WO2010058318A1 - 1-oxa-8-azaspiro [4, 5 ] decane- 8 -carboxamide compounds as faah inhibitors - Google Patents

1-oxa-8-azaspiro [4, 5 ] decane- 8 -carboxamide compounds as faah inhibitors Download PDF

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WO2010058318A1
WO2010058318A1 PCT/IB2009/054969 IB2009054969W WO2010058318A1 WO 2010058318 A1 WO2010058318 A1 WO 2010058318A1 IB 2009054969 W IB2009054969 W IB 2009054969W WO 2010058318 A1 WO2010058318 A1 WO 2010058318A1
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oxa
azaspiro
decane
carboxamide
phenyl
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PCT/IB2009/054969
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French (fr)
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Scott Allen Long
Marvin Jay Meyers
Matthew James Pelc
Barbara Ann Schweitzer
Atli Thorarensen
Lijuan Jane Wang
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Pfizer Inc.
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Priority to EP09759998A priority Critical patent/EP2367830A1/de
Priority to US13/129,824 priority patent/US20110230493A1/en
Priority to CA2741839A priority patent/CA2741839A1/en
Priority to JP2011536972A priority patent/JP2012509309A/ja
Publication of WO2010058318A1 publication Critical patent/WO2010058318A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to 1-oxa-8-azaspiro[4.5]decane-8-carboxamide compounds and the pharmaceutically acceptable salts of such compounds.
  • the invention also relates to the processes for the preparation of the compounds, intermediates used in their preparation, compositions containing the compounds, and the uses of the compounds in treating diseases or conditions associated with fatty acid amide hydrolase (FAAH) activity.
  • FAAH fatty acid amide hydrolase
  • Fatty acid amides represent a family of bioactive lipids with diverse cellular and physiological effects. Fatty acid amides are hydrolyzed to their corresponding fatty acids by an enzyme known as fatty acid amide hydrolase (FAAH).
  • FAAH is a mammalian integral membrane serine hydrolase responsible for the hydrolysis of a number of primary and secondary fatty acid amides, including the neuromodulatory compounds anandamide and oleamide.
  • Anandamide (arachidonoyl ethanolamide) has been shown to possess cannabinoid-like analgesic properties and is released by stimulated neurons. The effects and endogenous levels of anandamide increase with pain stimulation, implying its role in suppressing pain neurotransmission and behavioral analgesia.
  • Ar 1 , Ar 2 , R 1 , R 2 , R 3 and R 4 are as defined below, or a pharmaceutically acceptable salt thereof.
  • compositions comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Ar 1 is selected from:
  • C 1 -C 3 haloalkoxy substituents or g) pyridine, pyridazine, pyrimidine, or pyrazine; wherein the pyridine, pyridazine, pyrimidine, or pyrazine is optionally substituted by 1 to 3 halo, C 1 -C 3 alkyl, -(CH 2 ) n -(C 3 -C 6 cycloalkyl), C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy substituents;
  • Ar 2 is selected from: a) phenyl optionally substituted by 1 to 5 halo, C r C 6 alkyl, -(CH 2 V(C 3 -C 6 cycloalkyl), C r C 6 alkoxy, - (CH 2 V(C 3 -C 6 cycloalkoxy), C 1 -C 6 haloalkyl,
  • R 1 is hydrogen, F, or CH 3 ;
  • R 2 is hydrogen or CH 3 ;
  • R 3 is hydrogen, CH 3 , -0-CH 3 , OH, CN, or F;
  • R 4 is hydrogen, F, or CH 3 ;
  • R 5 is hydrogen, C 1 -C 6 alkyl, -(CH 2 V(C 3 -C 6 cycloalkyl), or C 1 -C 6 haloalkyl;
  • R 6a is C 1 -C 3 alkyl
  • R 6b is hydrogen, C 1 -C 6 alkyl, or C 1 -C 3 haloalkyl
  • R 7 is C 1 -C 3 alkyl, -(CH 2 V(C 3 -C 6 cycloalkyl), R 9 , or -CH 2 -O-R 9 ;
  • R 8 is phenyl optionally substituted by from 1 to 3 halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy substituents;
  • R 9 is selected from phenyl, naphthyl, or heteroaryl; wherein R 9 is optionally substituted by from 1 to 3 halo,
  • C 1 -C 3 alkyl -(CH 2 V(C 3 -C 6 cycloalkyl), C 1 -C 3 alkoxy, -(CH 2 V(C 3 -C 6 cycloalkoxy), C 1 -C 3 haloalkyl, or C 1 -C 3 haloalkoxy substituents;
  • m is 1 , 2 or 3;
  • n is O, 1 , 2, 3 or 4; and
  • p is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Ar 2 is selected from: a) phenyl optionally substituted by from 1 to 3 substituents selected from F, Cl, Br, methyl, ethyl, CF 3 , OCH 3 , or OCF 3 ; wherein the phenyl may also be further substituted by a substituent of the formulae -R 9 , -0-R 9 or -0-CH 2 -R 9 ; b) thiazole or oxadiazole substituted by a substituent of the formulae -R 9 ; or R 1 , R 2 , and R 4 are hydrogen; R is hydrogen or F;
  • R 5 , R 6a , and R 6b are methyl
  • R 9 is phenyl, pyridine, or pyrimidine; wherein the R 9 ring is optionally substituted by from 1 to 3 substituents selected from F, Cl, Br, CF 3 , or OCF 3 ; or a pharmaceutically acceptable salt thereof.
  • R 9 when present, is phenyl, pyridine or pyrimidine, each optionally by from 1 to 3 substituents selected from halo, C 1 -C 3 alkyl, -(CH 2 V(C 3 -C 6 cycloalkyl), C 1 -C 3 alkoxy, -(CH 2 ) n -(C 3 -C 6 cycloalkoxy), C 1 -C 3 haloalkyl or C 1 -C 3 haloalkoxy; and n is 0, 1 , 2, 3 or 4.
  • R 9 is optionally substituted by 1 to 3 substituents selected from F, Cl, Br, CF 3 , or OCF 3 ; or a pharmaceutically acceptable salt thereof.
  • Ar 1 is selected from:
  • Ar 2 is selected from formulae, wherein R, R', R" and Z in each case are as defined under each formula:
  • R 1 , R 2 , and R 4 are H; R 3 is H or F; and R 5 , R 6a , and R 6b are methyl; or a pharmaceutically acceptable salt thereof.
  • each of the groups of compounds described herein are compounds wherein, when Ar is oxadiazole, the oxadiazole is 1 ,2,4-oxadiazole; or a pharmaceutically acceptable salt thereof. Also provided within each of the groups of compounds described herein are compounds wherein, when Ar 2 is thiazole, the thiazole is 1 ,3-thiazole; or a pharmaceutically acceptable salt thereof. In each case the Ar 2 oxadiazole and thiazole groups may be optionally substituted as described herein. In each of the groups described herein it is understood that, when a list of optional substituents is provided, each of the substituents is indepedently selected from the group of substituents.
  • R 1 has the value of R 1 of any of the specific compounds mentioned below;
  • the compounds herein, and the pharmaceutically acceptable salts thereof may also be administered topically, intradermally, or transdermally to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, liposomes, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions using carriers and methods known in the art.
  • Compounds of Formula I can be prepared according to Scheme A.
  • Compounds of formula A1 , D1 , E4, E5, E6, F5, F8, G5 and H4 can be deprotected using conventional methods (for example, using HCI/dioxane in dichloromethane, acetyl chloride in ethanol, or trifluoroacetic acid (TFA) in dichloromethane) to provide the corresponding compounds of formula A2 which can be isolated as the free base or as the corresponding salt (hydrochloride or trifluoroacetate).
  • TFA trifluoroacetic acid
  • the reaction of a compound of formula A2 with a phenyl carbamate of formula A3 provides compounds of the Formula I.
  • the reaction can be conducted in a polar aproptic solvent such as DMSO or acetonitrile.
  • the temperature of the reaction may vary from about ambient temperature to about 60 0 C.
  • the reaction can also be conducted using a trifluoroacetate or hydrochloride salt of the compound of formula A2 in the presence of a base such as triethylamine (TEA) or diisopropylethyl amine (DIEA).
  • a base such as triethylamine (TEA) or diisopropylethyl amine (DIEA).
  • TAA triethylamine
  • DIEA diisopropylethyl amine
  • the reaction may be conducted in a solvent such as acetonitrile.
  • compounds of formula A2 may be reacted with phosgene in the presence of a base such as TEA or DIEA and a solvent such as dichloromethane at about 0 0 C to generate compounds of formula A6 which may be isolated as a crude material and reacted with aryl amines of formula A7 in the presence of a base such as TEA or DIEA and a catalyst such as 4- (dimethylamino)-pyridine (DMAP) in a suitable solvent such as acetonitrile, dichloromethane, and dichloroethane.
  • the reaction temperature may vary from about ambient temperature to about 70 0 C.
  • Scheme B illustrates a method for making phenyl carbamates of formula A3.
  • a solvent such as THF, DCM, 1 ,4-dioxane, acetonitrile, DMF, or DMSO
  • phenyl carbamates of formula A3 in a manner similar to that described in Synthesis, 1997, 1189- 1194.
  • the reaction may be performed in the presence of a base such as TEA, DIEA, 1 ,8- bis(dimethylamino)naphthalene (Proton Sponge®), and the like.
  • the temperature of the reaction may vary from about 0 0 C to reflux temperature of the solvent being used.
  • Compounds of formula C3 can be oxidized by conventional methods such as with pyridinium sulfur trioxide (Pyr-SO 3 ) and TEA in DMSO to give compounds of formula C4.
  • a strong base such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS or LiHMDS)
  • TMSCI trimethylsilylchloride
  • a fluorinating agent such as Selectfluor® (CAS#140681 -54-5) in a solvent such as THF
  • Ketones of formula C4 wherein R 2 is hydrogen and R 4 is methyl may be prepared from compound C6 (CAS# 123319-13-1 ; Tsukamoto et al., EP 0311313, publication date December 4, 1989).
  • Compound C6 may be oxidized by conventional methods as described above to give ketone C7.
  • the acetyl protecting group of ketone C7 may be hydrolized by conventional methods such as with sodium methoxide in methanol or with refluxing aqueous HBr to give the parent amine which may be then converted to the Boc protected compound of formula C4 using conventional methods such as treatment with di-tert-butyl dicarbonate in DCM with triethylamine.
  • a reducing agent such as sodium borohydride in methanol
  • Compounds of formula D2 or C3 can be converted to bromides of formula D3 with triphenylphosphine and carbon tetrabromide in a solvent such as THF.
  • Triflates of formula E3 can be reacted with an aryl or alkyl boronic acid of formula (R 1 B(OH) 2 ) under palladium-catalyzed Suzuki cross-coupling conditions (for a review, see Chem. Rev. 1995, 95, 2457), to give the corresponding compounds of formula E4.
  • the coupling can be conducted using a catalytic amount of tetrakis(triphenylphosphine)-palladium(0) or (1 ,1 '-bis- (diphenylphosphino)-ferrocene)palladium dichloride (Pd(dppf)CI 2 ) in the presence of a base such as aqueous sodium carbonate, cesium carbonate, sodium hydroxide, or sodium ethoxide, in a solvent such as THF, dioxane, ethylene glycol dimethylether, DMF, ethanol or toluene.
  • a base such as aqueous sodium carbonate, cesium carbonate, sodium hydroxide, or sodium ethoxide
  • a solvent such as THF, dioxane, ethylene glycol dimethylether, DMF, ethanol or toluene.
  • the temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used.
  • This reaction is preferably run in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, NaHMDS, triethylamine or diisopropylethylamine.
  • the solvent used may be DMF, DMA, NMP, DMSO, acetonitrile, tetrahydrofuran, dioxane or a combination of two or more of these solvents.
  • a base such as cesium carbonate, potassium carbonate, or sodium hydride in a solvent such as DMF, DMA, NMP, DMSO, dioxane, or acetonitrile
  • the temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used and may be heated under conventional or microwave conditions.
  • Sodium iodide or potassium iodide may be added to facilitate the alkylation.
  • the phenol of compounds E2 can be reacted with alkyl alcohols (R'OH) under Mitsunobu reaction conditions (Organic Reactions 1992, 279, 22-27; Org. Prep. Proc. int. 1996, 28, 127-164; Eur. J. Org. Chem. 2004, 2763-2772) such as polystyrene-triphenylphosphine (PS-PPh 3 ) and di-terf-butyl azodicarboxylate (DBAD) to give compounds of formula E6.
  • Mitsunobu reaction conditions Organic Reactions 1992, 279, 22-27; Org. Prep. Proc. int. 1996, 28, 127-164; Eur. J. Org. Chem. 2004, 2763-2772
  • PS-PPh 3 polystyrene-triphenylphosphine
  • DBAD di-terf-butyl azodicarboxylate
  • Compounds of formulae F5 and F8 can be prepared according to Scheme F.
  • Alcohols of formula D2 can be treated with methanesulfonyl chloride in a solvent such as dichloromethane in the presence of a base such as triethylamine or DIEA.
  • the meslyate intermediate can then be reacted with sodium cyanide in a suitable solvent such as DMF or DMSO at a temperature ranging from room temperature to about 90 0 C to give nitrile compounds of formula F1.
  • Nitriles of formula F1 can be treated with excess hydroxylamine hydrochloride and TEA in a solvent such as ethanol. The reaction is run at about 80 0 C to reflux temperature of the solvent used to give hydroxyamidines of formula F2.
  • Hydroxyamidines of formula F2 can be treated with acid chlorides of formula F3 in a solvent such as THF and the presence of a base such as DIEA or TEA.
  • the reaction can be run at reflux of the solvent used and may be heated by conventional or microwave conditions to give oxadiazoles of formula F5.
  • hydroxyamidines of formula F2 may be reacted with carboxylic acids of formula F4 in the presence of a coupling agent such as carbonyldiimidazole (CDI), O-(Benzotriazol-i-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate (HBTU), and the like, in a solvent such as DMF in the presence of a base such as TEA or DIEA.
  • CDI carbonyldiimidazole
  • HBTU O-(Benzotriazol-i-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate
  • a solvent such as DMF
  • a base such as TEA or DIEA
  • Nitriles of formula F1 can also be hydrolyzed by treatment with lithium hydroxide in a solvent such as ethanol/water at about reflux temperature to give carboxylic acids of formula F6.
  • Carboxylic acids of formula F6 may then be converted to their acid chloride with thionyl chloride or oxalyl chloride and reacted with hydroxyamidines of formula F7 as described above to give oxadiazoles of formula F8.
  • Scheme G F6 G1
  • Thiazole compounds of formula G5 can be prepared according to Scheme G.
  • Compounds of formula F6 can be treated with ⁇ /,O-dimethylhydroxylamine hydrochloride in the presence a coupling agent such as O-(7- azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate (HATU), and a base such as DIEA or TEA in a solvent such as dichloromethane to give the Weinreb amide of formula G1.
  • the compound of formula G1 can be treated with methyl magnesium bromide in a solvent such as THF at about 0 0 C to room temperature to give methyl ketone compounds of formula G2.
  • Thiazole compounds of formula H4 can be prepared according to Scheme H.
  • Carboxylic acid compounds of formula F6 can be treated with ammonia in methanol in the presence a coupling agent such as HATU, and a base such as DIEA or TEA in a solvent such as dichloromethane to give the carboxamide of formula H1.
  • Compounds of formula H1 can be treated with Lawesson's reagent in a solvent such as toluene. The reaction may be heated from about 65 0 C to reflux temperature of the solvent used to provide thioamides of formula H2.
  • Scheme J illustrates another method for the preparation of compounds of formula A1.
  • a ketone of formula C4 can be converted to a vinyl triflate of formula J1 by conventional methods such as treatment with a base such as LHMDS followed by a triflating agent such as 2-[N,N-bis(trifluoromethanesulphonyl)amino]-5- chloropyridine.
  • Compounds of formula J1 can be reacted with an aryl boronic acid of formula (Ar 2 B(OH) 2 ) under palladium-catalyzed Suzuki cross-coupling conditions (as described in Scheme E; for a review, see Chem. Rev. 1995, 95, 2457) to give the corresponding compounds of formula J2.
  • Olefin compounds of formula J2 can be reduced using conventional methods such as treatment with catalytic palladium on carbon under an atmosphere of hydrogen at atmospheric pressure to about 50 psi to give compounds of formula A1. Furthermore, the double bond of compounds of formula J2 may be reduced asymmetrically using catalytic asymmetric hydrogenation methods (for a review, see "Noyori Catalytic Asymmetric Hydrogenation.”, LaII, Manjinder S. Editors: Li, Jie Jack; Corey, E. J. Name Reactions for Functional Group Transformations (2007), p. 46-66. Publisher: John Wiley & Sons, Inc., Hoboken, N. J., and references therein) to give enantiomerically-enriched compounds of formula A1.
  • a compound of formula J2 wherein R 1 , R 2 , and R 4 are hydrogen and Ar 2 is 3-benzyloxyphenyl can be hydrogenated at 200 psig and 70 0 C in trifluoroethanol in the presence of a catalytic amount of (S)-1 -[(R)-2-di-(4- fluorophenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphinerhodium(l)cyclooctadiene trifluoromethanesulfonate, [Rh(COD)((S)-TCFP)] " BF 4 + , or [Rh(COD)((R)-TCFP)] " BF 4 + (see Hoge et al., J.
  • tert-butyl 4-allvl-4-hvdroxypiperidine-1-carboxvlate tert-butyl 4-oxopiperidine-i-carboxylate 1000 g, 5.02 mol was dissolved in allylbromide (1080 ml_, 12.4 mol, 2.5 eq), THF (1000 ml_) and saturated ammonium chloride solution (5000 ml_). The reaction was cooled to 10 0 C and zinc dust (650 g, 10 mol, 2 eq) was added portion wise. After addition the reaction mixture was stirred overnight. TLC was taken (heptane/EtOAc 7:1 ) and showed full conversion.
  • reaction mixture was diluted with water (5 L) and acidified with 10% H 2 SO 4 to pH ⁇ 6.
  • the reaction mixture was extracted with MTBE (3x).
  • the organic layers were combined and extracted with saturated solution of NaHCO 3 , brine and evaporated to give tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 95%).
  • tert-butyl (3RS)-3-hydroxy-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 4.8 mol) was dissolved in tert-butanol (10 L) and water (4 L). To the solution sodium periodate (1124 g, 5.3 mol, 1.1 eq) was added and the mixture was stirred at 50 0 C for 30 minutes. At 50 0 C a solution of Na 2 S 2 O 5 (1007 g, 5.3 mol, 1.1 eq) in water (4.2 L) was added dropwise over 4 hours to the solution.
  • the racemic tert-butyl (3RS)-3-(3- ⁇ [5-(trifluoromethyl)pyridin-2-yl]oxy ⁇ phenyl)-1-oxa-8-azaspiro[4.5]decane-8- carboxylate (1.47 g) was separated by chiral SFC on a 30x250 mm ChiralPak OD-H column (20% MeOH/CO 2 @ 70mL/min; 2 mL injections of a 100 mg/mL MeOH solution).
  • Example 3 (3R)-N-pyridazin-3-yl-3-(3-([5-(trifluoromethyl)pyridin-2-ylloxy)phenyl)-1-oxa-8- azaspiro[4.51decane-8-carboxamide
  • the title compound was prepared from (3R)-3-(3- ⁇ [5-(trifluoromethyl)pyridin-2-yl]oxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane hydrochloride (350 mg) as described for Example 1 to give the title compound as a solid (279 mg, 66%). m/z 500 (MH + ).
  • racemic tert-butyl (3RS)-3-(3-hydroxyphenyl)-1-oxa- 8-azaspiro[4.5]decane-8-carboxylate as a white solid (10.74 g, 96.7%).
  • the racemate was separated by chiral SFC on a 50x250 mm ChiralPak AD-H column (20% 50:50 MeOH:EtOH/CO 2 @ 200 mL/min; 4mL injections of a 50 mg/mL EtOH solution).
  • Step 1 Separate vials of 5-bromo-2-chloropyridine (0.5 mmol) or 5-chloro-2-chloropyridine (0.5 mmol) in dioxane (2 mL) were treated with tert-butyl (3RS)-3-(3-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8- carboxylate (0.25 mmol), DMA (0.25 mL), and NaHMDS (0.6 N in toluene; 0.5 mL, 0.300 mmol). The mixtures were heated under microwave irradiation at 185°C for 1 h in a Biotage Initiator 60. Upon completion of the reaction, the solvents were evaporated in vacuo.
  • the solution was concentrated. The residue was dissolved in EA (150 ml_) and treated with water (50 ml_) and brine (50 ml_). The layers were separated and the organic was washed with brine (50 ml_). The organic was dried over magnesium sulfate, filtered, and evaporated to give an oil. The oil was purified by flash chromatography (50-90% EA/Heptane with 5% IPA in the EA solvent) to give 3.8 g of a foam. The foam was dissolved mostly in EtOH (50 ml_) and transferred to a pear shaped flask. This was seeded with a seed crystal and allowed to stand until crystals started to form.
  • tert-butyl (3R)-3-(3-[(5-chloropyridin-2-yl)oxylphenyl)-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate To a mixture of tert-butyl (3R)-3-(3-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.82 g, 8.47 mmol) and cesium carbonate (5.52 g, 16.9 mmol) in DMF (5 ml_) was added 5-chloro-2-fluoropyridine (1.5 ml_, 15 mmol) and stirred at RT over several nights.
  • tert-butyl (3RS)-3-(4-hydroxyphenyl)-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate Method A. To a solution of tert-butyl (3RS)-3-[4-(benzyloxy)phenyl]-1-oxa-8-azaspiro[4.5]decane-8- carboxylate (6.48 g, 15.3 mmol) in 50% EA/methanol (50 mL) was added 10% Pd/C (200 mg, CAS#7440-05- 3) catalyst under nitrogen, and the mixture was stirred under 40 psi of hydrogen over several nights.
  • the reaction was warmed to room temperature, treated with more trifluoroacetic acid (12 ml_, 162 mmol) and then 3 hours later more triethylsilane (13 ml_, 81.3 mmol), borontrifluoride diethyl etherate (4 ml_, 32.4 mmol) and trifluoroacetic acid (30 ml_, 404 mmol) were added. After stirring over the weekend at RT, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the organic made basic with 2.5 N NaOH and water. The layers were separated and the aqueous layer was extracted with ethyl acetate.
  • racemate tert-butyl (3RS)-3-(3-chlorophenyl)-1-oxa-8-azaspiro[4.5]decane- ⁇ -carboxylate (4.7 g) was separated by chiral SFC on a 30x250 mm ChiralPak AD-H column (20% MeOH/CO 2 @ 70mL/min ; 2 mL injections of a 45 mg/mL MeOH solution).
  • Enantiomer 1 was then further purified by chiral SFC on a 30x250 mm ChiralCel OD-H column (20% MeOH/CO 2 @ 70mL/min; 2 mL injections of a 16 mg/mL 50% DCM/MeOH solution) to give Enantiomer 1 of the title compound as a solid (1.2 g, 51%). m/z 296 (MH + minus tBu).
  • tert-butyl S-O ⁇ -dichlorophenvD-i-oxa- ⁇ -azaspiro ⁇ . ⁇ ldecane- ⁇ -carboxylate Enantiomers 1 and 2
  • the racemic tert-butyl (3RS)-3-(3,4-dichlorophenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.45 g) was separated by chiral SFC on a 30x250 mm ChiralPak AD-H column (20% MeOH/CO 2 @ 70mL/min; 1 ml_ injections of a 49 mg/mL MeOH solution).
  • racemic tert-butyl (3RS)-3-(4-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (3.2 g, 9.60 mmol) was separated by chiral SFC on a 30x250 mm ChiralPak IA column (20% MeOH/CO 2 @ 70 mL/min; 3 mL injections of a 50 mg/mL MeOH solution).
  • the crude product was dissolved in methanol (25 ml_) to which was added di-tert butyl dicarbonate (1.0 g, 4.60 mmol) followed by triethylamine (0.49 ml_, 3.54 mmol) and the reaction stirred at r.t. for 1 hour.
  • the reaction was quenched with water and the aqueous phase extracted with ethyl acetate (2x 15 ml_), dried with magnesium sulfate and concentrated.
  • the crude product was purified by flash chromatography (ethyl acetate:heptanes) to give the title compound as a clear oil (1.16 g, 2.21 mmol, 37%).
  • Examples 53-56 A 0.1 M solution of tert-butyl (3RS)-3-(3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)-1-oxa-8-azaspiro[4.5]decane-8- carboxylate in DMF (1 ml_), a 0.025 M solution of Pd(PPh 3 ) 4 in DMF (0.2 ml_), and a 1 M aqueous solution of sodium carbonate (0.3 ml_) were added to the corresponding aryl boronic acids (0.125 mmol) in vials (Note: the solutions were purged with nitrogen prior to addition). The vials were capped and heated to 100 0 C for 18 h. The solvents were evaporated.
  • tert-butyl OSVS-O-lfdrifluoromethvDsulfonylloxylphenvD-i-oxa- ⁇ -azaspiroK. ⁇ ldecane- ⁇ -carboxylate To a solution of tert-butyl (3S)-3-(3-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.1g, 3.3 mmol) and pyridine (0.817 ml_, 9.9 mmol) in DCM (30 ml_) at 0 0 C was added trifluoromethanesulfonic anhydride (0.853 ml_, 4.95 mmol).
  • the title compound was prepared from tert-butyl (3S)-3-(3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane- ⁇ -carboxylate (365 mg, 0.7 ⁇ 4 mmol) and (3,4-difluorophenyl)boronic acid (1 ⁇ 6 mg, 1.18 mmol) as described for Example 59 except that the chromatography product was evaporated to give an oil. The oil was purified by reverse phase chromatography (10-95% acetonitrile/water/0.05% TFA) and evaporated to a small volume to give an aqueous mixture.
  • the title compound was prepared from tert-butyl (3R)-3-(3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (300 mg, 0.633 mmol) and (3,4-difluorophenyl)boronic acid (150 mg, 0.95 mmol) as described for Example 59 except that the chromatography product was evaporated to give a solid. The solid was purified by reverse phase chromatography (10-95% acetonitrile/water/0.05% TFA) and evaporated to a small volume to give an aqueous mixture. The mixture was treated with EA (20 ml_) and the layers separated.
  • the title compound was prepared from tert-butyl (3R)-3-(3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (300 mg, 0.633 mmol) and (4-chlorophenyl)boronic acid (150 mg, 0.95 mmol)as described for Example 59 except the chromatography product was evaporated to give a solid. Further purification by reverse phase chromatography (10-95% acetonitrile/water/0.05% TFA) and evaporation to a small volume gave an aqueous mixture. The mixture was treated with EA (100 ml_) and the layers separated.
  • the title compound was prepared from tert-butyl (3R)-3-(3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (300 mg, 0.633 mmol) and (4-trifluoromethoxyphenyl)boronic acid (196 mg, 0.95 mmol) as described for Example 58 to give the title compound as a solid upon standing (240 mg, 74%). m/z 516 (MH + ).
  • tert-butyl S-irftrifluoromethvOsulfonylloxyl-i-oxa- ⁇ -azaspiro ⁇ . ⁇ ldec-S-ene- ⁇ -carboxylate A solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (5.0 g, 20 mmol) in anhydrous THF (50 ml_) was cooled to -78 0 C and then treated with LiHMDS (1.0 M in THF, 27.4 ml_, 27.4 mmol).
  • tert-butyl S-rS-ftrifluoromethvDphenyll-i-oxa- ⁇ -azaspiro ⁇ . ⁇ ldec-S-ene- ⁇ -carboxylate The tert-butyl S-IKtrifluoromethylJsulfonylJoxyJ-i-oxa- ⁇ -azaspiro ⁇ . ⁇ Jdec-S-ene- ⁇ -carboxylate (2.0 g, 5.16 mmo) was dissolved in toluene (16 mL).
  • Example 65 (SRSVN-fS ⁇ -dimethylisoxazol- ⁇ -vO-S-P-ftrifluoromethvOphenyll-i-oxa- ⁇ -azaspiro ⁇ . ⁇ ldecane-
  • the title compound was prepared from 5-amino-3-n-propyl-4-methylisoxazole (CAS# 909132-91-8) (1.00 g, 7 mmol) using same procedure as described for preparing for phenyl (3-ethyl-4-methylisoxazol-5-yl)carbamate to provide the title compound (0.45 g, 20%) . m/z 261.1 (MH + ).
  • Enantiomers 1 and 2 A solution of tert-butyl (3RS)-3-[amino(hydroxyimino)methyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (650 mg, 2.17 mmol) in THF (10 mL) was added DIEA (1.51 mL, 8.68 mmol) and the 4-(trifluoromethoxy)benzoyl chloride (488 mg, 2.17 mmol) at room temperature. The reaction vessel was capped and heated to 150 0 C in a CEM discover microwave for 30 min. The solution was diluted with ethyl acetate (100 mL) and washed with water (50 mL), sat.
  • Enantiomer 1 (324 mg, 0.690 mmol) was added DCM (2 mL) followed by 4N HCI/dioxane (2 mL). The solution was stirred for 4 hr at RT and then evaporated to give the title compound as a solid (314 mg, quant.), m/z 370 (MH + ).
  • Example 86 (3R)-3-(4-[(3-fluorobenzyl)oxylphenyl)-N-(1-methyl-1 H-tetrazol-5-yl)-1-oxa-8- azaspiro[4.51decane-8-carboxamide
  • the title compound was prepared from (3R)-3- ⁇ 4-[(3-fluorobenzyl)oxy]phenyl ⁇ -1-oxa-8-azaspiro[4.5]decane hydrochloride (115 mg, 0.337 mmol) as described for Example 84.
  • the crude product was purified by flash chromatography (ethyl acetate(5% ethanol)/heptane) to produce the title compound as a light yellow solid.
  • the title compound was prepared from (3R)-3-(4- ⁇ [5-(trifluoromethyl)pyridin-2-yl]methoxy ⁇ phenyl)-1-oxa-8- azaspiro[4.5]decane (445 mgs, 1.13 mmol) as described for Example 84. Crude product was purified by flash chromatography (ethyl acetate(5% ethanol)/heptane) to produce the title compound as a light yellow solid. (127 mg, 0.246 mmol, 22%).
  • reaction mixture was heated at 85 0 C overnight. After cooling the reaction mixture was extracted with ethyl acetate (2x 10 ml_), diethyl ether (10 ml_), and concentrated in vacuo. The residue was dissolved in THF (-20 ml_) and treated with sodium sulfate and 3-mercaptopropyl silica gel ( ⁇ 0.3 g, Aldrich, silicycle). This mixture was stirred about 20 min, filtered and the filtrate evaporated. The resulting oil was chromatographed by flash chromatography (5-35% EA/heptane) to give the title compound as an oil (1.04 g, 87%). m/z 463 (MH + ).
  • the reaction was diluted with ethyl acetate (150 ml_) and washed with saturated sodium bicarbonate (1x100ml and 3x 5OmL). The organic layer was washed with brine (50 ml_), dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by reverse phase chromatography (5-95% acetonitrile/water) and the desired fractions were evaporated to a small volume. The aqueous mixture was treated with ethyl acetate (50 ml_) and made basic with 0.5N NaOH (50 ml_).
  • the title compound was prepared from (3RS)-3- ⁇ 3-[(5-chloropyridin-2-yl)oxy]phenyl ⁇ -1-oxa-8- azaspiro[4.5]decane hydrochloride (prepared from the racemate in a manner similar to that described for (SRJ-S-IS- ⁇ -chloropyridin ⁇ -ylJoxylphenylJ-i-oxa- ⁇ -azaspiro ⁇ . ⁇ ldecane hydrochloride) and phenyl 1 ,2- benzisoxazol-3-ylcarbamate using same procedure as described for the preparation of Example 13, Step 3 to give the racemic title compound (18.6 mg).
  • LCMS t R 2.16 min (Phenomenex Gemini C18 4.6 X 50 mm 5 ⁇ m; 0.04% Formic Acid, 0.01 % TFA / MeCN), m/z 505.45 (MH + ).
  • reaction mixture was heated to 70 0 C and then pressurized to 200 psig with hydrogen After 48 h at 70 0 C and 200 psig of hydrogen, the reaction was cooled to 30 0 C and purged with nitrogen.
  • the reactions were analyzed by chiral SFC (4.6 mm x 250 mm Chiralpak AD-H, 5% to 45% methanol/CO 2 /0.1 % diethylamine at 4 mL/min, 40 0 C): For catalyst [Rh(COD)((R)-TCFP)] " BF 4 + (CAS#705945-70-; Hoge et al., J. Am. Chem. Soc.
  • the FAAH assay was carried out in 384-well clear polystyrene plates (Evergreen Scientific) in a total volume of 50 ⁇ l per well in a manner similar to that described by Mileni et al., Proc. Nat. Acad. Sci. 2008, 705, 12820- 12824. All percents are by volume. Serial dilutions of compound were initially prepared in 100% DMSO, and then diluted two-fold into HPLC-grade H 2 O to give 50% DMSO.
  • reaction mixture (40 ⁇ l) containing 1-4 nM FAAH, 50 mM NaP 1 , pH 7.4, 3 mM ⁇ -ketoglutarate, 0.15 mM NADH, 7.5 U/ml glutamate dehydrogenase, 2 mM ADP, 1 mM EDTA, and 0.1% Triton X-100 (The concentration shown for each component is the final concentration in the assay).
  • concentration shown for each component is the final concentration in the assay.
  • To this mixture was added 5 ⁇ l of a compound of Examples 1 to 101 at various concentrations in 50% DMSO (or 5 ⁇ l 50% DMSO for controls).
  • the concentration of substrate in the assay was equal to the K m for oleamide of 50 ⁇ M. Therefore, reported k mact /K
  • values are obtained by multiplying resulting slopes by a factor of two (i.e. slope k mact /(K
  • Table 1 lists human FAAH (hFAAH) and rat FAAH (rFAAH) enzyme inhibition values for Examples 1- 101 as a ratio of /W t /MM ' V 1 ).
  • CFA efficacy assay For additional information on the CFA efficacy assay, see Jayamanne et al., Brit. J. Pharmacol. 2006, 747, 281-288. Experiments were performed on adult Male Sprague-Dawley Rats (20Og- 25Og). Inflammation was induced in the left hindpaw of the rat by an intra-plantar injection of 15OuL Complete Freund's Adjuvant (CFA) (SIGMA F5881 ). The CFA injection immediately induces local inflammation, paw swelling, and pain that persists for at least two weeks post-injection.
  • CFA Complete Freund's Adjuvant
  • Baseline paw withdrawal threshold was measured to determine the percent inhibition of allodynia using a set of Von Frey Hairs on day 4 post injection as illustrated by the Dixon Up and Down Method (WJ. Dixon, Ann. Rev. Pharmacol. Toxicol. 1980, 20:441-462). Animals that exhibit the pain criteria of 9 grams or less were then placed on study. Test compound was administered at a concentration of 3 mg/kg (mpk) orally with the dosing vehicle 5% N,N'-Dimethylacetamide (SIGMA D137510) and 95% (40% 2-hydroxypropyl-beta-cyclodextrin in water) (SIGMA H107). Following Dose administration PWT threshold was evaluated again at four hours postdose.
  • SIGMA D137510 N,N'-Dimethylacetamide
  • SIGMA H107 2-hydroxypropyl-beta-cyclodextrin in water
  • Sprague-Dawley rats used in this assay were purchased from Harlan, 8520 Allison Pointe Blvd., Indianapolis, IN, 46250, U.S.A.
  • Sprague- Dawley rats are an outbred breed of albino rats first produced by the Sprague Dawley farms in Madison, Wisconsin, U.S.A.
  • % Inhibition of Allodynia 100 x ⁇ PWT(test compound)-mean ⁇ PWT(vehicle)

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