which was washed with hexanes to obtain ethyl 5-(3,5-difiuorophenyl)-1,3-oxazole-4-carboxylate (5 g, 70 %) as a yellow solid. MS(ES) m/e 254 [M+H]+.

C: 5-(3,5-Difluorophenyl)-1,3-oxazole-4-carboxylic acid

To a solution of ethyl 5-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylate (4.29 g, 16.9 mmol) in MeOH (110 mL) was added 2 M sodium hydroxide (NaOH, 25.3 mL). The mixture was stirred at room temperature. The sodium salt precipitated out of solution within 10 minutes. The mixture was concentrated, diluted with water and washed with EtOAc. The aqueous layer was acidified with 1 N HCl (45 mL) and extracted with DCM. The DCM extract was dried overNa2SO4 and concentrated to give 5-(3,5- difluorophenyl)-1,3-oxazole-4-carboxylic acid (3.2 g, 84 %) as an off-white solid. MS(ES) m/e 226 [M+H]+.

D: 2-Chloro-5-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylic acid

To a solution of 5-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylic acid (2 g, 8.88 mmol) in THF (40 mL) was added LiHMDS (1 M in THF, 21 mL) at -78 ºC. After 1 h, hexachloro ethane (3.15 g, 13.3 mmol) was added. After stirring an additional 2 h, the mixture was diluted with 1 N HCl (20 mL) at -78 ºC. The resulting mixture was allowed to warm to room temperature and was extracted with EtOAc (20 mL). The organic extract was dried over Na₂SO₄ and concentrated to afford 2-chloro-5-(3,5- difluorophenyl)-1,3-oxazole-4-carboxylic acid (1.2 g, 52%). MS(ES) m/e 260 [M+H]-

E: 2-Chloro-5-(3,5-difluorophenyl)-l ,3-oxazole-4-carbonyl chloride

To thionyl chloride (0.09 g, 0.77 mmol) in dichloromethane (3 mL) was added 2-chloro- 5-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylic acid (0.2 g, 0.77 mmol) at room temperature followed by a few drops of DMF. The resulting mixture was refiuxed for 1 h until a clear solution was seen. The solution was then concentrated and dried under vacuum to obtain 2-chloro-5-(3,5-difluorophenyl)-1,3-oxazole-4-carbonyl chloride (0.18g, 83%). MS in MeOH (ES) m/e 274 [M -Cl + OMe]+.

F: 2-Chloro-5-(3,5-difluorophenyl)- 1 ,3-oxazole-4-carboxamide

To a solution of 2-chloro-5-(3,5-difluorophenyl)-1,3-oxazole-4-carbonyl chloride (1.0 g, 3.6 mmol) in THF (10 mL) was added ammonia (2M NH₃ in THF, 10 mL). After stirring at room temperature for 10 min, the mixture was concentrated. The residue was washed with EtOAc and dried to afford 2-chloro-5-(3,5-difluorophenyl)-1,3-oxazole-4- carboxamide (0.8 g, 86%) as a yellow solid. MS(ES) m/e 259 [M+H]+. G: 5-(3,5-Difluorophenyl)-2-(4-{(15)-2-[(3i?,3^)-3',6-dimethyl-1,2-dihydro-l'H- spiro [indole-3 ,4'-piperidin]- 1 '-yl]-l -hydroxy ethyl} - 1 -piperidinyl)- 1 ,3-oxazole-4- carboxamide

A mixture of the 2-chloro-5-(3,5-difiuorophenyl)-1,3-oxazole-4-carboxamide (37.6 mg, 0.146 mmol) , (lS)-2-[(3R,3'R)-3',6-dimethyl-1,2-dihydro-lΗ-spiro[indole-3,4'- piperidin]-r-yl]-1-(4-piperidinyl)ethanol (50 mg, 0.146 mmol), and DIEA (21 μL, 0.147 mmol) in DMF (1 mL) was heated in a microwave at 160 ºC for 5 min. The crude mixture was purified on a Waters HPLC system, eluting with 10-50% AcCN in Water (0.1 % TFA). The desired fractions were combined, basified with NaHCO₃ solution and extracted with DCM. The mixture was poured through a hydrophobic frit to remove water and the organic filtrates were concentrated in an N₂ blow down unit to obtain 5- (3,5-difiuorophenyl)-2-(4-{(1S)-2-[(3R ,3'R )-3',6-dimethyl-1,2-dihydro-rH-spiro[indole- 3,4'-piperidin]- 1 '-yl]- 1 -hydro xyethyl} - 1 -piperidinyl)- 1 ,3-oxazole-4-carboxamide (35 mg, 43 %). MS(ES) m/e 566 [M+Η]+.

Table 1 illustrates Examples 4-55 and the Schemes generally used to prepare them.

Claims

WHAT IS CLAIMED IS:

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof; wherein

Y is O, or S; is H and is:

or and together with the carbon atom to which they are attached, form:

wherein Z is

each R³ is independently halo, CH₃, OH, or CH₂OH;

R⁴ is H or OH;

each R⁵ is independently halo, CH₃, OH, or CH₂OH;

R⁶ and R⁷ are each independently H, C₁-C₆ alkyl, phenyl-(R¹¹)_r, heteroaryl-(R¹²)_r, CON(R¹³)₂, CN, COOH, COOCH₃, COOCH₂CH₃, or R⁶ and R⁷, together with the carbon atoms to which they are attached, form a fused benzo group;

each R⁸ is independently halo, CN, Ci-C₆-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, SO₂CH₃, or COOH;

R⁹ is H or C₁-C₆-alkyl;

each R is H or, together with the carbon atoms to which they are attached form a double bond;

each R¹¹ is independently halo, CN, Ci-C₆-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, or COOH;

each R¹² is halo, CN, C₁-C₆-alkyl, CH₂OH, CF₃, OCF₃, C(O)NH₂, or COOH;

each R¹³ is independently H, CH₃, or phenyl-(R¹¹)_r, or together with the nitrogen atom to which they are attached, form a piperidinyl, piperazinyl, pyrrolidinyl, or morpholino ring;

m, n, and p are each independently O, 1, or 2; and

r is O, 1, 2, or 3.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is H and R is:

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

4. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein Z is O.

5. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein Z is NH or N-CH₃.

6. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein Z is CR¹⁰, and each R¹⁰ is either H, or together with the carbon atoms to which they are attached, form a double bond.

7. The compound of any of Claims 1 to 6 wherein

R³ and R⁵ are each independently CH₃, OH, or CH₂OH;

R⁴ is H;

R⁶ is H, -C(O)-N(R¹³)₂, C₁-C₃-alkyl, or Cl; R is H is phenyl-(R¹¹)_r, CN, -C(O)-N(R , 13 )₂, or pyridinyl, with the proviso that one of R and R is not H;

each R¹¹ is independently F, Cl, CF₃, or CH₃;

Y is O;

m is O or 1 ;

n is O or 1 ; and

r is O, 1, or 2.

8. The compound of any of Claims 1, 3, 4, 5, and 7, or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

where R³ is CH₃ or OH; and

R is halo, CH₃, or CN.

9. The compound of any of Claims 1, 3, 4, 5, 7, and 8, or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

wherein R⁶ is H, Cl, CH₃, CH₂CH₃, or -C(O)-N(R¹³)₂;

R⁸ is Cl, CH₃, or CN;

each R¹³ is independently H, or C₁-C₃-alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl group;

m is 0 or 1 ; and

r is 1 or 2.

10. The compound of any of Claims 1 to 9 or a pharmaceutically acceptable salt thereof, where R is H.

11. The compound of any of Claims 1, 3, 4, 5, and 7 or a pharmaceutically acceptable

salt thereof, which compound is represented by the following structure:

where R³ is CH₃ or OH; and

R⁸ is halo, CH₃, or CN.

12. The compound of any of Claims 1, 3, 4, 5, 7, and 11 or a pharmaceutically acceptable salt thereof, which compound is represented by the following structure:

13. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

wherein R is OH or CH₃; R⁸ is CH₃ or Cl;

each R¹¹ is independently F, Cl, CF₃, or CH₃;

m is 0 or 1 ;

p is 0 or 1 ; and

r is 0, 1, or 2.

14. The compound of any of Claims 1, 3, and 4 or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

wherein R⁸ CH₃, CN, F or Cl;

R i l¹ l is F, Cl, CF₃, Or CH₃;

m is 0 or 1 ; and

r is 0, 1 or 2.

15. The compound of Claim 6 or a pharmaceutically acceptable salt thereof, which compound is represented by the following formula:

wherein R⁸ is CH₃, CN, F or Cl;

R¹¹ is F, Cl, CF₃, Or CH₃;

m is 0 or 1 ;

p is 0, 1, or 2;

and r is 0 or 1.

16. A composition comprising a compound of any of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method of treating a disease comprising administering the compound of any of Claims 1 to 15 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, ocular indications or diabetes.