WO2010059393A1 - Serotonin receptor modulators - Google Patents

Serotonin receptor modulators Download PDF

Info

Publication number
WO2010059393A1
WO2010059393A1 PCT/US2009/062627 US2009062627W WO2010059393A1 WO 2010059393 A1 WO2010059393 A1 WO 2010059393A1 US 2009062627 W US2009062627 W US 2009062627W WO 2010059393 A1 WO2010059393 A1 WO 2010059393A1
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
phenoxy
azetidine
phenyl
bromo
Prior art date
Application number
PCT/US2009/062627
Other languages
French (fr)
Inventor
Nicholas I. Carruthers
Brock T. Shireman
Vi T. Tran
Victoria D. Wong
Jill A. Jablonowski
Wenying Chai
Original Assignee
Janssen Pharmaceutica Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to US13/126,223 priority Critical patent/US8642583B2/en
Publication of WO2010059393A1 publication Critical patent/WO2010059393A1/en
Priority to US14/051,199 priority patent/US20140038943A1/en
Priority to US14/925,835 priority patent/US9981909B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention compounds that are serotonin receptor modulators. More particularly, there is provided by the present invention certain compounds that are serotonin receptor modulators useful for the treatment of disease states mediated by serotonin receptor activity.
  • Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, largely as the result of cDNA cloning.
  • 5-HT is implicated in many disease states, particularly conditions of the central nervous system including; depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, nociception, sexual behavior, hormone secretion, and cognition.
  • the atypical antipsychotics including olanzapine and clozapine, are considered to have positive therapeutic effects attributable to their actions at 5-HT 2 , D 2 and 5-HT 7 receptors.
  • their side effect liability is due to their affinities for a range of dopaminergic, serotonergic and adrenergic receptors.
  • Elucidating selective ligands has the potential to ameliorate untoward pharmacologies and provide novel efficacious therapies. More importantly, the ability to obtain compounds which portray receptor selectivity provides the prospect to target distinct therapeutic mechanisms and improve clinical responses with a single drug. Consequently, there remains a need for potent serotonin receptor modulators with desirable pharmaceutical properties.
  • R 1 is -H, -Ci -4 alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1 , 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1 ; R 2 and R 3 are each independently -H or -Ci -4 alkyl;
  • R 4 is -H, F, Ci -4 alkyl, or R 4 is -OH when L is -CH 2 -, -CF 2 -, or -CHF-, -OCH 2 -, or -OCH(CH 3 )-; L is -O-, -CH 2 -, -OCH 2 -, -OCH(CH 3 )-, -CH 2 O-, -CF 2 -, or -CHF-; Z is -O-, -C(O)-, -OCH(R b )-, or -OCH 2 C(R c )(R d )-; where where R b is -H; a -Ci -4 alkyl group unsubstituted or substituted with OH or halo; -CO 2 Ci -4 alkyl; or -CO 2 H; and R c and R d are each independently -H, -Ci -4 alkyl, -O
  • a naphthyl group unsubstituted or substituted with Ci -4 alkyl or halo
  • iii) a monocyclic heteroaryl group unsubstituted or substituted with one, two, or three R 9 substituents
  • iv) a fused bicyclic heteroaryl group unsubstituted or substituted with Ci -4 alkyl or halo
  • a monocyclic heterocycloalkyl group optionally fused to or substituted with phenyl
  • R 6 or R 7 are each independently -H, halo, -CF 3 , thiophene, or -C(O)N(R x )R y ; wherein R x and R y are each independently -H or -Ci -4 alkyl.
  • the invention also relates to stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of compounds of Formula (I).
  • the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below.
  • compositions each comprising: (a) an effective amount of an agent selected from compounds of Formula (I) and stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites thereof; and (b) a pharmaceutically acceptable excipient.
  • the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition (collectively, "indications") mediated by 5HT 7 activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a stereoisomeric form, hydrate, solvate, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of such compound.
  • the disease, disorder, or medical condition is selected from: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • alkyl groups include methyl (Me, which may also be structurally depicted by a bond, 7"), ethyl (Et), n-propyl (Pr), isopropyl (iPr), butyl (nBu), isobutyl (iBu), sec-butyl (sBu), tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and so on.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • Illustrative examples of cycloalkyl groups include the following entities (depicted without their bonds of attachment):
  • heterocycloalkyl refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples (depicted without their bonds of attachment) include:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • heteroaryl groups include the following entities (depicted without their bonds of attachment):
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. It is understood that some compounds referred to herein are chiral and/or have geometric isomeric centers, for example E- and Z- isomers. All optical isomers and stereoisomers of the compounds of any general structural formula, and mixtures thereof, are considered within the scope of the formula.
  • any general formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • a zwitterionic compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwittehons, and their synonyms zwitterionic compound(s) are standard lUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities.
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign.
  • aminoethanoic acid (the amino acid glycine) has the formula H 2 NCH 2 COOH, and it exists in some media (in this case in neutral media) in the form of the zwittehon + H 3 NCH 2 COO " .
  • Zwittehons, zwittehonic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art.
  • any general formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures of the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, 36 CI, and 125 I, respectively.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • S example is S 2 and S example is S 3 ; S example is S 2 and S example is S 4 ; and equivalents of each one of such choices.
  • S 1 ex ampie is one of Si and S 2
  • S 2 e ⁇ am P ie is one of S 3 and S 4 " is accordingly used herein for the sake of brevity, but not by way of limitation.
  • the foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.
  • Sexampie is S 3 ; Sexampie is One Of Si and S 2 ; Sexampie is One Of Si and S 3 ; Sexampie is one of S 2 and S 3 ; Sexampie is one of Si , S 2 and S 3 ; and Sexampie is any equivalent of each one of these choices.
  • the shorter terminology "S exa mpie is one of Si, S 2 , and S 3 " is accordingly used herein for the sake of brevity, but not by way of limitation.
  • the foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.
  • Ci-3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members
  • C n - m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ⁇ N ⁇ m, with m > n.
  • Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • reference to disubstituent -A-B-, where A ⁇ B refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as serotonin receptor modulators in the methods of the invention.
  • a "pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I) , that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G. S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S. M.
  • a compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an inorganic acid, such as hydrochloric acid,
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • suitable salts include organic salts derived from amino acids, such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, pipehdine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as N-methyl-D-glucamine, lysine, choline, glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as tromethamine, benzylamines, pyrrolidines, pipehdine, morpholine, and piperazine
  • inorganic salts
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I) , and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I) .
  • a "pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I) .
  • amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyhc acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • Additional types of prodrugs may be produced, for instance, by dehvatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters.
  • Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary Ci- ⁇ alkyl amines and secondary di(Ci- 6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
  • Preferred amides are derived from ammonia, Chalky! primary amines, and di(Ci- 2alkyl)amines.
  • esters of the invention include Ci -7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(d -6 )alkyl esters.
  • Preferred esters include methyl esters.
  • Prodrugs may also be prepared by dehvatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs.
  • Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs.
  • Prodrugs of this type may be prepared as described in Robinson et al., J Med Chem. 1996, 39 (1 ), 10-18. Free amines can also be dehvatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
  • the present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I) , which may also be used in the methods of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J Med Chem. 1997, 40, 2011 -2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220- 230; Bodor, Adv Drug Res.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the seratonin receptor in the methods of the invention.
  • the compounds may act as antagonists, agonists, or inverse agonists.
  • moduleators include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate seratonin receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate seratonin receptor expression or activity.
  • Many of the compounds of the present invention are 5-HT 7 modulators that act as 5-HT 7 antagonists. As such, the compounds are useful in the treatment of 5-HT 7 -mediated disease in which a decrease, prevention, inactivation, desensitization or down-regulation of serotonin receptor expression or activity is required.
  • treat or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of serotonin receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of serotonin receptor activity.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • an effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • An "effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • the invention may be particularly useful in the treatment or prevention of diseases, disorders, or conditions mediated by serotonin receptor activity, such as: central nervous system disorders such as sleep disorders (including insomnia), depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive- compulsive disorder, mood disorders, post-traumatic stress and other stress- related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flashes associated with menopause, alcohol abuse, drug abuse, and addictive disorders including drug addiction and alcohol addiction.
  • central nervous system disorders such as sleep disorders (including insomnia), depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive- compulsive disorder, mood disorders, post-traumatic stress and other stress- related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbance
  • Further diseases accociated with serotonin receptor activity for which the compounds may be useful for treating are nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
  • the compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence and other disorders related to the gastrointestinal and vascular systems.
  • compounds of the present invention may be used in methods for treating or preventing a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration. Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases.”
  • the compounds of the present invention are 5-HT 7 modulators, many of which are 5-HT 7 antagonists. As such, the compounds are useful in the treatment of 5-HT 7 mediated disease states. Where the compounds possess substantial 5-HT 7 modulating acitivity, they may be particularly useful in methods for treating depression/anxiety, sleep/wake disturbances, sleep disorders, jet lag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders, hypertension, analgesic, and irritable bowel syndrome.
  • the compounds of the present invention are useful in the treatment or prevention of depression, anxiety, sleep disorders, and circadian rhythm abnormalities.
  • the compounds of the invention are used, alone or in combination with one or more other active ingredients, to formulate pharmaceutical compositions of the invention.
  • the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by serotonin receptors or that are active against another target associated with the particular condition, disorder, or disease.
  • H 1 receptor antagonists H 2 receptor antagonists, H 3 receptor antagonists, topiramate (TOPAMAXTM), and neurotransmitter modulators such as norepinephrine reuptake inhibitors (NRIs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, Donepezil (ARICEPTTM), Rivastigmine, or Galantamine (REM I NYLTM)), modafinil, antipsychotics, sedatives, monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs).
  • NRIs norepinephrine reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • NSSRIs noradrenergic reuptake
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention.
  • the combination method employs doses containing additional active ingredients in the range of about 20 to 300 mg per dose.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
  • oral administration the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Cornstarch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
  • the active agents of this invention may also be administered by non-oral routes.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • Effective doses of the compounds of the present invention may be ascertained by conventional methods.
  • the specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.
  • the invention includes also pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described below. Pharmaceutically acceptable salts of the specific compounds exemplified herein are especially preferred.
  • R 1 is -H, -Ci -4 alkyl, monocyclic cycloalkyl, phenyl, or benzyl.
  • R 1 is -H, - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , cyclopropyl, cyclobutyl, or benzyl.
  • R 1 is -H.
  • m has the value of 1 , 2 or 3 and n has the value of 1 or 2; however, if m is 2 then n is not 1.
  • n is 1 and n is 1.
  • m is 1 and n is 2.
  • m is 2 and n is 2.
  • m is 3 and n is 1.
  • R 2 is -H or -Ci- 4 alkyl. In further embodiments, R 2 is -H, or -CH 3 . In certain embodiments of compounds of Formula (I), R 3 is -H or -Ci-
  • R 3 is -H, or -CH 3 .
  • R 2 and R 3 are each -H.
  • R 4 is -H, F, -Ci- 4 alkyl or R 4 may be -OH when L is -CH 2 -, -CF 2 -, -CHF-, -OCH 2 -, or -OCH(CH 3 )- .
  • R 4 is hydrogen.
  • L is -O-, -CH 2 -, - OCH 2 -, -OCH(CH 3 )-, -CH 2 O-, -CF 2 -, or -CHF-. In certain embodiments, L is -O-
  • Z is -O-, -C(O)-, - OCH(R b )-, or -OCH 2 C(R c )(R d )-; where R b is -H; a -Ci -4 alkyl group unsubstituted or substituted with OH or halo; -CO 2 Ci -4 alkyl; or -CO 2 H; and R c and R d are each independently -H, -Ci -4 alkyl, -O-Ci -4 alkyl, or halo.
  • R c and R d taken together form an oxime, a Ci- 4 alkyl oxime, or a carbonyl group.
  • R c and R d taken together with the carbon to which they are attached form a C 3-6 cycloalkyl group.
  • Z is -O-, -C(O)-, -OCH 2 -, -OCH(CH 3 )-, -OCH(CH 2 CH 3 )-, -
  • Z is -O-, -OCH 2 -, or -OCH(CH 3 )-.
  • R 5 is a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R 9 substituents; where each R 9 substituent is selected from the group consisting of -Ci -6 alkyl, -OH, -OCi -6 alkyl, -CN, -NO 2 , -C(O)Ci -6 alkyl, -S(O)o- 2 -Ci -6 alkyl, -OS(O) 0-2 -Ci -ealkyl, -SO 2 CF 3 , -SCF 3 , halo, -CF 3 , -OCF 3 , -CO 2 H, -CO 2 Ci -6 alkyl, -CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl.
  • R 9 substituents taken together form -OCH 2 O-, -OCF 2 O-, or -OCH 2 CH 2 O- group.
  • R 5 is a naphthyl group, unsubstituted or substituted with Ci -4 alkyl or halo.
  • R 5 is a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R 9 substituents.
  • R 5 is a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci -4 alkyl or halo.
  • R 5 is a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: - Ci -4 alkyl, -OCi -4 alkyl, halo, -CF 3 , oxime, -Ci -4 alkyl oxime, or phenyl.
  • R 5 is a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl.
  • R 5 is cyclohexyl, 2-indanyl, or furanyl optionally substituted with one or more substituents individually selected from halo, -CH 3 , -CF 3 , -OCF 3 , or -CN.
  • R 5 is selected from the group consisting of cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano- phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro- phenyl, 4-chloro-3-thfluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-thfluoromethyl- phenyl, 4-fluoro-3-thfluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or
  • R 6 and R 7 are each independently -H, halo, -CF 3 , thiophene, or -C(O)N(R x )R y ; wherein R x and R y are each independently -H or -Ci -4 alkyl.
  • R 6 and R 7 are each independently -H, halo, -CF 3 , thiophene-3-yl, or N,N-dimethyl-formamidyl.
  • R 6 is -H or halo.
  • R 6 is -H or halo and R 7 is -H, halo, -CF 3 , thiophene-3-yl, or N,N-dimethyl-formamidyl.
  • Preferred compounds are selected from the group consisting of:
  • the compounds of formula (I) may be prepared by a number of reaction schemes.
  • the following schemes represent certain synthesis steps for obtaining compounds of the invention. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme as compared to the other.
  • amines in the compounds below may be protected, as indicated by P 1 , as an alkyl or benzyl amine, amide, carbamate or other groups such as described in "Protecting Groups in Organic Synthesis", 3 rd ed.; T.W. Greene and P. G. Wuts, John Wiley and Sons, 1999.
  • a further preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide. This protecting group (P 1 ) on the nitrogen may be removed or converted directly into the desired compounds using generally accepted methods known to one skilled in the art.
  • a group such as a Boc group may be removed with an acid such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH 2 CI 2 , EtOAc, THF, 1 ,4- dioxane, MeOH or EtOH.
  • a group such as trifluoroacetamide was removed using a base such as NH 3 , NH 4 OH or K 2 CO 3 in an alcoholic solvent such as MeOH or EtOH and the like.
  • compounds of the formula A4 may also be obtained from compounds of the formula B1 when LG is OH using PPh 3 or similar trialkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-te/t-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH 2 CI 2 and the like.
  • DEAD diethyldiazodicarboxylate
  • DIAD diisopropyldiazodicarboxylate
  • DBAD di-te/t-butyldiazodicarboxylate
  • Compounds of the formula C3 were synthesized similar to compounds of the formula A5 (Scheme 1 ) from compounds of the formula C1.
  • Compounds of the formula C2 were obtained from compounds of the formula C1 and compounds of the formula A2 (Scheme 1 ) in a suitable solvent such as DMF, DMSO, NMP or THF in the presence of a base such as NaH, KOfBu or CS2CO3, preferably NaH in DMF.
  • Compounds of the formula C3 were obtained from compounds of the formula C2 upon basic hydrolysis of the compound obtained from the treatment of compounds of the formula C2 with an oxidant such as m- chloroperoxybenzoic acid (m-CPBA) in CH2CI2. The hydrolysis was performed using a base such as NaOH or KOH in a solvent such as MeOH, EtOH or H 2 O.
  • Compounds of the formula G4 were obtained from compounds of the formula G3 by partial reduction with hydride donors such as NaBH 4 in alcoholic solvents such as MeOH, EtOH or i-PrOH and the like followed by further reduction using H 2 in the presence of a hydrogenation catalyst such as Pd/C, PtO 2 or Pd(OH) 2 and the like at pressures up to 60 psi and temperatures ranging from rt to 60 0 C in solvents such as MeOH, EtOH or i-PrOH and the like.
  • hydride donors such as NaBH 4 in alcoholic solvents such as MeOH, EtOH or i-PrOH and the like
  • H 2 in the presence of a hydrogenation catalyst
  • Pd/C, PtO 2 or Pd(OH) 2 and the like at pressures up to 60 psi and temperatures ranging from rt to 60 0 C in solvents such as MeOH, EtOH or i-PrOH and the like.
  • the Boc protecting group in compounds of the formula G2 was exchanged for a trifluoroacetamide as shown in compounds of the formula G5 by treatment with acids such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH 2 CI 2 , EtOAc, THF, 1 ,4-dioxane, MeOH or EtOH.
  • acids such as trifluoroacetic acid or hydrochloric acid and the like
  • a solvent such as CH 2 CI 2 , EtOAc, THF, 1 ,4-dioxane, MeOH or EtOH.
  • TFAA in the presence of a base such as pyridine, thethylamine or diisopropylethylamine or the like in a solvent such as CH 2 CI 2 , THF, DMF, MeOH, EtOH or the like yields compounds of the formula G5.
  • a base such as pyridine, thethylamine or diisopropylethylamine or the like in a solvent such as CH 2 CI 2 , THF, DMF, MeOH, EtOH or the like
  • an electrophilic bromine source such as Br 2 , NBS, NaBr/oxone or chlorine source such as Cl 2 , KCI/oxone or NCS and the like in a solvent such as MeOH, CH 2 CI 2 , EtOH, DMF, acetone, H 2 O and the like or mixtures there of produces compounds of the formula G6.
  • a reagent such as LiI in collidine, HBr in AcOH, or preferrably BBr 3 in CH 2 CI 2
  • compounds of the formula H3 may also be obtained from compounds of the formula H2 when X is OH using PPh 3 or similar thalkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-te/t-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH 2 CI 2 and the like.
  • DEAD diethyldiazodicarboxylate
  • DIAD diisopropyldiazodicarboxylate
  • DBAD di-te/t-butyldiazodicarboxylate
  • the transformation when X is OH may also be performed using cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH 3 when heated in a microwave reactor at temperatures up to 120 0 C.
  • R 5 is a substituted aryl or heteroaryl
  • compounds of the formula H3 were obtained using Cu(OAc)2 and base such as pyridine or Et 3 N and the like in the presence of dehydrating agents such as MgSO 4 or 4 A molecular sieves.
  • H6 Compounds such as H6 were prepared from compounds of the formula H4 using methods such as reductive amination or alkylation.
  • a reductant such as NaBH 4 , NaBH 3 CN, NaBH(OAc) 3 or hydrogen gas in the presence of a catalyst in a solvent such as CH 2 CI 2 , THF, DCE, MeOH, EtOH or similar afforded compounds of the formula H6.
  • a reductant such as NaBH 4 , NaBH 3 CN, NaBH(OAc) 3
  • hydrogen gas in the presence of a catalyst in a solvent such as CH 2 CI 2 , THF, DCE, MeOH, EtOH or similar afforded compounds of the formula H6.
  • a catalyst such as CH 2 CI 2 , THF, DCE, MeOH, EtOH or similar
  • acids may include AcOH, Ti(O-iPr) 4 , trifluoroacetic acid or hydrochloric acid and the like.
  • compounds of the formula H6 may be obtained from H4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 . It will be generally recognized that compounds of the formula H6 represent a subset of compounds of the formula H4 where Ri is equal to H. Compounds of the formula H4 or H6 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.
  • R >10 _ substituted aryl or heteroaryl
  • R >10 _ substituted aryl or heteroaryl
  • R 13 substituted aryl or heteroaryl
  • R 13 substituted aryl or heteroaryl
  • R 14 alkyl or H
  • a nucleophile such as a compound of formula J3 in the presence of base such as pyridine, thethylamine, diisopropylamine, K2CO3, CS2CO3 or Na2CO3 in a suitable solvent such as THF, CH2CI2, DMF, MeCN, 1 ,4-dioxane or the like at a temperature ranging from rt to 100 0 C provided compounds of the formula J4.
  • Compounds of the formula L3 were prepared from compounds of the formula L2 and compounds of the formula C1 in the presence of base such as pyridine, triethylamine, diisopropylamine, K 2 CO 3 , Cs 2 CO 3 or Na 2 CO 3 in a suitable solvent such as THF, CH 2 CI 2 , DMF, MeCN, 1 ,4-dioxane or the like at a temperature ranging from rt to 100 0 C.
  • Compounds of the formula L2 were prepared from compounds of the formula L1 by treatment with a chlorinating agent such as SOCI 2 in a solvent such as CH 2 CI 2 .
  • Compounds of the formula N4 were prepared from compounds of the formula N2 and compounds of the formula N3 in the presence of a base such as diisopropyethylamine, Et 3 N or pyridine and the like upon heating in a microwave reactor at temperatures up to 145 0 C.
  • Precursors to compounds of the formula N2 were prepared from compounds of the formula N1 and bromomethyl acetate in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 .
  • Compounds of the formula 03 were prepared from compounds of the formula C3 and compounds of the formula 02 by heating the mixture up to 100 0 C in a microwave reactor in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 .
  • Compounds of the formula 02 were obtained by bromination of compounds of the formula 01 using (Bu)N 4 Br 3 (TBABr 3 ) in a solvent mixture of MeOH and CH 2 CI 2 .
  • Compounds of the formula Q4 may be obtained from compounds of the formula Q3 by removal of the P 1 group.
  • the amine in compounds of the formula Q3 may be protected, as indicated by P 1 as described previously.
  • a preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide.
  • Boc f-butyl carbamate
  • compounds of the formula Q4 represent a subset of compounds of the formula Q5 where Re is equal to H.
  • Compounds of the formula Q4 or Q5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.
  • compounds of the formula Q5 may be obtained from Q4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 .
  • a base such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CsF, KF, K 3 PO 4 , KOAc or the like
  • a ligand typically used in such reactions such as Q-Phos, dppf, dppe or PPh 3 and the like at temperatures ranging from rt to 160 0 C using conventional or microwave heating.
  • reaction mixtures were magnetically stirred at room temperature (rt). Where solutions were “dried,” they were generally dried over a drying agent such as Na 2 SO 4 or MgSO 4 then filtered and concentrated. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.
  • TLC Thin-layer chromatography
  • PTLC Preparative thin-layer chromatography
  • HPLC was performed on a Dionex APS2000 LC/MS with a Phenomenex Gemini C18 (5 ⁇ m, 30 x 100 mm) column, and a gradient of 5 to 100% acetonitrile/H 2 O (20 mM NH 4 OH) over 16.3 min, and a flow rate of 30 mL/min.
  • Preparative RP HPLC was also performed on an Agilent 1100 preparative system with a Waters X-Bridge C18 (5 ⁇ m, 30 x 100 mm) column, and a gradient of 5 to 99% acetonitrile/H 2 O (20 mM NH 4 OH) over 17 min, and a flow rate of 80 mL/min.
  • Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
  • Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers.
  • the format of the 1 H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference or relative to residual protic solvent (multiplicity, coupling constant J in Hz, integration). Chemical names were generated using ChemDraw Version 6.0.2
  • Boc groups were deprotected using TFA/CH 2 CI 2 (1 :1 ) or 4M HCI in dioxane/EtOAc (1 :1 ). The compounds were then either neutralized and extracted with CH 2 CI 2 or characterized as the hydrochloride or trifluoroacetate salt where indicated.
  • Trifluoroacetamide groups were deprotected using K 2 CO 3 (1 eq.) in MeOH (0.2 M), 2M NH 3 in MeOH or 5N NH 4 OH (aq.) in MeOH. After 15h, H 2 O was added and the mixture extracted with EtOAc (2X). The combined organics were dried and concentrated. Purification using silica gel chromatoraphy, reverse-phase HPLC or PTLC then provided the deprotected amines.
  • Example 1 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine.
  • Step A Preparation of (4-bromo-2-fluoro-benzylidene)-tert-butyl-amine.
  • tert-butylamine 42.3 ml_, 29.3 g, 400 mmol
  • MgSO 4 60.0 g, 499 mmol
  • the solution was filtered and concentrated to give 62.0 g (98%) of the title compound as a yellow liquid.
  • 1 H NMR (CDCI 3 ): 8.48 (s, 1 H), 7.89 (t, J 8.1 Hz, 1 H), 7.32-7.25 (m, 2H), 1.29 (s, 9H).
  • Step B Preparation of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester.
  • a 0 0 C DMF (720 ml_) solution of the title compound of Step A (37.2 g, 144 mmol) and 3-hydroxy-azetidine-i-carboxylic acid tert-butyl ester (25.0 g, 144 mmol) was added NaH (60 wt% in mineral oil, 7.50 g, 188 mmol) portionwise over 2h. The reaction was then allowed to warm to rt. After 18h, H 2 O was added and the reaction mixture was extracted with EtOAc (2X).
  • Step C Preparation of 3-(5-Bromo-2-hvdroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester.
  • Step D Preparation of 3-(2-benzyloxy-5-bromo-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester.
  • Step E Preparation of 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine. Synthesized according to general procedure 1 from the title compound of Step
  • Examples 2-74 were prepared similar to Example 1 using the appropriately substituted phenol and alkyl halide.
  • Example 3 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -cyclobutyl-azetidine.
  • Example 4 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -propyl-azetidine.
  • Example 5 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -isopropyl-azetidine.
  • Example 6 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -ethyl-azetidine.
  • Example 7 3-r5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy1-azetidine.
  • Example 8 3-[5-Bromo-2-(3-t ⁇ fluoromethyl-benzyloxy)-phenoxy1-azetidine.
  • Example 10 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine.
  • Example 11 3-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy1- azetidine.
  • Example 13 3-r5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy1- azetidine.
  • Example 14 3-r5-Bromo-2-(4-chloro-benzyloxy)-phenoxy1-azetidine trifluoroacetate.
  • Example 15 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy1-azetidine trifluoroacetate.
  • Example 16 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy1-1 -methyl-azetidine.
  • Example 17 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-azetidine trifluroacetate.
  • Example 18 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -ethyl-azetidine.
  • Example 19 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -propyl-azetidine.
  • Example 22 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
  • Example 24 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -isopropyl- azetidine.
  • Example 25 3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy1-azetidine hydrochloride.
  • Example 26 3-[5-Chloro-2-(3-nnethylsulfanyl-benzyloxy)-phenoxy1-azetidine.
  • Example 27 S-f ⁇ -Chloro ⁇ -O-methanesulfonyl-benzyloxyVphenoxyi-azetidine.
  • Step A Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester.
  • Step B Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)- phenoxyi-azetidine. Prepared from the title compound of Step A using general procedure 1.
  • Example 28 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -2-thiophen-2-yl- thiazole.
  • Example 29 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-methyl- thiazole.
  • Example 31 3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -phenyl1-5- methyl-[1 ,2,41oxadiazole hydrochloride.
  • Example 32 3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy1-azetidine.
  • Example 34 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -benzonitrile.
  • Example 35 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy1-azetidine trifluroacetate.
  • Example 38 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl-azetidine.
  • Example 40 3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine.
  • Example 41 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy1- azetidine.
  • Example 44 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-benzonitrile.
  • Example 46 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy1- azetidine.
  • Example 47 3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy1- azetidine.
  • Example 49 3-r5-Chloro-2-(4-chloro-3-trifluoronnethyl-benzyloxy)-phenoxy1- azetidine.
  • Example 50 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy1-azetidine.
  • Example 52 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -pyridine.
  • Example 53 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-pyridine.
  • Example 55 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -furan-2- carboxylic acid ethyl ester.
  • Example 56 3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy1- azetidine.
  • Example 62 4-(2-Benzyloxy-5-chloro-phenoxy)-pipehdine.
  • Example 63 4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- piperidine hydrochloride.
  • Example 64 4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- piperidine.
  • Example 65 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-pipehdine.
  • Example 66 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl-piperidine.
  • Example 70 ( ⁇ )-3-(2-Benzyloxy-5-chloro-phenoxy)-pipehdine.
  • Example 72 3-(5-Chloro-2-cvclopentyloxy-phenoxy)-azetidine trifluoroacetate.
  • Example 73 3-(5-Chloro-2-cvclohexylmethoxy-phenoxy)-azetidine trifluoroacetate.
  • Example 74 3-(5-Bromo-2-cvclohexylnnethoxy-phenoxy)-azetidine.
  • Example 75 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-trifluoromethyl- furan-3-carboxylic acid trifluoroacetate.
  • Step A Preparation of 5-Bromomethyl-2-trifluoromethyl-furan-3- carboxylic acid ethyl ester.
  • N- bromosuccinimide (0.84 g, 4.8 mmol)
  • AIBN 0.004 g, 0.01 mmol
  • Step B Preparation of 3-[2-(4-Carboxy-5-trifluoromethyl-furan-2- ylmethoxy)-5-chloro-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester.
  • the title compound was prepared as described in Example 1 Step D using 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.15 g, 0.50 mmol), the title compound of Step A (0.18 g, 0.60 mmol), Cs 2 CO 3 (0.41 g, 1.2 mmol), Kl (0.12 g,0.70 mmol ) in DMF, except upon completion of the reaction 1 N NaOH and EtOAc were added. The organic layer was washed with 1 N NaOH and dried. The crude material was purified by RP HPLC to provide the title compound.
  • Step C Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvH- 2-trifluoromethyl-furan-3-carboxylic acid trifluoroacetate: Prepared from the title compound of Step B using general procedure 1.
  • Example 76 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvn-2-trifluoromethyl- furan-3-carboxylic acid ethyl ester.
  • Step A Preparation of 3-[5-Chloro-2-(4-ethoxycarbonyl-5-trifluoromethyl- furan-2-ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester.
  • the title compound was prepared as described in Example 1 Step D using 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.3 g, 1.0 mmol), the title compound of Example 75 Step A (0.75 g, 2.5 mmol), Cs 2 CO 3 (0.80 g, 2.4 mmol) and Kl (0.23 g, 1.4 mmol ) in DMF (15 ml_).
  • Step B Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvH- 2-trifluoromethyl-furan-3-carboxylic acid ethyl ester: Prepared from the title compound of Step A using general procedure 1.
  • Example 77 5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)-phenoxymethyl1-2- trifluoromethyl-furan-3-yli-methanol.
  • Step A Preparation of 5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)- phenoxymethyl1-2-trifluoromethyl-furan-3-yl1-methanol.
  • DIBAL-H 1.0 M in THF, 0.24 ml_
  • Step A Preparation of (5-Methyl-2-trifluoromethyl-furan-3-yl)-methanol.
  • ⁇ -methyl ⁇ -thfluoromethyl-furan-S-carboxylic acid ethyl ester (0.83 g, 3.7 mmol) in Et 2 O at 0 0 C
  • DIBAL-H 1.0 M in THF, 1.5 ml_
  • the ice bath was removed and additional DIBAL-H was added (1.0 M in THF, 14.5 mL).
  • the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight.
  • Step B Preparation of 3-[5-chloro-2-(5-methyl-2-trifluoromethyl-furan-3- ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. Synthesized from the title compound of Step A and 3-(5-chloro-2-hydroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester using general procedure 7.
  • Step C Preparation of 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3- ylmethoxy)-phenoxy1-azetidine. Synthesized from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci6Hi 5 CIF 3 NO 3 , 361.1 ; m/z found, 362.1 [M+H] + .
  • Step A Preparation of (6-Trifluoronnethyl-pyridin-2-yl)-nnethanol.
  • 6-trifluoromethyl-pyhdine-2-carboxylic acid 500 mg, 3 mmol
  • triethylamine 0.36 ml_, 2.6 mmol
  • ethyl chloroformate 0.25 ml_, 2.6 mmol
  • LiBH 4 2 M in THF, 3.3 ml_, 6.5 mmol
  • Step B Preparation of 3-[5-Chloro-2-(6-trifluoromethyl-pyhdin-2- ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. Prepared from the title compound of Step A and 3-(5-Chloro-2-hydroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester using general procedure 7.
  • Step C Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1- 6-trifluoromethyl-pyhdine. Prepared from the title compound of Step B according to general procedure 1. MS (ESI): mass calcd. for Ci 6 Hi 4 CIF 3 N 2 O 2 , 358.1 ; m/z found, 359.0 [M+H] + .
  • Examples 80-89 were prepared using the appropriate alcohol and phenol according to general procedure 7.
  • Example 81 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -4-trifluoromethyl- pyridine.
  • Example 82 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-trifluoromethyl- pyhdine.
  • Example 83 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy1-azetidine.
  • Example 84 6-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-benzothiazole.
  • Example 85 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-1 -methyl-1 H- benzotriazole.
  • Example 87 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethv ⁇ -oxazole.
  • Example 88 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-thiazole.
  • Step A Preparation of 3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester.
  • Et 3 N 1.38 g, 0.94 ml_, 12.1 mmol
  • brine was added and the mixture extracted with CH 2 CI 2 (2X).
  • the combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1 - carboxylic acid tert-butyl ester that was used without further purification.
  • Step B Preparation of 3-(4-chloro-2-hvdroxy-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester.
  • a CH 2 CI 2 (25 ml_) solution of the title compound of Step A 1. g, 4.3 mmol was added 77% m-CPBA (1.4 g, 6.2 mmol).
  • Step C Preparation of 3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester. Prepared according to Example 1 Step D using the title compound of Step B.
  • Step D Preparation of (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine. Prepared according to general procedure 1 using the title compound of Step C. MS (ESI): mass calcd. for Ci 7 Hi 8 CINO 2 , 303.1 ; m/z found, 304.2 [M+H] + .
  • Examples 95-100 were prepared using 1 -methyl-pyrrolidin-3-ol and the appropriately substituted phenol (synthesized according to Example 90) according to general procedure 7 using resin bound PPh 3 .
  • Example 99 ( ⁇ )-Methanesulfonic acid 3-[4-bromo-2-(1 -methyl-pyrrolidin-3- yloxy)-phenoxynnethyl1-phenyl ester.
  • Example 100 ( ⁇ )-Methanesulfonic acid 3-[2-(1 -methyl-pyrrol id in-3-yloxy)- phenoxymethyli-phenyl ester.
  • Step A Preparation of (R)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)- ethoxyi-phenoxyi-azetidine-i -carboxylic acid tert-butyl ester.
  • Step B Preparation of (S)-3-r5-Chloro-2-ri-(3-trifluoromethyl-phenyl)- ethoxyi-phenoxyi-azetidine.
  • TFA 50 ml_
  • PhCH 3 50 ml_
  • the resulting oil was neutralized with saturated NaHCO 3 (aq.) and extracted with CH 2 CI 2 (2X). The combined organics were dried and concentrated.
  • Example 102 (S)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
  • Example 103 (S)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -methyl-azetidine.
  • Example 105 (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 106 (+)-3-f5-Chloro-2-f1 -(3-thfluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -isopropyl-azetidine.
  • Example 107 (+)-3-[5-Chloro-2-[1 -(3-thfluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -cyclobutyl-azetidine.
  • Example 108 (+)-1 -Benzyl-3-r5-chloro-2-H -(3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 109 (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -methyl-azetidine.
  • Example 110 (+)-3-[5-Bromo-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 112 (+)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 113 (R)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 114 (+)-3-[5-Chloro-2-[1 -(3-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 115 (+)-3-[5-Chloro-2-[1 -(3-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 116 (+)-3-r5-Chloro-2-ri -(2-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 117 (+)-3-r5-Chloro-2-ri -(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 118 (+)-3-r5-Chloro-2-ri -(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 119 (+)-3-r5-Chloro-2-ri -(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 120 (+)-3-f5-Chloro-2-f1 -(3-trifluoromethylsulfanyl-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 121 (+)-3-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 123 (+)-3-[5-Chloro-2-[1 -(4-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 124 (+)-3-[5-Chloro-2-[1 -(4-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 126 (+)-3-f5-Chloro-2-f1 -(3,4-dichloro-phenyl)-ethoxy1-phenoxy1- azetidine.
  • Example 127 (+)-3-f5-Chloro-2-f1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-azetidine.
  • Example 128 (+)-3-r5-Chloro-2- ⁇ -(3.4-difluoro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
  • Example 129 (+)-3-r5-Chloro-2-H -(2,5-dichloro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
  • Example 130 (+)-3-r5-Chloro-2- ⁇ -(2,5-difluoro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
  • Example 131 2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethv ⁇ -benzothiazole.
  • Example 132 5-[1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1-thiazole.
  • Example 134 5-[1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1-2,4-dimethyl- thiazole.
  • Example 135 (R)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- piperidine.
  • Example 137 (+)-4-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-piperidine.
  • Example 138 (+)-4-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy1-phenoxy1- piperidine.
  • Example 139 (R,S)-3-r5-Chloro-2-[1 -((R)-3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-piperidine.
  • Example 140 (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy1- phenoxyi-azetidine.
  • Example 142 3-r5-Bromo-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy1-azetidine.
  • Example 143 3-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy1-azetidine.
  • Example 145 ( ⁇ )-3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1-azetidine.
  • Step A Preparation of 1 -[3-(5-Chloro-2-hvdroxy-phenoxy)-azetidin-1 -vH- 2,2,2-thfluoro-ethanone.
  • 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester (0.80 g, 2.7 mmol) in EtOAc (2 ml_) was added 4M HCI in dioxane (5 ml_). After 18h, EtOAc was added and the resulting white solid filtered to give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a white solid.
  • Step B Preparation of ( ⁇ )-1 -r3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1- azetidin-1 -yl1-2,2,2-thfluoro-ethanone.
  • Cs 2 CO 3 (0.25 g, 0.80 mmol
  • Kl (0.09 g, 0.55 mmol
  • (i -bromoethyl)-benzene (0.10 g, 0.08 ml_, 0.56 mmol).
  • H 2 O was added and the mixture extracted with EtOAc (2X).
  • Step C Preparation of ( ⁇ )-3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1- azetidine.
  • K 2 CO 3 (0.10 g, 0.72 mmol).
  • H 2 O was added and the mixture extracted with EtOAc (2X). The combined organics were dried and concentrated.
  • Silica gel chromatography (1 -7 2M NH 3 /MeOH in CH 2 CI 2 ) gave 0.75 g (68% yield) of the title compound.
  • Example 146 ( ⁇ )-3-r5-Chloro-2-ri -(5-thfluoromethyl-furan-2-yl)-ethoxy1- phenoxyi-azetidine.
  • Step A Preparation of 1 -(5-Trifluoromethyl-furan-2-yl)-ethanol.
  • MeMgBr MeM in Et 2 O, 3 ml_, 6 mmol
  • ⁇ A saturated NH 4 CI was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried to give 0.81 g (97%) of the title compound.
  • Step B Preparation of 1 -(3-r5-Chloro-2-ri -(5-trifluoromethyl-furan-2-yl)- ethoxy1-phenoxy1-azetidin-1 -yl)-2,2,2-trifluoro-ethanone: Prepared from the title compound of Step A and the title compound of Example 145 Step A using general procedure 7.
  • Step C Preparation of ( ⁇ )-3-r5-Chloro-2-ri-(5-trifluoromethyl-furan-2-yl)- ethoxyi-phenoxyi-azetidine: Prepared from the title compound of Step B according to Example 145 Step C.
  • Example 147 3-[5-Chloro-2-(1 -phenyl-propoxy)-phenoxy1-azetidine.
  • Example 148 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-2-phenyl-ethanol.
  • Step A Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl- methoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester.
  • 3-(5-Chloro- 2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester 1.1 g, 3.7 mmol) in DMF (18 ml_) was added CS2CO3 (1.5 g, 4.4 mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 ml_, 4.0 mmol). After 15h, H 2 O was added and the mixture extracted with EtOAc (2X).
  • Step B Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl- methoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester.
  • LiBH 4 (2M in THF, 0.4 ml_, 0.8 mmol).
  • EtOAc 2X
  • the combined organic layers were washed with brine and dried.
  • Silica gel chromatography (5-25% EtOAc in hexanes) gave 0.17 g (82%) of the title compound.
  • Step C Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-2- phenyl-ethanol. Prepared from the title compound of Step B according to general procedure 1.
  • 1 H NMR (DMSO-D 6 ): 7.40 (m, 5H), 6.94-6.69 (m, 3H), 5.32-5.28 (m, 1 H), 5.11-4.79 (m, 2H), 3.80-3.75 (m, 3H), 3.61 (dd, J 11.4, 4.1 Hz, 1 H), 3.54-3.20 (m, 2H).
  • Example 149 r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-phenyl-acetic acid hydrochloride.
  • Step A Preparation of 3-[2-(Carboxy-phenyl-methoxy)-5-chloro- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester.
  • MeOH 3 ml_
  • 1 N NaOH 3 ml_
  • EtOAc 2X
  • Step B Preparation of [2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-phenyl- acetic acid hydrochloride. Prepared from the title compound of Step A according to general procedure 1. MS (ESI): mass calcd.
  • Example 150 ( ⁇ )-3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1-azetidine.
  • Step B Preparation of 1 -[3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1- azetidin-1 -yl1-2,2,2-thfluoro-ethanone. Prepared from the title compound of Step A and the title compound of Example 145 Step A according to the general procedure 7.
  • Step C Preparation of 3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1- azetidine. Prepared from the title compound of Step B using general procedure 2.
  • Examples 151-161 were prepared according to Example 150 using the appropriately substituted phenol and alcohol.
  • Example 151 ( ⁇ )-3-[5-Bromo-2-(indan-1 -yloxy)-phenoxy1-azetidine.
  • Example 152 ( ⁇ )-3-[5-Bromo-2-(5-chloro-indan-1 -yloxy)-phenoxy1-azetidine.
  • Example 154 ( ⁇ )-3-[5-Bromo-2-(5-fluoro-indan-1 -yloxy)-phenoxy1-azetidine.
  • Example 155 ( ⁇ )-3-[5-Bromo-2-(5-methyl-indan-1 -yloxy)-phenoxy1-azetidine.
  • Example 157 ( ⁇ )-3-[5-Bromo-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy1- azetidine.
  • Example 158 ( ⁇ )-3-[5-Chloro-2-(6-methyl-indan-1 -yloxy)-phenoxy1-azetidine. .
  • Example 160 3-[5-Chloro-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy1- azetidine.
  • Example 161 3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-1 -yloxy)-phenoxy1- azetidine.
  • Step A Preparation of 1 -(4-tert-Butyl-phenyl)-3-chloro-propan-1-one.
  • te/t-butyl benzene 1.0 g, 7.5 mmol
  • 3-chloropropionyl chloride 0.7 ml_, 7.5 mmoL
  • CH 2 CI 2 20 ml_
  • AICI 3 1.1 g, 8.2 mmol
  • Step B Preparation of 5-fe/f-butyl-indan-1-one.
  • the title compound of Step A (1.3 g, 5.8 mmol) was dissolved in cone. H 2 SO 4 (10 ml_) and heated at 95 0 C for 3 h. The reaction mixture was cooled to rt, poured onto ice, and extracted with Et 2 O (3 x 25 ml_). The combined organic extracts were washed with sat'd NaHCO 3 (aq.) and dried to provide the title compound (0.74 g, 68%).
  • Step B Preparation of 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)- phenoxyi-azetidine.
  • Example 163 3-[5-Chloro-2-(tetrahvdro-furan-3-ylmethoxy)-phenoxy1- azetidine.
  • Examples 164-174 were prepared according to Example 163 with the appropriate alcohols.
  • Example 164 3-[5-Chloro-2-(1 ,2,3,4-tetrahvdro-naphthalen-2-yloxy)-phenoxy1- azetidine.
  • Example 166 3-[5-Chloro-2-(tetrahvdro-furan-2-ylmethoxy)-phenoxy1- azetidine.
  • Example 169 3-r5-Chloro-2-(2,3-dihvdro-benzofuran-2-ylmethoxy)-phenoxy1- azetidine.
  • Example 170 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-1 ,3-dimethyl- 1 H-pyrazole.
  • Example 172 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -phenyl-azetidine.
  • Example 173 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy1-azetidine.
  • Example 175 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy1-azetidine.
  • Step A Preparation of 2-Bromo-5-fluoro-indan-1 -one.
  • 5-fluoro-indan-1 -one 10 mmol
  • MeOH/CH 2 CI 2 40 mL/120 ml_
  • Bu 4 NBr 3 11 mmol
  • the mixture was stirred at 25 0 C for 16 h, concentrated and partitioned between CH 2 CI 2 /H 2 O (150 mL/80 ml_). The organic layer was concentrated and purified providing the title compound (2 g).
  • Step B Preparation of 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy1- azetidine.
  • the mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5 mmol), and K 2 CO3 (1 mmol) in acetonitrile (3 ml_) was heated at 100 0 C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (150 mg).
  • Example 176 The compounds in Examples 176-178 were prepared according to Example 175 using the appropriately substituted indanone.
  • Example 176 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy1-azetidine.
  • Example 177 3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy1-azetidine.
  • Example 178 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy1-azetidine.
  • Step A Preparation of 3-[5-chloro-2-(6-fluoro-1 -oxo-indan-2-yloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester.
  • the mixture of 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.5 mmol), 1 -bromo-indan-2-one (0.5 mmol), and K2CO3 (1 mmol) in actetonithle (3 mL) was heated at 100 0 C in a microwave reactor for 1 h. The mixture was cooled down and separated through PTLC providing the title compound (150 mg).
  • Step B Preparation of 3-[5-Chloro-2-(1 -hvdroxyimino-indan-2-yloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester.
  • the title compound of Step A was dissolved into MeOH (2 mL), then NH 2 OH HCI (1 mmol) and K 2 CO 3 (2 mmol) were added. The mixture was heated at 100 0 C using a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (120 mg).
  • Step C Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-indan- 1 -one oxinne.
  • the title compound from Step B was dissolved in CH 2 CI 2 (20 mL), and CF 3 COOH (3 mL) was added. The mixture was stirred at 25 0 C for 4 h. After concentration and purification via PTLC, the title compound was obtained (91 mg).
  • Example 180-183 were prepared by the procedure of example 179 using the appropriate ⁇ -bromo-ketone and NH 2 OH or NH 2 OCH 3 .
  • Example 181 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-1 -phenyl-ethanone oxime.
  • Example 182 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-1 -phenyl-ethanone O- methyl-oxime.
  • Example 184 3-r5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy1-azetidine.
  • Example 185 3-r5-Chloro-2-r2-(3-chloro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Step A Preparation of Methanesulfonic acid 2-(3-chloro-phenyl)-ethyl ester.
  • 2-(3-chloro-phenyl)-ethanol 566 mg, 3.6 mmol
  • CH 2 CI 2 10 ml_
  • methanesulfonyl chloride 310 ⁇ l_, 4.0 mmol
  • Et 3 N 756 ⁇ l_, 5.4 mmol
  • Step C Preparation of 3-r5-Chloro-2-r2-(3-chloro-phenyl)-ethoxy1- phenoxyi-azetidine. Prepared from title compound of Step B using general procedure 1.
  • Example 185 using the appropriately substituted mesylates as prepared in Example 185 Step A.
  • Example 186 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
  • Example 188 3-[5-Chloro-2-[1 -(4-chloro-phenyl)-cvclobutylmethoxy1-phenoxy1- azetidine.
  • Example 190 3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 191 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 193 3-r5-Chloro-2-r2-(4-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 194 3-r5-Chloro-2-r2-(4-methoxy-phenyl)-ethoxy1-phenoxy1-azetidine.
  • Example 196 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine.
  • Step A Preparation of 2-benzyloxy-5-chloro-3-fluoro-pyhdine.
  • benzyl alcohol 2.7 g, 2.6 ml_, 25.0 mmol
  • 5-chloro-2,3-difluoro-pyhdine 3.73 g, 25.0 mmol
  • EtOAc 2X
  • Step B Preparation of 3-(2-Benzyloxy-5-chloro-pyhdin-3-yloxy)- azetidine-1-carboxylic acid tert-butyl ester.
  • NMP 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (0.35 g, 2.0 mmol) in NMP (3 ml_) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol). After 20 min at rt, the reaction was heated to 50 0 C for 20 min, cooled to rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1 ml_) was added.
  • Step C Preparation of 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro- pyridine. Prepared from the title compound of Step B using general procedure 1.
  • Step A Preparation of 4-Chloro-2,6-difluoro-benzaldehvde.
  • n-butyl lithium 1.6 M in hexane, 19 ml_.
  • DMF 5.2 ml_, 67 mmol
  • Step B Preparation of 3-(5-Chloro-3-fluoro-2-formyl-phenoxy)-azetidine- 1 -carboxylic acid tert-butyl ester.
  • Step C Preparation of 3-(5-Chloro-3-fluoro-2-hvdroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester.
  • m-CPBA 510 mg, 3.0 mmol.
  • Step D Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester. Prepared from the title compound of Step C using according to Example 1 Step D.
  • Step E Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)- azetidine. Prepared from the title compound of Step D using general procedure 1.
  • Example 198 3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)- phenoxyi-azetidine.
  • Example 199 3-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)- phenoxyi-azetidine.
  • Example 201 3-[2-(1 -Phenyl-ethoxy)-5-trifluoromethyl-phenoxy1-azetidine hydrochloride.
  • Example 202 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-azetidine hydrochloride.
  • Step A Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-benzaldehyde.
  • a mixture of 5-fluorosalicyladehyde (5.0 g, 36 mmol), 3-chloro-benzyl bromide (7.34 g, 35.7 mmol), K 2 CO 3 (6.0 g, 43 mmol) in DMF (50 ml_) was heated at 65 0 C for 18 h.
  • the reaction mixture was cooled to rt and diluted with a mixture of EtOAc (500 ml_) and H 2 O (300 ml_).
  • the organic phase was separated, washed with H 2 O (3x250 ml_), and dried to give the title compound (9.4 g, 99 %) that was used without further purification.
  • Step B Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-phenol.
  • Step C Preparation of 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1- azetidine-1-carboxylic acid tert-butyl ester.
  • DMF 5.0 ml_
  • 60 wt% NaH 34.3 mg, 0.86 mmol
  • the mixture was heated to 50 0 C for 1 h then cooled to rt and 3- methanesulfonyloxy-azetidine-1 -carboxylic acid tert-butyl ester (Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added.
  • Example 203 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -methyl-azetidine.
  • Example 204 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -isopropyl- azetidine.
  • Example 205 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -cvclobutyl- azetidine.
  • Example 206 3-r2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -propyl-azetidine.
  • Example 208 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine. .
  • Example 209 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1-1 - isopropyl-azetidine.
  • Example 210 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy1-azetidine.
  • Example 211 3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl- benzamide.
  • Example 212 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-methyl-azetidine.
  • Step A Preparation of 1 -benzhvdryl-3-methyl-azetidin-3-ol.
  • ether 100 ml_
  • CH 3 MgBr 1.5 ml_, 3M in ether
  • the mixture was warmed to rt over 1 h and 1 N NaOH (3 ml_) was added.
  • the organic layer was concentrated providing the title compound (1.1 g).
  • Step B Preparation of 1 -benzhvdryl-3-[5-bromo-2-(3-chloro-benzyloxy)- phenoxyi-3-methyl-azetidine.
  • the mixture of the title compound from Step A (0.5 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), and cyanomethyleneth-n-butylphosphorane (0.5 mmol) in toluene (3 ml_) was heated at 150 0 C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (120 mg).
  • Step C Preparation of 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3- methyl-azetidine.
  • the title compound from Step B (60 mg) was dissolved in DCE (10 ml_) and chloroethylformate (0.2 mmol) was added. The mixture was heated at 80-100 0 C for 1 h and concentrated. The residue was dissolved in MeOH (3 ml_) and heated at 150 0 C in a microwave reactor for another 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (30 mg).
  • Example 213 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-ethyl-azetidine.
  • Example 214 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-isopropyl- azetidine.
  • Example 215 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine.
  • Step A Preparation of (4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine.
  • the reaction mixture was filtered through a pad of celite and concentrated to give the title compound (9.9 g, 78%).
  • Step B Preparation of 3-hvdroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester.
  • a solution of 1 -Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 ml_ anh Et 2 O was cooled to 0 0 C and 3M MeMgBr in Et 2 O (10 ml_, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18h. Then Vi sat'd NH 4 CI (aq.) was added and the mixture extracted with EtOAc (2x).
  • Step C Preparation of 3-(5-Bromo-2-formyl-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester.
  • Step D Preparation of 3-(5-Bromo-2-hvdroxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester. Prepared according to Example 1 Step C using the title compound from Step C. Purification was accomplished by PTLC to give the title compound as a peach solid (152 mg, 64%).
  • Step E Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester.
  • Step F Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine.
  • a mixture of 3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester (20 mg) and TFA (1 mL) in CH 2 CI 2 (2 mL) was stirred at rt for 2 h.
  • the reaction was concentrated in vacuo and purified by PTLC followed by additional purification using RP HPLC (Agilent) to give the title compound as an oil (12 mg, 77%).
  • Example 216 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine.
  • Example 217 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy1-azetidine.
  • Example 219 ( ⁇ Hrans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2-methyl- azetidine.
  • Step A Preparation of ( ⁇ )-2-bromomethyl-3-methyl-oxirane. See Shimizu et al., Organic Process & Research Development, 2005, VoI 9(3), pp. 278-287. To a stirred solution of crotyl bromide (10 g, 63 mmol) in CH 2 CI 2 (200 ml_) was slowly added 77% m-CPBA (19.8 g, 88 mmol) portionwise over 45 min. After stirring at rt for 18 h, the solids were removed by filtration. The filtrate was treated with aqueous 10% aq. NaHSO 3 (150 ml_) and stirred at rt for 5 h.
  • Step B Preparation of cis and trans 1-benzhvdryl-2-methyl-azetidin-3- Pl See PCT pat appl. WO 01/01988.
  • Cis isomer as an off white solid (914 mg), 1 H NMR (CDCI 3 ): 7.42 - 7.36 (m, 4H), 7.28 - 7.22 (m, 4H), 7.18 - 7.16 (m, 2H), 4.37 (s, 1 H), 4.30 - 4.27 (m, 1 H), 3.46 - 3.42 (m, 1 H), 3.26 - 3.24 (m, 1 H), 3.06 - 3.04 (m, 1 H), 0.74 (d, J 6.5 Hz, 3H).
  • Step C Preparation of ( ⁇ Hrans-1 -3-[5-Bromo-2-(3-fluoro-benzyloxy)- phenoxyi-2-methyl-azetidine. Prepared according to Example 212 Steps B-C using the frans-isomer from Step B. MS (ESI): mass calcd. for Ci 7 Hi 7 BrFNO2, 365.0; m/z found, 366.1 [M+H] + .
  • Example 220 cis-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2- methyl-azetidine.
  • Example 221 frans-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2- methyl-azetidine.
  • Example 222 3-[5-Chloro-2-(1 -phenyl-azetidin-3-ol)-phenoxy1-azetidine.
  • Step A Preparation of 1 -phenyl-azetidin-3-ol.
  • the mixture of azetidin-3- ol (2 mmol), bromobenzene (2 mmol), Pd(OAc) 2 (0.1 mmol), 2-( ⁇ -tert- butylphosphino)biphenyl (0.2 mmol) and NaOfBu (3 mmol) in toluene (3 ml_) was heated at 100 0 C for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (15 mg).
  • Step B Preparation of 3-[5-Chloro-2-(1 -phenyl-azetidin-3-ol)-phenoxy1- azetidine.
  • the mixture of the title compound of Step A (15 mg), 3-(5-chloro-2- hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.2 mmol) and cyanomethylenetri-n-butylphosphorane (0.2 mmol) in toluene (2 ml_) was heated at 120 0 C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (20 mg).
  • Examples 223-225 were prepared similar to Example 222 using the appropriately substituted hydroxyazetidine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The biphenyic compounds of formula (I) are serotonin modulators useful in the treatment of serotonin-mediated diseases.

Description

SEROTONIN RECEPTOR MODULATORS
Cross Reference to Related Application
This application claims the benefit of US provisional patent application serial number 61/109,903, filed October 30, 2008.
Field of the Invention
There is provided by the present invention compounds that are serotonin receptor modulators. More particularly, there is provided by the present invention certain compounds that are serotonin receptor modulators useful for the treatment of disease states mediated by serotonin receptor activity.
Background of the Invention
Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, largely as the result of cDNA cloning.
These receptors have been grouped into seven families (5-HTi through 5-HT7) (Hoyer, D. et al. Pharmacol. Biochem. Behav., 2002, 71 , 533-554).
Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. 5-HT is implicated in many disease states, particularly conditions of the central nervous system including; depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, nociception, sexual behavior, hormone secretion, and cognition.
The identification of multiple 5-HT receptors has provided the opportunity to characterize existing therapeutic agents thought to act via the serotonergic system. Consequently, this has led to the realization that many drugs have non-selective properties (Roth, B. L. et al., Neuroscientist, 2000, 6(4), 252-262). For example, the antipsychotic drugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibit affinities for multiple serotonin receptors in addition to other families of receptors. Similar behavior has been noted for antidepressants including imipramine, nortriptaline, fluoxetine and sertraline. Similarly, the anti-migraine agent sumatriptan exhibits high affinity for several serotonin receptors. While the lack of selectivity often contributes to a favorable therapeutic outcome, it can also cause undesirable and dose-limiting side effects (Stahl, S. M., Essential Psychopharmacology, 2nd ed., Cambridge University Press, Cambridge, U.K., 2000). For example, the inhibition of serotonin and norepinephrine uptake together with 5-HT2 receptor blockade is responsible for the therapeutic effects of the tricyclic antidepressants. In contrast, their blockade of histamine Hi, muscarinic and alpha-adrenergic receptors can lead to sedation, blurred vision and orthostatic hypertension respectively. Likewise, the atypical antipsychotics, including olanzapine and clozapine, are considered to have positive therapeutic effects attributable to their actions at 5-HT2, D2 and 5-HT7 receptors. Conversely, their side effect liability is due to their affinities for a range of dopaminergic, serotonergic and adrenergic receptors.
Elucidating selective ligands has the potential to ameliorate untoward pharmacologies and provide novel efficacious therapies. More importantly, the ability to obtain compounds which portray receptor selectivity provides the prospect to target distinct therapeutic mechanisms and improve clinical responses with a single drug. Consequently, there remains a need for potent serotonin receptor modulators with desirable pharmaceutical properties.
Summary of the Invention Certain compounds have now been found to have 5HT-modulating activity, in particular 5HT7 and/or serotonin transporter modulating activity. In particular, the invention is directed to the general and preferred embodiments defined, respectively, and by the independent and dependent claims appended hereto, which are incorporated by reference herein. Thus, in one general aspect, the invention relates to compounds of
Formula (I):
Figure imgf000003_0001
wherein
R1 is -H, -Ci-4alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1 , 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1 ; R2 and R3 are each independently -H or -Ci-4alkyl;
R4 is -H, F, Ci-4alkyl, or R4 is -OH when L is -CH2-, -CF2-, or -CHF-, -OCH2-, or -OCH(CH3)-; L is -O-, -CH2-, -OCH2-, -OCH(CH3)-, -CH2O-, -CF2-, or -CHF-; Z is -O-, -C(O)-, -OCH(Rb)-, or -OCH2C(Rc)(Rd)-; where where Rb is -H; a -Ci-4alkyl group unsubstituted or substituted with OH or halo; -CO2Ci-4alkyl; or -CO2H; and Rc and Rd are each independently -H, -Ci-4alkyl, -O-Ci-4alkyl, or halo; or Rc and Rd taken together form an oxime, a Ci-4alkyl oxime, or a carbonyl group; or Rc and Rd taken together with the carbon to which they are attached form a C3-6cycloalkyl group; R5 is: i) a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R9 substituents; where each R9 substituent is selected from the group consisting of: -
Ci-6alkyl, -OH, -OCi-6alkyl, -CN, -NO2, -C(O)Ci -6alkyl, -S(O)0-2-Ci -ealkyl, -OS(O)0-2-Ci -6alkyl, -SO2CF3, -SCF3, halo, -CF3,
-OCF3, -CO2H, -CO2Ci -ealkyl, -CH2OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two R9 substituents taken together form -OCH2O-, -OCF2O-, or
-OCH2CH2O-; ii) a naphthyl group, unsubstituted or substituted with Ci-4alkyl or halo; iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R9 substituents; iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci-4alkyl or halo; v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: -Ci-4alkyl, -OCi-4alkyl, halo, -CF3, oxime, -Ci-4alkyl oxime, or phenyl; and vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; X is C or N; and
R6 or R7 are each independently -H, halo, -CF3, thiophene, or -C(O)N(Rx)Ry; wherein Rx and Ryare each independently -H or -Ci-4alkyl.
The invention also relates to stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of compounds of Formula (I). In certain preferred embodiments, the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below.
In a further general aspect, the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of an agent selected from compounds of Formula (I) and stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites thereof; and (b) a pharmaceutically acceptable excipient.
In another general aspect, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition (collectively, "indications") mediated by 5HT7 activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a stereoisomeric form, hydrate, solvate, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of such compound. In certain preferred embodiments of the inventive method, the disease, disorder, or medical condition is selected from: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
Preferred embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention. Detailed Description of the Invention and Its Preferred Embodiments
The invention may be more fully appreciated by reference to the following detailed description, including the following glossary of terms and the concluding examples. For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.
The terms "including", "containing" and "comprising" are used herein in their open, non-limiting sense.
The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which may also be structurally depicted by a bond, 7"), ethyl (Et), n-propyl (Pr), isopropyl (iPr), butyl (nBu), isobutyl (iBu), sec-butyl (sBu), tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and so on.
The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities (depicted without their bonds of attachment):
Figure imgf000006_0001
A "heterocycloalkyl" refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples (depicted without their bonds of attachment) include:
Figure imgf000006_0002
Figure imgf000007_0001
The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities (depicted without their bonds of attachment):
Figure imgf000007_0002
Those skilled in the art will recognize that the species of cycloalkyl, heterocycloalkyl, and heteroaryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.
The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. It is understood that some compounds referred to herein are chiral and/or have geometric isomeric centers, for example E- and Z- isomers. All optical isomers and stereoisomers of the compounds of any general structural formula, and mixtures thereof, are considered within the scope of the formula. Thus, any general formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any general formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof. Furthermore, certain compounds referred to herein can exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all such solvated and unsolvated forms that possess the activity that characterizes the compounds of this invention.
In another example, a zwitterionic compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form. Terms such as zwitterion, zwittehons, and their synonyms zwitterionic compound(s) are standard lUPAC-endorsed names that are well known and part of standard sets of defined scientific names. In this regard, the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As generally well known, a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term "inner salts". Other sources refer to these compounds as "dipolar ions", although the latter term is regarded by still other sources as a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H2NCH2COOH, and it exists in some media (in this case in neutral media) in the form of the zwittehon +H3NCH2COO". Zwittehons, zwittehonic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known by any one of ordinary skill in the art.
Any general formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures of the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, 36CI, and 125I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or 11C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
When referring to a formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a variable appears more than once in a formula, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula unless otherwise indicated.
By way of a first example on substituent terminology, if substituent S1exampie is one of Si and S2, and substituent S2 exampie is one of S3 and S4, then these assignments refer to embodiments of this invention given according to the choices S1 example is Si and S2 eχamPie is S3; S1 example is Si and S2exampie is S4;
S example is S2 and S example is S3; S example is S2 and S example is S4; and equivalents of each one of such choices. The shorter terminology "S1 exampie is one of Si and S2, and S2 eχamPie is one of S3 and S4" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as R1, R2, A, X4, X5, X6, X7, Ra, Rb, Rc, Rd, Re, Rf, R9, Rh, R', RJ, Rk, R1, Rm, and R0, and any other generic substituent symbol used herein.
Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent Sexampie is one of Si, S2, and S3, this listing refers to embodiments of this invention for which Sexampie is Si; Sexampie is S2;
Sexampie is S3; Sexampie is One Of Si and S2; Sexampie is One Of Si and S3; Sexampie is one of S2 and S3; Sexampie is one of Si , S2 and S3; and Sexampie is any equivalent of each one of these choices. The shorter terminology "Sexampie is one of Si, S2, and S3" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as as R1, R2, A, X4, X5, X6, X7, Ra, Rb, Rc, Rd, Re, Rf, R9, Rh, R', RJ, Rk, R1, Rm, and R0, and any other generic substituent symbol used herein. The nomenclature "C,./' with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term Ci-3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members
(C3).
The term Cn-malkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n < N < m, with m > n. Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as serotonin receptor modulators in the methods of the invention. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formula (I) , that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G. S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S. M. Berge, et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1 -19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.
When the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acidor glutamic acid, an aromatic acid, such as benzoic acid, 2- acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. When the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, pipehdine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I) , and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I) . A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I) . Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyhc acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs may be produced, for instance, by dehvatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary Ci-β alkyl amines and secondary di(Ci-6alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, Chalky! primary amines, and di(Ci- 2alkyl)amines. Representative pharmaceutically acceptable esters of the invention include Ci-7alkyl, C5-7cycloalkyl, phenyl, and phenyl(d-6)alkyl esters. Preferred esters include methyl esters. Prodrugs may also be prepared by dehvatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in Robinson et al., J Med Chem. 1996, 39 (1 ), 10-18. Free amines can also be dehvatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
The present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I) , which may also be used in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J Med Chem. 1997, 40, 2011 -2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220- 230; Bodor, Adv Drug Res. 1984, 13, 224-331 ; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991). The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the seratonin receptor in the methods of the invention. As such modulators, the compounds may act as antagonists, agonists, or inverse agonists. The term "modulators" include both inhibitors and activators, where "inhibitors" refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate seratonin receptor expression or activity, and "activators" are compounds that increase, activate, facilitate, sensitize, or up-regulate seratonin receptor expression or activity. Many of the compounds of the present invention are 5-HT7 modulators that act as 5-HT7 antagonists. As such, the compounds are useful in the treatment of 5-HT7-mediated disease in which a decrease, prevention, inactivation, desensitization or down-regulation of serotonin receptor expression or activity is required. The term "treat" or "treating" as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of serotonin receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of serotonin receptor activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human. In treatment methods according to the invention, an effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
The invention may be particularly useful in the treatment or prevention of diseases, disorders, or conditions mediated by serotonin receptor activity, such as: central nervous system disorders such as sleep disorders (including insomnia), depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive- compulsive disorder, mood disorders, post-traumatic stress and other stress- related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flashes associated with menopause, alcohol abuse, drug abuse, and addictive disorders including drug addiction and alcohol addiction. Further diseases accociated with serotonin receptor activity for which the compounds may be useful for treating are nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence and other disorders related to the gastrointestinal and vascular systems. In addition, compounds of the present invention may be used in methods for treating or preventing a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration. Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases."
The compounds of the present invention are 5-HT7 modulators, many of which are 5-HT7 antagonists. As such, the compounds are useful in the treatment of 5-HT7 mediated disease states. Where the compounds possess substantial 5-HT7 modulating acitivity, they may be particularly useful in methods for treating depression/anxiety, sleep/wake disturbances, sleep disorders, jet lag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders, hypertension, analgesic, and irritable bowel syndrome.
Particularly, as serotonin receptor modulators, the compounds of the present invention are useful in the treatment or prevention of depression, anxiety, sleep disorders, and circadian rhythm abnormalities.
The compounds of the invention are used, alone or in combination with one or more other active ingredients, to formulate pharmaceutical compositions of the invention. In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by serotonin receptors or that are active against another target associated with the particular condition, disorder, or disease. Suitable examples include: H1 receptor antagonists, H2 receptor antagonists, H3 receptor antagonists, topiramate (TOPAMAX™), and neurotransmitter modulators such as norepinephrine reuptake inhibitors (NRIs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, Donepezil (ARICEPT™), Rivastigmine, or Galantamine (REM I NYL™)), modafinil, antipsychotics, sedatives, monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs). The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention. In preferred embodiments, the combination method employs doses containing additional active ingredients in the range of about 20 to 300 mg per dose.
A pharmaceutical composition of the invention comprises: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.
A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation. For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Cornstarch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
The active agents of this invention may also be administered by non-oral routes. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery. Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
Effective doses of the compounds of the present invention may be ascertained by conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg. The invention includes also pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described below. Pharmaceutically acceptable salts of the specific compounds exemplified herein are especially preferred.
In certain embodiments of compounds of Formula (I), R1 is -H, -Ci-4alkyl, monocyclic cycloalkyl, phenyl, or benzyl. In certain embodiments, R1 is -H, - CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, or benzyl. In further embodiments, R1 is -H.
In certain embodiments of compounds of Formula (I), m has the value of 1 , 2 or 3 and n has the value of 1 or 2; however, if m is 2 then n is not 1. In preferred embodiments, m is 1 and n is 1. In further embodiments, m is 1 and n is 2. In further embodiments, m is 2 and n is 2. In further embodiments, m is 3 and n is 1.
In certain embodiments of compounds of Formula (I), R2 is -H or -Ci- 4alkyl. In further embodiments, R2 is -H, or -CH3. In certain embodiments of compounds of Formula (I), R3 is -H or -Ci-
4alkyl. In further embodiments, R3 is -H, or -CH3.
In certain embodiments of compounds of Formula (I), R2 and R3 are each -H. In certain embodiments of compounds of Formula (I), R4 is -H, F, -Ci- 4alkyl or R4 may be -OH when L is -CH2-, -CF2-, -CHF-, -OCH2-, or -OCH(CH3)- . In further embodiments, R4 is hydrogen.
In certain embodiments of compounds of Formula (I), L is -O-, -CH2-, - OCH2-, -OCH(CH3)-, -CH2O-, -CF2-, or -CHF-. In certain embodiments, L is -O-
In certain embodiments of compounds of Formula (I), Z is -O-, -C(O)-, - OCH(Rb)-, or -OCH2C(Rc)(Rd)-; where Rb is -H; a -Ci-4alkyl group unsubstituted or substituted with OH or halo; -CO2Ci-4alkyl; or -CO2H; and Rc and Rd are each independently -H, -Ci-4alkyl, -O-Ci-4alkyl, or halo. In certain embodiments of compounds of Formula (I), Rc and Rd taken together form an oxime, a Ci- 4alkyl oxime, or a carbonyl group. In certain embodiments of compounds of Formula (I), Rc and Rd taken together with the carbon to which they are attached form a C3-6cycloalkyl group. In certain embodiments of compounds of Formula (I), Z is -O-, -C(O)-, -OCH2-, -OCH(CH3)-, -OCH(CH2CH3)-, -
OCH(CH2OH)-, -OCH(CO2H)-, -OCH(CH2F)-, -OCH2CH2-, -OCH2CH(F)-, - OCH2CH(OCH3)-, -OCH2C(NOH)-, -OCH2C(NOCH3)-, -OCH2CF2-, -OCH2C(O)-
, or
Figure imgf000021_0001
. In further embodiments, Z is -O-, -OCH2-, or -OCH(CH3)-.
In certain embodiments of compounds of Formula (I), R5 is a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R9 substituents; where each R9 substituent is selected from the group consisting of -Ci-6alkyl, -OH, -OCi-6alkyl, -CN, -NO2, -C(O)Ci-6alkyl, -S(O)o-2-Ci-6alkyl, -OS(O)0-2-Ci -ealkyl, -SO2CF3, -SCF3, halo, -CF3, -OCF3, -CO2H, -CO2Ci-6alkyl, -CH2OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl. In further embodiments of compounds of Formula (I), two R9 substituents taken together form -OCH2O-, -OCF2O-, or -OCH2CH2O- group. In further embodiments, R5 is a naphthyl group, unsubstituted or substituted with Ci-4alkyl or halo. In further embodiments, R5 is a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R9 substituents. In further embodiments, R5 is a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci-4alkyl or halo. In further embodiments, R5 is a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: - Ci-4alkyl, -OCi-4alkyl, halo, -CF3, oxime, -Ci-4alkyl oxime, or phenyl. In further embodiments, R5 is a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl. In further embodiments, R5 is cyclohexyl, 2-indanyl, or furanyl optionally substituted with one or more substituents individually selected from halo, -CH3, -CF3, -OCF3, or -CN.
In certain embodiments, R5 is selected from the group consisting of cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano- phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro- phenyl, 4-chloro-3-thfluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-thfluoromethyl- phenyl, 4-fluoro-3-thfluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4- methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3- methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 2-, 3- or 4-thfluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-
trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-phenyl,
Figure imgf000022_0001
Figure imgf000022_0002
, 3-azetidinyl, 1 -benzyl-azetidin-3-yl, 1 -benzhydryl-azetidin-3-yl, 1 - isopropyl-azetidin-3-yl, benzo[1 ,3]dioxol-5-yl, 2,2-difluoro-benzo[1 ,3]dioxol-5-yl, 2-benzofuranyl, 5-benzofuranyl, 2,3-dihydro-benzofuran-2-yl, 2-benzothiazolyl, 6-benzothiazolyl, 1 H-benzotriazole-6-yl, 1 -methyl-1 H-benzothazole-6-yl, 2- or 3- chromanyl, 2-or 3-furanyl, 5-trifluoromethyl-2-furanyl, 2-indanyl, tetrahydro-3- furanyl, 1 -Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl, 5-fluoro-1 -indanyl, 5- methyl-1 -indanyl, 5- or 6-chloro-1-indanyl, 6-fluoro-1 -indanyl, 6-trifluoromethyl- 1 -indanyl, 6-methyl-1 -indanyl, 5-fluoro-2-indanyl, 5-methoxy-2-indanyl, [1 ,2,4]oxadiazole-5-yl, 3-cyclopropyl-[1 ,2,4]oxadiazole-5-yl, 3-cyclobutyl- [1 ,2,4]oxadiazole-5-yl, 3-isopropyl-[1 ,2,4]oxadiazole-5-yl, phenoxy, 4- piperidinyl, 2- or 3-pyrrolidinyl, 3-methyl-[1 ,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl, 4-thfluoromethyl-2-pyridinyl, 2-, 3- or 4-pyridinyl, 6- trifluoromethyl-2-pyhdinyl, 1 ,2,3,4-tetrahydro-naphthalen-1 -yl, 1 ,2,3,4- tetrahydro-naphthalen-2-yl, 1 -phenyl-3-azetidinyl, 4- or 5-thiazolyl, 2-methyl-
thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl,
Figure imgf000023_0001
j and 5-methyl- isoxazole-3-yl.
In certain embodiments of compounds of Formula (I), R6 and R7 are each independently -H, halo, -CF3, thiophene, or -C(O)N(Rx)Ry; wherein Rx and Ryare each independently -H or -Ci-4alkyl. In certain embodiments of compounds of Formula (I), R6 and R7 are each independently -H, halo, -CF3, thiophene-3-yl, or N,N-dimethyl-formamidyl. In certain embodiments, R6 is -H or halo. In certain embodiments, R6 is -H or halo and R7 is -H, halo, -CF3, thiophene-3-yl, or N,N-dimethyl-formamidyl.
Preferred compounds are selected from the group consisting of:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
291 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-methanone;
292 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone;
293 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone;
294 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone;
295 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1 ,3]dioxol-5-yl-methanone;
Benzo[1 ,3]dioxol-5-yl-[4-chloro-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]- methanone;
297 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone; and
298 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone; and stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and active metabolites thereof.
Exemplary chemical entities useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables in the formulas depicted in the schemes below are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 0C and the reflux temperature of the solvent.
List of abbreviations: Ac = Acetyl, AIBN = azobisisobutyronitrile, Boc = tert-Butylcarbamoyl, m-CPBA = meta-chloroperoxybenzoic acid, DCE = dichloroethane, DEAD = diethyldiazodicarboxylate, DIBAL-H = diisobutyl aluminum hydride, DIEA = N,N-Diisopropylethylamine, DMA = N1N- Dimethylacetamide, DME = Ethylene glycol dimethyl ether, DMF = dimethylformamide, DMSO = Dimethyl sulfoxide, Et3N = triethylamine, Et2O = diethyl ether, EtOAc = Ethyl acetate, MeCN = acetonitrile, MeOH = methanol, MsCI = Methanesulfonyl chloride, TFA = trifluoroacetic acid, TFAA = trifluoroacetic acid anhydride, THF = tetrahydrofuran, TLC = thin layer chromatography, Q-Phos=1 ,2,3,4, 5-pentaphenyl-1 '-(di-terf- butylphosphino)ferrocene.
The compounds of formula (I) may be prepared by a number of reaction schemes. The following schemes represent certain synthesis steps for obtaining compounds of the invention. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme as compared to the other.
The amines in the compounds below may be protected, as indicated by P1, as an alkyl or benzyl amine, amide, carbamate or other groups such as described in "Protecting Groups in Organic Synthesis", 3rd ed.; T.W. Greene and P. G. Wuts, John Wiley and Sons, 1999. Preferably, P1 is -Ci-6Alkyl, - COOCi-6Alkyl, -(C=O)Ci-6Alkyl, benzyl substituted or unsubstituted with -OCi- 6Alkyl or Ci-6Alkyl, or benzhydryl substituted or unsubstituted with -OCi-6Alkyl or -Ci-θAlkyI). A further preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide. This protecting group (P1) on the nitrogen may be removed or converted directly into the desired compounds using generally accepted methods known to one skilled in the art. More specifically a group such as a Boc group may be removed with an acid such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH2CI2, EtOAc, THF, 1 ,4- dioxane, MeOH or EtOH. A group such as trifluoroacetamide was removed using a base such as NH3, NH4OH or K2CO3 in an alcoholic solvent such as MeOH or EtOH and the like.
Scheme A
Figure imgf000035_0001
Intermediates of the formula A5 were prepared according to Scheme A. The variable Z in the formula depicted in Scheme 1 are as defined above in reference to Formula (I) except Z cannot be -C(O)- in Scheme 1. Compounds of the formula A1 were treated with te/f-butylamine in the presence of a dehydrating agent such as SiO2, CuSO4, Ti(OiPr)4, MgSO4 or molecular sieves in a suitable solvent such as THF, CH2CI2, benzene, toluene, MeOH or EtOH. A preferred method uses MgSO4 in CH2CI2 to give compounds of the formula A2. Compounds of the formula A2 were allowed to react with compounds of the formula A3 in a suitable solvent such as DMF, DMSO, NMP or THF in the presence of a base such as NaH, KOfBu or Cs2CO3, preferably NaH in DMF, to produce compounds of formula A4. Compounds of the formula A5 were obtained from compounds of the formula A4 upon basic hydrolysis of the compound obtained from the treatment of compounds of the formula A4 with an oxidant such as m-chloroperoxybenzoic acid (m-CPBA) in CH2CI2. The hydrolysis is performed using a base such as NaOH or KOH in a solvent such as MeOH, EtOH or H2O. Scheme B
Figure imgf000036_0001
B1 B2 A4
Intermediates of the formula A4 were alternatively prepared according to Scheme B. Compounds of the formula A4 were alternatively obtained from compounds of the formula B1 , where LG represents a chloride, bromide, iodide, mesylate or tosylate, upon treatment with a compound of the formula B2. The variable Z in the formulas depicted in Scheme 2 are as defined above in reference to Formula (I) except Z cannot be -C(O)- in Scheme 2. This type of reaction was carried out in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3. Alternatively, compounds of the formula A4 may also be obtained from compounds of the formula B1 when LG is OH using PPh3 or similar trialkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-te/t-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH2CI2 and the like. One skilled in the art will recognize this as a Mitsunobu reaction.
Scheme C
Figure imgf000036_0002
C1 C2 C3
Intermediates of the formula C3 were prepared according to Scheme C.
Compounds of the formula C3 were synthesized similar to compounds of the formula A5 (Scheme 1 ) from compounds of the formula C1. Compounds of the formula C2 were obtained from compounds of the formula C1 and compounds of the formula A2 (Scheme 1 ) in a suitable solvent such as DMF, DMSO, NMP or THF in the presence of a base such as NaH, KOfBu or CS2CO3, preferably NaH in DMF. Compounds of the formula C3 were obtained from compounds of the formula C2 upon basic hydrolysis of the compound obtained from the treatment of compounds of the formula C2 with an oxidant such as m- chloroperoxybenzoic acid (m-CPBA) in CH2CI2. The hydrolysis was performed using a base such as NaOH or KOH in a solvent such as MeOH, EtOH or H2O.
Scheme D
Figure imgf000037_0001
C2
Intermediates of the formula C2 were alternatively prepared according to Scheme D using compounds of the formula D1. The amine in compounds of the formula C2 may be protected with a protecting group, as indicated by P1, with previously described protecting groups. Treatment of compounds of formula D1 with a nucleophile such as a compound of formula B2 (Scheme 2) in the presence of base such as pyridine, thethylamine, diisopropylamine, K2CO3, Cs2CO3 or Na2CO3 in a suitable solvent such as THF, CH2CI2, DMF, MeCN, 1 ,4-dioxane or the like at a temperature ranging from rt to 100 0C provided compounds of the formula C2. Compounds of the formula D1 were obtained from compounds of the formula C1 when treated with methanesulfonyl chloride (MsCI) in the presence of a base such as pyridine, thethylamine or diisopropylamine and the like in a solvent such as CH2CI2, THF or DCE. Scheme E
Figure imgf000038_0001
E1 E3
Intermediates of the formula E2 were prepared according to Scheme E. Compounds of the formula E2 were obtained after addition of compounds of the formula E2 to compounds of the formula E1. One skilled in the art will recognize compounds of the formula E2 as Grignard reagents.
Scheme F
F1
Figure imgf000038_0002
F4
Intermediates of the formula F4 were prepared according to Scheme F. Compounds of the formula F4 were prepared from compounds of the formula F2, where LG represents a Cl or Br, and F3. Compounds of the formula F2 were prepared from compounds of the formula F1 upon treatment with an oxidizing agent such as m-CPBA in a solvent such as CH2C^.
Scheme G
Figure imgf000039_0001
G1 G2 G3
Figure imgf000039_0002
G4 G5
NaBr/oxone
Figure imgf000039_0003
Intermediates of the formula G7 were prepared according to Scheme G. Compounds of the formula G3 were synthesized from compounds of the formula G1 and compounds of the formula G2 using solvents such as Et2O, THF, CH2Cb, or dioxane and the like. One skilled in the art will recognize G1 as a Weinreb amide (Nahm, S. et al., Tet. Lett., 1981 , 22, 3815-3818) and G2 as a Grignard reagent. Compounds of the formula G4 were obtained from compounds of the formula G3 by partial reduction with hydride donors such as NaBH4 in alcoholic solvents such as MeOH, EtOH or i-PrOH and the like followed by further reduction using H2 in the presence of a hydrogenation catalyst such as Pd/C, PtO2 or Pd(OH)2 and the like at pressures up to 60 psi and temperatures ranging from rt to 60 0C in solvents such as MeOH, EtOH or i-PrOH and the like. The Boc protecting group in compounds of the formula G2 was exchanged for a trifluoroacetamide as shown in compounds of the formula G5 by treatment with acids such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH2CI2, EtOAc, THF, 1 ,4-dioxane, MeOH or EtOH. Treatment of the intermediate from this reaction with trifluoroacetic anhydride
(TFAA) in the presence of a base such as pyridine, thethylamine or diisopropylethylamine or the like in a solvent such as CH2CI2, THF, DMF, MeOH, EtOH or the like yields compounds of the formula G5. Treatment of compounds of the formula G5 with an electrophilic bromine source such as Br2, NBS, NaBr/oxone or chlorine source such as Cl2, KCI/oxone or NCS and the like in a solvent such as MeOH, CH2CI2, EtOH, DMF, acetone, H2O and the like or mixtures there of produces compounds of the formula G6. Treatment of compounds of the formula G6 with a reagent such as LiI in collidine, HBr in AcOH, or preferrably BBr3 in CH2CI2, produces compounds of the formula G7.
Scheme H
Figure imgf000040_0001
H4 H6
Intermediates of the formula H6 were prepared according to Scheme H. Compounds of the formula H3 were obtained from compounds of the formula C3 upon treatment with compounds of the formula H1 , representing an alkyl chloride, bromide, iodide, mesylate or tosylate in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3. Alternatively, compounds of the formula H3 may also be obtained from compounds of the formula H2 when X is OH using PPh3 or similar thalkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-te/t-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH2CI2 and the like. One skilled in the art will recognize this as a Mitsunobu reaction. The transformation when X is OH may also be performed using cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH3 when heated in a microwave reactor at temperatures up to 120 0C. When R5 is a substituted aryl or heteroaryl, compounds of the formula H3 were obtained using Cu(OAc)2 and base such as pyridine or Et3N and the like in the presence of dehydrating agents such as MgSO4 or 4 A molecular sieves.
Compounds such as H6 were prepared from compounds of the formula H4 using methods such as reductive amination or alkylation. Thus treatment of H4 with a compound of formula H5 containing a carbonyl in the presence of a reductant such as NaBH4, NaBH3CN, NaBH(OAc)3 or hydrogen gas in the presence of a catalyst in a solvent such as CH2CI2, THF, DCE, MeOH, EtOH or similar afforded compounds of the formula H6. One skilled in the art will recognize that the presence of Bronsted or Lewis acids may be required. Examples of acids may include AcOH, Ti(O-iPr)4, trifluoroacetic acid or hydrochloric acid and the like. One skilled in the art will also recognize that compounds of the formula H6 may be obtained from H4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3. It will be generally recognized that compounds of the formula H6 represent a subset of compounds of the formula H4 where Ri is equal to H. Compounds of the formula H4 or H6 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.
Scheme I
BH3Me2S, LiAIH4
R 10
-.0 or CICO2Me then LiBH4
R 10 .OH
OH
R >10 _ =substituted aryl or heteroaryl R >10 _ =substituted aryl or heteroaryl
R 1 H
Figure imgf000042_0001
R11 =Me, CH2CH3, CH2F R11 =Me, CH2CH3, CH2F R12=substituted aryl or heteroaryl R12=substituted aryl or heteroaryl
Figure imgf000042_0002
R13 =substituted aryl or heteroaryl R13 =substituted aryl or heteroaryl
R14=alkyl or H
Intermediates of the formula H1 were prepared according to Scheme I when not commercially available.
Scheme J
Figure imgf000042_0003
J4
Intermediates of the formula J4 were prepared according to Scheme J. Compounds of the formula J4 were prepared from compounds of the formula J1 and compounds of the formula J3 (prepared as in Scheme A) using cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH3 when heated in a microwave reactor at temperatures up to 120 0C. In this reaction scheme, the preferred protecting group, P1 is a benzhydryl group. Alternatively, compounds of the formula J4 were also synthesized from compounds of the formula D1 (Scheme D). Treatment of a compound of formula D1 with a nucleophile such as a compound of formula J3 in the presence of base such as pyridine, thethylamine, diisopropylamine, K2CO3, CS2CO3 or Na2CO3 in a suitable solvent such as THF, CH2CI2, DMF, MeCN, 1 ,4-dioxane or the like at a temperature ranging from rt to 100 0C provided compounds of the formula J4.
Scheme K
Figure imgf000043_0001
Intermediates of the formula K4 were prepared according to Scheme K. The variable Rn in the formulas depicted in Scheme K are -H or -Ci-4alkyl. The variable Z in the formulas depicted in Scheme K are as defined above in reference to Formula (I) except Z cannot be -C(O)- in Scheme K. Compounds of the formula K2 were obtained from compounds of the formula K1 and compounds of the formula A4 in the presence of cyanomethylene-tri-n- butylphosphine in a solvent such as PhCH3 when heated in a microwave reactor at temperatures up to 120 0C. Alternatively, when the protecting group on nitrogen was a benzhydryl as in compounds of the formula K3 compounds of the formula K4 were obtained using similar conditions. Scheme L
Figure imgf000044_0001
L3 L4
Intermediates of the formula L4 were prepared according to Scheme L. The variable Z in the formulas depicted in Scheme L are as defined above in reference to Formula (I) except Z cannot be -C(O)- in Scheme L. The amine in compounds of the formula L3 may be protected, as indicated by P1, as discussed previously. Compounds of the formula L3 were prepared from compounds of the formula L2 and compounds of the formula C1 in the presence of base such as pyridine, triethylamine, diisopropylamine, K2CO3, Cs2CO3 or Na2CO3 in a suitable solvent such as THF, CH2CI2, DMF, MeCN, 1 ,4-dioxane or the like at a temperature ranging from rt to 100 0C. Compounds of the formula L2 were prepared from compounds of the formula L1 by treatment with a chlorinating agent such as SOCI2 in a solvent such as CH2CI2. Compounds of the formula L1 were prepared from compounds of the formula A4 using a reducing agent such as NaBH4, LiBH4, Dibal-H, LiAIH4 and the like in a solvent such as CH2CI2, THF, DCE, MeOH or EtOH and the like. Scheme M
Figure imgf000045_0001
M1 M3
Figure imgf000045_0002
M4 M5
Intermediates of the formula M5 were prepared according to Scheme M. The variable Z in the formulas depicted in Scheme M are as defined above in reference to Formula (I) except Z cannot be -C(O)- in Scheme M. Compounds of the formula M4 may be prepared from compounds of the formula M3 and compounds of the formula C1 using a base such as NaH and the like in a solvent such as THF, DMF, NMP or DMSO at temperatures up to 145 0C in a microwave reactor. Compounds of the formula M3 may be prepared from compounds of the formula M1 and compounds of the formula M2 using a base such as NaH and the like in a solvent such as THF, DMF, NMP or DMSO and the like.
Compounds of the formula M5 may be obtained from compounds of the formula M4 by removal of the P1 group. The amine in compounds of the formula M4 may be protected, as indicated by P1, as described previously. A preferred protecting group is f-butyl carbamate (Boc) or thfluoroacetamide. It will be generally recognized that compounds of the formula M5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art. Scheme N
Figure imgf000046_0001
N4 N5
Intermediates of the formula N5 were prepared according to Scheme N. Compounds of the formula N5 may be obtained from compounds of the formula N4 by removal of the P1 group. The amine in compounds of the formula N4 may be protected, as indicated by P1, as described previously. A preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide. It will be generally recognized that compounds of the formula N5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.
Compounds of the formula N4 were prepared from compounds of the formula N2 and compounds of the formula N3 in the presence of a base such as diisopropyethylamine, Et3N or pyridine and the like upon heating in a microwave reactor at temperatures up to 145 0C. Precursors to compounds of the formula N2 were prepared from compounds of the formula N1 and bromomethyl acetate in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3. Subsequent hydrolysis using aqueous NaOH followed by formation of compounds of the formula N2 using oxalyl chloride in a solvent such as THF, CH2CI2 or PhCH3 in the presence of a catalytic amount of DMF provided compounds of the formula N2.
Scheme O
Figure imgf000047_0001
Intermediates of the formula 06 were prepared according to Scheme O. The amine in compounds of the formula 05 may be protected, as indicated by P1 as described previously. A preferred protecting group is f-butyl carbamate (Boc) or thfluoroacetamide. Compounds of the formula 06 were obtained from compounds of the formula 05 by removal of the P1 group. It will be generally recognized that compounds of the formula 06 may be converted to their corresponding salts using methods generally accepted to those skilled in the art. Compounds of the formula 05 were prepared form compounds of the formula 03 and compounds of the formula 04 using a base such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3 in solvents such as MeOH, EtOH or iPrOH. Compounds of the formula 03 were prepared from compounds of the formula C3 and compounds of the formula 02 by heating the mixture up to 100 0C in a microwave reactor in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3. Compounds of the formula 02 were obtained by bromination of compounds of the formula 01 using (Bu)N4Br3 (TBABr3) in a solvent mixture of MeOH and CH2CI2.
Scheme P
Figure imgf000048_0001
03 P1
Intermediates of the formula P1 were prepared according to Scheme P. Compounds of the formula P1 were synthesized from compounds of the formula 03 using a hydride donor such as Et3SiH in the presence of an acid such as trifluoroacetic acid in a solvent such as DCE or CH2CI2.
Scheme Q
Figure imgf000049_0001
C2
oxidation
Figure imgf000049_0002
aldehyde or ketone
Figure imgf000049_0003
Q5
Intermediates of the formula Q5 were prepared according to Scheme Q. Compounds of the formula Q3 were prepared from compounds of the formula Q2 by oxidation with an oxidant such as the Dess-Martin pehodinane in a solvent such as CH2C^. Compounds of the formula Q2 were prepared from compounds of the formula C2 (Scheme C) and compounds of the formula Q1 in solvents such as Et2O, THF, CH2CI2, or dioxane and the like.
Compounds of the formula Q4 may be obtained from compounds of the formula Q3 by removal of the P1 group. The amine in compounds of the formula Q3 may be protected, as indicated by P1 as described previously. A preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide. It will be generally recognized that compounds of the formula Q4 represent a subset of compounds of the formula Q5 where Re is equal to H. Compounds of the formula Q4 or Q5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.
Compounds such as Q5 were prepared from compounds of the formula Q4 using methods such as reductive amination or alkylation. Thus treatment of Q4 with a compound containing a carbonyl in the presence of a reductant such as NaBH4, NaBH3CN, NaBH(OAc)3 or hydrogen gas in the presence of a catalyst in a solvent such as CH2CI2, THF, DCE, MeOH, EtOH or similar afforded compounds of the formula Q5. One skilled in the art will recognize that the presence of Bronsted or Lewis acids may be required. Examples of acids may include AcOH, Ti(O-iPr)4, trifluoroacetic acid or hydrochloric acid and the like. One skilled in the art will also recognize that compounds of the formula Q5 may be obtained from Q4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3.
Scheme R
alkyl)
Figure imgf000050_0001
alkyl) remove P
Figure imgf000050_0002
Intermediates of the formula R3 were prepared according to Scheme R. Compounds of the formula R2 were synthesized from compounds of the formula R1 (prepared as outlined in Scheme G) using an oxidant such as m- CPBA in a solvent such as CH2CI2. Compounds of the formula R3 may be obtained from compounds of the formula R2 by removal of the P1 group. The amine in compounds of the formula R2 may be protected, as indicated by P1 as described previously. A preferred protecting group is f-butyl carbamate (Boc) or trifluoroacetamide.
Scheme S
Figure imgf000051_0001
S3 S4
Intermediates of the formula S4 were prepared according to Scheme S. Compounds of the formula S2 were obtained from compounds of the formula S1 by bromination using NBS in the presence of AIBN in solvents such as CCI4 at refluxing temperatures. Compounds of the formula S3 were obtained from compounds of the formula N1 and compounds of the formula S2 in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or CS2CO3 followed by a work-up with neutral H2O. A preferred protecting group on compounds of the formula N1 was Boc. Scheme T
Figure imgf000052_0001
T1 T2
Intermediates of the formula T2 were prepared according to Scheme T. Compounds of the formula T1 were obtained from compounds of the formula N1 and compounds of the formula S2 in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO3, Na2CO3, K2CO3 or Cs2CO3 followed by a work-up with basic H2O where the pH was > 10. A preferred protecting group on compounds of the formula N1 was Boc.
Scheme U
Figure imgf000052_0002
Intermediates of the formula U2 were prepared according to Scheme U. Compounds of the formula U2 were prepared from compounds of the formula U1 using reducing agents such as Dibal-H in solvents such as CH2CI2, THF or PhCH3 and the like.
Scheme V
Figure imgf000053_0001
H
V3
Intermediates of the formula V3 were prepared according to Scheme V. Compounds of the formula V2 were prepared from compounds of the formula V1 using reducing agents such as LiBH4 and the like in solvents such as CH2Cb, THF or PhCH3 and the like. Compounds of the formula V3 were prepared from compounds of the formula V2 using acids such as thfluoroacetic acid or hydrochloric acid and the like in a solvent such as CH2CI2, EtOAc, THF, 1 ,4-dioxane, MeOH or EtOH.
Scheme W
Figure imgf000054_0001
H
W2
Intermediates of the formula W2 were prepared according to Scheme W. Compounds of the formula W1 were prepared from compounds of the formula V1 by hydrolysis using aqueous hydroxide bases such as NaOH or KOH and the like with an organic co-solvent such as THF or MeOH. A preferred protecting group on compounds of the formula V1 was Boc.
Scheme X
Figure imgf000055_0001
H
X4
Intermediates of the formula X4 were prepared according to Scheme X. A preferred protecting group on compounds of the formula X1 was Boc. Compounds of the formula X3, were prepared from compounds of the formula X1 and compounds of the formula X2 by heating in a microwave reactor at temperatures up to 170 0C in the presence of Hermann's catalyst, Mo(CO)6 and bases such as Na2CO3 and the like.
Scheme Y
Figure imgf000055_0002
H Y3 Intermediates of the formula Y3 were prepared according to Scheme Y. A preferred protecting group on compounds of the formula X1 was Boc. Compounds of the formula Y2, were prepared from compounds of the formula X1 by treatment with compounds of the formula Y1 in the presence of a catalyst such as PdCI2(dppf), PdCI2(dppe) Pd2(dba)3, Pd(dba)2, PdCI2(PPh3)2,
Pd(PPh3)4 in a solvent such as PhCH3, 1 ,4-dioxane, THF, DMA, DMF or DME in the presence of a base such as Na2CO3, K2CO3, Cs2CO3, CsF, KF, K3PO4, KOAc or the like and a ligand typically used in such reactions such as Q-Phos, dppf, dppe or PPh3 and the like at temperatures ranging from rt to 160 0C using conventional or microwave heating.
Examples Chemistry
In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.
Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt). Where solutions were "dried," they were generally dried over a drying agent such as Na2SO4 or MgSO4 then filtered and concentrated. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure.
Thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 2.5 cm x 7.5 cm 250 μm or 5.0 cm x 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography (PTLC) was performed using EM Science silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone.
Normal-phase flash column chromatography (FCC) was performed on silica gel (SiO2) eluting with 2 M NH3 in MeOH/CH2CI2 or EtOAc in hexanes, unless otherwise noted. Preparative reversed-phase HPLC (RP HPLC) was performed on a
Hewlett Packard HPLC Series 1100, with a Phenomenex Luna C18 (5 μm, 4.6x150 mm) column. Detection was done at λ = 230, 254 and 280 nm. The gradient was 10 to 99% acetonithle/H2O (0.05% thfluoroacetic acid) over 5.0 min with a flow rate of 1 mL/min. Alternatively, HPLC was performed on a Dionex APS2000 LC/MS with a Phenomenex Gemini C18 (5 μm, 30 x 100 mm) column, and a gradient of 5 to 100% acetonitrile/H2O (20 mM NH4OH) over 16.3 min, and a flow rate of 30 mL/min. Preparative RP HPLC was also performed on an Agilent 1100 preparative system with a Waters X-Bridge C18 (5 μm, 30 x 100 mm) column, and a gradient of 5 to 99% acetonitrile/H2O (20 mM NH4OH) over 17 min, and a flow rate of 80 mL/min.
Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the 1H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference or relative to residual protic solvent (multiplicity, coupling constant J in Hz, integration). Chemical names were generated using ChemDraw Version 6.0.2
(CambridgeSoft, Cambridge, MA).
General Procedures
General Procedure 1 (Removal of Boc groups): Boc groups were deprotected using TFA/CH2CI2 (1 :1 ) or 4M HCI in dioxane/EtOAc (1 :1 ). The compounds were then either neutralized and extracted with CH2CI2 or characterized as the hydrochloride or trifluoroacetate salt where indicated.
General Procedure 2 (Removal of trifluroacetamide groups): Trifluoroacetamide groups were deprotected using K2CO3 (1 eq.) in MeOH (0.2 M), 2M NH3 in MeOH or 5N NH4OH (aq.) in MeOH. After 15h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were dried and concentrated. Purification using silica gel chromatoraphy, reverse-phase HPLC or PTLC then provided the deprotected amines.
General Procedure 3 (Reductive amination): To amine in CH2CI2 (0.1 M) was added ketone (1.2-5.0 eq.) and NaBH(OAc)3 (1.2 eq.). After 18h, the reaction was typically treated with 5% Na2CO3 (aq.) and extracted with CH2CI2 (2X). The combined organics were dried and purified using silica gel chromatography, reverse-phase HPLC or PTLC.
General Procedure 4 (Reductive amination): To amine in MeOH (0.1 M) was added ketone or aldehyde (1.2-5.0 eq.), AcOH (10 mol%) and NaCNBH3 (1.2 eq.). After 18h, the reaction was typically treated with 5% Na2CO3 (aq.) and extracted with CH2CI2 (2X). The combined organics were dried and purified using silica gel chromatography, reverse-phase HPLC or PTLC.
General Procedure 5 (NH to NMe): To amine in MeOH (0.1 M) was added excess 37 wt% [H2CO]n in H2O and NaBHOAc3 (1.2 eq.). After 18h, 5% Na2CO3 (aq.) was added and the mixture extracted with CH2CI2. The combined organics were dried and purified using silica gel chromatography, reverse- phase HPLC or PTLC to yield the corresponding methylated analogs.
General Procedure 6 (Cu(OAc)2-mediated diaryl ether synthesis): To a phenol in DCE (0.1 M) was added arylboronic acid (2 eq.), Cu(OAc)2 (1 eq.), MgSO4 (2 eq) or 4A molecular sieves and Et3N (5 eq). The reactions were allowed to stir open to the air for 12-48h, then filtered, concentrated and purified using silica gel chromatography, reverse-phase HPLC or PTLC.
General Procedure 7 (Mitsunobu Reaction): To phenol (1 eq), alcohol (1 eq) and either PPh3 (1.2 eq) or resin-bound PPh3 in THF (0.2 M) at 0 0C or rt was added DEAD (1.1 eq) dropwise. After judged complete, the reactions were concentrated and purified using silica gel chromatography, reverse phase HPLC or PTLC.
Example 1 : 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine.
Figure imgf000058_0001
Step A: Preparation of (4-bromo-2-fluoro-benzylidene)-tert-butyl-amine. To a CH2CI2 (900 ml_) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g, 246 mmol) was added tert-butylamine (42.3 ml_, 29.3 g, 400 mmol) and MgSO4 (60.0 g, 499 mmol). After 48h, the solution was filtered and concentrated to give 62.0 g (98%) of the title compound as a yellow liquid. 1H NMR (CDCI3): 8.48 (s, 1 H), 7.89 (t, J = 8.1 Hz, 1 H), 7.32-7.25 (m, 2H), 1.29 (s, 9H).
Step B: Preparation of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester. To a 0 0C DMF (720 ml_) solution of the title compound of Step A (37.2 g, 144 mmol) and 3-hydroxy-azetidine-i-carboxylic acid tert-butyl ester (25.0 g, 144 mmol) was added NaH (60 wt% in mineral oil, 7.50 g, 188 mmol) portionwise over 2h. The reaction was then allowed to warm to rt. After 18h, H2O was added and the reaction mixture was extracted with EtOAc (2X). The combined organic layers were washed with brine and concentrated to give a yellow liquid that was treated with THF (360 ml_), H2O (360 ml_) and AcOH (25 ml_). After 5h, this solution was made basic with 5% Na2CO3 (aq.) and extracted with EtOAc (2X). The combined organic layers were washed with brine and dried. The resulting solid was then triturated with 20% EtOAc in hexanes to give 41.9 g (82%) of the title compound as a white solid. 1H NMR (CDCI3): 10.43 (s, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.26-7.23 (m, 1 H), 6.77 (d, J = 1.6 Hz, 1 H), 5.01 -4.95 (m, 1 H), 4.39 (ddd, J = 9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J = 6.4, 0.8 Hz, 2H), 1.46 (s, 9H).
Step C: Preparation of 3-(5-Bromo-2-hvdroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester. To a CH2CI2 (280 ml_) solution of the title compound of Step B (24.7 g, 69.4 mmol) was added 77% m-CPBA (23.3 g, 104 mmol). After 15h, 10% Na2S2O5 (aq.) was added and the solution allowed to stir until the aqueous was Kl paper negative then extracted with CH2CI2 (2X). The combined organic layers were washed with saturated NaHCO3 (aq.), concentrated and treated with MeOH (220 ml_) and 1 N NaOH (220 ml_). After 15h, the reaction was partially concentrated to remove the MeOH, acidified with 1 M KHSO4 (220 ml_) and extracted with CH2CI2 (2X). The combined organic layers were washed with brine and dried providing a brown solid that was triturated with EtOAc/hexanes giving 17.6 g (74%) of the title compound as a white solid. 1H NMR (CDCI3): 7.03 (dd, J = 8.5, 2.1 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 6.64 (d, J = 2.2 Hz, 1 H), 4.93-4.89 (m, 1 H), 4.34 (dd, J = 10.1 , 6.8 Hz,
1 H), 4.03 (dd, J = 9.9, 3.7 Hz, 1 H), 1.46 (s, 9H).
Step D: Preparation of 3-(2-benzyloxy-5-bromo-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester. To a DMF (10 ml_) solution of the title compound of Step C (0.52 g, 1.5 mmol), Cs2CO3 (0.54 g, 1.7 mmol) and Kl
(0.20 g, 1.20 mmol) was added benzyl bromide (0.20 ml_, 0.29 g, 1.7 mmol).
After 48h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine (2X) and dried. Silica gel chromatography (5-20% EtOAc in hexanes) gave 0.65 g (99%) of the title compound as a clear oil. 1H NMR (CDCI3): 7.42-7.36 (m, 3H), 7.34-7.31 (m,
2H), 7.03 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.70 (d, J = 2.3 Hz,
1 H), 5.09 (s, 2H), 4.88-4.83 (m, 1 H), 4.26 (ddd, J = 9.7, 6.5, 0.9 Hz, 2H), 4.05
(dd, J = 9.8, 4.0 Hz, 2H), 1.45 (s, 9H).
Step E: Preparation of 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine. Synthesized according to general procedure 1 from the title compound of Step
D. MS (ESI): mass calcd. for Ci6Hi6BrNO2, 333.0; m/z found, 334.0 [M+H]+.
1H NMR (CDCI3): 7.08 (dd, J = 8.6, 2.3 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1 H), 6.67
(d, J = 2.2 Hz, 1 H), 4.86 (tt, J = 6.5, 4.3 Hz, 1 H), 4.29 (ddd, J = 9.7, 6.5, 0.8 Hz,
2H), 4.08 (dd, J = 10.1 , 4.2 Hz, 2H), 3.85 (s, 3H), 1.44 (s, 9H).
Unless otherwise specified the compounds in Examples 2-74 were prepared similar to Example 1 using the appropriately substituted phenol and alkyl halide.
Example 2: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000060_0001
MS (ESI): mass calcd. for Ci6Hi5BrCINO2, 367.0; m/z found, 368.1 [M+H]+. 1H NMR (CDCI3): 7.47-7.43 (m, 1 H), 7.31 -7.27 (m, 3H), 7.00 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78-6.73 (m, 2H), 5.06 (s, 2H), 5.01 -4.95 (m, 1 H), 3.94-3.83 (m, 4H). The compounds in Examples 3-6 were prepared from the title compound of Example 2 using general procedure 3 or 4.
Example 3: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -cyclobutyl-azetidine.
Figure imgf000061_0001
(ESI): mass calcd. or N Cl
MS r C20H2IBrCINO2, 422.7; m/z found, 423.9 [M+H]+. 1H NMR (CDCI3): 7.43 (s, 1 H), 7.32-7.26 (m, 3H), 6.98 (dd, J = 8.5, 2.3 Hz, 1 H), 6.75 (dd, J = 13.6, 5.4 Hz, 2H), 5.05 (s, 2H), 4.77-4.72 (m, 1 H), 3.78-3.65 (m, 2H), 3.12-3.16 (m, 3H), 2.01 -1.95 (m, 2H), 1.87-1.79 (m, 2H), 1.78-1.69 (m, 2H).
Example 4: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -propyl-azetidine.
Figure imgf000061_0002
MS (ESI): mass calcd. for Ci9H2i BrCINO2, 410.7; m/z found, 411.9 [M+H]+.
1H NMR (CDCI3): 7.44 (s, 1 H), 7.33-7.27 (m, 3H), 7.02-6.95 (m, 1 H), 6.76 (dd, J = 13.4, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.74 (m, 1 H), 3.88-3.80 (m, 2H), 3.14- 3.06 (m, 2H), 2.52-2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).
Example 5: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -isopropyl-azetidine.
Figure imgf000061_0003
MS (ESI): mass calcd. for Ci9H2i BrCINO2, 410.7; m/z found, 411.9 [M+H]+. 1H NMR (CDCI3): 7.44 (s, 1 H), 7.32-7.27 (m, 3H), 6.99 (dd, J = 8.6, 2.3 Hz, 1 H), 6.79 (d, J = 2.3 Hz, 1 H), 6.75 (d, J = 8.6 Hz, 1 H), 4.98 (s, 2H), 4.75-4.70 (m, 1 H), 3.88-3.71 (m, 2H), 3.15-2.94 (m, 2H), 2.43-2.38 (m, 1 H), 0.99-0.95 (m, 6H).
Example 6: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -ethyl-azetidine.
Figure imgf000062_0001
MS (ESI): mass calcd. for Ci8Hi9BrCINO2, 396.7; m/z found, 397.0 [IvRH]+. 1H NMR (CDCI3): 7.44 (d, J = 1.8, 1 H), 7.35-7.26 (m, 3H), 6.99 (dd, J = 8.6, 2.3 Hz, 1 H), 6.76 (dd, J = 14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.73 (m, 1 H), 3.873.79 (m, 2H), 3.11-3.08 (m, 2H), 2.55 (q, J = 7.2, 2H), 1.00 (t, J = 7.2 Hz, 3H).
Example 7: 3-r5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy1-azetidine.
Figure imgf000062_0002
MS (ESI): mass calcd. for Ci7Hi5BrF3NO3, 417.0; m/z found, 418.1
[M+H]+. 1H NMR (CDCI3): 7.40 (t, J = 8.1 Hz, 1 H), 7.34-7.33 (m, 2H), 7.18-7.16 (m, 1 H), 7.00 (dd, J = 8.6, 2.3 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 5.10 (s, 2H), 5.01-4.96 (m, 1 H), 3.93-3.86 (m, 4H).
Example 8: 3-[5-Bromo-2-(3-tπfluoromethyl-benzyloxy)-phenoxy1-azetidine.
Figure imgf000062_0003
MS (ESI): mass calcd. for Ci7Hi5BrF3NO2, 401.0; m/z found, 401.9 [M+H]+. 1H NMR (CDCI3): 7.75 (s, 1 H), 7.60 (t, J = 7.2 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1 H), 7.02 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.74 (d, J = 2.3 Hz, 1 H), 5.14 (s, 2H), 5.01-4.95 (m, 1 H), 3.93-3.86 (m, 4H).
Example 9: 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethvπ-benzonitrile.
Figure imgf000063_0001
1H NMR (CDCI3): 7.78 (s, 1 H), 7.67-7.61 (m, 2H), 7.50 (t, J = 7.7 Hz, 1 H), 7.01 (dd, J = 8.6, 2.3 Hz, 1 H), 6.76 (d, J = 8.6 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 5.12 (s, 2H), 5.02-4.96 (m, 1 H), 3.95-3.86 (m, 4H).
Example 10: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000063_0002
MS (ESI): mass calcd. for Ci5Hi3BrF3NO3, 391.0; m/z found, 392.1 [M+H]+. 1H NMR (CDCI3): 7.03 (dd, J = 8.6, 2.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.79-6.76 (m, 1 H), 6.74 (d, J = 2.3 Hz, 1 H), 6.47 (d, J = 3.3 Hz, 1 H), 5.06 (s, 2H), 5.00-4.93 (m, 1 H), 3.96-3.89 (m, 2H), 3.88-3.79 (m, 2H).
Example 11 : 3-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy1- azetidine.
Figure imgf000063_0003
MS (ESI): mass calcd. for Ci7Hi4BrCIF3NO3, 451.0; m/z found, 452.0 [M+H]+. 1H NMR (CDCI3): 7.62-7.59 (m, 2H), 7.35-7.32 (m, 2H), 7.02 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 6.74 (d, J = 2.3 Hz, 1 H), 5.06 (s, 2H), 5.03-4.96 (m, 1 H), 3.98-3.91 (m, 2H), 3.89-3.83 (m, 2H). Example 12: 3-r5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000064_0001
MS (ESI): mass calcd. for Ci6Hi4BrCIFNO2, 385.0; m/z found, 386.1 [M+H]+. 1H NMR (CDCI3): 7.52 (dd, J = 7.0, 2.1 Hz, 1 H), 7.31 -7.25 (m, 1 H), 7.15 (dd, J = 8.7, 8.6 Hz, 1 H), 7.01 (dd, J = 8.6, 2.3 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 5.03 (s, 2H), 5.01-4.95 (m, 1 H), 3.99-3.91 (m, 2H), 3.90-3.81 (m, 2H).
Example 13: 3-r5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy1- azetidine.
Figure imgf000064_0002
MS (ESI): mass calcd. for Ci7Hi7BrCINO3, 397.0; m/z found, 398.1 [M+H]+. 1H NMR (CDCI3): 7.48 (d, J = 2.1 Hz, 1 H), 7.29-7.25 (m, 1 H), 7.02 (dd, J = 8.6, 2.3 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 5.01 (s, 2H), 5.00-4.94 (m, 1 H), 3.96-3.83 (m, 4H), 3.92 (s, 3H).
Example 14: 3-r5-Bromo-2-(4-chloro-benzyloxy)-phenoxy1-azetidine trifluoroacetate.
Figure imgf000064_0003
MS (ESI): mass calcd. for Ci6Hi5BrCINO2, 367.00; m/z found, 368.1 [M+H]+. 1H NMR (CDCI3): 7.41 -7.30 (m, 4H), 7.12 (dd, J = 8.7, 2.3 Hz, 1 H), 6.87 (d, J = 2.3 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 5.06-4.99 (m, 3H), 4.31 -4.13 (m, 4H).
Example 15: 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy1-azetidine trifluoroacetate.
Figure imgf000065_0001
MS (ESI): mass calcd. for Ci6Hi5BrCINO2, 367.0; m/z found, 368.1 [M+H]+. 1H NMR (CDCI3): 7.46 (dd, J = 5.5, 3.8 Hz, 1 H), 7.41 (dd, J = 5.6, 3.7 Hz, 1 H), 7.32-7.27 (m, 2H), 7.13 (dd, J = 8.7, 2.2 Hz, 1 H), 6.89 (d, J = 2.3 Hz, 1 H), 6.83 (d, J = 8.7 Hz, 1 H), 5.14 (s, 2H), 5.07-4.99 (m, 1 H), 4.26-4.21 (m, 4H).
Example 16: 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy1-1 -methyl-azetidine.
Figure imgf000065_0002
Synthesized from the title compound of Example 15 according to general procedure 5. MS (ESI): mass calcd. for Ci7Hi7BrCINO2, 381.0; m/z found, 382.1 [M+H]+. 1H NMR (CDCI3): 7.59-7.51 (m, 1 H), 7.39 (dd, J = 7.4, 1.7 Hz, 1 H), 7.32-7.23 (m, 2H), 7.00 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78 (dd, J = 5.4, 3.1 Hz, 2H), 5.19 (s, 2H), 4.78-4.73 (m, 1 H), 3.92-3.78 (m, 2H), 3.21 -3.11 (m, 2H), 2.42 (s, 3H).
Example 17: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-azetidine trifluroacetate.
Figure imgf000065_0003
MS (ESI): mass calcd. for Ci6Hi5BrFNO2, 351.0; m/z found, 352.1 [M+H]+. 1H NMR (CDCI3): 7.36 (dt, J = 7.9, 5.9 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.13-7.08 (m, 2H), 7.03 (dt, J = 8.4, 2.1 Hz, 1 H), 6.86 (d, J = 2.2 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 5.04 (s, 3H), 4.29-4.22 (m, 4H).
The compounds in Examples 18-21 were prepared from the title compound of Example 17 using general procedure 3 or 4.
Example 18: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -ethyl-azetidine.
Figure imgf000066_0001
MS (ESI): mass calcd. for Ci8Hi9BrFNO2, 380.3; m/z found, 381.1 [M+H]+. 1H NMR (CDCI3): 7.35-7.31 (m, 1 H), 7.17-7.15 (m, 2H), 7.00-6.97 (m, 2H), 6.76 (dd, J = 16.1 , 5.4 Hz, 2H), 5.08 (s, 2H), 4.78-4.74 (m, 1 H), 3.85-3.82 (m, 2H), 3.13-3.05 (m, 2H), 2.57-2.53 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).
Example 19: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -propyl-azetidine.
Figure imgf000066_0002
MS (ESI): mass calcd. for Ci9H2i BrFNO2, 394.3; m/z found, 395.1 [M+H]+. 1H NMR (CDCI3): 7.34-7.21 (m, 1 H), 7.15-7.13 (m, 2H), 7.02-6.92 (m, 2H), 6.74 (dd, J = 14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.76-4.72 (m, 1 H), 3.85-3.77 (m, 2H), 3.11 -3.04 (m, 2H), 2.46 (dd, J = 8.8, 6.0 Hz, 2H), 1.43-1.32 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). Example 20: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -isopropyl-azetidine.
Figure imgf000067_0001
MS (ESI): mass calcd. for Ci9H2IBrFNO2, 394.3; m/z found, 395.1 [M+H]+. 1H NMR (CDCI3): 7.34-7.30 (m, 1 H), 7.18-7.12 (m, 2H), 7.02-6.94 (m, 2H), 6.80-6.71 (m, 2H), 5.07 (s, 2H), 4.74-4.69 (m, 1 H), 3.85-3.78 (m, 2H), 3.12-3.06 (m, 2H), 2.43-2.36 (m, 1 H), 0.96 (d, J = 6.2 Hz, 6H).
Example 21 : 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1-cvclobutyl-azetidine
Figure imgf000067_0002
MS (ESI): mass calcd. for C20H2! BrFNO2, 406.3; m/z found, 407.1 [M+H]+. 1H NMR (CDCI3): 7.34-7.30 (m, 1 H), 7.19-7.09 (m, 2H), 7.04-6.87 (m, 2H), 6.75 (dd, J = 14.4, 5.4 Hz, 2H), 5.07 (s, 2H), 4.77-4.72 (m, 1 H), 3.82-3.57 (m, 2H), 3.28-2.99 (m, 3H), 2.03-1.92 (m, 2H), 1.88-1.78 (m, 2H), 1.77-1.70 (m, 2H).
Example 22: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000067_0003
MS (ESI): mass calcd. for Ci6Hi5BrCINO2, 368.7; m/z found, 369.1 [M+H]+. 1H NMR (CDCI3): 7.47 (s, 1 H), 7.33-7.29 (m, 3H), 7.06 - 6.99 (m, 2H), 6.50 (d, J = 8.4 Hz, 1 H), 5.07 (s, 2H), 5.00-4.93 (m, 1 H), 3.94-3.82 (m, 4H). Example 23: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -cyclobutyl- azetidine.
Figure imgf000068_0001
Synthesized from the title compound of Example 22 according to general procedure 3. MS (ESI): mass calcd. for C2oH2i BrCINO2, 422.7; m/z found, 423.9 [IvRH]+. 1H NMR (CDCI3): 7.46-7.41 (m, 1 H), 7.35-7.25 (m, 3H), 7.03- 6.95 (m, 2H), 6.53 (d, J = 8.6 Hz, 1 H), 5.03 (s, 2H), 4.76-4.70 (m, 1 H), 3.73- 3.65 (m, 2H), 3.22-3.10 (m, 3H), 2.02-1.90 (m, 2H), 1.88-1.57 (m, 4H).
Example 24: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -isopropyl- azetidine.
Figure imgf000068_0002
Synthesized from the title compound of Example 22 according to general procedure 3. MS (ESI): mass calcd. for Ci9H2iBrCINO2, 410.7; m/z found, 412.0 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.34-7.22 (m, 3H), 7.04-6.99 (m, 2H), 6.59-6.53 (m, 1 H), 5.04 (s, 2H), 4.74-4.68 (m, 1 H), 3.83-3.76 (m, 2H), 3.11-3.04 (m, 2H), 2.43-2.34 (m, 1 H), 0.99-0.90 (m, 6H).
Example 25: 3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy1-azetidine hydrochloride.
Figure imgf000068_0003
MS (ESI): mass calcd. for Ci6Hi5CIFNO2, 307.1 ; m/z found, 308.2 [M+H]+. 1H NMR (DMSO-D6): 9.37 (s, 2H), 7.51 (dd, J= 8.7, 5.6 Hz, 2H), 7.23 (t, J = 8.9 Hz, 2H), 7.1 (d, J = 8.7 Hz, 1 H), 7.03 (dd, J = 8.7, 2.4 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 5.11 (s, 2H), 5.08-5.02 (m, 1 H), 4.37 (dd, J = 12.5, 6.7 Hz, 2H), 3.98 (dd, J = 12.5, 5.0 Hz, 2H).
Example 26: 3-[5-Chloro-2-(3-nnethylsulfanyl-benzyloxy)-phenoxy1-azetidine.
Figure imgf000069_0001
MS (ESI): mass calcd. for Ci7Hi8CINO2S, 335.1 ; m/z found, 336.1 [M+H]+. 1H NMR (CDCI3): 7.33-7.29 (m, 2H), 7.18 (dd, J = 13.3, 7.8 Hz, 2H), 6.86-6.81 (m, 2H), 6.59 (d, J = 2.1 Hz, 1 H), 5.07 (s, 2H), 5.01 -4.95 (m, 1 H), 3.94-3.84 (m, 4H), 2.49 (2, 3H).
Example 27: S-fδ-Chloro^-O-methanesulfonyl-benzyloxyVphenoxyi-azetidine.
Figure imgf000069_0002
Step A: Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester. To the title compound of Example 26 (0.050 g, 0.10 mmol) in CH2CI2 (1 ml_) was added 77% m-CPBA (0.06 g, 0.25 mmol). After 18h, 10% Na2S2O5 (aq.) was added and the mixture extracted with CH2CI2 (2X). The combined organics were dried. Silica gel chromatography gave 0.038 g (80%) of the title compound as a clear oil. MS (ESI): mass calcd. for C22H26CINO6S, 467.1 ; m/z found, 368.1 [M-I OO]+, 490.1 [M+Na]+. 1H NMR (CDCI3): 8.03 (s, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 6.91 (dd, J = 8.6, 2.3 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.57 (d, J = 2.3 Hz, 1 H), 5.17 (s, 2H), 4.91 -4.85 (m, 1 H), 4.31 (dd, J = 10.4, 6.4 Hz, 2H), 4.08-4.03 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H). Step B: Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)- phenoxyi-azetidine. Prepared from the title compound of Step A using general procedure 1. MS (ESI): mass calcd. for Ci7Hi8CINO4S, 367.1 ; m/z found, 368.0 [M+H]+. 1H NMR (CDCI3): 8.10 (s, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 7.7 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 6.89-6.83 (m, 2H), 6.60 (d, J = 2.1 Hz, 1 H), 5.17 (s, 2H), 5.03-4.97 (m, 1 H), 3.97-3.85 (m, 4H), 3.07 (s, 3H).
Example 28: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-2-thiophen-2-yl- thiazole.
Figure imgf000070_0001
MS (ESI): mass calcd. for Ci7Hi5CIN2O2S2, 378.0; m/z found, 379.1 [M+H]+. 1H NMR (CDCI3): 7.52 (dd, J = 3.7, 0.9 Hz, 1 H), 7.40 (dd, J = 5.0, 0.9 Hz, 1 H), 7.25 (m, 1 H), 7.08 (dd, J = 5.0, 3.7 Hz, 1 H), 6.92-6.86 (m, 2H), 6.60 (d, J = 2.3 Hz, 1 H), 5.25 (s, 2H), 5.01 -4.97 (m, 1 H), 3.95-3.85 (m, 4H).
Example 29: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-methyl- thiazole.
Figure imgf000070_0002
MS (ESI): mass calcd. for Ci7Hi5CIN2O2S, 310.1 ; m/z found, 311.2 [M+H]+. 1H NMR (CDCI3): 7.15 (d, J = 10.2 Hz, 1 H), 6.95-6.85 (m, 2H), 6.59 (d, J = 2.1 Hz, 1 H), 5.18 (d, J = 0.8 Hz, 2H), 5.00-4.95 (m, 1 H), 3.93-3.87 (m, 4H), 2.73 (s, 3H). Example 30: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-5-methyl- isoxazole.
Figure imgf000071_0001
MS (ESI): mass calcd. for Ci4Hi5CIN2O3, 294.1 ; m/z found, 295.2 [M+H]+. 1H NMR (CDCI3): 6.90 (d, J = 8.6 Hz, 1 H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2H), 4.99-4.94 (m, 1 H), 3.96-3.89 (m, 2H), 3.87-3.80 (m, 2H), 2.43 (s, 3H).
Example 31 : 3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-phenyl1-5- methyl-[1 ,2,41oxadiazole hydrochloride.
Figure imgf000071_0002
MS (ESI): mass calcd. for Ci9Hi8CIN3O3, 371.1 ; m/z found, 372.2 [M+H]+. 1H NMR (DMSO-D6): 9.22 (s, 2H), 8.10 (s, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.7 Hz, 1 H), 7.59 (t, J = 7.7 Hz, 1 H), 7.13 (d, J = 8.7 Hz, 1 H), 7.03 (dd, J = 8.7, 2.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 5.24 (s, 2H), 5.09-5.05 (m, 1 H), 4.41 (dd, J = 12.5, 6.7 Hz, 2H), 4.02 (dd, J = 12.3, 4.9 Hz, 2H), 2.67 (s, 3H).
Example 32: 3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy1-azetidine.
Figure imgf000071_0003
MS (ESI): mass calcd. for Ci7Hi5CIF3NO2, 357.1 ; m/z found, 358.0 [M+H]+. 1H NMR (CDCI3): 7.79 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.6, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 5.30 (s, 2H), 5.03-4.97 (m, 1 H),
3.96-3.85 (m, 4H). Example 33: 3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy1-azetidine.
Figure imgf000072_0001
MS (ESI): mass calcd. for Ci7Hi8CINO3, 319.1 ; m/z found, 320.2 [M+H]+. 1H NMR (CDCI3): 7.31 -7.22 (m, 1 H), 7.00-6.95 (m, 2H), 6.86-6.78 (m, 3H), 6.58 (d, J = 2.1 Hz, 1 H), 5.07 (s, 2H), 4.99-4.94 (m, 1 H), 3.94-3.82 (m, 4H), 3.80 (s, 3H).
Example 34: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-benzonitrile.
Figure imgf000072_0002
MS (ESI): mass calcd. for Ci7Hi5CIN2O2, 314.1 ; m/z found, 315.1 [M+H]+. 1H NMR (CDCI3): 7.78 (s, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 6.86 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 5.11 (s, 2H), 5.04-4.99 (m, 1 H), 3.98-3.91 (m, 2H), 3.89-3.81 (m, 2H).
Example 35: 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy1-azetidine trifluroacetate.
Figure imgf000072_0003
MS (ESI): mass calcd. for Ci6Hi5CI2NO2, 323.1 ; m/z found, 324.1
[M+H]+. 1H NMR (CDCI3): 7.46 (dd, J = 5.5, 3.8 Hz, 1 H), 7.43-7.39 (m, 1 H), 7.32-7.27 (m, 2H), 6.98 (dd, J = 8.7, 2.4 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 5.14 (s, 2H), 5.07-4.99 (m, 1 H), 4.34-4.19 (m, 4H). Example 36: 3-r5-Chloro-2-(4-chloro-benzyloxy)-phenoxy1-azetidine trifluoroacetate.
Figure imgf000073_0001
MS (ESI): mass calcd. for Ci6Hi5CI2NO2, 323.1 ; m/z found, 324.1 [M+H]+. 1H NMR (CDCI3): 7.35 (q, J = 8.6 Hz, 4H), 6.95 (dd, J = 8.7, 2.4 Hz, 1 H), 6.83 (d, J = 8.7 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 5.08-4.95 (m, 3H), 4.31 - 4.24 (m, 4H).
Example 37: 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000073_0002
MS (ESI): mass calcd. for Ci6Hi5CI2NO2, 323.1 ; m/z found, 324.1 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.32-7.27 (m, 3H), 6.85 (td, J = 8.5, 1.9 Hz, 1 H), 6.81 (dd, J = 8.6, 4.6 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 5.06 (d, J = 3.9 Hz, 2H), 5.00-4.95 (m, 1 H), 3.95-3.84 (m, 4H).
Example 38: 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl-azetidine.
Figure imgf000073_0003
Synthesized from the title compound of Example 37 according to general procedure 5. MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.32-7.27 (m, 3H), 6.84 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.63 (d, J = 2.3 Hz, 1 H), 5.06 (s, 2H), 4.74-4.69 (m, 1 H), 3.88-3.82 (m, 2H), 3.21 -3.11 (m, 2H), 2.42 (s, 3H). Example 39: S-rδ-Chloro^-O-trifluoronnethyl-benzyloxyVphenoxyi-azeticline.
Figure imgf000074_0001
MS (ESI): mass calcd. for Ci7H15CIF3NO2, 357.1 ; m/z found, 358.1 [M+H]+. 1H NMR (CDCI3): 7.74 (s, 1 H), 7.59 (t, J = 8.6 Hz, 2H), 7.50 (t, J = 7.7 Hz, 1 H), 6.87 (dd, J = 8.6, 2.2 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 1.7 Hz, 1 H), 5.13 (s, 2H), 5.01-4.96 (m, 1 H), 3.96-3.85 (m, 4H).
Example 40: 3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine.
Figure imgf000074_0002
MS (ESI): mass calcd. for Ci6H16CINO2, 289.1 ; m/z found, 290.1 [M+H]+.
1H NMR (CDCI3): 7.39 (d, J = 4.4 Hz, 4H), 7.36-7.31 (m, 1 H), 6.96 (dd, J = 8.7, 2.4 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 5.03 (s, 2H), 5.01-4.95 (m, 1 H), 4.39-4.15 (m, 4H).
Example 41 : 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy1- azetidine.
Figure imgf000074_0003
MS (ESI): mass calcd. for Ci7Hi4CI2F3NO3, 407.0; m/z found, 408.0 [M+H]+. 1H NMR (CDsOD/CDCIs): 7.61 -7.59 (m, 1 H), 7.38-7.30 (m, 2H), 6.87 (dd, J = 8.6, 2.3 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 5.06 (s, 2H), 5.03-4.93 (m, 1 H), 4.25-3.60 (m, 4H). Example 42: 3-r5-Chloro-2-(4-trifluoronnethoxy-benzyloxy)-phenoxy1-azetidine.
Figure imgf000075_0001
MS (ESI): mass calcd. for Ci7Hi5CIF3NO3, 373.1 ; m/z found, 374.0 [M+H]+. 1H NMR (CDCI3): 7.46 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.86 (dd, J = 8.6, 2.6 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 2.2 Hz, 1 H), 5.09 (s, 2H), 5.02-4.94 (m, 1 H), 4.00-3.80 (m, 4H).
Example 43: 3-r5-Chloro-2-(4-tπfluoromethyl-benzyloxy)-phenoxy1-azetidine.
Figure imgf000075_0002
MS (ESI): mass calcd. for Ci7Hi5CIF3NO2, 357.1 ; m/z found, 358.1
[M+H]+. 1H NMR (CDCI3): 7.64 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 5.15 (s, 2H), 5.02-4.94 (m, 1 H), 4.01 -3.79 (m, 4H).
Example 44: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-benzonitrile.
Figure imgf000075_0003
MS (ESI): mass calcd. for Ci7Hi5CIN2O2, 314.1 ; m/z found, 315.0 [M+H]+. 1H NMR (CDCI3): 7.68 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 6.86 (dd, J = 8.6, 2.4 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 5.15, (s, 2H), 5.04 - 4.94 (m, 1 H), 4.02-3.79 (m, 4H). Example 45: 3-[2-(2Λ-Bis-trifluoromethyl-benzyloxy)-5-chloro-phenoxy1- azetidine.
Figure imgf000076_0001
1H NMR (CDCI3, CD3OD): 8.04-7.92 (m, 2H), 7.01 (dd, J = 8.7, 2.3 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 6.84 (d, J = 2.3 Hz, 1 H), 5.36, (s, 2H), 5.20-2.11 (m, 1 H), 4.49 (dd, J = 12.4, 6.7 Hz, 2H), 4.22 (dd, J = 12.4, 5.2 Hz, 2H).
Example 46: 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy1- azetidine.
Figure imgf000076_0002
MS (ESI): mass calcd. for Ci7Hi5CIF3NO2S, 389.1 ; m/z found, 390.1 [M+H]+. 1H NMR (CDCI3): 7.67 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.86 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 5.13 (s, 2H), 5.05-4.93 (m, 1 H), 4.04-3.78 (m, 4H).
Example 47: 3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy1- azetidine.
Figure imgf000076_0003
MS (ESI): mass calcd. for Ci7Hi4CIF4NO2, 375.1 ; m/z found, 377.0 [M+H]+. 1H NMR (CDCI3): 7.77-7.70 (m, 1 H), 7.64-7.57 (m, 1 H), 7.25-7.18 (m, 1 H), 6.88 (dd, J = 8.6, 2.3 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 8.3 Hz, 1 H), 5.08 (s, 2H), 5.02-4.94 (m, 1 H), 3.98-3.90 (m, 2H), 3.87-3.80 (m, 2H). Example 48: 3-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy1- azetidine.
Figure imgf000077_0001
1H NMR (CDCI3): 7.70 (dd, J = 7.6, 7.4 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 9.8 Hz, 1 H), 6.88-6.84 (m, 2H), 6.61 (d, J = 2.0 Hz, 1 H), 5.20 (s, 2H), 5.02-4.94 (m, 1 H), 3.97-3.90 (m, 2H), 3.88-3.81 (m, 2H).
Example 49: 3-r5-Chloro-2-(4-chloro-3-trifluoronnethyl-benzyloxy)-phenoxy1- azetidine.
Figure imgf000077_0002
MS (ESI): mass calcd. for Ci7Hi4CI2F3NO2, 391.0; m/z found, 392.0 [M+H]+. 1H NMR (CDCI3): 7.73 (d, J = 6.3 Hz, 1 H), 7.63-7.58 (m, 1 H), 7.21 (dd, J = 9.4, 9.2 Hz, 1 H), 6.90-6.81 (m, 2H), 6.59 (d, J = 1.6 Hz, 1 H), 5.10-5.05 (m, 1 H), 5.08, (s, 2H), 5.05-4.95 (m, 4H).
Example 50: 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000077_0003
MS (ESI): mass calcd. for Ci6Hi4CI3NO2, 357.0; m/z found, 359.9 [M+H]+. 1H NMR (CDCI3): 7.56 (d, J = 1.8 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.24 (dd, J = 8.3, 1.9 Hz, 1 H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 5.04, (s, 2H), 5.05-5.00 (m, 1 H), 4.52-3.00 (m, 4H). Example 51 : 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl1-pyridine.
Figure imgf000078_0001
MS (ESI): mass calcd. for Ci5Hi5CIN2O2, 290.1 ; m/z found, 291.1 [M+H]+. 1H NMR (CDCI3): 8.62-8.57 (m, 1 H), 7.75-7.69 (m, 1 H), 7.55 (d, J 7.8 Hz, 1 H), 7.25-7.20 (m, 1 H), 6.85-6.82 (m, 2H), 6.60 (d, J = 1.6 Hz, 1 H), 5.24 (s, 2H), 5.09-4.94 (m, 1 H), 4.18-3.64 (m, 4H).
Example 52: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-pyridine.
Figure imgf000078_0002
MS (ESI): mass calcd. for Ci5Hi5CIN2O2, 290.1 ; m/z found, 291.1
[M+H]+. 1H NMR (CD3OD/CDCI3): 8.68-8.61 (m, 1 H), 8.53 (d, J = 4.3 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.45-7.37 (m, 1 H), 6.93-6.87 (m, 2H), 6.63-6.60 (m, 1 H), 5.13 (s, 2H), 5.04-4.94 (m, 1 H), 4.12-3.70 (m, 4H).
Example 53: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-pyridine.
Figure imgf000078_0003
MS (ESI): mass calcd. for Ci5Hi5CIN2O2, 290.1 ; m/z found, 291.1 [M+H]+. 1H NMR (CD3OD/CDCI3): 8.56-8.53 (m, 2H), 7.50-7.44 (m, 2H), 6.92- 6.86 (m, 2H), 6.66 (d, J = 2.1 Hz, 1 H), 5.18 (s, 2H), 5.09-5.01 (m, 1 H), 4.04- 3.94 (m, 2H), 3.88-3.80 (m, 2H). Example 54: 3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000079_0001
MS (ESI): mass calcd. for Ci5Hi3CIF3NO3, 347.1 ; m/z found, 348.2 [M+H]+. 1H NMR (CDCI3): 6.90-6.88 (m, 2H), 6.77-6.76 (m, 1 H), 6.60 (s, 1 H), 6.46-6.45 (m, 1 H), 5.05 (s, 2H), 4.98-4.93 (m, 1 H), 3.94-3.90 (m, 2H), 3.85- 3.82 (m, 2H).
Example 55: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-furan-2- carboxylic acid ethyl ester.
Figure imgf000079_0002
MS (ESI): mass calcd. for Ci7Hi8CINO5, 351.1 ; m/z found, 352.2 [M+H]+. 1H NMR (CDCI3): 7.13 (d, J = 3.4 Hz, 1 H), 6.89-6.85 (m, 2H), 6.58 (d, J = 1.6 Hz, 1 H), 6.50 (d, J = 3.4 Hz, 1 H), 5.08 (s, 2H), 4.98-4.93 (m, 1 H), 4.37 (q, J = 7.1 Hz, 1 H), 3.94-3.90 (m, 2H), 3.86-3.83 (m, 2H), 1.38 (t, J = 7.1 Hz, 1 H).
Example 56: 3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy1- azetidine.
Figure imgf000079_0003
1H NMR (CDsOD/CDCIs): 7.65 (s, 1 H), 7.33-7.27 (m, 2H), 6.64 (d, J =
8.7 Hz, 1 H), 6.58 (dd, J = 8.7, 2.3 Hz, 1 H), 6.37 (d, J = 2.3 Hz, 1 H), 5.03 (s, 2H), 4.71 -4.63 (m, 1 H), 3.99 (dd, J = 12.6, 6.6 Hz, 2H), 3.70 (dd, J = 12.5, 5.1 Hz, 2H), 2.84 (s, 3H). Example 57: 3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000080_0001
MS (ESI): mass calcd. for Ci6Hi4CIF2NO2, 325.1 ; m/z found, 327.1 [M+H]+. 1H NMR (CDCI3): 7.52-7.43 (m, 1 H), 6.92-6.80 (m, 4H), 6.60-6.58 (m, 1 H), 5.10 (s, 2H), 5.00-4.93 (m, 1 H), 4.11 -3.69 (m, 4H).
Example 58: (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-pyrrolidine.
Figure imgf000080_0002
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.43 (s, 1 H), 7.30-7.25 (m, 3H), 6.87-6.81 (m, 3H), 5.02 (s, 2H), 4.83-4.81 (m, 1 H), 3.23-3.17 (m, 2H), 2.99 (dd, J = 12.8, 4.7 Hz, 1 H), 2.91 (ddd, J = 11.3, 8.5, 5.5 Hz, 1 H), 2.11 -2.00 (m, 2H).
Example 59: (R)- 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-1-methyl- pyrrolidine.
Figure imgf000080_0003
Synthesized from the title compound of Example 58 according to general procedure 5. MS (ESI): mass calcd. for Ci8Hi9CI2NO2, 351.1 ; m/z found, 352.1 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.29-7.28 (m, 3H), 6.85-6.79 (m, 3H), 5.04 (s, 2H), 4.83-4.80 (m, 1 H), 2.96 (dd, J = 10.6, 6.1 Hz, 1 H), 2.80 -2.75 (m, 2H), 2.58-2.54 (m, 1 H), 2.41 (s, 3H), 2.32-2.36 (m, 1 H), 2.08-2.02 (m, 1 H). Example 60: (R)- 3-r5-Chloro-2-(2-chloro-benzyloxy)-phenoxy1-pyrrolidine.
Figure imgf000081_0001
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.56-7.54 (m, 1 H), 7.39-7.37 (m, 1 H), 7.30-7.24 (m, 2H), 6.88-6.86 (m, 3H) 5.15 (s, 2H), 4.84-4.82 (m, 1 H), 3.23-3.16 (m, 2H), 2.98 (dd, J = 12.8, 4.6 Hz, 1 H), 2.90 (ddd, J = 11.3, 8.5, 5.5 Hz, 1 H), 2.12-2.00 (m, 2H).
Example 61 : (R)- 3-r5-Chloro-2-(2-chloro-benzyloxy)-phenoxy1-1-methyl- pyrrolidine.
Figure imgf000081_0002
Synthesized from the title compound of Example 60 according to general procedure 5. MS (ESI): mass calcd. for Ci8Hi9CI2NO2, 351.1 ; m/z found, 352.1 [M+H]+. 1H NMR (CDCI3): 7.60-7.58 (m, 1 H), 7.38-7.37 (m, 1 H), 7.29-7.23 (m, 2H), 6.85-6.82 (m, 3H) 5.17 (s, 2H), 4.85-4.81 (m, 1 H), 2.95 (dd, J = 10.6, 6.1 Hz, 1 H), 2.78 -2.73 (m, 2H), 2.57-2.53 (m, 1 H), 2.39 (s, 3H), 2.32-2.36 (m, 1 H), 2.08-2.02 (m, 1 H).
Example 62: 4-(2-Benzyloxy-5-chloro-phenoxy)-pipehdine.
Figure imgf000081_0003
MS (ESI): mass calcd. for CI8H20CINO2, 317.1 ; m/z found, 318.3 [M+H]+. 1H NMR (CDCI3): 7.42-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.29 (m, 1 H), 6.93-6.93 (m, 1 H), 6.87-6.82 (m, 2H), 5.08 (s, 2H), 4.35-4.29 (m, 1 H), 3.17- 3.11 (m, 2H), 2.68 (ddd, J = 12.6, 9.3, 3.1 Hz, 2H), 2.02-1.96 (m, 2H), 1.74- 1.66 (m, 2H).
Example 63: 4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- piperidine hydrochloride.
Figure imgf000082_0001
MS (ESI): mass calcd. for Ci7H17CIF3NO3, 375.1 ; m/z found, 378.2. 1H NMR (DMSO-D6): 9.10-9.00 (m, 2H), 7.24-7.23 (m, 2H), 7.15 (d, J = 8.7 Hz, 1 H), 7.01 (d, J = 8.7, 2.5 Hz, 1 H), 6.80 (d, J = 3.2 Hz, 1 H), 5.17 (s, 2H), 4.59- 4.55 (m, 1 H), 3.20-3.17 (m, 2H), 3.03-3.00 (m, 2H), 2.07-2.02 (m, 2H), 1.86- 1.82 (m, 2H).
Example 64: 4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- piperidine.
Figure imgf000082_0002
MS (ESI): mass calcd. for Ci7H17BrF3NO3, 419.0; m/z found, 420.1 [M+H]+. 1H NMR (CDCI3): 7.09 (d, J = 2.3 Hz, 1 H), 7.04 (dd, J = 8.5, 2.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.79-6.75 (m, 1 H), 6.45 (d, J = 3.3 Hz, 1 H), 5.06 (s, 2H), 4.37-4.29 (m, 1 H), 3.21 -3.10 (m, 2H), 2.78-2.66 (m, 2H), 2.06-1.95 (m, 2H), 1.76-1.66 (m, 2H).
Example 65: 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-pipehdine.
Figure imgf000082_0003
MS (ESI): mass calcd. for Ci8Hi9BrCINO2, 395.0; m/z found, 396.1 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.29-7.27 (m, 3H), 7.07 (d, J = 7.1 Hz, 1 H), 7.01 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 5.04 (s, 2H), 4.36- 4.30 (m, 1 H), 3.18-3.12 (m, 2H), 2.73-2.67 (m, 2H), 2.02-1.97 (m, 2H), 1.75- 1.67 (m, 2H).
Example 66: 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl-piperidine.
Figure imgf000083_0001
Synthesized from the title compound of Example 65 according to general procedure 5. MS (ESI): mass calcd. for Ci9H2iBrCINO2, 409.0; m/z found, 410.1 [M+H]+. 1H NMR (CDCI3): 7.46 (s, 1 H), 7.30-7.28 (m, 3H), 7.06 (d, J = 2.3 Hz, 1 H), 7.01 (dd, J = 8.6, 2.3 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 5.04 (s, 2H), 4.32-4.29 (m, 1 ), 2.73-2.67 (m, 2H), 2.35-2.27 (m, 4H), 2.02-1.85 (m, 4H).
Example 67: 4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy1-pipehdine.
Figure imgf000083_0002
MS (ESI): mass calcd. for Ci8Hi9BrFNO2, 379.1 ; m/z found, 380.2 [M+H]+. 1H NMR (CDCI3): 7.52-7.49 (m, 1 H), 7.33-7.28 (m, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.09-7.05 (m, 2H), 7.03-7.01 (m, 1 H), 6.83 (dd, J = 8.6, 2.4 Hz, 1 H), 5.12 (s, 2H), 4.34-4.29 (m, 1 H), 3.15-3.13 (m, 2H), 2.71 -2.62 (m, 2H), 2.00- 1.94 (m, 2H), 1.72-1.66 (m, 2H). Example 68: 4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-piperidine.
Figure imgf000084_0001
MS (ESI): mass calcd. for Ci8Hi9BrFNO2, 379.1 ; m/z found, 380.2 [M+H]+. 1H NMR (CDCI3): 7.35-7.31 (m, 1 H), 7.18-7.15 (m, 2H), 7.07 (d, J = 2.3 Hz, 1 H), 7.02-6.98 (m, 2H), 6.78 (d, J = 8.6 Hz, 1 H), 5.07 (s, 2H), 4.36-4.31 (m, 1 H), 3.17-3.14 (m, 2H), 2.71 (t, J = 9.6 Hz, 2H), 2.03-2.00 (m, 2H), 1.75- 1.67 (m, 2H).
Example 69: (±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- piperidine.
Figure imgf000084_0002
MS (ESI): mass calcd. for Ci7Hi7CIF3NO3, 375.1 ; m/z found, 376.0 [M+H]+. 1H NMR (CDCI3): 6.96-6.95 (m, 1 H), 6.88-6.87 (m, 2H), 6.76-6.75 (m, 1 H), 6.45-6.44 (m, 1 H), 5.04 (s, 2H), 4.22-4.17 (m, 1 H), 3.12 (dd, J = 2.2, 12.7 Hz, 1 H), 2.88-2.82 (m, 2H), 2.78-2.72 (m, 1 H), 2.02-1.96 (m, 1 H), 1.85-1.74 (m, 2H), 1.53-1.45 (m, 1 H).
Example 70: (±)-3-(2-Benzyloxy-5-chloro-phenoxy)-pipehdine.
Figure imgf000084_0003
MS (ESI): mass calcd. for Ci8H20CINO2, 317.12; m/z found, 318.1
[M+H]+. 1H NMR (CDCI3): 7.45 - 7.28 (m, 5H), 6.95 (d, J = 2.1 Hz, 1 H), 6.90 - 6.81 (m, 2H), 5.08 (s, 2H), 4.20 (dq, J = 10.2, 3.3 Hz, 1 H), 3.11 (dd, J = 12.7, 2.3 Hz, 1 H), 2.91 - 2.78 (m, 2H), 2.78 - 2.69 (m, 1 H), 2.05 - 1.94 (m, 1 H), 1.88 1.74 (m, 2H), 1.53 - 1.41 (m, 1 H).
Example 71 : (±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy1- piperidine.
Figure imgf000085_0001
MS (ESI): mass calcd. for Ci9H19CIF3NO2, 385.11 ; m/z found, 386.0 [M+H]+. 1H NMR (CDCI3): 7.75 (s, 1 H), 7.62 - 7.56 (m, 2H), 7.50 (t, J = 7.7 Hz, 1 H), 6.96 (d, J = 2.3 Hz, 1 H), 6.89 (dd, J = 8.6, 2.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 5.12 (s, 2H), 4.28-4.16 (m, 1 H), 3.13 (dd, J = 12.6, 2.3 Hz, 1 H), 2.91 - 2.80 (m, 2H), 2.78 - 2.67 (m, 1 H), 2.08 - 1.94 (m, 1 H), 1.88 - 1.73 (m, 2H), 1.55 - 1.40 (m, 1 H).
Example 72: 3-(5-Chloro-2-cvclopentyloxy-phenoxy)-azetidine trifluoroacetate.
H
Figure imgf000085_0002
MS (ESI): mass calcd. for Ci4Hi8CINO2, 267.1 ; m/z found, 268.2 [M+H]+. 1H NMR (CDCI3): 6.97 (dd, J = 8.7, 2.5 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.75 (d, J = 2.5 Hz, 1 H), 5.04-4.99 (m, 1 H), 4.76-4.67 (m, 1 H), 4.38-4.27 (m, 4H), 1.96-1.87 (m, 2H), 1.84-1.74 (m, 4H), 1.69-1.59 (m, 2H).
Example 73: 3-(5-Chloro-2-cvclohexylmethoxy-phenoxy)-azetidine trifluoroacetate.
Figure imgf000085_0003
MS (ESI): mass calcd. for Ci6H22CINO2, 295.1 ; m/z found, 296.2 [M+H]+. 1H NMR (CDCI3): 6.97 (dd, J = 8.7, 2.3 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 5.15-4.97 (m, 1 H), 4.44-4.36 (m, 2H), 4.30 (s, 2H), 3.74 (d, J = 6.3 Hz, 2H), 1.89-1.65 (m, 6H), 1.36-1.14 (m, 3H), 1.03 (m, 2H).
Example 74: 3-(5-Bromo-2-cvclohexylnnethoxy-phenoxy)-azetidine.
Figure imgf000086_0001
MS (ESI): mass calcd. for Ci6H22BrNO2, 339.1 ; m/z found, 340.1 [M+H]+. 1H NMR (CDCI3): 7.01 (dd, J = 8.6, 2.3 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.71 (d, J = 2.3 Hz, 1 H), 4.97-4.92 (m, 1 H), 3.92-3.83 (m, 4H), 3.75 (d, J = 6.4 Hz, 2H), 1.95-1.63 (m, 6H), 1.36-1.14 (m, 3H), 1.10-0.93 (m, 2H).
Example 75: 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-trifluoromethyl- furan-3-carboxylic acid trifluoroacetate.
Figure imgf000086_0002
Step A: Preparation of 5-Bromomethyl-2-trifluoromethyl-furan-3- carboxylic acid ethyl ester. To a solution of 5-methyl-2-trifluoromethyl-furan-3- carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCI4 (12 ml_) was added N- bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH2CI2 and sat'd NaHCO3 (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C9H8BrF3O3, 300.0; m/z found, 302.9 [M+H]+. 1H NMR (CDCI3): 6.84 (s, 1 H), 4.44 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). Step B: Preparation of 3-[2-(4-Carboxy-5-trifluoromethyl-furan-2- ylmethoxy)-5-chloro-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. The title compound was prepared as described in Example 1 Step D using 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.15 g, 0.50 mmol), the title compound of Step A (0.18 g, 0.60 mmol), Cs2CO3 (0.41 g, 1.2 mmol), Kl (0.12 g,0.70 mmol ) in DMF, except upon completion of the reaction 1 N NaOH and EtOAc were added. The organic layer was washed with 1 N NaOH and dried. The crude material was purified by RP HPLC to provide the title compound. 1H NMR (CDCI3): 7.20-6.92 (m, 1 H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1 H), 6.53 (d, J = 2.1 Hz, 1 H), 4.87 (s, 2H), 4.79-4.69 (m, 1 H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).
Step C: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvH- 2-trifluoromethyl-furan-3-carboxylic acid trifluoroacetate: Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci6Hi3CIF3NO5 [M-TFA], 391.0; m/z found, 392.9 [M+H]+. 1H NMR (CD3OD): 7.10 (d, J= 8.7 Hz, 1 H), 7.03 (dd, J = 8.7, 2.4 Hz, 1 H), 6.99 (s, 1 H), 6.88 (d, J = 2.4 Hz, 1 H), 5.14 (s, 2H), 5.11 -5.04 (m, 1 H), 4.49 (dd, J = 12.4, 6.6 Hz, 2H), 4.22 (dd, J= 12.4, 4.9 Hz, 2H).
Example 76: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvn-2-trifluoromethyl- furan-3-carboxylic acid ethyl ester.
Figure imgf000087_0001
Step A: Preparation of 3-[5-Chloro-2-(4-ethoxycarbonyl-5-trifluoromethyl- furan-2-ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. The title compound was prepared as described in Example 1 Step D using 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.3 g, 1.0 mmol), the title compound of Example 75 Step A (0.75 g, 2.5 mmol), Cs2CO3 (0.80 g, 2.4 mmol) and Kl (0.23 g, 1.4 mmol ) in DMF (15 ml_). The crude material was purified by RP HPLC to provide the title compound (0.37 g, 71 %). 1H NMR (CDCI3): 7.20-6.92 (m, 1 H), 6.91 -6.80 (m, 2H), 6.77-6.69 (m, 1 H), 6.53 (d, J = 2.1 Hz, 1 H), 4.87 (s, 2H), 4.79-4.69 (m, 1 H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).
Step B: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvH- 2-trifluoromethyl-furan-3-carboxylic acid ethyl ester: Prepared from the title compound of Step A using general procedure 1. MS (ESI): mass calcd. for Ci8Hi7CIF3NO5, 419.1 ; m/z found, 420.0 [M+H]+. 1H NMR (CDCI3): 6.94-7.80 (m, 3H), 6.65-6.56 (m, 1 H), 5.05 (s, 2H), 5.01 -4.92 (m, 1 H), 4.34 (q, J = 7.2 Hz, 2H), 3.97-3.81 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H).
Example 77: 5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)-phenoxymethyl1-2- trifluoromethyl-furan-3-yli-methanol.
Figure imgf000088_0001
Step A: Preparation of 5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)- phenoxymethyl1-2-trifluoromethyl-furan-3-yl1-methanol. To a solution of the title compound of Example 76 Step A (0.05 g, 0.1 mmol) at -78 0C was added DIBAL-H (1.0 M in THF, 0.24 ml_). After addition was complete, the bath was replaced with a 0 0C bath and allowed to stir for 1 h. Then, an additional aliquot of DIBAL-H (1.0 M in THF, 1 mL) was added. After 3h, the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight. The mixture was extracted with EtOAc (2X) and the combined organic layers were dried. The product was purified by RP HPLC to provide the title compound (0.004 g, 10%). MS (ESI): mass calcd. for
Ci7Hi7CIF3NO4, 391.1 ; m/z found, 392.1 [M+H]+. 1H NMR (CDCI3): 6.94 (d, J = 8.6 Hz, 1 H), 6.89 (dd, J = 8.6, 2.3 Hz, 1 H), 6.65 (s, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 5.02 (s, 2H), 4.73-4.66 (m, 1 H), 4.64 (d, J = 1.4 Hz, 2H), 3.76-3.69 (m, 2H), 3.27-3.21 (m, 2H), 2.41 (s, 3H). Example 78: 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)- phenoxyi-azetidine.
Figure imgf000089_0001
Step A: Preparation of (5-Methyl-2-trifluoromethyl-furan-3-yl)-methanol. To a solution of δ-methyl^-thfluoromethyl-furan-S-carboxylic acid ethyl ester (0.83 g, 3.7 mmol) in Et2O at 0 0C, was added DIBAL-H (1.0 M in THF, 1.5 ml_). After 10 min, the ice bath was removed and additional DIBAL-H was added (1.0 M in THF, 14.5 mL). After 2h, the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight. After 18h, EtOAc was added and the organic layer separated and dried provide the title compound (0.39 g, 58%). 1H NMR (CDCI3): 6.19 (s, 1 H), 4.62 (s, 2H), 2.36-2.28 (m, 3H).
Step B: Preparation of 3-[5-chloro-2-(5-methyl-2-trifluoromethyl-furan-3- ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. Synthesized from the title compound of Step A and 3-(5-chloro-2-hydroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester using general procedure 7. MS (ESI): mass calcd. for C2IH23CIF3NO5, 461.1 ; m/z found, 485.9 [M+Na]+. 1H NMR 6.91 (dd, J = 8.6, 2.3 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 6.22 (s, 1 H), 5.07-5.00 (m, 2H), 4.90-4.81 (m, 1 H), 4.30 (ddd, J = 9.7, 6.5, 0.8 Hz, 2H), 4.06 (dd, J = 9.8, 4.0 Hz, 2H), 2.34 (s, 3H), 1.45 (s, 9H).
Step C: Preparation of 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3- ylmethoxy)-phenoxy1-azetidine. Synthesized from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci6Hi5CIF3NO3, 361.1 ; m/z found, 362.1 [M+H]+. 1H NMR (CDCI3): 6.86 (dd, J = 8.6, 2.2 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 2.2 Hz, 1 H), 6.23 (s, 1 H), 5.03 (s, 2H), 5.01-4.93 (m, 1 H), 4.01-3.77 (m, 4H), 2.33 (s, 3H). Example 79: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl1-6-trifluoroιinethyl- pyridine.
Figure imgf000090_0001
Step A: Preparation of (6-Trifluoronnethyl-pyridin-2-yl)-nnethanol. To a solution of 6-trifluoromethyl-pyhdine-2-carboxylic acid (500 mg, 3 mmol) in dry THF at 0 0C, was added triethylamine (0.36 ml_, 2.6 mmol) followed by ethyl chloroformate (0.25 ml_, 2.6 mmol). After 30 min, LiBH4 (2 M in THF, 3.3 ml_, 6.5 mmol) was added. After an additional 30 min, the ice bath was removed. After 1 h, the reaction was cooled to 0 0C and quenched with MeOH followed by 1 N NaOH and EtOAc. The pH of the solution was adjusted to pH=5 with 1 N HCI and the mixture extracted with EtOAc (2X). The combined organic fractions were dried to provide the title compound that was used without further purification. 1H NMR (CDCI3): 7.89 (dd, J = 7.8, 7.8 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 4.85 (s, 2H). Step B: Preparation of 3-[5-Chloro-2-(6-trifluoromethyl-pyhdin-2- ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. Prepared from the title compound of Step A and 3-(5-Chloro-2-hydroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester using general procedure 7.
Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1- 6-trifluoromethyl-pyhdine. Prepared from the title compound of Step B according to general procedure 1. MS (ESI): mass calcd. for Ci6Hi4CIF3N2O2, 358.1 ; m/z found, 359.0 [M+H]+. 1H NMR (CDCI3): 7.92 (dd, J = 7.8, 7.8 Hz, 1 H), 7.81 (d, J = 7.9 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 6.87 (dd, J = 8.6, 2.1 Hz, 1 H), 6.61 (d, J = 2.1 , 1 H), 5.29 (s, 2H), 5.21-4.99 (m, 1 H), 4.21 -1.15 (br m, 4H).
Examples 80-89 were prepared using the appropriate alcohol and phenol according to general procedure 7. Example 80: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvn-2-methyl-6- trifluoromethyl-pyridine.
Figure imgf000091_0001
MS (ESI): mass calcd. for Ci7Hi6CIF3N2O2, 372.1 ; m/z found, 373.0 [IvRH]+. 1H NMR (CDCI3): 7.93 (d, J = 7.9 Hz, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 6.89 (dd, J = 8.6, 2.2 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.2 Hz, 1 H), 5.11 (s, 2H), 5.03-4.92 (m, 1 H), 4.08-3.69 (m, 4H), 2.66 (s, 3H).
Example 81 : 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-4-trifluoromethyl- pyridine.
Figure imgf000091_0002
MS (ESI): mass calcd. for Ci6Hi4CIF3N2O2, 358.1 ; m/z found, 358.9 [M+H]+. 1H NMR (CDCI3): 8.86 (s, 1 H), 7.98 (d, J = 7.9 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 6.87 (dd, J = 8.6, 2.1 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.61 (d, J 1.9 Hz, 1 H), 5.28 (s, 2H), 5.08-4.98 (m, 1 H), 4.08-3.97 (m, 2H), 3.96-3.85 (m, 2H).
Example 82: 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-2-trifluoromethyl- pyhdine.
Figure imgf000091_0003
MS (ESI): mass calcd. for Ci6Hi4CIF3N2O2, 358.1 ; m/z found, 359.0 [M+H]+. 1H NMR (CDCI3): 8.81 (s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 6.90 (dd, J = 8.6, 2.2 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.60 (d, J 2.2 Hz, 1 H), 5.18 (s, 2H), 5.03-4.95 (m, 1 H), 4.02-3.95 (m, 2H), 3.89-3.82 (m, 2H).
Example 83: 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy1-azetidine.
Figure imgf000092_0001
MS (ESI): mass calcd. for Ci8Hi6CINO3, 329.1 ; m/z found, 330.1 [M+H]+. 1H NMR (CDCI3): 7.65-7.64 (m, 2H) 7.50 (d, J = 8.5 Hz, 1 H), 7.35 (dd, J = 8.5, 1.6 Hz, 1 H), 6.87-6.82 (m, 2H), 6.76 (d, J = 1.3 Hz, 1 H), 6.59 (s, 1 H), 5.18 (s, 2H), 5.02-4.92 (m, 1 H), 4.06-3.79 (m, 4H).
Example 84: 6-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-benzothiazole.
Figure imgf000092_0002
MS (ESI): mass calcd. for Ci7Hi5CIN2O2S, 346.1 ; m/z found, 347.0 [M+H]+. 1H NMR (CDCI3): 9.01 (s, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.05 (s, 1 H), 7.57 (dd, J = 8.4, 1.6 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 2H), 6.60 (s, 1 H), 5.35 (s, 2H), 5.00-4.98 (m, 1 H), 3.93-3.87 (m, 4H).
Example 85: 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-1 -methyl-1 H- benzotriazole.
Figure imgf000092_0003
MS (ESI): mass calcd. for Ci7Hi7CIN4O2, 344.1 ; m/z found, 345.0 [M+H]+. 1H NMR (CDCI3): 8.10 (s, 1 H), 7.61 (dd, J = 8.6, 1.3 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 6.88-6.80 (m, 2H), 6.59 (d, J = 1.9 Hz, 1 H), 5.26 (s, 2H), 5.02- 4.96 (m, 1 H), 4.31 (s, 3H), 3.97-3.82 (m, 4H). Example 86: 3-r5-Chloro-2-(2,2-difluoro-benzoπ ,31dioxol-5-ylmethoxy)- phenoxyi-azetidine.
Figure imgf000093_0001
MS (ESI): mass calcd. for Ci7H14CIF2NO4, 369.1 ; m/z found, 370.0 [M+H]+. 1H NMR (CDCI3): 7.20 (d, J = 1.2 Hz, 1 H), 7.11 (dd, J = 8.2, 1.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 6.86 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 5.06 (s, 2H), 5.01-4.95 (m, 1 H), 3.96-3.83 (m, 4H).
Example 87: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-oxazole.
Figure imgf000093_0002
MS (ESI): mass calcd. for Ci3H13CIN2O3, 280.1 ; m/z found, 281.1 [M+H]+. 1H NMR (CDCI3): 7.91 (s, 1 H), 7.13 (s, 1 H), 6.90-6.87 (m, 2H), 6.59 (d, J = 1.9 Hz, 1 H), 5.10 (s, 2H), 5.00-4.91 (m, 1 H), 3.97-3.89 (m, 2H), 3.87- 3.79 (m, 2H).
Example 88: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-thiazole.
Figure imgf000093_0003
MS (ESI): mass calcd. for Ci3Hi3CIN2O2S, 296.0; m/z found, 297.0
[M+H]+. 1H NMR (CDCI3): 7.80 (t, J = 3.1 Hz, 1 H), 7.38 (t, J = 3.3 Hz, 1 H), 6.96-6.84 (m, 2H), 6.63 (dd, J = 11.1 , 2.3 Hz, 1 H), 5.41 -5.37 (m, 2H), 5.04-4.78 (m, 1 H), 4.01 -3.93 (m, 1 H), 3.92-3.83 (m, 2H), 3.31 -3.23 (m, 1 H) Example 89: 3-r2-(Benzofuran-2-ylnnethoxy)-5-chloro-phenoxy1-azetidine.
Figure imgf000094_0001
MS (ESI): mass calcd. for Ci8Hi6CINO3, 329.1 ; m/z found, 330.0 [M+H]+. 1H NMR (CDCI3): 7.56 (d, J = 7.7 Hz, 1 H), 7.50 (dd, J = 8.2, 0.7 Hz, 1 H), 7.34- 7.28 (m, 1 H), 7.23 (dt, J = 7.5, 1.0 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 1 H), 6.87 (dd, J = 8.6, 2.4 Hz, 1 H), 6.73 (d, J = 0.5 Hz, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 5.17 (s, 2H), 4.95-4.89 (m, 1 H), 3.93-3.69 (m, 4H).
Example 90: (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine.
Figure imgf000094_0002
Step A: Preparation of 3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester. To (SJ-S-hydroxy-pyrrolidine-i-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH2CI2 (50 ml_) at 0 0C was added Et3N (1.4 g, 1.9 ml_, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 ml_, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH2CI2 (2X). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1 - carboxylic acid tert-butyl ester that was used without further purification.
To this compound in DMF (50 ml_) was added 5-chloro-2-hydroxy- benzaldehyde (1.9 g, 12.1 mmol) and K2CO3 (1.8 g, 13.1 mmol). The reaction was heated at 90 0C for 2h, then cooled to rt and H2O was added. The mixture was extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (10-50% EtOAc in hexanes) gave 1.85 g (52%) of the title compound. 1H NMR (CDCI3): 10.36 (s, 1 H), 7.81 (s, 1 H), 7.50 (s, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 5.00 (s, 1 H), 3.72-3.50 (m, 4H), 2.26-2.18 (m, 2H), 1.47 (s, 9H). Step B: Preparation of 3-(4-chloro-2-hvdroxy-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester. To a CH2CI2 (25 ml_) solution of the title compound of Step A (1.4 g, 4.3 mmol) was added 77% m-CPBA (1.4 g, 6.2 mmol). After 18h, additional CH2CI2 was added and the reaction washed with saturated NaHCO3 (aq.) and 10% Na2S2O5 until Kl paper negative. The combined organic layers were dried then treated with MeOH (25 ml_) and 1 N NaOH (25 ml_). After 15h, the reaction was acidified with 1 M KHSO4 then extracted with EtOAc (2X). The combined organic layers were washed with brine and dried to give the title compound as a white solid. 1H NMR (CDCI3): 6.96 (s, 1 H), 6.82-6.80 (m, 1 H), 6.73 (d, J=8.6 Hz, 1 H), 5.62 (s, 1 H), 4.91 (s, 1 H), 3.66-3.46 (m, 4H), 2.20-2.11 (m, 2H), 1.47 (s, 9H).
Step C: Preparation of 3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester. Prepared according to Example 1 Step D using the title compound of Step B. MS (ESI): mass calcd. for C22H26CINO4, 403.2; m/z found, 426.2 [M+Na]+, 348.2 [M-56]+. 1H NMR (CDCI3): 7.43-7.36 (m, 4H), 7.35-7.30 (m, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.5, 2.4 Hz, 1 H), 6.82 (d, J = 8.5 Hz, 1 H), 5.07 (s, 2H), 4.89-4.85 (m, 1 H), 3.71 -3.45 (m, 4H), 2.24- 2.12 (m, 1 H), 2.07-1.94 (m, 1 H), 1.46 (s, 9H).
Step D: Preparation of (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine. Prepared according to general procedure 1 using the title compound of Step C. MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.1 ; m/z found, 304.2 [M+H]+. 1H NMR (CDCI3): 7.45-7.36 (m, 4H), 7.35-7.30 (m, 1 H), 6.94 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.6, 2.4 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 5.06 (s, 2H), 4.86 (s, 1 H), 3.25 (d, J = 2.1 Hz, 2H), 2.25-1.73 (m, 4H).
Example 91 : (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1 -methyl-pyrrolidine.
Figure imgf000095_0001
Synthesized from the title compound of Example 90 according to general procedure 5. MS (ESI): mass calcd. for Ci8H20CINO2, 317.1 ; m/z found, 318.2 [M+H]+. 1H NMR (CDCI3): 7.44-7.32 (m, 5H), 6.91 (d, J = 2.3 Hz, 1 H), 6.86 (dd, J = 8.5, 2.4 Hz, 1 H), 6.75 (d, J = 8.6 Hz, 1 H), 5.08 (s, 2H), 4.81 (td, J = 10.4, 5.1 Hz, 1 H), 2.90 (dd, J = 10.1 , 6.1 Hz, 1 H), 2.74 (d, J = 8.9 Hz, 2H), 2.53 (dd, J = 13.8, 7.9 Hz, 1 H), 2.38 (s, 3H), 2.28-2.21 (m, 1 H), 2.08-1.98 (m, 1 H).
Example 92: (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-pyrrolidine.
Figure imgf000096_0001
Synthesized according to Example 90 using 3-chlorobenzyl bromide. MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.40 (s, 1 H), 7.29-7.20 (m, 3H), 6.86 (dd, J = 7.1 , 2.2 Hz, 2H), 6.79- 6.74 (m, 1 H), 4.99 (s, 2H), 4.77 (t, J = 5.1 Hz, 1 H), 3.18-3.13 (m, 2H), 2.92-2.86 (m, 2H), 2.11 -1.81 (m, 2H).
Example 93: (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl- pyrrolidine.
Figure imgf000096_0002
Synthesized from the title compound of Example 92 according to general procedure 5. MS (ESI): mass calcd. for Ci8Hi9CI2NO2, 351.1 ; m/z found, 352.2 [M+H]+. 1H NMR (CDCI3): 7.47 (s, 1 H), 7.30 (s, 3H), 6.88 (dd, J = 7.3, 2.2 Hz, 2H), 6.77-6.74 (m, 1 H), 5.04 (s, 2H), 4.85-4.73 (m, 1 H), 2.96-2.86 (m, 1 H), 2.79-2.68 (m, 2H), 2.56-2.50 (m, 1 H), 2.39 (s, 3H), 2.31-2.17 (m, 1 H), 2.05- 1.95 (m, 1 H). Example 94: (S)-3-r4-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-pyrrolidine.
Figure imgf000097_0001
Synthesized according to Example 90 using (R)-3-hydroxy-pyrrolidine-1 - carboxylic acid tert-butyl ester and 3-chlorobenzyl bromide. MS (ESI): mass calcd. for Ci7H17CI2NO2, 337.1 ; m/z found, 338.2 [M+H]+. 1H NMR (CDCI3): 7.44 (s, 1 H), 7.36-7.24 (m, 3H), 6.94-6.86 (m, 2H), 6.84-6.78 (m, 1 H), 5.08 (s, 2H), 4.81 (t, J = 5.0 Hz, 1 H), 3.26-3.08 (m, 2H), 3.00-2.84 (m, 2H), 2.12-1.91 (m, 2H).
Examples 95-100 were prepared using 1 -methyl-pyrrolidin-3-ol and the appropriately substituted phenol (synthesized according to Example 90) according to general procedure 7 using resin bound PPh3.
Example 95: (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-1 -methyl- pyrrolidine.
Figure imgf000097_0002
MS (ESI): mass calcd. for Ci8Hi9BrCINO2, 395.0; m/z found, 396.0 [M+H]+. 1H NMR (CDCI3): 7.46 (s, 1 H), 7.33 - 7.24 (m, 3H), 6.98 (dd, J = 8.5, 2.3 Hz, 1 H), 6.94 (d, J = 2.3 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 5.04 (s, 2H), 4.82 (m, 1 H), 2.95 (dd, J = 10.5, 6.1 Hz, 1 H), 2.82 - 2.73 (m, 2H), 2.55 (m, 1 H), 2.41 (s, 3H), 2.31 (m, 1 H), 2.10 - 2.00 (m, 1 H). Example 96: (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy1-1 -methyl- pyrrolidine.
Figure imgf000098_0001
MS (ESI): mass calcd. for Ci9H22BrNO3, 391.1 ; m/z found, 391.1 [M+H]+. 1H NMR (CDCI3): 7.31 - 7.23 (m, 1 H), 6.99 - 6.96 (m, 3H), 6.93 (d, J = 2.3 Hz, 1 H), 6.87 - 6.82 (m, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 5.06 (s, 2H), 4.86 - 4.79 (m, 1 H), 3.81 (s, 3H), 2.94 (dd, J = 10.6, 6.1 Hz, 1 H), 2.79 - 2.73 (m, 2H), 2.54 (m, 1 H), 2.39 (s, 3H), 2.29 (m, 1 H), 2.05 (m, 1 H).
Example 97: (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -methyl- pyrrolidine.
Figure imgf000098_0002
MS (ESI): mass calcd. for Ci8Hi9BrFNO2, 379.1 ; m/z found, 380.1 [M+H]+. 1H NMR (400 MHz, DMSO-D6): 7.32 (m, 1 H), 7.17 (d, J = 7.3 Hz, 2H), 7.02 - 6.96 (m, 2H), 6.94 (d, J = 2.3 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 5.07 (s, 2H), 4.82 (m, 1 H), 2.94 (m, 1 H), 2.82 - 2.73 (m, 2H), 2.55 (m, 1 H), 2.40 (s, 3H), 2.31 (m, 1 H), 2.07-2.02 (m, 1 H).
Example 98: (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1 -methyl-pyrrolidine.
Figure imgf000098_0003
MS (ESI): mass calcd. for Ci8H20BrNO2, 361.1 ; m/z found, 362.1 [M+H]+. 1H NMR (CDCI3): 7.41 (m, 2H), 7.39 - 7.34 (m, 2H), 7.30 (m, 1 H), 6.97 (dd, J = 8.5, 2.3 Hz, 1 H), 6.93 (d, J = 2.3 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 5.08 (s, 2H), 4.86 - 4.76 (m, 1 H), 2.93 (m, 1 H), 2.80 - 2.72 (m, 2H), 2.57 - 2.50 (m, 1 H), 2.39 (s, 3H), 2.29 (m, 1 H), 2.09 - 1.99 (m, 1 H).
Example 99: (±)-Methanesulfonic acid 3-[4-bromo-2-(1 -methyl-pyrrolidin-3- yloxy)-phenoxynnethyl1-phenyl ester.
Figure imgf000099_0001
MS (ESI): mass calcd. for Ci9H22BrNO5S, 455.1 ; m/z found, 456.1 [M+H]+. 1H NMR (CDCI3): 7.46 - 7.35 (m, 3H), 7.23 (m, 1 H), 6.98 (dd, J = 8.5, 2.3 Hz, 1 H), 6.93 (d, J = 2.2 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 5.08 (s, 2H), 4.81 (m, 1 H), 3.13 (s, 3H), 2.89 (m, 1 H), 2.82 - 2.74 (m, 2H), 2.55 - 2.46 (m, 1 H), 2.39 (s, 3H), 2.31 (m, 1 H), 2.03 (m, 1 H).
Example 100: (±)-Methanesulfonic acid 3-[2-(1 -methyl-pyrrol id in-3-yloxy)- phenoxymethyli-phenyl ester.
Figure imgf000099_0002
MS (ESI): mass calcd. for Ci9H23NO5S, 377.1 ; m/z found, 378.1 [M+H]+. 1H NMR (CDCI3): 7.42 (m, 3H), 7.26-7.20 (m, 1 H), 6.98 - 6.80 (m, 4H), 5.13 (s, 2H), 4.86 (m, 1 H), 3.12 (s, 3H), 2.93 (dd, J = 10.5, 6.1 Hz, 1 H), 2.81 - 2.71 (m, 2H), 2.60-2.49 (m, 1 H), 2.40 (s, 3H), 2.30 (m, 1 H), 2.11 -2.00 (m, 1 H). Example 101 : (S)-3-r5-Chloro-2-ri -(3-trifluoronnethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000100_0001
Step A: Preparation of (R)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)- ethoxyi-phenoxyi-azetidine-i -carboxylic acid tert-butyl ester. To (S)-I -(3- trifluoromethyl-phenyl)-ethanol (2.3O g, 12.1 mmol), 3-(5-chloro-2-hydroxy- phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (3.80 g, 12.7 mmol) and PPh3 (3.80 g, 14.5 mmol) in THF (60 ml_) at 0 0C was added DEAD (2.3 g, 2.1 ml_, 13 mmol) in THF (10 ml_) dropwise over 30 min. After 48h, the reaction was concentrated and 15% EtOAc in hexanes was added. The flask was cooled to 0 0C and filtered. The filtrate was concentrated and this procedure repeated 2 more times. The resulting oil was then purified using silica gel chromatography (10-40% EtOAc in hexanes) to give 5.17 g (91 %) of the title compound as a clear oil. 1H NMR (CDCI3): 7.66 (s, 1 H), 7.56-7.53 (m, 2H), 7.46 (t, J = 7.7 Hz, 1 H), 6.79 (dd, J = 8.6, 2.4 Hz, 1 H), 6.71 (d, J = 8.6 Hz, 1 H), 6.52 (d, J = 2.4 Hz, 1 H), 5.29 (q, J = 6.5 Hz, 1 H), 4.88-4.82 (m, 1 H), 4.33-4.29 (m, 2H), 4.08-4.01 (m, 2H), 1.67 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H).
Step B: Preparation of (S)-3-r5-Chloro-2-ri-(3-trifluoromethyl-phenyl)- ethoxyi-phenoxyi-azetidine. To the title compound of Step A (5.1 g, 10.8 mmol) in CH2CI2 (50 ml_) at 0 0C was added TFA (50 ml_). After 1 h, PhCH3 (50 ml_) was added and the mixture concentrated. The resulting oil was neutralized with saturated NaHCO3 (aq.) and extracted with CH2CI2 (2X). The combined organics were dried and concentrated. Silica gel chromatography (1-7% 2M NH3/MeOH in CH2CI2) gave 3.38 g (83% yield) of the title compound as a clear oil. MS (ESI): mass calcd. for Ci8Hi7CIF3NO2, 371.1 ; m/z found, 372.0 [M+H]+. 1H NMR (CDCI3): 7.70 (s, 1 H), 7.56-7.53 (m, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.77 (dd, J = 8.6, 2.3 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.30 (q, J = 6.3 Hz, 1 H), 5.00-4.94 (m, 1 H), 3.97-3.93 (m, 2H), 3.89-3.81 (m, 2H), 1.66 (d, J = 6.5 Hz, 3H). Unless otherwise specified the compounds in Examples 102-144 were prepared similar to Example 101 using the appropriately substituted phenols and alcohols.
Example 102: (S)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
Figure imgf000101_0001
Prepared using (R)-1 -(3-thfluoromethyl-phenyl)-ethanol. MS (ESI): mass calcd. for Ci8Hi7CIF3NO2, 371.1 ; m/z found, 372.0 [M+H]+. 1H NMR (CDCI3): 7.61 (s, 1 H), 7.55-7.45 (m, 3H), 6.86 (dd, J = 8.7, 2.2 Hz, 1 H), 6.68-6.66 (m, 2H), 5.30 (q, J = 6.3 Hz, 1 H), 5.11 (s, 1 H), 4.44-4.32 (m, 4H), 1.66 (d, J = 6.4 Hz, 3H).
Example 103: (S)-3-r5-Chloro-2-ri -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -methyl-azetidine.
Figure imgf000101_0002
Prepared according to general procedure 5 using the title compound of Example 102. MS (ESI): mass calcd. for Ci9Hi9CIF3NO2, 385.1 ; m/z found, 386.2 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.54 (t, J = 8.0 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 5.29 (q, J = 6.4 Hz, 1 H), 4.76-4.65 (m, 1 H), 3.85 (s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J = 6.5 Hz, 3H). Example 104: (S)-1 -Benzyl-3-f5-chloro-2-f1 -(3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000102_0001
Prepared according to general procedure 3 or 4 using the title compound of Example 102. MS (ESI): mass calcd. TOr C25H23CIF3NO2, 461.1 ; m/z found, 462.3 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.54 (t, J = 7.1 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 7.37-7.23 (m, 5H), 6.75 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 5.28 (q, J = 6.5 Hz, 1 H), 4.80-4.71 (m, 1 H), 3.85-3.80 (m, 2H), 3.71 (s, 2H), 3.24-3.14 (m, 2H), 1.66 (d, J = 6.5 Hz, 3H).
Example 105: (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000102_0002
MS (ESI): mass calcd. for Ci8Hi7CIF3NO2, 371.1 ; m/z found, 372.1 [M+H]+. 1H NMR (CDCI3): 7.61 (s, 1 H), 7.54 (d, J = 7.8 Hz, 2H), 7.51 -7.45 (m, 1 H), 6.85 (dd, J = 8.7, 2.4 Hz, 1 H), 6.67 (s, 1 H), 6.66 (d, J = 7.1 Hz, 1 H), 5.31 (q, J = 6.4 Hz, 1 H), 5.13-5.09 (m, 1 H), 4.58-4.30 (m, 4H), 1.67 (d, J = 6.5 Hz, 3H).
Example 106: (+)-3-f5-Chloro-2-f1 -(3-thfluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -isopropyl-azetidine.
Figure imgf000102_0003
Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C2iH23CIF3NO2, 413.1 ; m/z found, 414.0 [M+H]+. 1H NMR (CDCI3): 7.68 (s, 1 H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.62 (d, J = 2.4 Hz, 1 H), 5.28 (q, J = 6.5 Hz, 1 H), 4.75-4.69 (m, 1 H), 3.86-3.82 (m, 2H), 3.11 -3.04 (m, 2H), 2.40 (td, J = 12.4, 6.2 Hz, 1 H), 1.65 (d, J = 6.5 Hz, 3H), 0.98 (dd, J = 6.2, 0.8 Hz, 6H).
Example 107: (+)-3-[5-Chloro-2-[1 -(3-thfluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -cyclobutyl-azetidine.
Figure imgf000103_0001
Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C22H23CIF3NO2, 425.1 ; m/z found, 426.0 [M+H]+. 1H NMR (CDCI3): 7.67 (s, 1 H), 7.55 (t, J = 8.7 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.76 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 5.28 (q, J = 6.4 Hz, 1 H), 4.78-4.72 (m, 1 H), 3.75 (dd, J = 8.5, 6.1 Hz, 2H), 3.26-3.09 (m, 3H), 2.07-1.94 (m, 2H), 1.92-1.68 (m, 4H), 1.66 (d, J = 6.5 Hz, 3H).
Example 108: (+)-1 -Benzyl-3-r5-chloro-2-H -(3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000103_0002
Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C25H23CIF3NO2, 461.1 ; m/z found, 462.0 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.54 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1 H), 7.37-7.22 (m, 5H), 6.75 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 5.28 (q, J = 6.4 Hz, 1 H), 4.79-4.73 (m, 1 H), 3.86-3.79 (m, 2H), 3.70 (s, 2H), 3.24-3.13 (m, 2H), 1.66 (d, J = 6.5 Hz, 3H).
Example 109: (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- 1 -methyl-azetidine.
Figure imgf000104_0001
Synthesized from the title compound of Example 105 according to general procedure 5. MS (ESI): mass calcd. for C19H19CIF3NO2, 385.1 ; m/z found, 386.0 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.54 (t, J = 8.5 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.76 (dd, J = 8.6, 2.3 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 5.29 (q, J = 6.4 Hz, 1 H), 4.74-4.68 (m, 1 H), 3.85 (s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J = 6.5 Hz, 3H).
Example 110: (+)-3-[5-Bromo-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000104_0002
MS (ESI): mass calcd. for Ci8H17BrF3NO3, 431.0; m/z found, 431.9 [M+H]+. 1H NMR (CDCI3): 7.36 (t, J = 8.1 Hz, 1 H), 7.27 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1 H), 6.91 (dd, J = 8.6, 2.3 Hz, 1 H), 6.70 (d, J = 2.3 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 5.25 (q, J = 6.5 Hz, 1 H), 5.01-4.93 (m, 1 H), 4.01 -3.80 (m, 4H), 1.65 (d, J = 6.5 Hz, 3H). Example 111 : (+)-3-[5-Bromo-2-[1 -(3-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000105_0001
MS (ESI): mass calcd. for Ci7Hi7BrCINO2, 381.0; m/z found, 382.0 [M+H]+. 1H NMR (CDCI3): 7.42 (s, 1 H), 7.29-7.19 (m, 3H), 6.90 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 2.3 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 5.20 (q, J = 6.4 Hz, 1 H)), 5.00-4.92 (m, 1 H), 3.95-3.80 (m, 4H), 1.64 (d, J = 6.5 Hz, 3H).
Example 112: (+)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000105_0002
MS (ESI): mass calcd. for Ci8Hi7BrF3NO2, 415.0; m/z found, 416.0 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.53 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1 H), 6.89 (dd, J = 8.6, 2.3 Hz, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 6.65 (d, J = 8.6 Hz, 1 H), 5.29 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.95-3.92 (m, 2H), 3.87- 3.80 (m, 2H), 1.65 (d, J = 6.5 Hz, 3H).
Example 113: (R)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000105_0003
MS (ESI): mass calcd. for Ci8Hi7BrF3NO2, 415.0; m/z found, 418.0 [M+H]+. 1H NMR (CDCI3): 7.69 (s, 1 H), 7.58-7.50 (m, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.91 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 2.3 Hz, 1 H), 6.66 (d, J = 8.6 Hz, 1 H), 5.30 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 4.01 -3.74 (m, 4H), 1.67 (d, J 6.5 Hz, 3H).
Example 114: (+)-3-[5-Chloro-2-[1 -(3-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000106_0001
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.43 (s, 1 H), 7.32-7.17 (m, 3H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.56 (d, J = 2.3 Hz, 1 H), 5.20 (q, J = 6.5 Hz, 1 H), 5.02-4.92 (m, 1 H), 3.94 (s, 2H), 3.92-3.78 (m, 2H), 1.65 (d, J = 6.5 Hz, 3H).
Example 115: (+)-3-[5-Chloro-2-[1 -(3-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000106_0002
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.1 ; m/z found, 322.1
[M+H]+. 1H NMR (CDCI3): 7.35-7.23 (m, 1 H), 7.21 -7.07 (m, 2H), 7.00-6.91 (m, 1 H), 6.71 -6.65 (m, 2H), 6.64-6.52 (m, 1 H), 5.28-5.18 (m, 1 H), 5.05-4.93 (m, 1 H), 4.10-3.95 (s, 4H), 1.70-1.60 (s, 3H).
Example 116: (+)-3-r5-Chloro-2-ri -(2-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000106_0003
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.0 [M+H]+. 1H NMR (CDCI3): 7.55 (dd, J = 7.6, 1.8 Hz, 1 H), 7.34 (dd, J = 7.8, 1.4 Hz, 1 H), 7.28-7.14 (m, 2H), 6.73 (dd, J = 8.6, 2.4 Hz, 1 H), 6.59 (d, J = 8.7 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 5.66 (q, J = 6.4 Hz, 1 H), 5.00-4.94 (m, 1 H), 4.02- 3.81 (m, 4H), 1.64 (d, J = 6.4 Hz, 3H).
Example 117: (+)-3-r5-Chloro-2-ri -(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000107_0001
MS (ESI): mass calcd. for Ci8H16CIF4NO2, 389.1 ; m/z found, 390.0 [M+H]+. 1H NMR (CDCI3): 7.68 (dd, J = 6.7, 1.9 Hz, 1 H), 7.58-7.51 (m, 1 H), 7.19-7.14 (m, 1 H), 6.78 (dd, J = 8.6, 2.4 Hz, 1 H), 6.71 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 5.27 (q, J = 6.4 Hz, 1 H), 4.95-4.90 (m, 1 H), 3.95-3.84 (m, 4H), 1.65 (d, J = 6.5 Hz, 3H).
Example 118: (+)-3-r5-Chloro-2-ri -(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000107_0002
MS (ESI): mass calcd. for Ci8Hi6CIF4NO2, 389.1 ; m/z found, 390.0 [M+H]+. 1H NMR (CDCI3): 7.57 (t, J = 7.6 Hz, 1 H), 7.31-7.22 (m, 2H), 6.77 (dd, J = 8.6, 2.4 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 5.26 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.97-3.80 (m, 4H), 1.65 (d, J = 6.5 Hz, 3H).
Example 119: (+)-3-r5-Chloro-2-ri -(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000107_0003
MS (ESI): mass calcd. for Ci8Hi6CIF4NO2, 389.1 ; m/z found, 390.0 [M+H]+. 1H NMR (CDCI3): 7.33 (d, J = 9.3 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 6.79 (dd, J = 8.6, 2.3 Hz, 1 H), 6.73 (d, J = 8.6 Hz, 1 H), 6.56 (d, J = 2.3 Hz, 1 H), 5.28 (q, J = 6.5 Hz, 1 H), 4.99-4.92 (m, 1 H), 7.47 (s, 1 H), 4.05-3.74 (m, 4H), 1.66 (d, J = 6.5 Hz, 3H).
Example 120: (+)-3-f5-Chloro-2-f1 -(3-trifluoromethylsulfanyl-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000108_0001
MS (ESI): mass calcd. for Ci8Hi7CIF3NO2S, 403.1 ; m/z found, 404.0 [M+H]+. 1H NMR (CDCI3): 7.70 (s, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 6.75 (dd, J = 8.6, 2.3 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.2 Hz, 1 H), 5.26 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.94-3.83 (m, 4H), 1.66 (d, J = 6.5 Hz, 3H).
Example 121 : (+)-3-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000108_0002
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.1 ; m/z found, 322.0 [M+H]+. 1H NMR (CDCI3): 7.50 (dt, J = 7.6, 1.7 Hz, 1 H), 7.24-7.21 (m, 1 H), 7.12 (dt, J = 7.6, 1.0 Hz, 1 H), 7.06-6.99 (m, 1 H), 6.75 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.56 (d, J = 2.3 Hz, 1 H), 5.60 (q, J = 6.4 Hz, 1 H), 5.00- 4.94 (m, 1 H), 4.00-3.79 (m, 4H), 1.67 (d, J = 6.4 Hz, 3H). Example 122: (+)-3-[5-Chloro-2-[1 -(2-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000109_0001
MS (ESI): mass calcd. for Ci8Hi7CIF3NO2, 371.1 ; m/z found, 372.0 [M+H]+. 1H NMR (CDCI3): 7.85 (d, J = 7.9 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.56 (t, J = 7.7 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 6.72 (dd, J = 8.6, 2.3 Hz, 1 H), 6.67 (d, J = 8.6 Hz, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 5.68 (q, J = 6.2 Hz, 1 H), 5.00- 4.94 (m, 1 H), 4.01 -3.79 (m, 4H), 1.66 (d, J = 6.3 Hz, 3H).
Example 123: (+)-3-[5-Chloro-2-[1 -(4-chloro-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000109_0002
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 337.1 ; m/z found, 338.0 [M+H]+. 1H NMR (CDCI3): 7.30 (s, 4H), 6.74 (dd, J = 8.6, 2.4 Hz, 1 H), 6.65 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.21 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.96-3.83 (m, 4H), 1.64 (d, J = 6.5 Hz, 3H).
Example 124: (+)-3-[5-Chloro-2-[1 -(4-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000109_0003
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.1 ; m/z found, 322.0
[M+H]+. 1H NMR (CDCI3): 7.39-7.29 (m, 2H), 7.06-6.97 (m, 2H), 6.74 (dd, J = 8.6, 2.4 Hz, 1 H), 6.66 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.22 (q, J 6.4 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.99-3.78 (m, 4H), 1.64 (d, J = 6.4 Hz, 3H). Example 125: (+)-3-f1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1- benzonitrile.
Figure imgf000110_0001
MS (ESI): mass calcd. for Ci8Hi7CIN2O2, 328.1 ; m/z found, 329.1 [M+H]+. 1H NMR (CDCI3): 7.76 (s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.57 (td, J = 7.7, 1.3 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 5.27 (q, J = 6.6 Hz, 1 H), 5.01 -4.95 (m, 1 H), 4.02-3.76 (m, 4H), 1.65 (d, J = 6.5 Hz, 3H).
Example 126: (+)-3-f5-Chloro-2-f1 -(3,4-dichloro-phenyl)-ethoxy1-phenoxy1- azetidine.
Figure imgf000110_0002
MS (ESI): mass calcd. for Ci7Hi6CI3NO2, 371.0; m/z found, 372.0 [M+H]+. 1H NMR (CDCI3): 7.52 (d, J = 2.0 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J = 8.3, 2.0 Hz, 1 H), 6.77 (dd, J = 8.6, 2.4 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.18 (q, J = 6.5 Hz, 1 H), 4.99-4.93 (m, 1 H), 4.00-3.76 (m, 4H), 1.63 (d, J = 6.5 Hz, 3H).
Example 127: (+)-3-f5-Chloro-2-f1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000110_0003
MS (ESI): mass calcd. for Ci8Hi7CIF3NO3, 387.1 ; m/z found, 388.0 [M+H]+. 1H NMR (CDCI3): 7.36 (t, J = 8.1 Hz, 1 H), 7.30-7.27 (m, 2H), 7.16-7.08
(m, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.25 (q, J = 6.4 Hz, 1 H), 5.00-4.93 (m, 1 H), 3.98-3.77 (m, 4H), 1.65 (d, J = 6.5 Hz, 3H).
Example 128: (+)-3-r5-Chloro-2-π -(3.4-difluoro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
Figure imgf000111_0001
MS (ESI): mass calcd. for Ci7Hi6CIF2NO2, 339.1 ; m/z found, 340.1 [M+H]+. 1H NMR (CDCI3): 7.21 -7.09 (m, 2H), 7.08-7.02 (m, 1 H), 6.85 (dd, J = 8.7, 2.4 Hz, 1 H), 6.68 (d, J = 2.4 Hz, 1 H), 6.65 (d, J = 8.8 Hz, 1 H), 5.20 (q, J 6.4 Hz, 1 H), 5.13-5.05 (m, 1 H), 4.44-4.32 (m, 4H), 1.62 (d, J = 6.4 Hz, 3H).
Example 129: (+)-3-r5-Chloro-2-H -(2,5-dichloro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
Figure imgf000111_0002
MS (ESI): mass calcd. for Ci7Hi6CI3NO2, 371.0; m/z found, 372.0 [M+H]+. 1H NMR (CDCI3): 7.43 (d, J = 2.5 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.19 (dd, J = 8.5, 2.5 Hz, 1 H), 6.86 (dd, J = 8.7, 2.4 Hz, 1 H), 6.69 (d, J = 2.4 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 5.59 (q, J = 6.3 Hz 1 H), 5.14 (s, 1 H), 4.49- 4.37 (m, 4H), 1.63 (d, J = 6.4 Hz, 3H).
Example 130: (+)-3-r5-Chloro-2-π -(2,5-difluoro-phenyl)-ethoxy1-phenoxy1- azetidine trifluoroacetate.
Figure imgf000111_0003
MS (ESI): mass calcd. for Ci7Hi6CIF2NO2, 339.1 ; m/z found, 340.0 [M+H]+. 1H NMR (CDCI3): 7.43 (d, J = 2.5 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.19 (dd, J = 8.5, 2.5 Hz, 1 H), 6.86 (dd, J = 8.7, 2.4 Hz, 1 H), 6.69 (d, J = 2.4 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 5.59 (q, J = 6.3 Hz, 1 H), 5.14 (s, 1 H), 4.47- 4.34 (m, 4H), 1.63 (d, J = 6.4 Hz, 3H).
Example 131 : 2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethvπ-benzothiazole.
Figure imgf000112_0001
MS (ESI): mass calcd. for Ci8Hi7CIN2O2S, 360.1 ; m/z found, 361.0 [M+H]+. 1H NMR (CDCI3): 8.01 -7.99 (m, 1 H), 7.92-7.86 (m, 1 H), 7.48 (ddd, J = 8.3, 7.3, 1.3 Hz, 1 H), 7.39 (ddd, J = 8.3, 7.3, 1.2 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 6.80 (dd, J = 8.6, 2.4 Hz, 1 H), 6.59 (d, J = 2.4 Hz, 1 H), 5.66 (q, J = 6.5 Hz, 1 H), 5.01 -4.95 (m, 1 H), 3.95-3.88 (m, 2H), 3.86-3.80 (m, 2H), 1.86 (d, J = 6.5 Hz, 3H).
Example 132: 5-[1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1-thiazole.
Figure imgf000112_0002
MS (ESI): mass calcd. for Ci4Hi5CIN2O2S, 310.1 ; m/z found, 311.0
[M+H]+. 1H NMR (CDCI3): 8.77 (s, 1 H), 7.73 (s, 1 H), 6.83-6.77 (m, 2H), 6.57- 6.56 (m, 1 H), 5.56 (q, J = 6.4 Hz, 1 H), 5.02-4.89 (m, 1 H), 3.98-3.90 (m, 2H), 3.87-3.75 (m, 2H), 1.77 (d, J = 6.4 Hz, 3H). Example 133: 2-[1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1-thiazole.
Figure imgf000113_0001
MS (ESI): mass calcd. for Ci4Hi5CIN2O2S, 310.1 ; m/z found, 311.1 [M+H]+. 1H NMR (CDCI3): 7.74 (d, J = 3.2 Hz, 1 H), 7.33 (d, J = 3.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 6.81 (dd, J = 8.6, 2.3 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 5.59 (q, J = 6.5 Hz, 1 H), 5.02-4.92 (m, 1 H), 4.04-3.72 (m, 4H), 1.79 (dd, J = 6.4, 2.2 Hz, 3H).
Example 134: 5-[1 -r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-ethyl1-2,4-dimethyl- thiazole.
Figure imgf000113_0002
MS (ESI): mass calcd. for Ci6Hi9CIN2O2S, 338.1 ; m/z found, 339.1 [M+H]+. 1H NMR (CDCI3): 6.78 (dd, J = 8.5, 2.4 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.48 (q, J = 6.4 Hz, 1 H), 5.00-4.90 (m, 1 H), 4.02- 3.76 (m, 4H), 2.63 (s, 3H), 2.19 (s, 3H), 1.69 (d, J = 6.4 Hz, 3H).
Example 135: (R)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy1-phenoxy1- piperidine.
Figure imgf000113_0003
MS (ESI): mass calcd. for C20H2iCIF3NO2, 399.1 ; m/z found, 400.0 [M+H]+. 1H NMR (CDCI3): 7.68 (s, 1 H), 7.57-7.52 (m, 2H), 7.45 (t, J = 7.7 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.77 (d, J = 8.6, 2.4 Hz, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 5.30 (q, J = 6.4 Hz, 1 H), 4.36-4.32 (m, 1 H), 3.17 (br s, 2H), 2.74 (br s, 2H), 2.02 (br s, 2H), 1.72 (br s, 2H), 1.64 (d, J = 6.4 Hz, 3H). Example 136: (+)-4-r5-Chloro-2-H -(3-chloro-phenyl)-ethoxy1-phenoxy1- piperidine.
Figure imgf000114_0001
MS (ESI): mass calcd. for Ci9H2ICI2NO2, 349.1 ; m/z found, 350.1 [M+H]+. 1H NMR (CDCI3): 7.40 (s, 1 H), 7.29-7.19 (m, 3H), 6.89 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 5.21 (q, J = 6.4 Hz, 1 H), 4.38-4.27 (m, 1 H), 3.17 (td, J = 7.8, 4.6 Hz, 2H), 2.72 (ddd, J = 12.5, 9.3, 3.2 Hz, 2H), 2.09-1.93 (m, 2H), 1.79-1.66 (m, 2H), 1.62 (d, J = 6.5 Hz, 3H).
Example 137: (+)-4-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy1- phenoxyi-piperidine.
Figure imgf000114_0002
MS (ESI): mass calcd. for C20H21CIF3NO3, 415.1 ; m/z found, 416.0 [M+H]+. 1H NMR (CDCI3): 7.36 (t, J = 7.9 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 5.26 (q, J = 6.4 Hz, 1 H), 4.43-4.24 (m, 1 H), 3.22-3.09 (m, 2H), 2.73 (ddd, J = 12.5, 9.2, 3.1 Hz, 2H), 2.02 (d, J = 9.1 Hz, 2H), 1.72 (dt, J = 12.7, 9.0, 2H), 1.63 (d, J = 6.4 Hz, 3H).
Example 138: (+)-4-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy1-phenoxy1- piperidine.
Figure imgf000114_0003
MS (ESI): mass calcd. for C19H21CIFNO2, 349.1 ; m/z found, 350.0 [M+H]+. 1H NMR (CDCI3): 7.50 (dt, J = 7.6, 1.7 Hz, 1 H), 7.26-7.20 (m, 1 H), 7.12 (dt, J = 7.5, 1.0 Hz, 1 H), 7.02 (ddd, J = 10.2, 8.2, 1.1 Hz, 1 H), 6.89 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 8.7, 2.4 Hz, 1 H), 6.69 (d, J = 8.7 Hz, 1 H), 5.59 (q, J = 6.4 Hz, 1 H), 4.38-4.27 (m, 1 H), 3.16 (td, J = 9.8, 4.6 Hz, 2H), 2.71 (ddd, J = 12.4, 9.3, 3.1 Hz, 2H), 2.01 (ddd, J = 13.2, 5.0, 3.0 Hz, 2H), 1.72 (ddt, J = 11.7, 8.3, 3.1 Hz, 2H), 1.64 (d, J = 6.4 Hz, 3H).
Example 139: (R,S)-3-r5-Chloro-2-[1 -((R)-3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-piperidine.
Figure imgf000115_0001
H
MS (ESI): mass calcd. for C20H21CIF3NO2, 399.1 ; m/z found, 400.0 [M+H]+. 1H NMR (CDCI3): 7.68 (s, 1 H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 1 H), 6.92 (dd, J = 2.4, 1.1 Hz, 1 H), 6.79-6.76 (m, 1 H), 6.69 (dd, J = 8.6, 6.1 Hz, 1 H), 5.33-5.26 (m, 1 H), 4.24-4.17 (m, 1 H), 3.14-3.11 (m, 1 H), 2.89-2.73 (m, 3H), 2.05-1.98 (m, 1 H), 1.87-1.73 (m, 2H), 1.64 (d, J = 6.5 Hz, 3H), 1.54-1.45 (m, 1 H).
Example 140: (+)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy1- phenoxyi-azetidine.
Figure imgf000115_0002
MS (ESI): MS (ESI): mass calcd. for Ci9Hi9CIF3NO2, 385.1 ; m/z found, 386.0 [M+H]+. 1H NMR (CDCI3): 7.66 (s, 1 H), 7.52 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1 H), 6.73 (dd, J = 8.6, 2.4 Hz, 1 H), 6.65 (d, J = 8.6 Hz, 1 H), 6.54 (d, J == 2.4 Hz, 1 H), 5.05-5.00 (m, 1 H), 4.99-4.92 (m, 1 H), 4.01 -3.72 (m, 4H), 2.31 - 1.97 (m, 1 H), 1.97-1.83 (m, 1 H), 1.02 (t, J = 7.4 Hz, 3H). Example 141 : (+)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy1- phenoxyi-piperidine.
Figure imgf000116_0001
MS (ESI): mass calcd. for C2IH23CIF3NO2, 413.1 ; m/z found, 414.0 [M+H]+. 1H NMR (CDCI3): 7.61 (s, 1 H), 7.51 (dd, J = 7.4, 4.4 Hz, 2H), 7.47- 7.40 (m, 1 H), 6.88 (d, J = 2.5 Hz, 1 H), 6.72 (dd, J = 8.6, 2.5 Hz, 1 H), 6.61 (d, J = 8.7 Hz, 1 H), 5.05 (t, J = 6.3 Hz, 1 H), 4.37-4.28 (m, 1 H), 3.23-3.10 (m, 2H), 2.71 (ddd, J = 12.6, 9.4, 3.2 Hz, 2H), 2.13-1.97 (m, 3H), 1.96-1.84 (m, 1 H), 1.76-1.65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).
Example 142: 3-r5-Bromo-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000116_0002
MS (ESI): mass calcd. for Ci7Hi7BrFNO2, 365.0; m/z found, 366.0 [M+H]+. 1H NMR (CDCI3): 7.41 -7.30 (m, 5H), 6.88 (dd, J = 8.6, 2.3 Hz, 1 H), 6.69 (dd, J = 13.3, 5.4 Hz, 2H), 5.35 (ddd, J = 14.3, 7.7, 3.3 Hz, 1 H), 5.00-4.93 (m, 1 H), 4.75 (ddd, J = 48.0, 10.1 , 7.7 Hz, 1 H), 4.59 (ddd, J = 46.7, 10.1 , 3.4 Hz, 1 H), 3.93-3.79 (m, 4H).
Example 143: 3-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000116_0003
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.1 ; m/z found, 322.1 [M+H]+. 1H NMR (CDCI3): 7.42-7.31 (m, 5H), 6.75-6.71 (m, 2H), 6.56 (s, 1 H), 5.35 (ddd, J = 14.3, 7.7, 3.3 Hz, 1 H), 5.00 (s, 1 H), 4.75 (ddd, J = 48.0, 10.0, 7.7, Hz, 1 H), 4.59 (ddd, J = 46.7, 10.1 , 3.3 Hz, 1 H), 4.26-3.53 (m, 4H).
Example 144: (+)-4-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy1-piperidine.
Figure imgf000117_0001
MS (ESI): mass calcd. for C19H21CIFNO2, 349.1 ; m/z found, 350.1 [M+H]+. 1H NMR (CDCI3): δ 7.45-7.28 (m, 5H), 6.90 (d, J = 2.2 Hz, 1 H), 6.77- 6.67 (m, 2H), 5.36 (ddd, J = 14.5, 7.6, 3.3 Hz, 1 H), 4.80-4.50 (m, 2H), 4.35 (dt, J = 12.3, 4.0 Hz, 1 H), 3.14 (dd, J = 12.0, 4.9 Hz, 2H), 2.70 (dd, J = 11.9, 9.7 Hz, 2H), 2.00 (dd, J = 7.9, 3.9 Hz, 2H), 1.77-1.62 (m, 2H).
Example 145: (±)-3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000117_0002
Step A: Preparation of 1 -[3-(5-Chloro-2-hvdroxy-phenoxy)-azetidin-1 -vH- 2,2,2-thfluoro-ethanone. To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester (0.80 g, 2.7 mmol) in EtOAc (2 ml_) was added 4M HCI in dioxane (5 ml_). After 18h, EtOAc was added and the resulting white solid filtered to give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a white solid. To a CH2CI2 (25 ml_) solution of this compound was added Et3N (0.30 g, 0.42 ml_, 3.0 mmol) and TFAA (0.58 g, 0.38 ml_, 2.8 mmol). After 18h, H2O was added and the reaction extracted with CH2CI2 (2X). The combined organics were dried and concentrated to give 0.54 g (74% yield 2 steps) of the title compound as a brown oil that was used in the next step without further purification. Step B: Preparation of (±)-1 -r3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1- azetidin-1 -yl1-2,2,2-thfluoro-ethanone. To the title compound of Step A (0.17 g, 0.56 mmol) in DMF (3 ml_) was added Cs2CO3 (0.25 g, 0.80 mmol), Kl (0.09 g, 0.55 mmol) and (i -bromoethyl)-benzene (0.10 g, 0.08 ml_, 0.56 mmol). After 15h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 0.14 g (64%) of the title compound. 1H NMR (CDCI3): 7.37-7.27 (m, 5H), 6.82 (dd, J = 8.7, 2.4 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 5.2 (q, J = 6.5 Hz, 1 H), 5.0- 4.9 (m, 1 H), 4.75-4.69 (m, 1 H), 4.52-4.42 (m, 2H), 4.32-4.21 (m, 1 H), 1.67 (d, J = 6.4 Hz, 3H).
Step C: Preparation of (±)-3-r5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy1- azetidine. To the title compound of Step B in MeOH (4 ml_) was added K2CO3 (0.10 g, 0.72 mmol). After 15h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were dried and concentrated. Silica gel chromatography (1 -7 2M NH3/MeOH in CH2CI2) gave 0.75 g (68% yield) of the title compound. MS (ESI): mass calcd. for Ci7H18CINO2, 303.10; m/z found, 304.1 [M+H]+. 1H NMR (CDCI3): 7.38-7.31 (m, 4H), 7.28-7.24 (m, 1 H), 6.72
(dd, J = 8.6, 2.4 Hz, 1 H), 6.67 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 5.23 (q, J = 6.4 Hz, 1 H), 4.99-4.93 (m, 1 H), 3.95-3.81 (m, 4H), 1.66 (d, J = 6.5 Hz, 3H).
Example 146: (±)-3-r5-Chloro-2-ri -(5-thfluoromethyl-furan-2-yl)-ethoxy1- phenoxyi-azetidine.
Figure imgf000118_0001
Step A: Preparation of 1 -(5-Trifluoromethyl-furan-2-yl)-ethanol. To 5- trifluoromethyl-furan-2-carbaldehyde (0.76 g, 4.6 mmol) in THF (20 ml_) at 0 0C was added MeMgBr (3M in Et2O, 3 ml_, 6 mmol) dropwise over 1 h. After an additional 1 h, ΛA saturated NH4CI (aq.) was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried to give 0.81 g (97%) of the title compound. 1H NMR (CDCI3): 6.74-6.73 (m, 1 H), 6.32-6.31 (m, 1 H), 4.91 (q, J = 6.5 Hz, 1 H), 1.57 (d, J = 6.6 Hz, 3H). Step B: Preparation of 1 -(3-r5-Chloro-2-ri -(5-trifluoromethyl-furan-2-yl)- ethoxy1-phenoxy1-azetidin-1 -yl)-2,2,2-trifluoro-ethanone: Prepared from the title compound of Step A and the title compound of Example 145 Step A using general procedure 7. 1H NMR (CDCI3): 6.94 (dd, J = 8.6, 2.3 Hz, 1 H), 6.88 (dd, J = 8.7, 1.4 Hz, 1 H), 6.73 (m, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 6.33 (d, J = 3.3 Hz, 1 H), 5.27-5.22 (m, 1 H), 5.01 -4.94 (m, 1 H), 4.76-4.69 (m, 1 H), 4.52-4.44 (m, 2H), 4.27-4.21 (m, 1 H), 1.74 (d, J = 6.6 Hz, 3H).
Step C: Preparation of (±)-3-r5-Chloro-2-ri-(5-trifluoromethyl-furan-2-yl)- ethoxyi-phenoxyi-azetidine: Prepared from the title compound of Step B according to Example 145 Step C. MS (ESI): mass calcd. for Ci6H15CIF3NO3, 361.1 ; m/z found, 362.0 [M+H]+. 1H NMR (CDCI3): 6.84-6.79 (m, 2H), 6.72- 6.71 (m, 1 H), 6.57 (d, J = 1.9 Hz, 1 H), 6.32 (d, J = 3.4 Hz, 1 H), 5.24 (q, J = 6.6 Hz, 1 H), 4.98-4.92 (m, 1 H), 3.93-3.82 (m, 4H), 1.72 (d, J = 6.6 Hz, 3H).
Example 147: 3-[5-Chloro-2-(1 -phenyl-propoxy)-phenoxy1-azetidine.
Figure imgf000119_0001
Synthesized according to Example 146 using 1 -phenyl-propan-1 -ol. MS (ESI): mass calcd. for Ci8H20CINO2, 317.1 ; m/z found, 318.1 [M+H]+. 1H NMR (CDCI3): 7.33-7.23 (m, 5H), 6.70 (dd, J = 8.6, 2.4 Hz, 1 H), 6.62 (d, J = 8.6 Hz, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 4.97-4.92 (m, 2H), 4.03-3.78 (m, 4H), 2.11 -2.02 (m, 1 H), 1.95-1.85 (m, 1 H), 1.01 (t, J = 7.4 Hz, 3H).
Example 148: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-2-phenyl-ethanol.
Figure imgf000119_0002
Step A: Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl- methoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. To 3-(5-Chloro- 2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (1.1 g, 3.7 mmol) in DMF (18 ml_) was added CS2CO3 (1.5 g, 4.4 mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 ml_, 4.0 mmol). After 15h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 1.6 g (96%) of the title compound. 1H NMR (CDCI3): 7.55-7.33 (m, 2H), 7.43-7.36 (m, 3H), 6.85 (d, J=1.2, 2H), 6.51 (t, J=1.2 Hz, 1 H), 5.58 (s, 1 H), 4.91-4.85 (m, 1 H), 4.31 -4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.89-3.74 (m, 3H), 1.46 (s, 9H).
Step B: Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl- methoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. To the title compound of Step A (0.22 g, 0. 50 mmol) in THF at 0 0C was added LiBH4 (2M in THF, 0.4 ml_, 0.8 mmol). After 2h, 1 N KHSO4 (aq.) was added and the mixture extracted with EtOAc (2X). The combined organic layers were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 0.17 g (82%) of the title compound. 1H NMR (CDCI3): 7.36-7.30 (m, 5H), 6.75 (dd, J = 8.6, 2.3 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 1 H), 6.51 (d, J = 2.3 Hz, 1 H), 5.09 (dd, J = 8.7, 3.4 Hz, 1 H), 4.90-4.85 (m, 1 H), 4.35-4.30 (m, 2H), 4.15-3.94 (m, 4H), 3.80-3.77 (m, 1 H), 1.47 (s, 9H).
Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-2- phenyl-ethanol. Prepared from the title compound of Step B according to general procedure 1. MS (ESI): mass calcd. for Ci7Hi8CINO3, 319.1 ; m/z found, 320.1 [M+H]+. 1H NMR (DMSO-D6): 7.40 (m, 5H), 6.94-6.69 (m, 3H), 5.32-5.28 (m, 1 H), 5.11-4.79 (m, 2H), 3.80-3.75 (m, 3H), 3.61 (dd, J = 11.4, 4.1 Hz, 1 H), 3.54-3.20 (m, 2H).
Example 149: r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-phenyl-acetic acid hydrochloride.
Figure imgf000120_0001
Step A: Preparation of 3-[2-(Carboxy-phenyl-methoxy)-5-chloro- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester. To the title compound of Example 148 Step A (0.16 g, 0.36 mmol) in MeOH (3 ml_) was added 1 N NaOH (3 ml_). After 18h, the solution was acidified with 1 N KHSO4 and extracted with EtOAc (2X). The combined organics were washed with brine and dried to give 0.16 g (>98%) of the title compound. 1H NMR (CDCI3): 8.56-8.19 (broad s, 1 H), 7.55-7.51 (m, 2H), 7.41 -7.36 (m, 3H), 6.85-6.84 (m, 2H), 6.54 (s, 1 H), 5.55 (s, 1 H), 4.88-4.83 (m, 1 H), 4.29-4.24 (m, 2H), 4.06-3.97 (m, 2H), 1.44 (s, 9H). Step B: Preparation of [2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-phenyl- acetic acid hydrochloride. Prepared from the title compound of Step A according to general procedure 1. MS (ESI): mass calcd. for Ci7Hi6CINO4, 333.1 ; m/z found, 334.1 [M+H]+. 1H NMR (DMSO-D6): 13.3 (s, 1 H), 9.27 (s, 2H), 7.58-7.56 (m, 2H), 7.46-7.37 (m, 3H), 7.05-6.99 (m, 2H), 6.96 (d, J = 2.2 Hz, 1 H), 5.86 (s, 1 H), 5.11-5.06 (m, 1 H), 4.45-4.37 (m, 2H), 4.05-3.98 (m, 2H).
Example 150: (±)-3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000121_0001
Step A: Preparation of (±)-6-fluoro-indan-1-ol. To a solution of 6-fluoro- indan-1 -one (0.50 g, 3.3 mmol) in DCE (10 ml_) and MeOH (10 ml_) was added NaBH4 (0.25 g, 6.6 mmol). After 30 min the reaction was quenched with H2O (10 ml_) and extracted with CH2CI2 (3 x 20 ml_). The organic layers were combined and dried to give the title compound (0.49 g, 97%). MS (ESI): mass calcd. for C9H7FO, 150.1 ; m/z found, 151.4 [M+H]+. 1H NMR (CDCI3): 7.23 - 7.13 (m, 1 H), 7.09 (dd, J = 8.6, 2.5 Hz, 1 H), 6.99 - 6.90 (m, 1 H), 5.21 (t, J = 6.3 Hz, 1 H), 3.13 - 2.91 (m, 1 H), 2.85 - 2.68 (m, 1 H), 2.63 - 2.44 (m, 1 H), 2.09 - 1.74 (m, 2H). Step B: Preparation of 1 -[3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1- azetidin-1 -yl1-2,2,2-thfluoro-ethanone. Prepared from the title compound of Step A and the title compound of Example 145 Step A according to the general procedure 7.
Step C: Preparation of 3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy1- azetidine. Prepared from the title compound of Step B using general procedure 2. MS (ESI): mass calcd. for Ci8Hi7CIFNO2, 333.1 ; m/z found, 334.1 [M+H]+. 1H NMR (CDCI3): 7.23 (dd, J = 8.2, 5.0 Hz, 1 H), 7.10 - 6.87 (m, 4H), 6.65 (s, 1 H), 5.68 - 5.53 (m, 1 H), 4.94 (s, 1 H), 4.15 - 4.06 (m, 4H), 3.19 - 2.99 (m, 1 H), 2.97 - 2.66 (m, 1 H), 2.67 - 2.43 (m, 1 H), 2.40 - 2.17 (m, 1 H).
Unless otherwise specified the compounds in Examples 151-161 were prepared according to Example 150 using the appropriately substituted phenol and alcohol.
Example 151 : (±)-3-[5-Bromo-2-(indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000122_0001
MS (ESI): mass calcd. for Ci8Hi8BrNO2, 359.1 ; m/z found, 360.0 [M+H]+. 1H NMR (CDCI3): 7.40 - 7.16 (m, 4H), 7.11 (d, J = 8.5 Hz, 1 H), 7.05 - 6.90 (m, 2H), 5.67 (d, J = 3.4 Hz, 1 H), 4.05 - 3.84 (m, 2H), 3.82 - 3.52 (m, 2H), 3.24 - 3.10 (m, 1 H), 2.93 (d, J = 4.5 Hz, 1 H), 2.65 - 2.43 (m, 1 H), 2.34 - 2.17 (m, 2H).
Example 152: (±)-3-[5-Bromo-2-(5-chloro-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000122_0002
MS (ESI): mass calcd. for Ci8Hi7BrCINO2, 393.0; m/z found, 394.0 [M+H]+. 1H NMR (CDCI3): 7.36 - 7.12 (m, 4H), 7.00 - 6.87 (m, 1 H), 6.79 (s, 1 H), 5.65 (s, 1 H), 4.98 - 4.74 (m, 1 H), 4.46 - 4.29 (m, 1 H), 4.29 - 4.04 (m, 2H), 3.25 - 3.10 (m, 1 H), 3.03 - 2.83 (m, 1 H), 2.60 - 2.46 (m, 1 H), 2.36 - 2.20 (m, 2H). Example 153: (±)-3-r5-Bromo-2-(6-chloro-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000123_0001
MS (ESI): mass calcd. for Ci8Hi7BrCINO2, 393.0; m/z found, 394.0 [M+H]+. 1H NMR (CDCI3): 7.42 - 7.09 (m, 5H), 7.02 - 6.83 (m, 1 H), 5.62 (s, 1 H), 4.38 (s, 1 H), 4.27 - 3.90 (m, 2H), 3.73 - 3.54 (m, 1 H), 3.12 (s, 1 H), 2.90 (s, 1 H), 2.53 (s, 1 H), 2.35 - 2.14 (m, 2H).
Example 154: (±)-3-[5-Bromo-2-(5-fluoro-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000123_0002
MS (ESI): mass calcd. for Ci8Hi7BrFNO, 377.0; m/z found, 378.0
[M+H]+. 1H NMR (CDCI3): 7.23 (d, J = 5.2, 1 H), 7.13 - 7.03 (m, 1 H), 6.98 - 6.79 (m, 4H), 4.95 - 4.68 (m, 1 H), 4.37 - 3.96 (m, 4H), 3.08 (s, 1 H), 2.86 (s, 1 H), 2.53 - 2.38 (m, 1 H), 2.31 - 2.11 (m, 2H).
Example 155: (±)-3-[5-Bromo-2-(5-methyl-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000123_0003
MS (ESI): mass calcd. for Ci9H20BrNO2, 373.1 ; m/z found, 374.0 [M+H]+. 1H NMR (CDCI3): 7.25 - 7.10 (m, 4H), 7.04 - 6.78 (m, 2H), 5.65 (s, 2H), 4.31 (s, 1 H), 4.12 (s, 2H), 3.10 (s, 1 H), 2.89 (s, 1 H), 2.46 (s, 2H), 2.35 (d, J = 6.6 Hz, 4H). Example 156: (±)-3-[5-Bromo-2-(6-methyl-irιdan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000124_0001
MS (ESI): mass calcd. for Ci9H20BrNO2, 373.1 ; m/z found, 374.0 [M+H]+. 1H NMR (CDCI3): 7.36 - 7.18 (m, 3H), 7.08 (d, J = 8.2, 1 H), 7.02 - 6.92 (m, 2H), 5.67 (d, J = 3.4 Hz, 1 H), 4.02 - 3.84 (m, 2H), 3.80 - 3.53 (m, 2H), 3.24 - 3.10 (m, 1 H), 2.93 (d, J = 4.5 Hz, 1 H), 2.65 - 2.46 (m, 1 H), 2.37 - 2.18 (m, 5H).
Example 157: (±)-3-[5-Bromo-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy1- azetidine.
Figure imgf000124_0002
MS (ESI): mass calcd. for Ci9Hi7BrF3NO2, 427.1 ; m/z found, 429.0 [M+H]+. 1H NMR (CDCI3): 7.69 - 7.35 (m, 3H), 7.07 (dd, J = 8.5, 2.3 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 6.76 (d, J = 2.3 Hz, 1 H), 5.72 - 5.56 (m, 1 H), 4.95 (s, 1 H), 3.91 (s, 4H), 3.21 (d, J = 9.4 Hz, 1 H), 3.07 - 2.85 (m, 1 H), 2.61 - 2.46 (m, 1 H), 2.42 - 2.22 (m, 1 H).
Example 158: (±)-3-[5-Chloro-2-(6-methyl-indan-1 -yloxy)-phenoxy1-azetidine. .
Figure imgf000124_0003
MS (ESI): mass calcd. for CI9H20CINO2, 329.1 ; m/z found, 330.4 [M+H]+. 1H NMR (CDCI3): 7.22 - 7.08 (m, 3H), 7.02 - 6.89 (m, 2H), 6.67 - 6.60 (m, 1 H), 5.63 (dd, J = 6.5, 4.1 Hz, 1 H), 4.96 - 4.86 (m, 1 H), 4.04-3.72 (m, 4H), 3.21 - 3.02 (m, 1 H), 2.94 - 2.77 (m, 1 H), 2.57 - 2.40 (m, 1 H), 2.33 (d, J = 8.2 Hz, 3H), 2.29 - 2.17 (m, 1 H). Example 159: (±)-3-[5-Chloro-2-(6-chlorc)-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000125_0001
MS (ESI): mass calcd. for Ci8Hi7CI2NO2, 349.1 ; m/z found, 350.0 [M+H]+. 1H NMR (CDCI3): 7.38 - 7.19 (m, 3H), 7.06 - 6.93 (m, 2H), 6.76 - 6.59 (m, 1 H), 5.74 - 5.54 (m, 1 H), 5.05 - 4.78 (m, 1 H), 4.30 - 3.89 (m, 3H), 3.13 (d, J = 8.2 Hz, 1 H), 2.91 (d, J = 5.1 Hz, 1 H), 2.63 - 2.45 (m, 1 H), 2.27 (s, 1 H), 2.19 (s, 1 H).
Example 160: 3-[5-Chloro-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy1- azetidine.
Figure imgf000125_0002
MS (ESI): mass calcd. for Ci9Hi7CIF3NO2, 383.1 ; m/z found, 384.1 [M+H]+. 1H NMR (CDCI3): 7.74 - 7.40 (m, 3H), 7.03 - 6.88 (m, 2H), 6.65 (d, J = 2.2 Hz, 1 H), 5.73 - 5.59 (m, 1 H), 4.99 (s, 1 H), 4.33 - 3.65 (m, 2H), 3.23 (s, 1 H), 3.01 (s, 2H), 2.68 - 2.48 (m, 2H), 2.44 - 2.31 (m, 1 H).
Example 161 : 3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-1 -yloxy)-phenoxy1- azetidine.
Figure imgf000125_0003
MS (ESI): mass calcd. for CI9H20CINO2, 329.1 ; m/z found, 330.2 [M+H]+.
1H NMR (CDCI3): 7.29 - 7.13 (m, 4H), 7.01 (d, J = 8.7 Hz, 3H), 5.27 (s, 1 H), 4.96 - 4.71 (m, 1 H), 4.08 (s, 3H), 2.91 (s, 1 H), 2.79 (s, 1 H), 2.19 - 2.04 (m, 4H), 1.86 (s, 1 H). Example 162: 3-[5-Bromo-2-(5-tert-butyl-indan-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000126_0001
Step A: Preparation of 1 -(4-tert-Butyl-phenyl)-3-chloro-propan-1-one. To a solution of te/t-butyl benzene (1.0 g, 7.5 mmol) and 3-chloropropionyl chloride (0.7 ml_, 7.5 mmoL) in CH2CI2 (20 ml_) was added dropwise to a suspension of AICI3 (1.1 g, 8.2 mmol) in CH2CI2 (10 ml_) at 0 0C. The reaction was allowed to warm to rt. After 15 h, the reaction was quenched with H2O (10 ml_) and extracted with CH2CI2 (2 x 20 ml_). The organic layers were combined and dried to give the title compound that was used without further purification (1.3 g).
Step B.: Preparation of 5-fe/f-butyl-indan-1-one. The title compound of Step A (1.3 g, 5.8 mmol) was dissolved in cone. H2SO4 (10 ml_) and heated at 95 0C for 3 h. The reaction mixture was cooled to rt, poured onto ice, and extracted with Et2O (3 x 25 ml_). The combined organic extracts were washed with sat'd NaHCO3 (aq.) and dried to provide the title compound (0.74 g, 68%). MS (ESI): mass calcd. for Ci3Hi6O, 188.1 ; m/z found, 189.2 [M+H]+. 1H NMR (CDCI3): 7.67 - 7.58 (m, 1 H), 7.44 - 7.32 (m, 2H), 3.09 - 3.02 (m, 2H), 2.65 - 2.68 (m, 2H), 1.27 (d, J = 8.5 Hz, 9H).
Step B.: Preparation of 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)- phenoxyi-azetidine. MS (ESI): mass calcd. for C22H26BrNO2, 415.1 ; m/z found, 418.1 [M+H]+. 1H NMR (CDCI3): 7.38 - 7.13 (m, 4H), 7.08 - 6.84 (m, 2H), 5.71 (s, 1 H), 4.32 (s, 2H), 3.71 - 3.50 (m, 2H), 3.14 (s, 1 H), 2.94 (s, 1 H), 2.53 (s, 1 H), 2.24 (s, 2H), 1.43 - 1.20 (m, 9H).
Example 163: 3-[5-Chloro-2-(tetrahvdro-furan-3-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000126_0002
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), tetrahydro-furan-3-yl-methanol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 ml_) was heated at 120 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(tetrahydro-furan-3-ylmethoxy)- phenoxy]-azetidine-1 -carboxylic acid tert-butyl ester (120 mg). To this compound was added CH2CI2 (20 ml_) and TFA (3 ml_). After 4 h at rt the mixture was concentrated to give the title compound (161 mg). MS (ESI): mass calcd. for Ci4Hi8CINO3, 283.1 ; m/z found, 284.0 [M+H]+. 1H NMR (MeOD): 7.05-6.96 (m, 2H), 6.88 (d, J = 1.9 Hz, 1 H), 5.15-5.05 (m, 1 H), 4.57-4.48 (m, 2H), 4.28-4.19 (m, 2H), 4.04-3.88 (m 4H), 3.82-3.70 (m 2H), 2.82-2.70 (m, 1 H), 2.20-2.09 (m, 1 H), 1.84-1.73 (m, 1 H).
The compounds in Examples 164-174 were prepared according to Example 163 with the appropriate alcohols.
Example 164: 3-[5-Chloro-2-(1 ,2,3,4-tetrahvdro-naphthalen-2-yloxy)-phenoxy1- azetidine.
Figure imgf000127_0001
MS (ESI): mass calcd. for CI9H20CINO2, 329.1 ; m/z found, 330.0 [M+H]+.
1H NMR (MeOD): 7.18-6.90 (m, 7H), 4.98-4.89 (m, 1 H), 4.87-4.78 (m, 1 H), 4.35-4.25 (m, 2H), 4.12-3.95 (m, 2H), 3.30-2.80 (m, 4H), 2.18-2.02 (m, 2H). Example 165: 3-r5-Chloro-2-(chroman-2-ylmethoxy)-phenoxy1-azetidine.
Figure imgf000128_0001
MS (ESI): mass calcd. for Ci9H20CINO3, 345.1 ; m/z found, 346.1 [M+H]+. 1H NMR (400 MHz, CDCI3): 7.13-6.75 (m, 7H), 5.15-4.98 (m, 1 H), 4.55-4.09 (m, 7H), 3.00-2.75 (m, 2H), 2.18-1.85 (m, 2H).
Example 166: 3-[5-Chloro-2-(tetrahvdro-furan-2-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000128_0002
MS (ESI): mass calcd. for Ci4Hi8CINO3, 283.1 ; m/z found, 284.0 [M+H]+.
1H NMR (MeOD): 7.05-6.86 (m, 3H), 5.12-5.02 (m, 1 H), 4.60-4.46 (m, 2H), 4.32-4.20 (m, 3H), 4.09-4.00(m, 1 H), 3.95-3.87 (m, 2H), 3.86-3.70 (m, 1 H), 2.20-1.90 (m, 3H), 1.80-1.68 (m, 1 H).
Example 167: 3-r5-Chloro-2-(chroman-3-ylmethoxy)-phenoxy1-azetidine.
Figure imgf000128_0003
MS (ESI): mass calcd. for Ci9H20CINO3, 345.1 ; m/z found, 346.1 [M+H]+. 1H NMR (MeOD): 7.15-6.63 (m, 7H), 5.15-4.98 (m, 1 H), 4.60-3.90 (m, 8H), 3.10-2.93 (m, 1 H), 2.78-2.50 (m, 2H). Example 168: 3-r5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000129_0001
MS (ESI): mass calcd. for Ci8H20CINO3, 333.1 ; m/z found, 334.1 [M+H]+. 1H NMR (CDCI3): 7.45-7.25 (m, 5H), 7.04-6.88 (m, 3H), 5.05-4.96 (m, 1 H), 4.63-4.57 (m, 1 H), 4.53-4.42 (m, 2H), 4.26-4.05 (m, 4H), 4.33 (s, 3H).
Example 169: 3-r5-Chloro-2-(2,3-dihvdro-benzofuran-2-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000129_0002
MS (ESI): mass calcd. for Ci8Hi8CINO3, 331.1 ; m/z found, 332.1 [M+H]+. 1H NMR (CDCI3): 7.20-6.66 (m, 7H), 5.20-5.05 (m, 1 H), 4.98-4.88 (m, 1 H), 4.35-4.03 (m, 6H), 3.42-3.32 (m, 1 H), 3.12-3.03 (m, 1 H).
Example 170: 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-1 ,3-dimethyl- 1 H-pyrazole.
Figure imgf000129_0003
MS (ESI): mass calcd. for Ci5Hi8CIN3O2, 307.1 ; m/z found, 308.1 [M+H]+. 1H NMR (MeOD): 7.12 (d, J = 8.7 Hz, 1 H), 7.00 (dd, J = 8.7, 2.1 Hz, 1 H), 6.87 (d, J = 2.1 Hz, 1 H), 6.17 (s, 1 H), 5.13-5.05 (m, 3H), 4.48-4.39 (m, 2H), 4.18-4.12 (m, 2H), 3.85 (s, 3H), 2.20 (s, 3H). Example 171 : 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy1-azetidine.
Figure imgf000130_0001
MS (ESI): mass calcd. for Ci7Hi8CINO3, 319.1 ; m/z found, 320.0 [M+H]+. 1H NMR (MeOD): 7.34-7.26 (m, 2H), 7.12-6.92 (m, 6H), 5.14-4.95 (m, 2H), 4.83-4.74 (m, 1 H), 4.48-4.42 (m, 1 H), 4.39-4.30 (m, 4H), 4.24-4.16 (m, 1 H).
Example 172: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -phenyl-azetidine.
Figure imgf000130_0002
Prepared by the procedure of Example 163 using 5-bromo-2-(3-fluoro- benzyloxy)-phenol and 1-phenyl-azetidin-3-ol. MS (ESI): mass calcd. for C22Hi9BrFNO2, 427.1 ; m/z found, 428.2 [M+H]+. 1H NMR (CDCI3): 7.34-6.47 (m, 12H), 5.11 -5.03 (m, 3H), 4.36-4.28 (m, 2H), 3.98-3.91 (m, 2H).
Example 173: 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000130_0003
MS (ESI): mass calcd. for Ci8Hi8CINO2, 315.1 ; m/z found, 316.1 [M+H]+. 1H NMR (MeOD): 7.35-7.06 (m, 6H), 6.93-6.90 (m, 1 H), 5.28-5.21 (m, 1 H), 4.86-4.78 (m, 1 H), 4.28-4.18 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m, 2H), 3.18-3.08 (m, 2H). Example 174: 3-[5-Bromo-2-(indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000131_0001
MS (ESI): mass calcd. for Ci8Hi8BrNO2, 359.1 ; m/z found, 359.9 [M+H]+. 1H NMR (MeOD): 7.33-7.02 (m, 7H), 5.28-5.21 (m, 1 H), 4.86-4.78 (m, 1 H), 4.28-4.16 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m, 2H), 3.18-3.08 (m, 2H).
Example 175: 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000131_0002
Step A: Preparation of 2-Bromo-5-fluoro-indan-1 -one. To the solution of 5-fluoro-indan-1 -one (10 mmol) in MeOH/CH2CI2 (40 mL/120 ml_) was added Bu4NBr3 (11 mmol). The mixture was stirred at 25 0C for 16 h, concentrated and partitioned between CH2CI2 /H2O (150 mL/80 ml_). The organic layer was concentrated and purified providing the title compound (2 g).
Step B: Preparation of 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy1- azetidine. The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5 mmol), and K2CO3 (1 mmol) in acetonitrile (3 ml_) was heated at 100 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (150 mg). To this product was added DCE (5 ml_), Et3SiH (1 ml_) and TFA (3 ml_). The mixture was stirred at 80 0C for 16 h. After concentration, the title compound was obtained (91 mg). MS (ESI): mass calcd. for Ci8Hi7CIFNO2, 333.1 ; m/z found, 334.1 [M+H]+. 1H NMR (CDCI3): 7.20-7.13 (m, 1 H), 6.96-6.60 (m, 5H), 5.18-5.08 (m, 1 H), 4.93-4.83 (m, 1 H), 3.98-3.70 (m, 4H), 3.38-3.05 (m, 4H).
The compounds in Examples 176-178 were prepared according to Example 175 using the appropriately substituted indanone. Example 176: 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000132_0001
MS (ESI): mass calcd. for Ci8Hi7CI2NO2, 349.1 ; m/z found, 350.0 [M+H]+. 1H NMR (CDCI3): 7.26-6.63 (m, 6H), 5.20-5.05 (m, 1 H), 4.93-4.83 (m, 1 H), 4.10-3.85 (M, 4H), 3.45-3.05 (m, 4H).
Example 177: 3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000132_0002
MS (ESI): mass calcd. for CI9H20CINO3, 345.1 ; m/z found, 346.0 [M+H]+.
1H NMR (MeOD): 7.15 (d, J = 8.2 Hz, 1 H), 7.08-7.03 (m, 2H), 6.94-6.73 (m, 3H), 5.25-5.17 (m, 1 H), 4.90-4.81 (m, 1 H), 4.80-4.70 (m, 2H), 4.12-4.02 (m, 2H), 3.77 (s, 3H), 3.37-3.24 (m, 2H), 3.12-2.98 (m, 2H).
Example 178: 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy1-azetidine.
Figure imgf000132_0003
MS (ESI): mass calcd. for CI9H20CINO3, 345.1 ; m/z found, 346.1 [M+H]+. 1H NMR (MeOD): 7.22-6.76 (m, 6H), 5.26-5.18 (m, 1 H), 4.94-4.83 (m, 1 H), 4.18-4.10 (m, 2H), 3.98-3.88 (m, 2H), 3.83 (s, 3H), 3.40-3.20 (m, 2H), 3.15- 3.02 (m, 2H). Example 179: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-indan-1 -one oxinne.
Figure imgf000133_0001
Step A: Preparation of 3-[5-chloro-2-(6-fluoro-1 -oxo-indan-2-yloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester. The mixture of 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.5 mmol), 1 -bromo-indan-2-one (0.5 mmol), and K2CO3 (1 mmol) in actetonithle (3 mL) was heated at 100 0C in a microwave reactor for 1 h. The mixture was cooled down and separated through PTLC providing the title compound (150 mg). Step B: Preparation of 3-[5-Chloro-2-(1 -hvdroxyimino-indan-2-yloxy)- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester. The title compound of Step A was dissolved into MeOH (2 mL), then NH2OH HCI (1 mmol) and K2CO3 (2 mmol) were added. The mixture was heated at 100 0C using a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (120 mg).
Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-indan- 1 -one oxinne. The title compound from Step B was dissolved in CH2CI2 (20 mL), and CF3COOH (3 mL) was added. The mixture was stirred at 25 0C for 4 h. After concentration and purification via PTLC, the title compound was obtained (91 mg). MS (ESI): mass calcd. for Ci8Hi7CIN2O3, 344.1 ; m/z found, 345.0 [M+H]+. 1H NMR (MeOD): 8.40 (d, J = 8.0 Hz, 1 H), 7.50-6.80 (m, 6H), 5.48-5.46 (m, 1 H), 5.18-5.10 (m, 1 H), 4.45-4.32 (m, 2H), 4.18-4.08 (m, 2H), 3.62-3.52 (m, 1 H), 3.16-3.08 (m, 1 H).
Example 180-183 were prepared by the procedure of example 179 using the appropriate α-bromo-ketone and NH2OH or NH2OCH3. Example 180: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-indan-1 -one O-methyl- oxinrie.
Figure imgf000134_0001
MS (ESI): mass calcd. for Ci9Hi9CIN2O3, 358.1 ; m/z found, 359.0 [M+H]+. 1H NMR (MeOD): 8.70 (d, J = 8.0 Hz, 1 H), 7.60-6.90 (m, 6H), 6.03- 5.98 (m, 1 H), 5.15-5.05 (m, 1 H), 4.56-4.43 (m, 2H), 4.22-1.18 (m, 2H), 3.93 (s, 3H), 3.76-3.64 (m, 1 H), 3.24-3.16 (m, 1 H).
Example 181 : 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-1 -phenyl-ethanone oxime.
Figure imgf000134_0002
MS (ESI): mass calcd. for Ci7Hi7CIN2O3, 332.1 ; m/z found, 333.0 [M+H]+. 1H NMR (MeOD): 8.12-6.80 (m, 8H), 5.56-5.30 (m, 2H), 5.25-4.80 (m, 1 H), 4.60-3.98 (m, 4H).
Example 182: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-1 -phenyl-ethanone O- methyl-oxime.
Figure imgf000134_0003
MS (ESI): mass calcd. for Ci8Hi9CIN2O3, 346.1 ; m/z found, 347.0 [M+H]+. 1H NMR (MeOD): 8.18-6.80 (m, 8H), 5.56-5.33 (m, 2H), 5.32-4.80 (m, 1 H), 4.60- 3.98 (m, 7H). Example 183: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-1 -(4-chloro-phenyl)- ethanone.
Figure imgf000135_0001
1H NMR (CDCI3): 7.97 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 6.59 (d, J = 8.6 Hz, 1 H), 5.25 (s, 2H), 5.00-4.97 (m, 1 H), 3.98-3.80 (m, 4H).
Example 184: 3-r5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000135_0002
The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.5 mmol), (2-bromo-1 ,1 -difluoro-ethyl)-benzene (1 mmol), and K2CO3 (1 mmol) in acetonitrile (3 ml_) was heated at 180 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3- [5-chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (90 mg). To this compound was added CH2CI2 (20 mL) and CF3COOH (3 mL). The mixture was stirred at rt for 4 h and concentrated to give the title compound (50 mg). MS (ESI): mass calcd. for Ci7H16CIF2NO2, 339.1 ; m/z found, 340.0 [M+H]+. 1H NMR (MeOD): 7.66-7.46 (m, 5H), 7.02- 6.83 (m, 3H), 5.05-4.95 (m, 1 H), 4.50 (t, J = 12.7 Hz, 2H), 4.30-4.20 (m, 2H), 4.10-3.98 (m, 2H).
Example 185: 3-r5-Chloro-2-r2-(3-chloro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000135_0003
Step A. Preparation of Methanesulfonic acid 2-(3-chloro-phenyl)-ethyl ester. To a solution of 2-(3-chloro-phenyl)-ethanol (566 mg, 3.6 mmol) in CH2CI2 (10 ml_) was added methanesulfonyl chloride (310 μl_, 4.0 mmol). After 5 min, Et3N (756 μl_, 5.4 mmol) was added and the reaction was allowed to stir for 18 h. The reaction was then diluted with H2O. The organic layer was separated and washed with H2O, brine, then dried and concentrated to give a yellow oil (770 mg, 91 %). 1H NMR (CDCI3): 7.27 - 7.23 (m, 3H), 7.14 - 7.11 (m, 1 H), 4.41 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.90 (s, 3H). Step B. Preparation of 3-r5-Chloro-2-r2-(3-chloro-phenyl)-ethoxyl- phenoxyi-azetidine-1-carboxylic acid tert-butyl ester. To a solution of 3-(5- chloro-2-hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (60 mg, 0.20 mmol) in DMF (2 ml_) was added NaH (10 mg, 0.24 mmol). After 5 min, the title compound of Step A (56 mg, 0.24 mmol) was added and the resulting mixture was heated at 65 0C for 18 h. The reaction was diluted with H2O and extracted EtOAc (3x). The organics were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (47 mg, 54%). MS (ESI): mass calcd. for C22H25CI2NO4, 438.3; m/z found, 382.0 [M-56+H]+. 1H NMR (CDCI3): 7.34 - 7.32 (m, 1 H), 7.25 - 7.22 (m, 2H), 7.19 - 7.16 (m, 1 H), 6.90 (dd, J = 8.8, 2.0 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.85 - 4.79 (m, 1 H), 4.30 - 4.25 (m, 2H), 4.16 (t, J = 6.7 Hz, 2H), 4.07 - 4.03 (m, 2H), 3.10 (t, J = 6.7 Hz, 2H), 1.46 (s, 9H).
Step C: Preparation of 3-r5-Chloro-2-r2-(3-chloro-phenyl)-ethoxy1- phenoxyi-azetidine. Prepared from title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci7H17CI2NO2, 338.2; m/z found, 338.1 [M+H]+. 1H NMR (CDCI3): 7.35 - 7.34 (m, 1 H), 7.25 - 7.21 (m, 3H), 7.18 - 7.16 (m, 1 H), 6.88 - 6.85 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 4.98 - 4.91 (m, 1 H), 4.17 (t, J = 6.8 Hz, 2H), 3.96 - 3.85 (m, 4H), 3.10 (t, J = 6.7 Hz, 2H).
The compounds in Examples 186-195 were synthesized according to
Example 185 using the appropriately substituted mesylates as prepared in Example 185 Step A. Example 186: 3-r5-Chloro-2-(3-chloro-benzyloxy)-phenoxy1-azetidine.
Figure imgf000137_0001
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.8; m/z found, 304.1 [M+H]+. 1H NMR (CDCI3): 7.39 - 7.19 (m, 7H), 6.93 - 6.73 (m, 2H), 6.58 (d, J = 2.4 Hz, 1 H), 4.94 (s, 1 H), 4.18 (t, J = 7.3 Hz, 2H), 3.91 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H).
Example 187: 3-r5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy1-azetidine.
Figure imgf000137_0002
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.8; m/z found, 322.1 [M+H]+. 1H NMR (CDCI3): 7.42 (s, 5H), 6.87-6.61 (m, 2H), 6.62 (d, J = 2.2 Hz, 1 H), 5.85 (dd, J = 48.0, 8.0 Hz, 1 H), 5.02 (bs, 1 H), 4.40 - 4.08 (m, 7H).
Example 188: 3-[5-Chloro-2-[1 -(4-chloro-phenyl)-cvclobutylmethoxy1-phenoxy1- azetidine.
Figure imgf000137_0003
MS (ESI): mass calcd. for C20H2iCI2NO2, 378.3; m/z found, 378.0 [M+H]+. 1H NMR (CDCI3): 7.34 - 7.27 (m, 5H), 7.21 - 7.20 (m, 1 H), 7.19 - 7.18 (m 1 H), 6.81 (s, 1 H), 6.70 (d, J = 8.6, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.97 - 4.87 (m, 1 H), 4.01 (s, 2H), 3.94-3.90 (m, 2H), 3.82-3.78 (m, 2H), 2.42 (t, J = 7.7 Hz, 4H). Example 189: 3-[5-Chloro-2-[1 -O-chloro-phenvD-cvclobutylnnethoxyi-phenoxyi- azetidine.
Figure imgf000138_0001
MS (ESI): mass calcd. for C20H2ICI2NO2, 378.3; m/z found, 378.0. 1H NMR (CDCI3): 7.28 - 7.22 (m, 5H), 7.19-7.16 (m, 1 H), 7.13-7.10 (m, 1 H), 6.82 (dd, J = 8.6, 2.4 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 1 H), 6.54 (d, J = 2.4, 1 H), 4.92 (m, 1 H), 4.03 (s, 2H), 3.94 - 3.76 (m, 3H), 2.42 (d, J = 8.8 Hz, 3H), 2.17 (s, 2H).
Example 190: 3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000138_0002
MS (ESI): mass calcd. for CI8H20CINO3, 333.8; m/z found, 334.1 [M+H]+. 1H NMR (CDCI3): 7.24 - 7.22 (m, 2H), 6.90 - 6.86 (m, 3H), 6.81 - 6.77 (m, 2H), 6.60 (d, J = 2.4, 1 H), 5.00 - 4.87 (m, 1 H), 4.18 (t, J = 7.2, 2H), 4.03 - 3.94 (m, 2H), 3.90 - 3.86 (m, 2H), 3.80 (s, 3H), 3.11 (t, J = 7.1 Hz, 2H).
Example 191 : 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000138_0003
MS (ESI): mass calcd. for Ci7H17CIFNO2, 321.8; m/z found, 322.0 [M+H]+. 1H NMR (CDCI3): 7.30 - 7.24 (m, 2H), 7.09 - 7.05 (m, 2H), 6.96 - 6.91 (m, 1 H), 6.88 - 6.85 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.57 (d, J = 2.4, 1 H), 4.95 (s, 1 H), 4.18 (t, J = 6.8 Hz, 2H), 3.95-3.84 (m, 4H), 3.12 (t, J = 6.8 Hz, 2H). Example 192: 3-r5-Chloro-2-r2-(4-chloro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000139_0001
MS (ESI): mass calcd. for Ci7Hi7CI2NO2, 338.2; m/z found, 338.0. 1H NMR (CDCI3): 7.34 - 7.17 (m, 5H), 6.89 (dd, J = 8.6, 2.4 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 4.95 (t, J = 6.2 Hz, 1 H), 4.16 - 4.13 (m, 2H), 4.04 - 3.99 (m, 2H), 3.93 - 3.89 (m, 2H), 3.09 (t, J = 6.9 Hz, 2H).
Example 193: 3-r5-Chloro-2-r2-(4-fluoro-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000139_0002
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.8; m/z found, 322.1 [M+H]+. 1H NMR (CDCI3): 7.32 - 7.20 (m, 4H), 7.00 (t, J = 8.7 Hz, 1 H), 6.87 - 6.85 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 5.00 - 4.87 (m, 1 H), 4.15 (t, J = 7.0 Hz, 2H), 3.94 - 3.90 (m, 2H), 3.85- 3.81 (m, 2H), 3.10 (t, J = 7.0 Hz, 2H).
Example 194: 3-r5-Chloro-2-r2-(4-methoxy-phenyl)-ethoxy1-phenoxy1-azetidine.
Figure imgf000139_0003
MS (ESI): mass calcd. for CI8H20CINO3, 333.8; m/z found, 334.1 [M+H]+. 1H NMR (CDCI3): 7.22 - 7.20 (m, 2H), 6.93 - 6.85 (m, 3H), 6.77 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 4.98 - 4.91 (m, 1 H), 4.13 (t, J = 7.3 Hz, 2H), 3.96 - 3.92 (m, 2H), 3.89 - 3.85 (m, 2H), 3.79 (s, 3H), 3.07 (t, J = 7.3 Hz, 2H). Example 195: 3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine.
Figure imgf000140_0001
Prepared according to Example 185 using 3-(5-Bromo-2-hydroxy- phenoxy)-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for Ci7H18BrNO2, 348.2; m/z found, 348.0. 1H NMR (CDCI3): 7.39 - 7.20 (m, 6H), 7.05 (dd, J = 8.6, 2.3 Hz, 1 H), 6.76 (dd, J = 6.8, 5.5 Hz, 2H), 4.99 - 4.87 (m, 1 H), 4.18 (t, J = 7.2 Hz, 2H), 4.03 - 3.98 (m, 2H), 3.95 - 3.91 (m, 2H), 3.13 (t, J = 7.2 Hz, 2H).
Example 196: 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine.
Figure imgf000140_0002
Step A: Preparation of 2-benzyloxy-5-chloro-3-fluoro-pyhdine. To 60% NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 ml_) was added benzyl alcohol (2.7 g, 2.6 ml_, 25.0 mmol) dropwise. After 1 h, 5-chloro-2,3-difluoro-pyhdine (3.73 g, 25.0 mmol) was added in THF (5 ml_). After an additional 18h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (1 -15% EtOAc in hexanes) gave 4.02 g (67% yield) of the title compound as a clear oil. 1H NMR (CDCI3): 7.91 (d, J = 2.2 Hz, 1 H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).
Step B: Preparation of 3-(2-Benzyloxy-5-chloro-pyhdin-3-yloxy)- azetidine-1-carboxylic acid tert-butyl ester. To 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (0.35 g, 2.0 mmol) in NMP (3 ml_) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol). After 20 min at rt, the reaction was heated to 50 0C for 20 min, cooled to rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1 ml_) was added. The reaction was then heated in a microwave reactor at 145 0C for 1 h, cooled to rt, poured into H2O and extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (2-15% EtOAc in hexanes) gave 0.34 g (51 % yield) of the title compound as a white solid. 1H NMR (CDCI3): 7.74 (d, J = 2.1 Hz, 1 H), 7.46 (d, J = 7.0 Hz, 2H), 7.39-7.30 (m, 3H), 6.77 (d, J = 2.1 Hz, 1 H), 5.42 (s, 2H), 4.87-4.82 (m, 1 H), 4.26 (dd, J = 10.5, 6.4 Hz, 2H), 4.05 (dd, J = 10.3, 4.2 Hz, 2H), 1.44 (s, 9H).
Step C: Preparation of 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro- pyridine. Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci5Hi5CIN2O2, 290.1 ; m/z found, 291.1 [M+H]+. 1H NMR (CDCI3): 7.70 (d, J = 2.2 Hz, 1 H), 7.46 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.33-7.29 (m, 1 H), 6.77 (d, J = 2.2 Hz, 1 H), 5.43 (s, 2H), 4.99-4.93 (m, 1 H), 3.96-3.81 (m, 4H).
Example 197: 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine.
Figure imgf000141_0001
Step A: Preparation of 4-Chloro-2,6-difluoro-benzaldehvde. To a -78 0C solution of 1 -chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 ml_) at was added n-butyl lithium (1.6 M in hexane, 19 ml_). After 50 min, DMF (5.2 ml_, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5 M HCI (150 ml_) and ether (150 ml_), the aqueous layer was extracted with Et2O (3X). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41 %). 1H NMR (CDCI3): 10.3 (s, 1 H), 7.06 (d, J = 8.1 Hz, 2H).
Step B: Preparation of 3-(5-Chloro-3-fluoro-2-formyl-phenoxy)-azetidine- 1 -carboxylic acid tert-butyl ester. To a solution of the title compound of Step A (270 mg, 1.5 mmol) and 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (270 mg, 1.5 mmol) in dry DMF (10 ml_) at 0 0C was added NaH (60% in mineral oil, 22 mg, 1.5 mmol). After 18 h, H2O and EtOAc were added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried and concentrated. The crude residue was purified by RP HPLC to provide the title compound (75 mg, 15%). MS (ESI): mass calcd. for Ci5Hi7CIFNO4, 329.1 ; m/z found, 274.0 [M+H-56]+. 1H NMR (CDCI3): 10.4 (s, 1 H), 6.84 (dd, J = 10.0, 1.6 Hz, 1 H), 6.39 (dd, J = 1.4, 1.3 Hz, 1 H), 5.00-4.92 (m, 1 H), 4.38 (dd, J = 9.9, 6.3 Hz, 2H), 4.08 (dd, J = 10.7, 4.0 Hz, 2H), 1.46 (s, 9H).
Step C: Preparation of 3-(5-Chloro-3-fluoro-2-hvdroxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester. To a solution of the title compound of Step B (650 mg, 2.0 mmol) in CH2CI2 (100 ml_) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirring for 72 h, the starting aldehyde remained as determined by analytical HPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol) was added. After 18 h, analytical HPLC analysis indicated that the reaction was complete. A solution of 10% aqueous sodium bisulfite (100 mL) was added to the reaction mixture. After an additional 18h, CH2CI2 was added and the aqueous portion extracted three times with CH2CI2. The combined organic extracts were washed with saturated NaHCO3 (2X) and concentrated. The residue was then treated with MeOH (500 mL) and 1 N NaOH (250 mL). The solution immediately turned dark brown. After 2 h, the MeOH was removed by rotary evaporation and 1 M KHSO4 was added to the residue until the pH of the solution reached pH=4. The reaction mixture was then extracted with EtOAc (3X). The combined organic layers were washed with brine and dried. The residue was purified by RP HPLC to provide the desired phenol (290 mg, 46%). 1H NMR (CDCI3): 6.74 (dd, J = 10.1 , 2.3 Hz, 1 H), 6.30 (dd, J = 2.0, 2.1 Hz, 1 H), 4.87-4.80 (m, 1 H), 4.26 (dd, J = 9.9, 6.4 Hz, 2H), 4.00 (dd, J = 9.9, 3.8 Hz, 2H), 3.29-3.13 (m, 1 H), 1.40 (s, 9H).
Step D: Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester. Prepared from the title compound of Step C using according to Example 1 Step D. MS (ESI): mass calcd. for C2IH23CIFNO4, 407.1 ; m/z found, 430.0 [M+Na]+. 1H NMR (CDCI3): 7.46-7.29 (m, 5H), 6.79 (dd, J = 9.9, 2.4 Hz, 1 H), 6.29 (dd, J = 2.1 , 2.1 Hz, 1 H), 5.06 (s, 2H), 4.82-4.72 (m, 1 H), 4.25 (ddd, J = 9.7, 6.4, 1.0 Hz, 2H), 3.92 (dd, J = 9.8, 3.9 Hz, 2H), 1.46 (s, 9H).
Step E: Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)- azetidine. Prepared from the title compound of Step D using general procedure 1. MS (ESI): mass calcd. for Ci6Hi5CIFNO2, 307.1 ; m/z found, 308.0 [M+H]+. 1H NMR (CDCI3): 7.47-7.41 (m, 2H), 7.37-7.30 (m, 3H), 6.76 (dd, J = 9.9, 2.4 Hz, 1 H), 6.34 (dd, J = 2.1 , 2.1 Hz, 1 H), 5.06 (s, 2H), 4.97-4.86 (m, 1 H), 4.05- 3.63 (m, 4H), 2.27-2.00 (m, 1 H).
Example 198: 3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)- phenoxyi-azetidine.
Figure imgf000143_0001
Prepared according to Example 199 using 2-bromomethyl-5- trifluoromethyl-furan. MS (ESI): mass calcd. for Ci5Hi2CIF4NO3, 365.0; m/z found, 367.0 [M+H]+. 1H NMR (CDCI3): 6.78-6.72 (m, 2H), 6.42 (d, J = 3.3 Hz, 1 H), 6.36 (dd, J = 2.1 , 2.1 Hz, 1 H), 5.04 (s, 2H), 4.98-4.85 (m, 1 H), 4.05-3.69 (m, 4H), 2.20-1.99 (m, 1 H).
Example 199: 3-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)- phenoxyi-azetidine.
Figure imgf000143_0002
Prepared according to Example 1 using 3-(2-hydroxy-5-trifluoromethyl- phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and 2-bromomethyl-5- thfluoromethyl-furan. MS (ESI): mass calcd. for Ci6Hi3F6N3O3, 381.1 ; m/z found, 382.0 [M+H]+. 1H NMR (CDCI3): 7.21 (dd, J = 8.4, 1.2 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.83 (d, J = 2.0 Hz, 1 H), 6.79-6.78 (m, 1 H), 6.51 (d, J = 3.1 Hz, 1 H), 5.13 (s, 2H), 5.05-4.99 (m, 1 H), 3.94-3.87 (m, 4H). Example 200: 3-[5-Trifluoronnethyl-2-[1 -O-trifluoromethyl-phenvD-ethoxyi- phenoxyi-azetidine.
Figure imgf000144_0001
Prepared according to Example 101 using 3-(2-hydroxy-5- trifluoromethyl-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for Ci9Hi7F6NO2, 405.1 ; m/z found, 406.0 [M+H]+. 1H NMR (CDCI3): 7.70 (s, 1 H), 7.56 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.83-6.80 (m, 2H), 5.41 (q, J = 6.4 Hz, 1 H), 5.07 (br s, 1 H), 4.33-3.64 (m, 4H), 1.70 (d, J = 6.5 Hz, 3H).
Example 201 : 3-[2-(1 -Phenyl-ethoxy)-5-trifluoromethyl-phenoxy1-azetidine hydrochloride.
Figure imgf000144_0002
Prepared according to Example 1 using 3-(2-hydroxy-5-trifluoromethyl- phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and benzyl bromide. MS (ESI): mass calcd. for Ci7Hi6F3NO2, 323.1 ; m/z found, 324.1 [M+H]+. 1H NMR (DMSO-D6): 9.39 (s, 2H), 7.49-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.30 (d, J = 8.5 Hz, 1 H), 7.13 (d, J = 1.9 Hz, 1 H), 5.23 (s, 2H), 5.14-5.10 (m, 1 H), 4.39-4.34 (m, 2H), 4.01 -3.98 (m, 2H).
Example 202: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-azetidine hydrochloride.
Figure imgf000144_0003
Step A: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-benzaldehyde. A mixture of 5-fluorosalicyladehyde (5.0 g, 36 mmol), 3-chloro-benzyl bromide (7.34 g, 35.7 mmol), K2CO3 (6.0 g, 43 mmol) in DMF (50 ml_) was heated at 65 0C for 18 h. The reaction mixture was cooled to rt and diluted with a mixture of EtOAc (500 ml_) and H2O (300 ml_). The organic phase was separated, washed with H2O (3x250 ml_), and dried to give the title compound (9.4 g, 99 %) that was used without further purification.
Step B: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-phenol. To the title compound from Step A (9.4 g, 36 mmol) in CH2CI2 (200 ml_) was added 77% m-CPBA (12.0 g, 54.0 mmol). The mixture was allowed to stir for 36 h at rt and 10 wt% NaHSO3 (aq.) solution was added. After 48h, the reaction mixture was washed with H2O (2 x 250 ml_). The organic layer was dried and treated with 1 N NaOH (100 ml_) and MeOH (100 ml_). After 48h, the MeOH was removed and 1 N H2SO4 was added slowly to adjust the pH to 1.5. The resulting solution was extracted with CH2CI2 (3 x 15OmL). The combined extracts were washed with H2O and dried to give a red oil (8.4 g). Chromatography (SiO2. 0-20 % EtOAc/hexane) gave the title compound (5.0 g, 56 %). 1H NMR (CDCI3) 7.50-7.16 (m, 4H), 6.87-6.57 (m, 2H), 6.50 (t, J = 8.6, 3.0 Hz, 1 H), 5.80 (s, 1 H), 5.05-4.89 (m, 2H). Step C: Preparation of 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1- azetidine-1-carboxylic acid tert-butyl ester. To the title compound of Step B (200 mg, 0.79 mmol) in DMF (5.0 ml_) was added 60 wt% NaH (34.3 mg, 0.86 mmol). The mixture was heated to 50 0C for 1 h then cooled to rt and 3- methanesulfonyloxy-azetidine-1 -carboxylic acid tert-butyl ester (Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added. This mixture was heated to 80 0C for 18 h, cooled to rt and treated with EtOAc (50 ml_) and H2O (100 ml_). The organic layer was separated, washed with H2O (2x50 ml_) and dried to give a solid (400 mg). This solid was purified on RP HPLC to yield the title compound (90 mg, 28 %). 1H NMR (CDCI3) 7.44 (s, 1 H), 7.36-7.23 (m, 3H), 6.86 (dd, J = 8.9, 5.4 Hz, 1 H), 6.60 (dd, J = 8.0, 2.9 Hz, 1 H), 6.33 (dd, J = 9.6, 2.9 Hz, 1 H), 5.03 (s, 2H), 4.90-4.80 (m, 1 H), 4.33-4.22 (m, 2H), 4.07-4.02 (m, 2H), 1.54-1.28 (m, 9H). Step D: Preparation of 3-r2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1- azetidine hydrochloride. The title compound from step C (85 mg) was dissolved in MeOH (5 ml_) and 4M HCI in dioxane (3 ml_) was added. The mixture was stirred at rt for 18 h. The reaction was concentrated and dried under vacuum to yield the title compound (75 mg). MS (ESI): mass calcd. for Ci6H15CIFNO2, 307.8; m/z found, 310.2 [M+H]+. 1H NMR (MeOD): 7.46 (s, 1 H), 7.37-7.28 (m, 3H), 7.04 (dd, J = 9.0 Hz, 5.3, 1 H), 6.75-6.61 (m, 2H), 5.09-5.00 (m, 3H), 4.42 (dd, J = 12.7, 6.6 Hz, 2H), 4.14 (dd, J = 12.7, 4.9 Hz, 2H).
Example 203: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -methyl-azetidine.
Figure imgf000146_0001
Prepared according to general procedure 5 using the title compound from Example 202. MS (ESI): mass calcd. for Ci7H17CIFNO2, 321.8; m/z found, 322.2 [M+H]+. 1H NMR (CDCI3): 7.47-7.39 (m, 1 H), 7.31-7.25 (m, 3H), 6.81 (dd, J = 8.9, 5.5 Hz , 1 H), 6.56-6.52 (m, 1 H), 6.38 (dd, J = 9.9, 2.9 Hz, 1 H), 5.02 (s, 2H), 4.72-4.67 (m, 1 H), 3.87-3.78 (m, 2H), 3.17-3.08 (m, 2H), 2.40 (s, 3H).
Example 204: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -isopropyl- azetidine.
Figure imgf000146_0002
Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for Ci9H2iCIFNO2, 349.8; m/z found, 350.2 [M+H]+. 1H NMR (CDCI3): 7.44 (s, 1 H), 7.29-7.26 (m, 3H), 6.81 (dd, J = 8.9, 5.5 Hz, 1 H), 6.54-6.52 (m, 1 H), 6.41 (dd, J = 9.9, 2.9, 1 H), 5.01 (s, 2H), 4.73-4.68 (m, 1 H), 3.85-3.77 (m, 2H), 3.11 -3.04 (m, 2H), 2.43-2.36 (m, 1 H), 0.95 (d, J = 6.2 Hz, 6H).
Example 205: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -cvclobutyl- azetidine.
Figure imgf000147_0001
Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for C20H21CIFNO2, 361.8; m/z found, 362.2 [IvRH]+. 1H NMR (CDCI3): 7.44 (s, 1 H), 7.32-7.22 (m, 3H), 6.82 (dd, J = 8.9, 5.5 Hz, 1 H), 6.57-6.53 (m, 1 H), 6.41 (dd, J = 9.8, 2.9 Hz, 1 H), 5.02 (s, 2H), 4.77-4.72 (m, 1 H), 3.77-3.69 (m, 2H), 3.23-3.12 (m, 3H), 2.01 -1.95 (m, 2H), 1.87-1.62 (m, 4H).
Example 206: 3-r2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -propyl-azetidine.
Figure imgf000147_0002
Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for C19H21CIFNO2, 349.8; m/z found, 350.2 [M+H]+. 1H NMR (CDCI3): 7.46 (s, 1 H), 7.30 (m, 3H), 6.83 (dd, J = 8.9, 5.5 Hz, 1 H), 6.59-6.51 (m, 1 H), 6.42 (dd, J = 9.9, 2.9 Hz, 1 H), 5.04 (s, 2H), 4.78-4.73 (m, 1 H), 3.8- 3.80 (m, 2H), 3.13-3.05 (m, 2H), 2.52 - 2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). Example 207: 3-r2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy1-1 -ethyl-azetidine.
Figure imgf000148_0001
Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI) mass calcd. for Ci8Hi9CIFNO2, 335.8; m/z found, 338.2 [IvRH]+. 1H NMR (CDCI3) 7.47 (s, 1 H), 7.32-7.28 (m, 3H), 6.84 (dd, J = 8.9, 5.5 Hz, 1 H), 6.59-6.55 (m, 1 H), 6.43 (dd, J = 9.8, 2.9 Hz, 1 H), 5.04 (s, 2H), 4.79-4.74 (m, 1 H), 3.87-3.80 (m, 2H), 3.15 -3.06 (m, 2H), 2.59-2.54 (m, 2H), 1.01 (dd, J = 8.8, 5.6 Hz, 3H).
Example 208: 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine. .
Figure imgf000148_0002
Prepared according top Example 202 using 2-bromomethyl-5- trifluoromethyl-furan. MS (ESI): mass calcd. for Ci5Hi3F4NO3, 331.26; m/z found, 332.2 [M+H]+. 1H NMR (CDCI3): 6.91 (dd, J = 8.9, 5.5 Hz, 1 H), 6.77 (d, J = 2.3, 1 H), 6.66 - 6.53 (m, 1 H), 6.49 - 6.29 (m, 2H), 5.04 (s, 2H), 5.00-4.92 (m, 1 H), 3.98-3.94 (m, 4H), 2.44 (s br, 1 H).
Example 209: 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1-1 - isopropyl-azetidine.
Figure imgf000148_0003
Prepared according to general procedure 3 or 4 using the title compound from Example 208. MS (ESI): mass calcd. for Ci8Hi9F4NO3, 373.3; m/z found, 374.1 [M+H]+. 1H NMR (CDCI3): 6.89 (dd, J = 8.9, 5.5 Hz, 1 H), 6.77-6.75 (m, 1 H), 6.63-6.51 (m, 1 H), 6.44-6.41 (m, 2H), 5.01 (s, 2H), 4.78-4.58 (m, 1 H), 3.83 (dd, J = 8.8, 6.0 Hz, 2H), 3.09 (dd, J = 8.8, 6.0 Hz, 2H), 2.47 - 2.31 (m, 1 H), 0.97 (d, J = 6.2 Hz, 6H).
Example 210: 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy1-azetidine.
Figure imgf000149_0001
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1 -carboxylic acid tert-butyl ester (188 mg, 0.4 mmol), 3-thiophene boronic acid (53 mg, 0.41 mmol), Q-Phos (23 mg, 0.032 mmol), Pd(dba)2 (9.2 mg, 0.016 mmol) and
K3PO4 (255 mg, 1.2 mmol) were taken into toluene (3 ml_) and heated at 80 0C. After the reaction was complete it was cooled to rt, diluted with CH2CI2 (20 ml_), filtered, washed with H2O (2 x 25 ml_) and concentratd to give 3-[2-(3-chloro- benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine-1 -carboxylic acid tert-butyl ester. To this compound was added MeOH (10 ml_) followed by 4M HCI in dioxane (4 ml_). After 4 h the reaction was concentrated and purified on RP HPLC (basic) to yield the title compound (12 mg). MS (ESI): mass calcd. for C20Hi8CINO2S, 371.9; m/z found, 372.2 [M+H]+. 1 H NMR (CDCI3): 10.30-9.57 (m, 1 H), 7.43 (s, 1 H), 7.40-7.28 (m, 6H), 7.24 (dd, J = 8.4, 2.1 Hz, 1 H), 7.01 (d, J = 2.1 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 5.24-4.99 (m, 3H), 4.40-4.11 (m, 4H).
Example 211 : 3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl- benzamide.
Figure imgf000149_0002
A suspension of 3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine- 1 -carboxylic acid tert-butyl ester (94 mg, 0.2 mmol), Na2CO3 (53 mg, 0.5 mmol), 40% Me2NH in H2O (0.17 mmol), Hermann's catalyst (8 mg, 0.008 mmol) and Mo(CO)6 (22 mg, 0.083 mmol) in H2O (2 ml_) was heated to 170 0C in a microwave reactor for 10 min. The reaction was cooled rt, and saturated NaHCO3 (aq.) was added. This solution was extracted with CH2CI2 (3X). The combined organic layers were concentrated to give a solid (30 mg) that was dissolved in MeOH (2 ml_) and treated with 4M HCI in dioxane (1 ml_). After 3h, the mixture was concentrated to give a residue that was purified on RP HPLC providing the title compound (5 mg). MS (ESI): mass calcd. for Ci9H2iCIN2O3, 360.8; m/z found, 361.5 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.29-7.27 (m, 3H), 6.96 (dd, J = 8.2, 1.9 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.72 (d, J = 1.9 Hz, 1 H), 5.11 (s, 2H), 5.05-4.95 (m, 1 H), 3.92-3.85 (m, 4H), 3.00 (s br, 6H).
Example 212: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-methyl-azetidine.
Figure imgf000150_0001
Step A: Preparation of 1 -benzhvdryl-3-methyl-azetidin-3-ol. To 1- benzhydryl-azetidin-3-one (1.0 g, 4.2 mmol) in ether (100 ml_) at 0 0C was added CH3MgBr (1.5 ml_, 3M in ether). The mixture was warmed to rt over 1 h and 1 N NaOH (3 ml_) was added. The organic layer was concentrated providing the title compound (1.1 g). MS (ESI): mass calcd. for C17H19NO, 253.2; m/z found, 254.2 [M+H]+. 1H NMR (CDCI3): 7.42-7.11 (m, 10H), 4.32 (s, 1 H), 3.14 (d, J = 8.5 Hz, 2H), 2.96 (d, J = 8.5 Hz, 2H), 1.43 (s, 3H).
Step B: Preparation of 1 -benzhvdryl-3-[5-bromo-2-(3-chloro-benzyloxy)- phenoxyi-3-methyl-azetidine. The mixture of the title compound from Step A (0.5 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), and cyanomethyleneth-n-butylphosphorane (0.5 mmol) in toluene (3 ml_) was heated at 150 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (120 mg). MS (ESI): mass calcd. for C30H27BrCINO2, 547.1 ; m/z found, 548.0 [IvRH]+.
Step C: Preparation of 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3- methyl-azetidine. The title compound from Step B (60 mg) was dissolved in DCE (10 ml_) and chloroethylformate (0.2 mmol) was added. The mixture was heated at 80-100 0C for 1 h and concentrated. The residue was dissolved in MeOH (3 ml_) and heated at 150 0C in a microwave reactor for another 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (30 mg). MS (ESI): mass calcd. for Ci7Hi7BrCINO2, 381.0; m/z found, 382.0 [M+H]+. 1H NMR (CDCI3): 7.43-7.23 (m, 4H), 7.12-7.06 (m, 1 H), 6.86-6.78 (m, 2H), 5.12 (s, 2H), 4.24-4.16 (m, 2H), 3.78-3.67 (m, 2H), 1.67 (s, 3H).
Example 213: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-ethyl-azetidine.
Figure imgf000151_0001
Prepared according to Example 212 using the ethylmagnesium bromide in Step A. MS (ESI): mass calcd. for Ci8Hi9BrCINO2, 395.0; m/z found, 396.1 [M+H]+. 1H NMR (CDCI3): 7.41 -7.25 (m, 4H), 7.15-7.05 (m, 1 H), 6.84-6.73 (m, 2H), 5.13 (s, 2H), 4.26-4.19 (m, 2H), 3.85-3.74 (m, 2H), 2.19-2.00 (m, 2H), 1.00-0.90 (m, 3H).
Example 214: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-3-isopropyl- azetidine.
Figure imgf000151_0002
Prepared according to Example 212 using the isopropylmagnesium bromide in Step A. MS (ESI): mass calcd. for Ci9H2IBrCINO2, 409.0; m/z found, 409.9 [M+H]+. 1H NMR (CDCI3): 7.43-7.23 (m, 4H), 7.14-6.78 (m, 3H), 5.13 (s, 2H), 3.98-3.85 (m, 2H), 3.48-3.33 (m, 2H), 1.45-1.36 (m, 1 H), 0.63- 0.50 (m, 6H).
Example 215: 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine.
Figure imgf000152_0001
Step A: Preparation of (4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine. A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 47 mmol), tert-butyl amine (6.1 ml_, 57 mmol) and 4A powder molecular sieves (8.0 g) in 160 ml_ CH2CI2 (160 ml_) was stirred at rt for 18 h. The reaction mixture was filtered through a pad of celite and concentrated to give the title compound (9.9 g, 78%). MS (ESI): mass calcd. for CnHi3BrFNO, 258.1 ; m/z found, 260.0 [M+H]+. 1H NMR (CDCI3): 10.32 (s, 1 H), 8.48 (s, 1 H), 7.89 (t, J = 8.1 Hz, 1 H), 7.50 - 7.20 (m, 1 H), 1.49 - 1.08 (m, 9H).
Step B: Preparation of 3-hvdroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester. A solution of 1 -Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 ml_ anh Et2O was cooled to 0 0C and 3M MeMgBr in Et2O (10 ml_, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18h. Then Vi sat'd NH4CI (aq.) was added and the mixture extracted with EtOAc (2x). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84%). 1H NMR (CDCI3): 3.84 (q, J = 9.2 Hz, 4H), 1.97 (bs, 1 H), 1.52 (s, 3H), 1.44 (m, 9H).
Step C: Preparation of 3-(5-Bromo-2-formyl-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester. To a solution of the title compound from Step B (400 mg, 2.2 mmol) in DMSO (8 ml_) was added 60% NaH (120 mg, 3.0 mmol). After 30 min, the title compound from Step A was added and the resulting mixture was heated at 125 0C for 1 h in a microwave reactor. An additional quantity of the title compound from Step B (100 mg) and 60% NaH (32 mg) were added to the reaction. Heating was then resumed at 125 0C for another 1 h in a microwave reactor. The reaction was diluted with H2O and extracted with EtOAc (3x) followed by methanolic EtOAc (2x). The organics were dried , then THF (5 ml_), H2O (5 ml_) and AcOH (3 ml_) were added. After 18 h at rt, the reaction was diluted with H2O and extracted with CH2CI2. The organics were dried and purified by PTLC to give the title compound as an off white solid (247 mg, 31 %). 1H NMR (CDCI3): 10.36 (s, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.22 - 7.20 (m, 1 H), 6.68 (d, J = 1.6 Hz, 1 H), 4.25 (d, J = 9.2 Hz, 2H), 4.03 (d, J = 9.8 Hz, 2H), 1.55 (s, 3H), 1.46 (m, 9H).
Step D: Preparation of 3-(5-Bromo-2-hvdroxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester. Prepared according to Example 1 Step C using the title compound from Step C. Purification was accomplished by PTLC to give the title compound as a peach solid (152 mg, 64%). 1H NMR (CDCI3): 7.02 (dd, J = 8.5, 2.2 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 6.63 (d, J = 2.2 Hz, 1 H), 4.22 (d, J = 9.2 Hz, 2H), 3.98 (d, J = 9.5 Hz, 2H), 3.49 (s, 1 H), 1.69 (s, 3H), 1.46 (s, 9H).
Step E. Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester. A mixture of 3-(5-bromo-2-hydroxy- phenoxy)-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester (30 mg. 0.08 mmol), (2-bromoethyl)benzene (29 μl_, 0.21 mmol), Kl (42 mg, 0.25 mmol) and Cs2CO3 (82 mg, 0.25 mmol) in 3 mL DMF was stirred at rt for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The organic layers were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (22 mg, 58%). MS (ESI): mass calcd. for C23H28BrNO4,
462.4; m/z found, 408.0 [M-56+H]+. 1H NMR (CDCI3): 7.38 - 7.18 (m, 5H), 7.07 (dd, J = 8.6, 2.3 Hz, 1 H), 6.76 - 6.74 (m, 2H), 4.24 - 4.08 (m, 4H), 3.84 (d, J = 9.7 Hz, 2H), 3.11 (t, J = 7.1 Hz, 2H), 1.58 (s, 3H), 1.45 (s, 9H).
Step F: Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine. A mixture of 3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl- azetidine-1-carboxylic acid tert-butyl ester (20 mg) and TFA (1 mL) in CH2CI2 (2 mL) was stirred at rt for 2 h. The reaction was concentrated in vacuo and purified by PTLC followed by additional purification using RP HPLC (Agilent) to give the title compound as an oil (12 mg, 77%). MS (ESI): mass calcd. for Ci8H20BrNO2, 362.3; m/z found, 362.0 [M+H]+. 1H NMR (CDCI3): 7.38 - 7.18 (m, 5H), 7.04 (dd, J = 8.6, 2.3 Hz, 1 H), 6.74 (dd, J = 5.5, 3.1 , 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.97 (d, J = 8.9 Hz, 2H), 3.45 (d, J = 9.2 Hz, 2H), 3.11 (t, J = 7.1 Hz, 2H), 1.98 (s, 1 H), 1.65 (s, 3H).
The compounds in Examples 216-217 were prepared according to Example 215 using the appropriate alkyl halide in Step E.
Example 216: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy1- azetidine.
Figure imgf000154_0001
MS (ESI): mass calcd. for Ci6H15BrF3NO3, 406.2; m/z found, 407.9 [M+H]+. 1H NMR (CDCI3): 7.05 (dd, J = 8.6, 2.3 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.76 - 6.75 (m, 2H), 6.45 - 6.44 (m, 1 H), 5.02 (s, 2H), 4.00 (d, J = 9.0 Hz, 2H), 3.59 - 3.43 (m, 2H), 2.35 (br s, 1 H), 1.67 (s, 3H).
Example 217: 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy1-azetidine.
Figure imgf000154_0002
MS (ESI): mass calcd. for Ci8H17BrF3NO2, 416.2; m/z found, 416.0
[M+H]+. 1H NMR (CDCI3): 7.72 (bs, 1 H), 7.59 - 7.57 (m, 2H), 7.51 - 7.46 (m, 2H), 7.03 (dd, J = 8.6, 2.3 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 5.11 (s, 2H), 4.03 (br s, 2H), 3.54 (bs, 2H), 1.71 (s, 3H). Example 218: 3-(5-Bromo-2-phenoxy-phenoxy)-3-methyl-azetidine.
Figure imgf000155_0001
Prepared according to general procedure 6 using the title compound of Example 215 Step D. MS (ESI): mass calcd. for Ci6Hi6BrNO2, 334.2; m/z found, 334.0 [M+H]+. 1H NMR (CDCI3): 7.34 - 7.24 (m, 2H), 7.08 - 7.04 (m, 2H), 6.94 - 6.86 (m, 3H), 6.80 (d, J = 2.3, 1 H), 3.88 (d, J = 8.3 Hz, 2H), 3.46 (d, J = 8.7 Hz, 2H), 1.85 (br s, 1 H), 1.65 (s, 3H).
Example 219: (±Hrans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2-methyl- azetidine.
Figure imgf000155_0002
Step A. Preparation of (±)-2-bromomethyl-3-methyl-oxirane. See Shimizu et al., Organic Process & Research Development, 2005, VoI 9(3), pp. 278-287. To a stirred solution of crotyl bromide (10 g, 63 mmol) in CH2CI2 (200 ml_) was slowly added 77% m-CPBA (19.8 g, 88 mmol) portionwise over 45 min. After stirring at rt for 18 h, the solids were removed by filtration. The filtrate was treated with aqueous 10% aq. NaHSO3 (150 ml_) and stirred at rt for 5 h. The organic layer was separated, washed with sat'd NaHCO3 (3X), brine (2X) and dried to give the title compound as a colorless oil (6.6 g, 70%). 1H NMR (CDCI3): 3.43 - 3.39 (m, 1 H), 3.35 - 3.18 (m, 1 H), 3.04 - 2.89 (m, 2H), 1.35 (d, J = 5.2 Hz, 3H).
Step B. Preparation of cis and trans 1-benzhvdryl-2-methyl-azetidin-3- Pl See PCT pat appl. WO 01/01988. A mixture of 2-bromomethyl-3-methyl- oxirane (3.6 g, 23.8 mmol) and aminodiphenylmethane (4.1 ml_, 23.8 mmol) in 12 ml_ MeOH was stirred at rt for 72 h. Next, the reaction was heated at reflux for 72 h. After cooling to rt, the reaction was purified by reverse phase basic
HPLC (Agilent) to give the cis and trans isomers of the title compound. Trans isomer as an oil (424 mg), 1H NMR (CDCI3): 7.44 - 7.35 (m, 4H), 7.28 - 7.12 (m, 7H), 4.34 (s, 1 H), 3.93 - 3.90 (m, 1 H), 3.67 - 3.64 (m, 1 H), 3.03 - 2.99 (m, 1 H), 2.57 - 2.55 (m, 1 H), 0.75 (d, J = 6.1 , 3H). Cis isomer as an off white solid (914 mg), 1H NMR (CDCI3): 7.42 - 7.36 (m, 4H), 7.28 - 7.22 (m, 4H), 7.18 - 7.16 (m, 2H), 4.37 (s, 1 H), 4.30 - 4.27 (m, 1 H), 3.46 - 3.42 (m, 1 H), 3.26 - 3.24 (m, 1 H), 3.06 - 3.04 (m, 1 H), 0.74 (d, J = 6.5 Hz, 3H).
Step C. Preparation of (±Hrans-1 -3-[5-Bromo-2-(3-fluoro-benzyloxy)- phenoxyi-2-methyl-azetidine. Prepared according to Example 212 Steps B-C using the frans-isomer from Step B. MS (ESI): mass calcd. for Ci7Hi7BrFNO2, 365.0; m/z found, 366.1 [M+H]+. 1H NMR (MeOD): 7.43-6.95 (m, 7H), 5.12 (s, 2H), 4.68-4.62 (m, 1 H), 4.32-4.25 (m, 1 H), 3.98-3.92 (m, 1 H), 3.75-3.68 (m, 1 H), 1.44 (d, J = 6.7 Hz, 3H).
Example 220: cis-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2- methyl-azetidine.
Figure imgf000156_0001
Prepared from c/s-f±J-i -benzyl^-methyl-azetidin-S-ol according to Example 219. MS (ESI): mass calcd. for C24H23BrFNO2, 455.1 ; m/z found, 456.0 [M+H]+. 1H NMR (CDCI3): 7.39-6.94 (m, 11 H), 6.78-6.69 (m, 2H), 5.08 (s, 2H), 4.78-4.72 (m, 1 H), 3.76-3.62 (m, 3H), 3.54-3.48 (m, 1 H), 3.34-3.26 (m, 1 H), 1.20 (d, J = 6.4 Hz. 3H).
Example 221 : frans-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy1-2- methyl-azetidine.
Figure imgf000156_0002
Prepared from frans-('±)-1 -benzyl-2-nnethyl-azetidin-3-ol according to Example 219. MS (ESI): mass calcd. TOr C24H23BrFNO2, 455.1 ; m/z found, 456.0 [M+H]+. 1H NMR (CDCI3): 7.38-7.22 (m, 5H), 7.17-7.16 (m, 2H), 7.05- 6.96 (m, 2H), 6.84 (d, J = 2.2 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 5.07 (s, 2H), 4.33 (q, J = 6.0 Hz, 1 H), 3.82-3.80 (m, 2H), 3.57 (d, J = 6.9 Hz, 1 H), 3.41 -3.39 (m, 1 H), 2.87 (t, J = 7.0 Hz, 1 H), 1.21 (d, J = 6.2 Hz, 3H).
Example 222: 3-[5-Chloro-2-(1 -phenyl-azetidin-3-ol)-phenoxy1-azetidine.
Figure imgf000157_0001
Step A: Preparation of 1 -phenyl-azetidin-3-ol. The mixture of azetidin-3- ol (2 mmol), bromobenzene (2 mmol), Pd(OAc)2 (0.1 mmol), 2-(ό\-tert- butylphosphino)biphenyl (0.2 mmol) and NaOfBu (3 mmol) in toluene (3 ml_) was heated at 100 0C for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (15 mg). Step B: Preparation of 3-[5-Chloro-2-(1 -phenyl-azetidin-3-ol)-phenoxy1- azetidine. The mixture of the title compound of Step A (15 mg), 3-(5-chloro-2- hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.2 mmol) and cyanomethylenetri-n-butylphosphorane (0.2 mmol) in toluene (2 ml_) was heated at 120 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (20 mg). This compound was dissolved in CH2CI2 (5 mL) and TFA (1 mL) was added. The mixture was stirred at rt for 4 h and concentrated to provide the title compound (25 mg). MS (ESI): mass calcd. for Ci8Hi9CIN2O2, 330.1 ; m/z found, 331.1 [M+H]+. 1H NMR (MeOD): 7.26-6.58 (m, 8H), 5.20-5.05 (m, 2H), 4.55-4.45 (m, 2H), 4.37- 4.28 (m, 2H), 4.25-4.16 (m, 2H), 3.88-3.85 (m, 2H).
Examples 223-225 were prepared similar to Example 222 using the appropriately substituted hydroxyazetidine. Example 223: (±)-3-f5-Chloro-2-(frans-1 -benzyl-2-methyl-azetidin-3-ol)- phenoxyi-azetidine.
Figure imgf000158_0001
Prepared from frans-('±)-1 -benzyl-2-methyl-azetidin-3-ol. MS (ESI): mass calcd. for C20H23CIN2O2, 358.1 ; m/z found, 359.1 [M+H]+. 1H NMR (MeOD): 7.61 -7.43 (m, 5H), 7.03-6.87 (m, 3H), 5.23-5.16 (m, 1 H), 4.88-4.78 (m, 1 H), 4.76-4.65 (m, 1 H), 4.63-4.45 (m, 5H), 4.29-4.19 (m, 2H), 4.18-4.09 (m, 1 H), 1.40 (d, J = 6.7 Hz, 3H).
Example 224: 3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy1-azetidine.
Figure imgf000158_0002
Prepared from i-isopropyl-azetidin-3-ol. MS (ESI): mass calcd. for Ci5H2iCIN2O2, 296.1 ; m/z found, 297.0 [M+H]+. 1H NMR (MeOD): 7.70 (dd, J = 8.7, 2.5 Hz, 1 H), 6.78-6.67 (m, 2H), 5.04-4.97 (m, 1 H), 4.76-4.67 (m, 1 H), 3.98- 3.92 (m, 2H), 3.80-3.67 (m, 4H), 3.34-3.26 (m, 2H), 2.53-2.46 (m, 1 H), 0.98 (d, J = 6.3 Hz, 6H). Example 225: 3-[5-Chloro-2-(1 -benzhvdryl-azetidin-3-ol)-phenoxy1-azetidine.
Figure imgf000159_0001
Prepared from i-benzhydryl-azetidin-3-ol. MS (ESI): mass calcd. for C25H25CIN2O2, 420.2; m/z found, 421.0 [M+H]+. 1H NMR (MeOD): 7.58-7.39 (m, 10H), 7.02-6.81 (m, 3H), 5.81 (s, 1 H), 5.19-5.10 (m, 2H), 4.67-4.50 (m, 4H), 4.39-4.31 (m, 2H), 4.23-4.16 (m, 2H).
Example 226: 3-[5-Chloro-2-(1 -azetidin-3-ol)-phenoxy1-azetidine.
Figure imgf000159_0002
Prepared according to the procedure of Example 222 Step B using 3- hydroxy-azetidine-1 -carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for Ci2Hi5CIN2O2, 254.1 ; m/z found, 255.1 [M+H]+. 1H NMR (MeOD): 7.00 (dd, J = 8.6, 2.4 Hz, 1 H). 6.91 (d, J = 2.4 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 5.22-5.11 (m, 2H), 4.62-4.53 (m, 4H), 4.31 -4.22 (m, 4H).
Example 227: 3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy1-1 -isopropyl- azetidine.
Figure imgf000159_0003
To the title compound of Step 226 (100 mg) in CH2CI2 (50 ml_) was added acetone (100 μl_) and NaBH3CN (1 ml_, 1 M in CH2CI2). The mixture was stirred at rt for 16 h. Then, NaOH solution (2 ml_, 1 M in H2O) was added. After 1 h, the organic layer was separated and concentrated. PTLC provided the title compound (20 mg). MS (ESI): mass calcd. for Ci8H27CIN2O2, 338.2; m/z found, 339.3 [IvRH]+. 1H NMR (CDCI3): 6.85 (dd, J = 8.6, 2.4 Hz, 1 H). 6.63 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 8.6 Hz, 1 H), 4.83-4.67 (m, 2H), 3.96-3.76 (m, 4H), 3.26-3.05 (m, 4H), 2.47-2.38 (m, 2H), 1.00 (d, J = 6.1 Hz, 12H).
Example 228: 3-r5-Chloro-2-(3-phenyl-cvclobutoxy)-phenoxy1-azetidine.
Figure imgf000160_0001
Step A: Preparation of 3-phenyl-cvclobutanol. To the solution of 3- phenyl-cyclobutanone (100 mg) in THF (10 ml_) was added LiAIH4 (0.2 mL, 2M in THF). The mixture was stirred at rt for 2 h, then 2M NaOH (1 mL) was added. The organic layer was concentrated and purified by PTLC providing the title compound (80 mg). Step B: Preparation of 3-r5-Chloro-2-(3-Dhenyl-cvclobutoxy)-Dhenoxy1- azetidine. The mixture of the title compound of Step A (80 mg), 3-(5-chloro-2- hydroxy-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (200 mg) and cyanomethylenetri-n-butylphosphorane (1.0 mmol) in toluene (2 mL) was heated at 120 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]- azetidine-1-carboxylic acid tert-butyl ester (120 mg). The ester was re- dissolved into CH2CI2 (10 mL), and TFA (2 mL) was added. The mixture was stirred at rt for 4 h then concentrated to give the title compound (168 mg). MS (ESI): mass calcd. for CI9H20CINO2, 329.1 ; m/z found, 330.1 [M+H]+. 1H NMR (MeOD): 7.26-6.64 (m, 8H), 5.30-5.15 (m, 2H), 4.95-4.83 (m, 2H), 4.60-4.52 (m, 1 H), 3.78-3.65 (m, 1 H), 2.68-2.58 (m, 4H). Example 229: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 -fe/f-butyl- azetidine.
Figure imgf000161_0001
Step A: Preparation of 1 -fe/f-butyl-azetidin-3-ol: To a solution of tert- butylamine (10 mmol) in isopropylalcohol (20 ml_) was added dropwise epichlorohydrine (10 mmol). The mixture was stirred at 25 0C for 16 h. After concentration, the residue was re-dissolved in acetonitrile (20 ml_) and triethylamine (20 mmol) was added. The mixture was heated at 100 0C for 24 h, cooled to rt and filtered. The filtrate was concentrated providing 1 -te/t-butyl- azetidin-3-ol (1.1g ). MS (ESI): mass calcd. for C7Hi5NO, 129.1 ; m/z found, 130.1 [IvRH]+. 1H NMR (CDCI3): 6.15-5.70 (br s, 1 H), 4.84-4.72 (m, 1 H), 4.24- 4.12 (m, 2H), 4.03-3.87 (m, 2H), 1.37 (s, 9H).
Step B: Preparation of 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy1-1 - fe/f-butyl-azetidine: To a solution of the title compound of Step A (3 mmol), and triethylamine (6 mmol) in CH2CI2 (50 ml_), was added MeSO3CI (4 mmol). The mixture was stirred at 25 0C for 16 h. After concentration, 1/3 of the residue was dissolved in MeCN (20 ml_). Next, 5-bromo-2-(3-fluoro-benzyloxy)-phenol (0.5 mmol) and K2CO3 (2 mmol) were added. The mixture was stirred at 100 0C for 16 h, concentrated and purified via PTLC providing the title compound (189 mg). MS (ESI): mass calcd. for C20H23BrFNO2, 407.1 ; m/z found, 408.0 [M+H]+. 1H NMR (CDCI3): 7.37-7.28 (m, 1 H), 7.19-7.12 (m, 2H), 7.04-6.95 (m, 2H), 6.84-6.63 (m, 2H), 5.08 (s, 2H), 4.78-4.48 (m, 1 H), 3.68-3.62 (m, 2H), 3.35-3.26 (m, 2H), 1.00 (s, 9H).
Example 230-231 was prepared by the procedure of Example 229 using the appropriately substituted phenols. Example 230: 1 -ferf-Butyl-3-r5-chloro-2-(3-trifluoromethyl-benzyloxy)- phenoxyi-azetidine
Figure imgf000162_0001
MS (ESI): mass calcd. for C2IH23CIF3NO2, 413.1 ; m/z found, 413.9 [M+H]+. 1H NMR (CDCI3): 7.75-7.46 (m, 4H), 6.90-6.65 (m, 3H), 5.12 (s, 2H), 4.80-4.71 (m, 1 H), 3.71 -3.62 (m, 2H), 3.35-3.26 (m, 2H), 0.99 (s, 9H).
Example 231 : 1 -fert-Butyl-3-f5-chloro-2-f1 -(3-trifluoromethyl-phenyl)-ethoxy1- phenoxyi-azetidine
Figure imgf000162_0002
MS (ESI): mass calcd. for C22H25CIF3NO2, 427.2; m/z found, 428.3 [M+H]+. 1H NMR (CDCI3): 7.68-7.42 (m, 4H), 6.78-6.62 (m, 3H), 5.32-5.23 (m, 1 H), 4.78-4.68 (m, 1 H), 3.70-3.62 (m, 2H), 3.33-3.25 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), 0.99 (s, 9H).
Example 232: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzvπ- azetidine.
Figure imgf000162_0003
Step A: Preparation of 3-(Methoxy-methyl-carbamoyl)-azetidine-1 - carboxylic acid tert-butyl ester. To a solution of azetidine-1 ,3-dicarboxylic acid mono-tert-butyl ester (3.5 g, 17 mmol) in DMF (50 ml_) was added O1N- dimethyl-hydroxylamine hydrochloride (3.4 g, 34 mmol), thethylamine (9.6 mL, 69 mmol), HATU (13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturated NaHCO3 solution and ethyl acetate were added. The aqueous portion was extracted three times with ethyl acetate. The combined organic fractions were dried (Na2SO4) and concentrated and the crude product was purified using RP HPLC (basic conditions) to provide the title compound (3.5 g, 83%) MS (ESI): mass calcd. for CnH2ON2O4, 244.1 ; m/z found, 189.1 [M-t- Bu]+. 1H NMR (CDCI3): 4.14-4.03 (m, 2H), 4.05 (t, J = 8.7 Hz, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 1 H), 3.21 (s, 1 H), 1.43 (s, 9H).
Step B: Preparation of 3-(2-Methoxy-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester. To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1 - carboxylic acid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0 0C was added 2-methoxylphenylmagnesium bromide (1.0 M in THF, 17 mL, 17 mmol). The reaction was allowed to slowly warm to rt and stirred for 36 h. Then a solution of 1 M KHSO4 and EtOAc were added and the aqueous portion was extracted once with EtOAc. The combined organic fractions were dried (Na2SO4) and concentrated to provide the title compound. This material was used in subsequent reactions without additional purifications. MS (ESI): mass calcd. for Ci6H21NO4, 291.1 ; m/z found, 236.1 [M-t-Bu]+. 1H NMR (CDCI3): 7.83 (dd, J = 7.8, 1.8 Hz, 1 H), 7.51 (ddd, J = 8.5, 7.3, 1.8 Hz, 1 H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H), 3.90 (s, 3H), 1.44 (s, 9H). Step C: Preparation of 3-(2-Methoxy-benzyl)-azetidine-1 -carboxylic acid tert-butyl ester. To a solution of 3-(2-methoxy-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester (2.1 g, 7.2 mmol) in methanol (50 mL) was added sodium borohydhde (1.08 g, 28.8 mmol). After stirring for 36 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried
(Na2SO4) and concentrated. To a solution of this material in ethanol (50 mL) was added 10% Pd/C. This reaction was then placed on a Parr hydrogenation apparatus with 60 psi of hydrogen gas. After 72 h, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (370 mg, 19%). MS (ESI): mass calcd. for Ci6H23NO3, 277.2; m/z found, 222.2 [M-t- Bu]+. 1H NMR (CDCI3): 7.23-7.10 (m, 1 H), 7.06 (d, J = 7.3 Hz, 1 H), 6.92 - 6.77 (m, 2H), 3.96 (t, J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.65-3.63 (m, 2H), 2.94-2.78 (m, 5H), 1.44 (s, 9H).
Step D: Preparation of 2,2,2-Trifluoro-1 -[3-(2-methoxy-benzyl)-azetidin- 1 -yli-ethanone. To a solution of 3-(2-methoxy-benzyl)-azetidine-1 -carboxylic acid tert-butyl ester (370 mg, 1.3 mmol) in DCM (10 ml_) was added TFA (3 ml_). After stirring for 16 h, TLC analysis indicated complete consumption of the starting material. To quench the reaction, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated. To a solution of this material in DCM (20 mL) was added thethylamine (370 μL, 2.60 mmol) followed by thfluoroacetic anhydride (204 μL, 1.50 mmol). After 1 h, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated to provide the title compound (274 mg, 75%). MS (ESI): mass calcd. for Ci3Hi4F3NO2, 273.1 ; m/z found, 274.2 [M+H]+. 1H NMR (CDCI3): 7.26-7.20 (m, 1 H), 7.07 (dd, J = 7.4, 1.6 Hz, 1 H), 6.94-6.82 (m, 2H), 4.41 (dd, J = 9.6, 8.4 Hz, 1 H), 4.23-4.14 (m, 1 H), 4.12-4.08 (m, 1 H), 3.93-3.84 (m, 1 H), 3.82 (s, 3H), 3.18-3.00 (m, 1 H), 2.95-2.91 (m, 2H).
Step E: Preparation of 1 -[3-(5-Bromo-2-methoxy-benzyl)-azetidin-1 -yl1- 2,2,2-thfluoro-ethanone. To a solution of 2,2,2-trifluoro-1 -[3-(2-methoxy- benzyl)-azetidin-1-yl]-ethanone (95 mg, 0.35 mmol) in acetone (2 mL) and water (2 mL) was added NaBr (143 mg, 1.40 mmol) followed by Oxone (210 mg, 0.35 mmol). After 5 h, 10% sodium metabisulfite solution was added. After 1 h, EtOAc was added and the aqueous portion extracted twice with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (66 mg, 53%). MS (ESI): mass calcd. for Ci3Hi3BrF3NO2, 352.1 ; m/z found, 354.1 [M+H]+. 1H NMR (CDCI3): 7.32 (dd, J = 8.7, 2.5 Hz, 1 H), 7.17 (d, J = 2.5 Hz, 1 H), 6.75 (t, J = 10.2 Hz, 1 H), 4.43 (dd, J = 9.6, 8.4 Hz, 1 H), 4.26-4.14 (m, 1 H), 4.09 (dd, J = 9.6, 5.7 Hz, 1 H), 3.89 (dd, J = 10.7, 5.7 Hz, 1 H), 3.81 (s, 3H), 3.14-2.96 (m, 1 H), 2.90 (d, J = 7.8 Hz, 2H).
Step F: Preparation of 1-[3-(5-Bromo-2-hvdroxy-benzyl)-azetidin-1 -vH- 2,2,2-trifluoro-ethanone. To a solution of 1 -[3-(5-bromo-2-methoxy-benzyl)- azetidin-1 -yl]-2,2,2-thfluoro-ethanone (66 mg, 0.19 mmol) in dry DCM (10 ml_) at 0 0C was added BBr3 (1.0 M in DCM, 370 ml_, 0.37 mmol). After warming to rt overnight, saturated NaHCO3 solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated to provide the title compound (59 mg, 92%). MS (ESI): mass calcd. for Ci2H11BrF3NO2, 337.0; m/z found, 338.0
[M+H]+. 1H NMR (CDCI3): 7.23-7.10 (m, 2H), 6.70 (t, J = 8.7 Hz, 1 H), 4.53-4.40 (m, 1 H), 4.27-4.11 (m, 2H), 3.97 (dd, J = 10.7, 6.0 Hz, 1 H), 3.17-3.01 (m, 1 H), 3.01-2.78 (m, 2H).
Step G: Preparation of 1 -{3-[5-Bromo-2-(5-trifluoromethyl-furan-2- ylmethoxy)-benzyl1-azetidin-1 -yl)-2,2,2-thfluoro-ethanone. To a solution of 1 -[3- (5-bromo-2-hydroxy-benzyl)-azetidin-1 -yl]-2,2,2-trifluoro-ethanone (59 mg, 0.17 mmol) in DMF (10 ml_) was added Kl (40 mg, 0.24 mmol), Cs2CO3 (170 mg, 0.51 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (56 mg, 0.24 mmol). After 16 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na2SO4) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (76 mg, 91 %). MS (ESI): mass calcd. for C18H14BrF6NO3, 486.2; m/z found, 488.1 [M+H]+. 1H NMR (CDCI3): 7.34 (dd, J = 8.7, 2.5 Hz, 1 H), 7.21 (d, J = 2.5 Hz, 1 H), 6.89-6.76 (m, 2H), 6.48 (d, J = 3.4 Hz, 1 H), 5.02 (s, 2H), 4.40 (dd, J = 9.6, 8.4 Hz, 1 H), 4.22-4.11 (m, 1 H), 4.08-4.02 (m, 1 H), 3.84 (dd, J = 10.7, 5.7 Hz, 1 H), 3.11 -2.97 (m, 1 H), 2.97-2.82 (m, 2H).
Step H: Preparation of 3-[5-Bromo-2-(5-trifluoromethyl-furan-2- ylmethoxyVbenzyli-azetidine. To a solution of 1 -{3-[5-bromo-2-(5- trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1 -yl}-2,2,2-thfluoro- ethanone (76 mg, 0.16 mmol) in methanol (10 ml_) was added K2CO3 (94 mg, 0.70 mmol). After 1 h, TLC analysis indicated complete consumption of the starting material. Brine and EtOAc were added to the reaction mixture and the aqueous portion was extracted with EtOAc (3X). The combined organic layers were dried. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (50 mg, 76%). MS (ESI): mass calcd. for Ci6Hi5BrF3NO2, 390.2; m/z found, 393.2 [IvRH]+. 1H NMR (CDCI3): 7.50-7.41 (m, 1 H), 7.35-7.26 (m, 1 H), 6.89-6.79 (m, 2H), 6.53 (s, 1 H), 5.05 (s, 2H), 4.43- 4.20 (m, 1 H), 3.63 (t, J = 8.2 Hz, 2H), 3.44 (t, J = 7.7 Hz, 2H), 2.85 (d, J = 7.6 Hz, 2H).
Example 233: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethvH-azetidine.
Figure imgf000166_0001
Prepared similar to Example 1 using 3-hydroxymethyl-azetidine-1 - carboxylic acid tert-butyl ester. MS (ESI): mass calcd.for Ci7Hi7BrCINO2, 381.0: m/z found, 382.1 [M+H]+. 1H NMR (CDCI3): 7.45 (s, 1 H), 7.35-7.21 (m, 3H), 7.15-6.96 (m, 2H), 6.77 (d, J = 8.5, 1 H), 5.04 (s, 2H), 4.16 (d, J = 6.4, 2H), 3.81 (m, 2H), 3.63 (m, 1 H), 3.62-3.52 (m, 1 H), 3.21 (m, 1 H), 2.17 (m, 1 H).
Example 234: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethvH-1 -methyl- azetidine.
Figure imgf000166_0002
Prepared from Example 233 using general procedure 5. MS (ESI): mass calcd. for Ci8Hi9BrCINO2, 395.0; m/z found, 396.1 [M+H]+. 1H NMR (CDCI3): 7.52 (d, J = 2.5, 1 H), 7.40 (s, 1 H), 7.36-7.22 (m, 4H), 6.74 (d, J = 8.7, 1 H), 5.04 (s, 2H), 4.45 (s, 2H), 4.23-4.15 (m, 1 H), 3.64 (s, 2H), 2.93 (s, 2H), 2.35 (s, 3H).
Example 235: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethvπ-azetidin-3- QL
Figure imgf000167_0001
Step A: Preparation of 1 -Boc-3-[5-bromo-2-(3-chloro-benzyloxy)- phenoxymethvH-azetidin-3-ol. The mixture of the title compound of Example 215 Step B (2.3 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (1.3 mmol), and cyanomethyleneth-n-butylphosphorane (2 mmol) in toluene (5 ml_) was heated at 150 0C in a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (580 mg). MS (ESI): mass calcd. for C22H25BrCINO5, 497.1 ; m/z found, 504.2 [M-OH+Na]+. 1H NMR (CDCI3): 7.52-7.23 (m, 4H), 6.99-6.68 (m, 3H), 5.70-5.10 (br S, 1 H), 5.04 (s, 2H), 4.99-4.97 (m, 2H), 4.50-4.46 (m, 4H), 1.45 (s, 9H).
Step B: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl1-azetidin-3- ol. The the title compound of Step A (160 mg) was dissolved in CH2CI2 (20 ml_), and TFA (3 ml_) was added. The mixture was stirred at rt for 4 h and concentrated. The resulting residue was dissolved into MeOH (20 ml_), and Dowex 66 ion-exchange resin (Dowex hydroxide, weakly basic anion,
Macroporous) was added to adjust the pH to 7. The resin was filtered and the filtrate concentrated providing the title compound (120 mg). MS (ESI): mass calcd. for Ci7H17BrCINO3, 397.0; m/z found, 382.2 [M-OH+H]+. 1H NMR (MeOD): 7.52-7.28 (m, 4H), 6.97-6.81 (m, 3H), 5.18-5.15 (m, 2H), 5.12 (s, 2H), 4.73-4.68 (m, 4H). Example 236: 3-[1 -[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy1-ethvπ-azetidin- 3-ol.
Figure imgf000168_0001
Prepared according to Example 235 using 3-ethyl-3-hydroxy-azetidine-1 - carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for Ci8Hi9BrCINO3, 411.0; m/z found, 396.0 [M-OH+H]+. 1H NMR (MeOD): 7.52-7.27 (m, 4H), 6.98-6.80 (m, 3H), 5.57-5.48 (m, 1 H), 5.12 (s, 2H), 4.73-4.61 (br s, 4H), 1.63- 1.57 (m, 3H).
Example 237: 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy1-azetidine.
Figure imgf000168_0002
Step A: Preparation of [5-Bromo-2-(3-chloro-benzyloxy)-phenvπ- methanol. To a solution of 5-bromo-2-(3-chloro-benzyloxy)-benzaldehyde (6.0 g, 18.4 mmol) in MeOH (90 ml_) at rt was added NaBH4 (1.07g, 27.7 mmol) over 1 h. After 18 h at rt, H2O was added (5 ml_) and the reaction concentrated to a residual mass, which was dissolved into EtOAc (150 ml_). This EtOAc solution was washed with H2O (2x100 ml_) and dried to yield the title compound as a light yellow (6.0 g, 100%). MS (ESI): mass calcd. for Ci4Hi2BrCIO, 327.6; m/z found, 328.3 [M+H]+. 1H NMR (CDCI3) 7.48 (d, J = 2.5 Hz, 1 H), 7.42-7.20 (m, 5H), 6.76 (d, J = 8.7 Hz, 1 H), 5.07 (d, J = 19.2 Hz, 2H), 4.69 (d, J = 17.5 Hz, 2H), 2.15 (t, J = 10.0 Hz, 1 H).
Step B. 5-Bromo-2-(3-chloro-benzyloxy)-benzyl chloride. The title compound of Step A was dissolved into CH2CI2 (8 ml_) and thionyl chloride (114 mg, 0.95 mmol) was added at rt. The reaction mixture was stirred for 2 h and concentrated to yield the title compound (300 mg). 1H NMR (CDCI3): 7.51 (d, J = 2.5 Hz, 1 H), 7.48-7.22 (m, 6H), 6.76 (t, J = 11.1 Hz, 1 H), 5.14-4.99 (m, 2H), 4.65 (d, J = 14.7 Hz, 2H). Step C. 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy1-azetidine. To a
DMF (5 ml_) solution of 3-hydroxy-azetidine-i -carboxylic acid tert-butyl ester (150 mg, 0.87 mmol) at rt was added 60% NaH (36 mg, 0.91 mmol). The reaction mixture was stirred at rt for 0.5 h. Then a DMF solution of the title compound of Step B (300 mg, 0.87 mmol) was added. After 18 h, the reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried and concentrated to yield the title compound (380 mg). This material was purified by chromatography (SiO2) using 0-25 % EtOAc in hexanes to give 3-[5- bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine-1 -carboxylic acid tert-butyl ester (70 mg, 37 %). This compound was treated with 4M HCI in dioxane and stirred 6 h at rt and concentrated. Purification by RP HPLC (basic system) gave the title compound (26 mg, 7 %) MS (ESI): mass calcd. for Ci7Hi7BrCINO2, 381.7; m/z found, 383.0 [M+H]+. 1H NMR (CDCI3): 7.52 (d, J = 2.5 Hz, 1 H), 7.41 (s, 1 H), 7.36-7.21 (m, 4H), 6.74 (d, J = 8.7 Hz, 1 H), 5.03 (s, 2H), 4.49-4.39 (m, 3H), 3.68 (m, 4H), 1.75 (s, 1 H).
Example 238: 3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine.
Figure imgf000169_0001
Prepared according to Example 237 using 5-chloro-2-(3-chloro- benzyloxy)-benzaldehyde. MS (ESI): mass calcd.for Ci7Hi7CI2NO2, 337.06; m/z found, 338.2 [M+H]+. 1H NMR (CDCI3): 7.43-7.15 (m, 6H), 6.79 (d, J = 8.7 Hz, 1 H), 5.04 (s, 2H), 4.49-4.39 (m, 3H), 3.71 -3.67 (m, 3H), 1.92 (m, 1 H), 1.90- 1.83 (m, 1 H). Example 239: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ-3-methyl- [1 ,2,41oxadiazole.
Figure imgf000170_0001
Step A: Preparation of 3-(5-Chloro-2-ethoxycarbonylmethoxy-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester. To 3-(5-Chloro-2-hydroxy- phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (1.5 g, 5.0 mmol) in DMF (20 ml_) was added Cs2CO3 (2.1 g, 6.4 mmol), Kl (0.84 g, 5.0 mmol) and bromoethyl acetate (0.84 g, 0.55 ml_, 5.0 mmol). After 18h, H2O was added and the mixture extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (5-30% EtOAc in hexanes) gave 1.95 g (99%) of the title compound as a clear oil. 1H NMR (CDCI3): 6.91 (dd, J = 8.7, 2.4 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 4.91 -4.87 (m, 1 H), 4.65 (s, 2H), 4.32-4.25 (m, 4H), 4.01 (dd, J = 10.5, 4.2 Hz, 2H), 1.44 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H). Step B: Preparation of 3-(2-Carboxymethoxy-5-chloro-phenoxy)- azetidine-1-carboxylic acid tert-butyl ester. To the title compound from Step A (1.70 g, 4.40 mmol) in MeOH (10 ml_) was added 4N NaOH (10 ml_). After 2h, CH2CI2 was added and the mixture acidified with 1 N KHSO4 (50 ml_) then extracted with CH2CI2 (2X). The combined organics were dried to give a 0.90 g (57%) of the title compound as a white solid that was used without further purification. MS (ESI): mass calcd. for Ci6H20CINO6, 357.1 ; m/z found, 380.1 [M+Na]+. 1H NMR (400 MHz): 6.92 (dd, J = 8.6, 2.3 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 4.92-4.86 (m, 1 H), 4.67 (s, 2H), 4.31 (dd, J = 9.9, 6.5 Hz, 2H), 4.07 (dd, J = 10.0, 4.1 Hz, 2H), 1.45 (s, 9H). Step C: Preparation of 3-r5-Chloro-2-(3-methyl-ri ,2,41oxadiazol-5- ylmethoxy)-phenoxy1-azetidine-1 -carboxylic acid tert-butyl ester. To the title compound of Step B (0.15 g, 0.42 mmol) in CH2CI2 (4 ml_) was added DMF (catalytic) and 2M COCI2 in CH2CI2 (0.3 ml_, 0.6 mmol). After 2h, the reaction was concentrated and THF (2 ml_) was added. This solution was added to N- hydroxy-acetamidine (0.035 g, 0.46 mmol) and Λ/,Λ/-diisopropylethylamine (0.065 g, 0.088 ml_, 0.50 mmol) in THF (2 ml_). The mixture was then heated for 20 min at 155 0C in a microwave reactor, cooled to rt and concentrated. Silica gel chromatography (5-30% EtOAc in hexanes) gave 0.155 g (93%) of the title compound as a clear oil. MS (ESI): mass calcd. for C18H22CIN3O5, 395.1 ; m/z found, 295.3 [M-I OO]+. 1H NMR (400 MHz): 6.94 (d, J = 8.6 Hz, 1 H), 6.91 (dd, J = 8.6, 2.2 Hz, 1 H), 6.57 (d, J = 2.1 Hz, 1 H), 5.27 (s, 2H), 4.89- 4.85 (m, 1 H), 4.32-4.29 (m, 2H), 4.04 (dd, J = 10.4, 4.2 Hz, 2H), 2.43 (s, 3H), 1.45 (s, 9H).
Step D: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethvπ- 3-methyl-π ,2,41oxadiazole hydrochloride. Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for Ci3Hi4CIN3O3, 295.1 ; m/z found, 296.2 [M+H]+. 1H NMR (DMSO-D6): 9.30 (s, 2H), 7.14 (d, J = 8.7 Hz, 1 H), 7.05 (dd, J = 8.7, 2.4 Hz, 1 H), 6.96 (d, J = 2.4 Hz, 1 H), 5.52 (s, 2H), 5.10-5.05 (m, 1 H), 4.42 (dd, J = 12.5, 6.7 Hz, 2H), 4.01 (dd, J = 12.5, 4.8 Hz, 2H) 2.36 (s, 3H).
The compounds in Examples 240-243 were synthesized according to Example 239 using the appropriately substituted /V-hydroxyamidine.
Example 240: 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-3-cvclobutyl- [1 ,2,41oxadiazole.
Figure imgf000171_0001
MS (ESI): mass calcd. for Ci6H18CIN3O3, 335.1 ; m/z found, 336.2 [M+H]+. 1H NMR (CDCI3): 6.95 (d, J = 8.6 Hz, 1 H), 6.87 (dd, J = 8.6, 2.3 Hz, 1 H), 6.62 (s, 1 H), 5.28 (s, 2H), 4.99-4.89 (m, 1 H), 3.98-3.66 (m, 5H), 2.41 -2.36 (m, 4H), 2.17-1.98 (m, 2H). Example 241 : 5-r2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl1-3-cvclopropyl- [1 ,2,41oxadiazole hydrochloride.
Figure imgf000172_0001
MS (ESI): mass calcd. for Ci5Hi6CIN3O3, 321.1 ; m/z found, 322.2 [IvRH]+. 1H NMR (DMSO-D6): 9.31 (s, 2H), 7.12 (d, J = 8.8 Hz, 1 H), 7.05 (dd, J = 8.7, 2.4 Hz, 1 H), 6.96 (d, J = 2.4 Hz, 1 H), 5.49 (s, 2H), 5.09-5.04 (m, 1 H), 4.42 (dd, J = 12.2, 6.6 Hz, 2H), 4.03-3.99 (m, 2H), 2.17-2.13 (m, 1 H), 1.11 -1.07 (m, 2H), 0.90-0.87 (m, 2H).
Example 242: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-3-isopropyl- [1 ,2,41oxadiazole hydrochloride.
Figure imgf000172_0002
MS (ESI): mass calcd. for Ci5Hi8CIN3O3, 323.1 ; m/z found, 324.2 [M+H]+. 1H NMR (DMSO-D6): 9.28 (s, 2H), 7.14 (d, J = 8.7 Hz, 1 H), 7.06 (dd, J = 8.7, 2.4 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 5.51 (s, 2H), 5.10-5.05 (m, 1 H), 4.43 (dd, J = 12.3, 6.6 Hz, 2H), 4.02 (dd, J = 12.3, 4.7 Hz, 2H), 3.12-3.07 (m, 1 H), 1.28 (d, J= 6.9 Hz, 6H).
Example 243: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl1-3-ethyl- [1 ,2,41oxadiazole hydrochloride.
Figure imgf000172_0003
MS (ESI): mass calcd. for Ci4Hi6CIN3O3, 309.1 ; m/z found, 310.2 [M+H]+. 1H NMR (DMSO-D6): 9.34 (s, 2H), 7.14 (d, J = 8.7 Hz, 1 H), 7.06 (dd, J = 8.7, 2.4 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 5.51 (s, 2H), 5.10-5.05 (m, 1 H), 4.42 (dd, J = 12.6, 6.7 Hz, 2H), 4.02 (dd, J = 12.5, 4.9 Hz, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 2H).
Compounds in Examples 244-278 were synthesized according to general procedure 6.
Example 244: 3-(5-Bromo-2-phenoxy-phenoxy)-azetidine.
Figure imgf000173_0001
MS (ESI): mass calcd. for Ci5Hi4BrNO2, 320.2; m/z found, 322.1 [M+H]+.
1H NMR (CDCI3): 7.32-7.28 (m, 2H), 7.07-7.05 (m, 2H), 6.94-6.92 (m, 2H), 6.88-6.84 (m, 2H), 4.97-4.91 (m, 1 H), 3.85-3.81 (m, 2H), 3.71 -3.67 (m, 2H).
Example 245: 3-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy1-azetidine.
H
Figure imgf000173_0002
MS (ESI): mass calcd. for Ci5Hi3Br2NO2, 399.1 ; m/z found, 401.0 [M+H]+. 1H NMR (CDCI3): 7.21 -7.12 (m, 2H), 7.09 (dd, J = 8.5, 2.2 Hz, 1 H), 7.04-6.98 (m, 1 H), 6.91 (d, J = 8.5, 1 H), 6.88-6.77 (m, 2H), 4.96-4.92 (m, 1 H), 3.90-3.78 (m, 2H), 3.72-3.60 (m, 2H).
Example 246: 3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy1-azetidine .
Figure imgf000173_0003
MS (ESI) mass calcd. for Ci5Hi3BrFNO2, 337.01 ; m/z found, 338.3 [M+H]+. 1H NMR (CD3OD) 7.37-7.21 (m, 2H), 7.18 (d, J = 2.2 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 1 H), 6.83 (t, J = 8.4, 2.4 Hz, 1 H), 6.75-6.63 (m, 2H), 5.15 (m, 1 H), 4.47 (dd, J = 12.4, 6.6 Hz, 2H), 4.05 (dd, J = 12.4, 4.7 Hz, 2H).
Example 247: 3-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine .
Figure imgf000174_0001
MS (ESI) mass calcd. for Ci6Hi6BrFNO2, 333.04; m/z found, 334.1 [M+H]+. 1H NMR (CD3OD) 7.25-7.10 (m, 3H), 6.92 (dd, J = 12.9, 8.1 Hz, 2H), 6.80-6.64 (m, 2H), 5.19-5.03 (m, 1 H), 4.45 (dd, J = 12.7, 6.7 Hz, 2H), 4.09 (dd, J = 12.6, 4.9 Hz, 2H). Example 248: 3-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy1-azetidine.
Figure imgf000174_0002
MS (ESI):mass calcd. for Ci6Hi6BrNO3, 350.2; m/z found, 351.1 [M+H]+. 1H NMR (CDCI3): 7.18 (t, J = 8.1 Hz, 1 H), 7.06 (dd, J = 8.5, 2.2 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.83 (d, J = 2.2 Hz, 1 H), 6.62 (dd, J = 8.2, 1.7 Hz, 1 H), 6.53 - 6.45 (m, 2H), 5.00-4.90 (m, 1 H), 3.95-3.62 (m, 7H).
Example 249: 3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy1-azetidine.
Figure imgf000174_0003
MS (ESI): mass calcd. for Ci5Hi3BrFNO2, 338.2; m/z found, 339.1 [M+H]+. 1H NMR (CDCI3): 7.05 (dd, J = 8.5, 2.2 Hz, 1 H), 7.01-6.97 (m, 2H), 6.90-6.88 (m, 2H), 6.82 (dd, J = 5.4, 3.1 Hz, 2H), 4.99-4.90 (m, 1 H), 3.92-3.64 (m, 4H). Example 250: 3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy1-azetidine.
Figure imgf000175_0001
MS (ESI): mass calcd. for Ci5Hi3Br2NO2, 399.1 ; m/z found, 401.0 [M+H]+. 1H NMR (CDCI3): 7.43-7.33 (m, 2H), 7.08 (dd, J = 8.5, 2.3 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.83-6.78 (m, 3H), 4.99-4.90 (m, 1 H), 3.95-3.55 (m, 4H).
Example 251 : 3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy1-azetidine.
Figure imgf000175_0002
MS (ESI): mass calcd. for Ci5Hi3BrCINO2, 354.6; m/z found, 355.0 [M+H]+. 1H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J = 2.2 Hz, 1 H), 7.10 (dd, J = 8.0, 1.9 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 6.94 (t, J = 2.2 Hz, 1 H), 6.85 (dd, J = 8.3, 2.4 Hz, 1 H), 5.18-5.10 (m, 1 H), 4.50-4.41 (m, 2H), 4.07-4.04 (m, 2H).
Example 252: 3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy1-azetidine.
Figure imgf000175_0003
MS (ESI): mass calcd. for Ci5Hi3BrCINO2, 354.6; m/z found, 355.0 [M+H]+. 1H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J = 2.2 Hz, 1 H), 7.10 (dd, J = 8.0, 1.9 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 6.94 (t, J = 2.2 Hz, 1 H), 6.85 (dd, J = 8.3, 2.4 Hz, 1 H), 5.18-5.10 (m, 1 H), 4.50-4.41 (m, 2H), 4.07-4.04 (m, 2H). Example 253: 3-[5-Bromo-2-(3-trifluoromethoxy-phenoxy)-phenoxy1-azetidine.
Figure imgf000176_0001
MS (ESI): mass calcd. for Ci6Hi3BrF3NO3, 403.0; m/z found, 404.1 [M+H]+. 1H NMR (MeOD): 7.41 (t, J = 8.3 Hz, 1 H), 7.31 -7.13 (m, 2H), 7.06- 7.02 (m, 1 H), 7.02-6.97 (m, 1 H), 6.93-6.78 (m, 2H), 5.21 - 5.09 (m, 1 H), 4.50- 4.47 (m, 2H), 4.06-4.03 (m, 2H), 3.34 - 3.24 (m, 1 H).
Example 254: 3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy1-azetidine.
Figure imgf000176_0002
MS (ESI): mass calcd. for Ci9Hi6BrNO2, 369.0; m/z found, 370.1 [M+H]+.
1H NMR (MeOD): 7.92-7.77 (m, 2H), 7.70 (d, J = 8.1 Hz, 1 H), 7.49-6.97 (m, 7H), 5.20-5.12 (m, 1 H), 4.44 (dd, J = 12.5, 6.6 Hz, 2H), 4.05 (dd, J = 12.5, 5.0 Hz, 2H).
Example 255: 3-[5-Bromo-2-(naphthalen-1 -yloxy)-phenoxy1-azetidine.
Figure imgf000176_0003
MS (ESI): mass calcd. for Ci9Hi6BrNO2, 369.0; m/z found, 370.1 [M+H]+. 1H NMR (MeOD): 8.25-8.16 (m, 1 H), 7.95-7.85 (m, 1 H), 7.65-7.16 (m, 6H), 6.95-6.72 (m, 2H), 5.21-5.12 (m, 1 H), 4.42 (m, 2H), 4.05 (dd, J = 12.5, 5.0 Hz, 2H). Example 256: 3-(5-Chloro-2-phenoxy-phenoxy)-azetidine.
Figure imgf000177_0001
MS (ESI): mass calcd. for Ci5Hi4CINO2, 275.1 ; m/z found, 276.1 [M+H]+. 1H NMR (CDCI3): 7.33-7.26 (m, 2H), 7.11 -6.99 (m, 1 H), 6.99-6.84 (m, 4H), 6.70 (d, J = 1.3 Hz, 1 H), 4.97-4.91 (m, 1 H), 3.88-3.79 (m, 2H), 3.75-3.64 (m, 2H).
Example 257: 3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy1-azetidine maleate.
Figure imgf000177_0002
MS (ESI): mass calcd. for Ci5Hi3CI2NO2, 309.0; m/z found, 310.1 [M+H]+. 1H NMR (CDCI3): 7.22 (t, J = 8.2 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J = 8.6 Hz, 2.3 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 6.89 (t, J = 2.1 Hz, 1 H), 6.80 (dt, J = 5.2, 2.5 Hz, 2H), 6.29 (s, 2H), 5.18-5.08 (m, 1 H), 4.44 (d, J = 6.7 Hz, 2H), 4.21 (s, 2H).
Example 258: 3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy1-azetidine trifluoroacetate.
Figure imgf000177_0003
MS (ESI): mass calcd. for Ci5Hi3CI2NO2, 309.0; m/z found, 310.8 [M+H]+. 1H NMR (CDCI3): 7.31 -7.27 (m, 2H), 7.02 (dd, J = 8.7, 2.4 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 6.88-6.83 (m, 2H), 6.79 (d, J = 2.3 Hz, 1 H), 5.11 -5.06 (m, 1 H), 4.34 (dd, J = 11.8, 6.8 Hz, 2H), 4.14 (dd, J = 11.7, 5.5 Hz, 2H). Example 259: 3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine trifluoroacetate.
Figure imgf000178_0001
MS (ESI): mass calcd. for Ci6Hi6CINO2, 289.1 ; m/z found, 290.2 [M+H]+. 1H NMR (CDCI3): 7.25 (d, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 6.95 (dd, J = 8.7, 2.4 Hz, 1 H), 6.81 (d, J = 2.4 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 1 H), 5.10 (s, 1 H), 4.34 (s, 2H), 4.19 (s, 2H), 2.24 (s, 3H).
Example 260: 3-r5-Chloro-2-(naphthalen-2-yloxy)-phenoxy1-azetidine.
Figure imgf000178_0002
MS (ESI): mass calcd. for Ci9Hi6CINO2, 325.1 ; m/z found, 326.2 [M+H]+. 1H NMR (MeOD): 7.90-7.79 (m, 2H), 7.70 (d, J = 8.0 Hz, 1 H), 7.48-7.03 (m, 7H), 5.20-5.12 (m, 1 H), 4.44 (dd, J = 12.6, 6.6 Hz, 2H), 4.05 (dd, J = 12.6, 5.0 Hz, 2H).
Example 261 : 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-benzothiazole.
Figure imgf000178_0003
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), 2-chloro-benzothiazole (0.5 mmol), and K2CO3 (1 mmol) in CH3CN (3 ml_) was heated at 120-150 0C via Microwave for 1 h. The mixture was cooled down and separated through PTLC providing 3-[2- (benzothiazol-2-yloxy)-5-chloro-phenoxy]-azetidine-1 -carboxylic acid tert-butyl ester (180 mg). The ester was re-dissolved into CH2CI2 (20 ml_), and CF3COOH (3 ml_) was added. The mixture was stirred at 25 0C for 4 h. After concentration, the title compound was obtained (192 mg). MS (ESI): mass calcd. for Ci6H13CIN2O2S, 332.0; m/z found, 333.1 [M+H]+. 1H NMR (MeOD): 7.23-7.07 (m, 4H), 6.92-6.81 (m, 3H), 5.14-5.08 (m, 1 H), 4.51 (dd, J =12.5, 6.6 Hz, 2H), 4.23 (dd, J =12.5, 5.0 Hz, 2H).
Example 262: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-benzooxazole.
Figure imgf000179_0001
MS (ESI): mass calcd. for Ci6Hi3CIN2O3, 316.1 ; m/z found, 317.1 [M+H]+. 1H NMR (MeOD): 7.83-7.78 (m, 1 H), 7.67-7.62 (m, 1 H), 7.46-7.41 (m, 2H), 7.26-7.21 (m, 1 H), 7.20 (dd, J = 8.6, 2.3 Hz, 1 H), 7.11 (d, J = 2,3 Hz, 1 H), 5.26-5.21 (m, 1 H), 4.50 (dd, J =12.7, 6.6 Hz, 2H), 4.07 (dd, J =12.7, 4.8 Hz, 2H).
Example 263: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-[1 ,81naphthyridine.
Figure imgf000179_0002
MS (ESI): mass calcd. for Ci7Hi4CIN3O2, 327.1 ; m/z found, 328.1 [M+H]+. 1H NMR (MeOD): 9.06-9.04 (m, 1 H), 8.97 (d, J = 4.7 Hz, 1 H), 8.74 (d, J = 8.9 Hz, 1 H), 7.92 (dd, J = 8.1 , 5.4 Hz, 1 H), 7.70 (d, J = 8.9 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 7.20 (dd, J = 8.6, 2.3 Hz, 1 H), 7.08 (d, J = 2.3 Hz, 1 H), 5.27- 5.18 (m, 1 H), 4.46 (dd, J =12.7, 6.6 Hz, 2H), 3.97 (dd, J =12.7, 4.8 Hz, 2H).
Example 264: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy1-quinoline.
Figure imgf000179_0003
MS (ESI): mass calcd. for Ci8Hi5CIN2O2, 327.1 ; m/z found, 328.1 [M+H]+. 1H NMR (CDCI3): 8.75 (s, 1 H), 8.12-8.06 (m, 1 H), 7.65-7.58 (m, 3H), 7.20 (d, J = 8.6 Hz, 1 H), 7.04 (dd, J = 8.6, 2.3 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 4.99-4.88 (m, 1 H), 3.86-3.72 (m, 2H), 3.61 -3.47 (m, 2H).
Example 265: 4-(5-Chloro-2-phenoxy-phenoxy)-piperidine.
Figure imgf000180_0001
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.8; m/z found, 304.2 [M+H]+. 1H NMR (CDCI3): 7.29-7.26 (m, 2H), 7.04-7.01 (m, 1 H), 6.99-6.97 (m, 2H), 6.93-6.89 (m, 3H), 4.35-4.30 (m, 2H), 2.95-2.91 (m, 2H), 2.62 (ddd, J = 12.3, 8.6, 3.3 Hz, 2H), 1.88-1.82 (m, 2H), 1.57-1.45 (m, 2H).
Example 266: (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine.
Figure imgf000180_0002
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.1 ; m/z found, 304.2 [M+H]+. 1H NMR (CDCI3): 7.09 (t, J = 7.7 Hz, 2H), 7.04 (dd, J = 8.7, 2.5 Hz, 1 H), 6.99 (d, J = 2.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 6.84-6.78 (m, 2H), 4.79 (dd, J = 5.7, 4.4 Hz, 1 H), 3.06 (d, J = 12.8 Hz, 1 H), 2.98-2.89 (m, 1 H), 2.82-2.71 (m, 2H), 2.32 (s, 3H), 1.99-1.89 (m, 1 H), 1.87-1.78 (m, 1 H).
Example 267: (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine.
Figure imgf000180_0003
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.1 ; m/z found, 304.2 [M+H]+. 1H NMR (CDCI3): 7.09 (d, J = 8.3 Hz, 2H), 7.04 (dd, J = 8.7, 2.5 Hz, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.83-6.79 (m, 2H), 4.79 (t, J = 4.8 Hz, 1 H), 3.05 (d, J = 12.8 Hz, 1 H), 2.97-2.89 (m, 1 H), 2.78 (d, J = 9.3 Hz, 2H), 2.31 (s, 3H), 1.99-1.89 (m, 1 H), 1.86-1.77 (m, 1 H).
Example 268: (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1 -methyl-pyrrolidine.
Figure imgf000181_0001
Prepared from Example 261 using general procedure 5. MS (ESI): mass calcd. for Ci8H20CINO2, 317.1 ; m/z found, 318.2 [M+H]+. 1H NMR (CDCI3): 7.10 (d, J = 8.4 Hz, 2H), 7.00 (dd, J = 8.7, 2.5 Hz, 1 H), 6.90 (d, J = 2.5 Hz, 1 H), 6.87-6.79 (m, 3H), 4.84-4.74 (m, 1 H), 2.91 (dd, J = 10.6, 6.1 Hz, 1 H), 2.58 (dd, J = 6.9, 6.3 Hz, 2H), 2.54-2.48 (m, 1 H), 2.32 (d, J = 4.5 Hz, 6H), 2.23- 2.16 (m, 1 H), 1.98-1.86 (m, 1 H).
Example 269: (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy1-pyrrolidine.
Figure imgf000181_0002
MS (ESI): mass calcd. for Ci6Hi5CIFNO2, 307.1 ; m/z found, 308.2 [M+H]+. 1H NMR (CDCI3): 7.07 (dd, J = 8.7, 2.5 Hz, 1 H), 7.03-6.96 (m, 3H), 6.92-6.84 (m, 3H), 4.78 (dd, J = 5.9, 4.5 Hz, 1 H), 3.04 (d, J = 12.8 Hz, 1 H), 2.95 (dt, J = 11.3, 7.4 Hz, 1 H), 2.89-2.75 (m, 2H), 2.02-1.92 (m, 1 H), 1.85-1.77 (m, 1 H). Example 270: (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy1-pyrrolidine.
Figure imgf000182_0001
MS (ESI): mass calcd. for Ci6Hi5CIFNO2, 307.1 ; m/z found, 308.2 [M+H]+. 1H NMR (CDCI3): 7.06 (dd, J = 8.7, 2.5 Hz, 1 H), 7.02-6.96 (m, 3H), 6.91-6.84 (m, 3H), 4.78 (dd, J = 5.8, 4.5 Hz, 1 H), 3.05 (d, J = 12.8 Hz, 1 H), 2.96 (dt, J = 11.3, 7.4 Hz, 1 H), 2.90-2.74 (m, 2H), 2.03-1.92 (m, 1 H), 1.85-1.77 (m, 1 H).
Example 271 : (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy1-1 -methyl- pyrrolidine.
Figure imgf000182_0002
Prepared from Example 264 using general procedure 5. MS (ESI): mass calcd. for C17H17CIFNO2, 321.1 ; m/z found, 322.2 [M+H]+. 1H NMR (CDCI3): 7.05-6.96 (m, 3H), 6.94-6.86 (m, 3H), 6.81 (d, J = 8.7 Hz, 1 H), 4.93-4.53 (m, 1 H), 2.91 (dd, J = 10.6, 6.1 Hz, 1 H), 2.63-2.41 (m, 3H), 2.32 (s, 3H), 2.23-2.16 (m, 1 H), 1.90-1.81 (m, 1 H).
Example 272: (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine.
Figure imgf000182_0003
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.1 ; m/z found, 304.2 [M+H]+.
1H NMR (CDCI3): 7.23 (d, J = 6.8 Hz, 1 H), 7.11 -7.06 (m, 1 H), 7.04-6.98 (m, 2H), 6.91 (d, J = 2.5 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 4.79 (dd, J = 5.6, 4.4 Hz, 1 H), 3.04 (d, J = 12.9 Hz, 1 H), 2.89 (dt, J = 11.4, 7.4 Hz, 1 H), 2.81 -2.71 (m, 2H), 2.29 (s, 3H), 1.98-1.89 (m, 1 H), 1.85-1.75 (m, 1 H).
Example 273: (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrc)lidine.
Figure imgf000183_0001
MS (ESI): mass calcd. for Ci7Hi8CINO2, 303.1 ; m/z found, 304.2 [M+H]+. 1H NMR (CDCI3): 7.17 (t, J = 7.8 Hz, 1 H), 7.08-7.02 (m, 2H), 7.04-7.00 (m, 1 H), 6.91-6.85 (m, 2H), 6.76-6.66 (m, 2H), 4.81 -4.75 (m,1 H), 3.03 (d, J = 12.8 Hz, 1 H), 2.89 (dt, J = 11.3, 7.5 Hz, 1 H), 2.80-2.70 (m, 2H), 2.31 (s, 3H), 1.96-1.88 (m, 1 H), 1.85-1.74 (m, 1 H).
Example 274: (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy1- pyrrolidine.
Figure imgf000183_0002
MS (ESI): mass calcd. for Ci7Hi7CIFNO2, 321.1 ; m/z found, 322.2 [M+H]+. 1H NMR (CDCI3): 7.05 (dd, J = 8.7, 2.5 Hz, 1 H), 6.95 (d, J = 2.5 Hz, 1 H), 6.92 (d, J = 8.9 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.75 (dd, J = 6.2, 3.0 Hz, 1 H), 6.72-6.65 (m, 1 H), 4.79 (dd, J = 5.8, 4.5 Hz, 1 H), 3.07 (d, J = 12.8 Hz, 1 H), 2.98 (dt, J = 11.4, 7.4 Hz, 1 H), 2.88-2.76 (m, 2H), 2.24 (d, J = 1.8 Hz, 3H), 2.00-1.93 (m, 1 H), 1.88-1.79 (m, 1 H). Example 275: (S)-3-r4-Chloro-2-(4-chloro-phenoxy)-phenoxy1-pyrrolidine.
Figure imgf000184_0001
MS (ESI): mass calcd. for Ci6Hi5CI2NO2, 323.1 ; m/z found, 324.1 [M+H]+. 1H NMR (CDCI3): 7.27-7.22 (m, 2H), 7.09 (dd, J = 8.7, 2.5 Hz, 1 H), 7.03 (d, J = 2.5 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.86-6.75 (m, 2H), 4.76 (dd, J = 5.7, 4.5 Hz, 1 H), 3.01 (d, J = 12.8 Hz, 1 H), 2.96-2.74 (m, 3H), 2.01 -1.89 (m, 1 H), 1.85-1.71 (m, 1 H).
Example 276: (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy1-pyrrolidine.
Figure imgf000184_0002
MS (ESI): mass calcd. for Ci6Hi5CI2NO2, 323.1 ; m/z found, 324.1 [M+H]+. 1H NMR (CDCI3): 7.21 (t, J = 8.1 Hz, 1 H), 7.12 (dd, J = 8.7, 2.6 Hz, 1 H), 7.08 (d, J = 2.5 Hz, 1 H), 7.03 (ddd, J = 8.0, 1.9, 0.9 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 1 H), 6.85 (t, J = 2.2 Hz, 1 H), 6.80 (ddd, J = 8.3, 2.4, 0.9 Hz, 1 H), 4.87- 4.51 (m, 1 H), 3.00 (d, J = 12.8 Hz, 1 H), 2.94-2.70 (m, 3H), 2.00-1.89 (m, 1 H), 1.82-1.71 (m, 1 H).
Example 277: (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy1-pyrrolidine.
Figure imgf000184_0003
MS (ESI): mass calcd. for Ci6Hi5BrCINO2, 367.0; m/z found, 368.1
[M+H]+. 1H NMR (CDCI3): 7.43-7.35 (m, 2H), 7.10 (dd, J = 8.7, 2.6 Hz, 1 H),
7.03 (dd, J = 8.7, 2.5 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.80-6.73 (m, 2H), 4.76 (dd, J = 5.9, 4.4 Hz, 1 H), 3.01 (d, J = 12.8 Hz, 1 H), 2.92 (dt, J = 11.4, 7.4 Hz, 1 H), 2.87-2.72 (m, 2H), 2.02-1.89 (m, 1 H), 1.84-1.72 (m, 1 H).
Example 278: (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy1-pyrrolidine.
Figure imgf000185_0001
MS (ESI): mass calcd. for Ci9H22CINO2, 331.1 ; m/z found, 332.2 [M+H]+. 1H NMR (CDCI3): 7.15 (d, J = 8.5 Hz, 2H), 7.07-7.00 (m, 2H), 6.85 (dd, J = 11.0, 8.6 Hz, 3H), 4.77 (d, J = 4.6 Hz, 1 H), 3.04 (d, J = 12.8 Hz, 1 H), 2.92-2.81 (m, 2H), 2.76-2.70 (m, 2H), 1.95-1.87 (m, 1 H), 1.82-1.73 (m, 1 H), 1.24 (d, J = 6.9 Hz, 6H).
Example 279: (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy1-1 -ethyl- pyrrolidine.
Figure imgf000185_0002
Prepared using 5-bromo-2-(3-bromo-phenoxy)-phenol and (±)-1 -ethyl- pyrrol id in-3-ol according to general procedure 7. MS (ESI): mass calcd. for Ci8Hi9Br2NO2, 439.1 ; m/z found, 441.0 [M+H]+. 1H NMR (CDCI3): 7.16 - 7.12 (m, 2H), 7.08 (dd, J = 8.4, 2.2 Hz, 1 H), 7.02 (d, J = 2.2 Hz, 1 H), 7.01 - 6.98 (m, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.87 - 6.82 (m, 1 H), 4.74 (m, 1 H), 3.02 (dd, J = 10.7, 6.2 Hz, 1 H), 2.69 - 2.54 (m, 1 H), 2.44 (m, 4H), 2.17 (m, 1 H), 1.88 - 1.77 (m, 1 H), 1.07 (t, J = 7.2 Hz, 3H). Example 280: 2-(Azetidin-3-yloxy)-4-bronno-phenyl1-phenyl-nnethanone.
Figure imgf000186_0001
Step A: Preparation of 3-[5-Bromo-2-(hvdroxy-phenyl-methyl)-phenoxy1- azetidine-1-carboxylic acid tert-butyl ester. To a solution of 3-(5-bromo-2- formyl-phenoxy)-azetidine-1 -carboxylic acid tert-butyl ester (0.25 g, 0.70 mmol) in CH2CI2 (10 ml_) was added a solution of PhMgBr (1 M in THF, 1 ml_). The reaction was allowed to stir for 15 h then quenched with 1 N HCI (4 ml_). After 10 min, the mixture was made basic with 1 N NaOH (10 ml_), and extracted with CH2CI2 (3 x 20 ml_). The organic layers were combined and dried. Chromatography of the resulting residue (SiO2; EtOAc/Hexanes) gave the title compound (0.24 g, 79%). MS (ESI): mass calcd. for C2iH24BrNO4, 433.1 ; m/z found, 434.4 [M+H]+. 1H NMR (CDCI3): 7.41 - 7.23 (m, 6H), 7.17 (dd, J = 8.2, 1.7, 1 H), 6.61 (d, J = 1.7, 1 H), 6.04 (s, 1 H), 4.90 - 4.68 (m, 1 H), 4.32 - 4.01 (m, 2H), 3.95 - 3.68 (m, 2H), 2.04 - 2.10, 1 H), 1.44 (s, 9H). Step B: Preparation of 3-(2-Benzoyl-5-bromo-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester. A solution of the title compound of Step A (0.12 g, 0.28 mmol) and Dess-Martin periodane (0.17 g, 0.39 mmol) in CH2CI2 (15 ml_) was stirred at rt for 15 h and filtered. The resulting filtrate was concentrated and purified (SiO2; EtOAc/Hexanes) providing the title compound (0.10g, 84%). MS (ESI): mass calcd. for C2i H22BrNO4, 431.1 ; m/z found, 432.4 [M+H]+. 1H NMR (CDCI3): 7.70 - 7.64 (m, 2H), 7.55 - 7.45 (m, 1 H), 7.40 - 7.31 (m, 2H), 7.27 (d, J = 8.1 Hz, 1 H), 7.18 (dd, J = 8.0, 1.7 Hz, 1 H), 6.69 (d, J = 1.6 Hz, 1 H), 4.72 (tt, J = 6.4, 4.2 Hz, 1 H), 4.16 - 3.97 (m, 2H), 3.59 (dd, J = 10.6, 4.1 Hz, 2H), 1.46 - 1.25 (m, 9H). Step C: Preparation of 2-(azetidin-3-yloxy)-4-bromo-phenyl1-phenyl- methanone. To a solution of 3-(2-benzoyl-5-bromo-phenoxy)-azetidine-1 - carboxylic acid tert-butyl ester (0.10 g, 0.23 mmol) in CH2CI2 (10 ml_) was added 2M HCI in Et2O (0.5 ml_). After 15 h, the reaction was concentrated to give the title compound as the hydrochloride salt which was neutralized with 1 N NaOH (5 ml_) and extracted with CH2CI2 (3 x 15 ml_). The organic layers were combined and dried to give the title compound (0.07 g, 90%). MS (ESI): mass calcd. for Ci6H14BrNO2, 331.0; m/z found 332.2, [M+H]+. 1H NMR (CD3OD): 7.82 - 7.74 (m, 2H), 7.67 (t, J = 7.4 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 2H), 7.43-7.32 (m, 2H), 5.47 - 5.36 (m, 1 H), 4.46 (dd, J = 12.4, 6.7 Hz, 2H), 3.94 - 3.81 (m, 2H).
Examples 275-292 were synthesized according to Example 274 using the appropriately substituted aryl magnesium halide and aldehyde.
Example 281 : [2-(Azetidin-3-yloxy)-4-bromo-phenylH4-chloro-phenyl)- methanone.
Figure imgf000187_0001
MS (ESI): mass calcd. for Ci6Hi3BrCINO2, 365.0; m/z found, 366.0 [M+H]+. 1H NMR (CD3OD): 7.91 - 7.79 (m, 2H), 7.68 - 7.55(m, 2H), 7.52 - 7.41 (m, 2H), 5.39 - 5.26 (m, 1 H), 4.65 - 4.47 (m, 2H), 4.01 (d, J = 7.4 Hz, 2H).
Example 282: [2-(Azetidin-3-yloxy)-4-bromo-phenylH3-chloro-phenyl)- methanone.
Figure imgf000187_0002
MS (ESI): mass calcd. for Ci6Hi3BrCINO2, 365.0; m/z found, 366.0
[M+H]+. 1H NMR (CD3OD): 7.77 (t, J = 1.8, 1 H), 7.71 - 7.61 (m, 2H), 7.51 (t, J = 7.9, 1 H), 7.44 - 7.34 (m, 2H), 7.17 (d, J = 1.3, 1 H), 5.19 (t, J = 4.9, 1 H), 4.45 (dd, J = 12.7, 6.6, 2H), 3.89 (dd, J = 12.6, 4.8, 2H). Example 283: [4-Bronno-2-(1 -methyl-azetidin-3-yloxy)-phenylH3-chlorc)- phenvD-methanone.
Figure imgf000188_0001
Prepared according to general procedure 5 using the title compound from Example 276. MS (ESI): mass calcd. for Ci7H15BrCINO2, 379.0; m/z found, 380.1 [M+H]+. 1H NMR (CD3OD): 7.74 (t, J = 1.7, 1 H), 7.71 - 7.60 (m, 2H), 7.51 (t, J = 7.9, 1 H), 7.44 - 7.34 (m, 2H), 7.17 (d, J = 1.3, 1 H), 5.19 (t, J = 4.9, 1 H), 4.50 - 4.40 (m, 2H), 3.90-3.82 (m, 2H). 2.19 (s, 3H).
Example 284: [2-(Azetidin-3-yloxy)-4-bromo-phenyl1-m-tolyl-methanone.
H
Figure imgf000188_0002
MS (ESI): mass calcd. for Ci7H16BrNO2, 345.0; m/z found, 346.1 [M+H]+. 1H NMR (CDCI3): 7.67 - 7.48 (m, 2H), 7.43 - 7.13 (m, 4H), 6.90 - 6.74 (m, 1 H), 4.98 - 4.86 (m, 1 H), 3.80 (s, 1 H), 3.52 (s, 1 H), 2.40 (s, 2H), 2.02 (s, 3H).
Example 285: [2-(Azetidin-3-yloxy)-4-bromo-phenyl1-o-tolyl-methanone.
Figure imgf000188_0003
MS (ESI): mass calcd. for Ci7Hi6BrNO2, 345.0; m/z found, 346.1 [M+H]+. 1H NMR (CDCI3): 7.46 (d, J = 8.2, 1 H), 7.36 (s, 1 H), 7.27 (s, 3H), 7.23 - 7.10 (m, 2H), 6.75 (s, 1 H), 4.81 (s, 1 H), 3.69 (s, 2H), 3.32 (s, 2H), 2.44 (s, 3H). Example 286: [2-(Azetidin-3-yloxy)-4-bromo-phenylH3-methoxy-phenyl)- methanone.
Figure imgf000189_0001
MS (ESI): mass calcd. for Ci7Hi6BrNO3, 361.0; m/z found, 362.1 [M+H]+. 1H NMR (CDCI3): 7.39 - 7.07 (m, 6H), 6.91 - 6.79 (m, 1 H), 4.66 (s, 1 H), 3.84 (s, 3H), 3.50 (s, 2H), 2.97 (s, 2H).
Example 287: [2-(Azetidin-3-yloxy)-4-bromo-phenyl1-naphthalen-2-yl- methanone.
H
Figure imgf000189_0002
MS (ESI): mass calcd. for C20Hi6BrNO2, 381.0; m/z found, 382.1 [M+H]+. 1H NMR (CDCI3): 8.19 (s, 1 H), 7.96 - 7.85 (m, 4H), 7.65 - 7.50 (m, 2H), 7.39 - 7.21 (m, 2H), 6.85 (d, J = 1.6 Hz, 1 H), 4.95-4.89 m, 1 H), 3.77 - 3.66 (m, 2H), 3.51 - 3.40 (m, 2H).
Example 288: [4-Bromo-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl1-naphthalen-2- yl-methanone.
Figure imgf000189_0003
Prepared according to general procedure 3 or 4 using the title compound from Example 281. MS (ESI): mass calcd. for C23H22BrNO2, 423.1 ; m/z found, 426.1 [M+H]+. 1H NMR (CDCI3): 8.16 - 8.10 (m, 1 H), 7.95 - 7.85 (m, 4H), 7.65 - 7.50 (m, 2H), 7.39 - 7.21 (m, 2H), 6.90 - 6.82 (m, 1 H), 4.96 - 4 .80 (m, 1 H), 3.77 - 3.66 (m, 2H), 3.51 - 3.40 (m, 2H), 2.34 - 2.20 (m, 1 H), 0.91 (d, J = 6.1 Hz, 6H). Example 289: [2-(Azetidin-3-yloxy)-4-bromo-phenyl1-benzo[1 ,31dioxol-5-yl- methanone.
H
Figure imgf000190_0001
MS (ESI): mass calcd. for Ci7H14BrNO4, 375.1 ; m/z found, 376.1 [M+H]+.
1H NM RR ((CCDDCCII33)):: 77..3388 -- 77..1111 ((mm,, 44HH)),, i 6.81 (d, J = 8.0 Hz, 2H), 6.06 (s, 2H), 4.94 (s, 1 H), 3.81 (s, 2H), 3.59 (s, 2H).
Example 290: BenzoH ,31dioxol-5-yl-[4-bromo-2-(1 -isopropyl-azetidin-3-yloxy)- phenyli-methanone.
Figure imgf000190_0002
Prepared according to general procedure 3 or 4 using the title compound from Example 283. MS (ESI): mass calcd. for C2oH2oBrNO4, 417.1 ; m/z found, 418.1 [M+H]+. 1H NMR (CDCI3): 7.36 - 7.15 (m, 4H), 6.76 - 6.61 (m, 2H), 6.06 (d, J = 4.1 Hz, 2H), 4.76 - 4.61 (m, 1 H), 3.79 - 3.63 (m, 2H), 2.87 - 2.75 (m, 2H), 2.34 - 2.18 (m, 1 H), 0.90 (d, J = 6.2 Hz, 6H).
Example 291 : [2-(Azetidin-3-yloxy)-4-bromo-phenylH4-methoxy-phenyl)- methanone.
Figure imgf000190_0003
MS (ESI): mass calcd. for Ci7Hi6BrNO3, 361.0; m/z found, 362.1 [M+H]+. 1H NMR (CDCI3): 7.38 - 7.12 (m, 6H), 6.96 - 6.83 (m, 1 H), 4.65 (s, 1 H), 3.84 (s, 3H), 3.54 (s, 2H), 2.99 (s, 2H). Example 292: [2-(Azetidin-3-yloxy)-4-bromo-phenylH4-chloro-3-fluoro-phenyl)- methanone.
Figure imgf000191_0001
MS (ESI): mass calcd. for Ci6Hi2BrCIFNO2, 383.0; m/z found, 384.2 [M+H]+. 1H NMR (CDCI3): 7.63 - 7.40 (m, 3H), 7.38 - 7.15 (m, 2H), 6.88 - 6.67 (m, 1 H), 4.91 (s, 1 H), 3.80 (s, 2H), 3.50 (s, 2H).
Example 293: [2-(Azetidin-3-yloxy)-4-bromo-phenylH3,4-dichloro-phenyl)- methanone.
Figure imgf000191_0002
MS (ESI): mass calcd. for Ci6Hi2BrCI2NO2, 399.0; m/z found, 400.1 [M+H]+. 1H NMR (CDCI3): 7.83 (d, J = 1.9 Hz, 1 H), 7.63 - 7.51 (m, 2H), 7.35 - 7.19 (m, 2H), 6.82 (d, J = 1.6 Hz, 1 H), 5.00 - 4.85 (m, 1 H), 4.02 - 3.31 (m, 4H).
Example 294: [2-(Azetidin-3-yloxy)-4-chloro-phenyl1-naphthalen-2-yl- methanone.
Figure imgf000191_0003
MS (ESI): mass calcd. for C20Hi6CINO2, 337.1 ; m/z found, 338.2 [M+H]+. 1H NMR (CDCI3): 8.19 (s, 1 H), 7.98 - 7.85 (m, 3H), 7.63 - 7.37 (m, 4H), 7.10 (dd, J = 8.1 , 1.7 Hz, 1 H), 6.70 (d, J = 1.6 Hz, 1 H), 4.97 - 4.84 (m, 1 H), 3.74 (s, 2H), 3.50 - 3.37 (m, 2H). Example 295: r2-(Azetidin-3-yloxy)-4-chloro-phenyl1-benzoπ ,31dioxol-5-yl- methanone.
Figure imgf000192_0001
MS (ESI): mass calcd. for Ci7Hi4CINO4, 331.1 ; m/z found, 332.2 [M+H]+. 1H NMR (CDCI3): 7.35 - 7.21 (m, 3H), 7.04 (dd, J = 8.1 , 1.8 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 1.7 Hz, 1 H), 6.05 (d, J = 8.9 Hz, 2H), 5.02 - 4.87 (m, 1 H), 3.86 (s, 2H), 3.62 (s, 2H).
Example 296: BenzoH ,31dioxol-5-yl-[4-chloro-2-(1 -isopropyl-azetidin-3-yloxy)- phenyli-methanone.
Figure imgf000192_0002
Prepared according to general procedure 3 or 4 using the title compound from Example 289. MS (ESI): mass calcd. for C20H2OCINO4, 373.1 ; m/z found, 374.2 [M+H]+. 1H NMR (CDCI3): 7.40 - 7.25 (m, 4H), 6.76 - 6.61 (m, 2H), 6.10 - 6.04 (m, 2H), 4.81 - 4.64 (m, 1 H), 3.75 - 3.63 (m, 2H), 2.85 - 2.74 (m, 2H), 2.28 - 2.18 (m, 1 H), 0.96 (d, J = 6.1 Hz, 6H).
Example 297: [2-(Azetidin-3-yloxy)-4-chloro-phenyl1-(4-chloro-phenyl)- methanone.
Figure imgf000192_0003
MS (ESI): mass calcd. for Ci6Hi3CI2NO2, 321.0; m/z found, 322.2 [M+H]+. 1H NMR (CD3OD): 7.79 - 7.62 (m, 2H), 7.56 - 7.35 (m, 3H), 7.16 (s, 1 H), 7.00 - 6.76 (m, 1 H), 5.19 - 5.08 (m, 1 H), 4.16 (s, 2H), 3.87 (s, 1 H), 3.49 (s, 1 H). Example 298: [2-(Azetidin-3-yloxy)-4-chloro-phenvπ-(3-chloro-phenyl)- methanone.
Figure imgf000193_0001
MS (ESI): mass calcd. for Ci6Hi3CI2NO2, 321.0; m/z found, 322.2
[M+H]+. 1H NMR (CDCI3): 7.70 (t, J = 1.7, 1 H), 7.62 (dd, J = 7.8, 1.3 Hz, 1 H), 7.58 - 7.51 (m, 1 H), 7.47 - 7.34 (m, 2H), 7.12 (dd, J = 8.2, 1.8 Hz, 1 H), 6.61 (d, J = 1.7 Hz, 1 H), 4.87 - 4.68 (m, 1 H), 4.21 - 4.13 (m, 2H), 3.67 (dd, J = 9.9, 4.0 Hz, 2H).
Biological Assays
r5-HT7 Binding Assay
Receptor binding was performed using membrane fractions prepared from the HEK-293 cell line recombinantly expressing rat 5-HT7 receptors (NCBI accession NM_022938). Compound affinity for the rat 5-HT7 receptor subtype was evaluated by competitive radioligand binding assays using 5- carboxamido[3H]tryptamine ([3H]5-CT) (Amersham Biosciences, cat. 90000403) detection. HitHunter™ cAMP assays are in-vitro based competitive immunoassays. The assay was performed on the HEK-293 cell line stably transfected with r5-HT7 receptor. Cells were pre-incubated with test compounds for 10 minutes. For antagonist testing, the cells were then challenged with 100 nM 5-CT for 20 minutes. Cells were then lysed and cAMP measured according to manufacturers protocol (Amersham, cat. NET791250UC) or [3H]mesulergine (Amersham, cat. TRK1041 ). The assay was performed on membranes prepared from HEK-293 cells stably transfected with h5-HT6. Following centrifugation, membranes were resuspended and incubated for 60 min at room temperature with 1.7 nM [3H]LSD in the presence of increasing concentration of test compounds. Nonspecific binding was defined in the presence of 10 μM clozapine (Tocris, cat. TRK1068). Homogenized HEK-293 membranes expressing the human SERT were incubated in 50 mM Tris-HCI (pH 7.5), 120 mM NaCI, 5 mM KCI with [3H]- citalopram (3 nM) with or without test compounds. Nonspecific binding was determined in the presence of 10 μM fluoxetine. Radioactivity readouts and K1 values were performed as previously described for r5-HT7. Table 1 shows assay results for exemplified compounds of the invention. Compounds were assayed in their free form or as salts, as indicated in the Examples section above.
Table 1.
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
*ND symbolizes not determined. While the invention has been illustrated by reference to exemplary and preferred embodiments, it will be understood that the invention is intended not to be limited by the foregoing detailed description, but to be defined by the appended claims as properly construed under principles of patent law.

Claims

What is claimed is:
1. A compound selected from the group consisting of (a) compounds of Formula (I):
Figure imgf000201_0001
wherein
R1 is -H, -Ci-4alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1 , 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1 ; R2 and R3 are each independently -H or -Ci-4alkyl;
R4 is -H, F, Ci-4alkyl, or R4 is -OH when L is -CH2-, -CF2-, -CHF-, -OCH2-, or - OCH(CH3)-;
L is -O-, -CH2-, -OCH2-, -OCH(CH3)-, -CH2O-, -CF2-, or -CHF-; Z is -O-, -C(O)-, -OCH(Rb)-, or -OCH2C(Rc)(Rd)-; where Rb is -H; a -Ci-4alkyl group unsubstituted or substituted with OH or halo; -CO2Ci-4alkyl; or -CO2H; and
Rc and Rd are each independently -H, -Ci-4alkyl, -O-Ci-4alkyl, or halo; or Rc and Rd taken together form an oxime, a Ci-4alkyl oxime, or a carbonyl group; or Rc and Rd taken together with the carbon to which they are attached form a C3-6cycloalkyl group; R5 is: i) a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R9 substituents; where each R9 substituent is selected from the group consisting of: -
Ci-6alkyl, -OH, -OCi-6alkyl, -CN, -NO2, -C(O)Ci -6alkyl, -S(O)0-2-Ci -ealkyl, -OS(O)0-2-Ci -6alkyl, -SO2CF3, -SCF3, halo, -CF3, -OCF3, -CO2H, -CO2Ci -ealkyl, -CH2OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two Rg substituents taken together form -OCH2O-, -OCF2O-, or
-OCH2CH2O-; ii) a naphthyl group, unsubstituted or substituted with Ci-4alkyl or halo; iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three Rg substituents; iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci-4alkyl or halo; v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: -Ci-4alkyl, -OCi-4alkyl, halo, -CF3, oxime, -Ci-4alkyl oxime, or phenyl; and vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; X is C or N, R6 or R7 are each independently -H, halo, -CF3, thiophene, or -C(O)N(Rx)Ry; wherein Rx and Ryare each independently -H or -Ci-4alkyl; and (b) pharmaceutically acceptable salts of the compounds of Formula (I), pharmaceutically acceptable prodrugs of the compounds of Formula (I), and pharmaceutically active metabolites of the compounds of Formula (I).
2. A chemical entity as defined in claim 1 , wherein R1 is -H, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, or benzyl.
3. A chemical entity as defined in claim 2, wherein R1 is -H.
4. A chemical entity as defined in claim 1 , wherein m and n are each 1.
5. A chemical entity as defined in claim 1 , wherein m and n are each 2.
6. A chemical entity as defined in claim 1 , wherein m is 1 and n is 2.
7. A chemical entity as defined in claim 1 , wherein m is 3 and n is 1.
8. A chemical entity as defined in claim 1 , wherein R2 is -H or -CH3.
9. A chemical entity as defined in claim 1 , wherein R3 is -H or -CH3.
10. A chemical entity as defined in claim 1 , wherein R2 and R3 are each -H.
11. A chemical entity as defined in claim 1 , wherein R4 is -H.
12. A chemical entity as defined in claim 1 , wherein L is -O-, -CH2-, -OCH2-, -OCH(CH3)-, -CH2O-, -CHF-, or -CF2-.
13. A chemical entity as defined in claim 1 , wherein L is -O-.
14. A chemical entity as defined in claim 1 , wherein Z is -O-, -C(O)-, -OCH2-, - OCH(CH3)-, -OCH(CH2CH3)-, -OCH(CH2OH)-, -OCH(CO2H)-, -OCH(CH2F)-, -
OCH2CH2-, -OCH2CH(F)-, -OCH2CH(OCH3)-, -OCH2C(NOH)-, -
OCH2C(NOCH3)-, -OCH2CF2-, -OCH2C(O)-, or H .0
15. A chemical entity as defined in claim 1 , wherein Z is -O-, -OCH2-, - OCH2CH2-, or -OCH(CH3)-.
16. A chemical entity as defined in claim 1 , wherein R5 is phenyl, optionally substituted with halo, -OCH3, -OSO2CH3, CF3,
17. A chemical entity as defined in claim 1 , wherein R5 is cyclohexyl, 2- indanyl, or furanyl optionally substituted with one or more substituents individually selected from halo, -CH3, -CF3, -OCF3, or -CN.
18. A chemical entity as defined in claim 1 , wherein R5 is selected from the group consisting of: i) cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro- 3-fluoro-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy- phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4- trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy- phenyl, 3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3- trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl, 4-fluoro-3- trifluoromethyl-phenyl, 3- or 4-trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-
phenyl,
Figure imgf000204_0001
; and
ii) 3-azetidinyl, 1 -benzyl-azetidin-3-yl, 1 -benzhydryl-azetidin-3-yl, 1 - isopropyl-azetidin-3-yl, benzo[1 ,3]dioxol-5-yl, 2,2-difluoro-benzo[1 ,3]dioxol-5-yl, 2-benzofuranyl, 5-benzofuranyl, 2,3-dihydro-benzofuran-2-yl, 2-benzothiazolyl, 6-benzothiazolyl, 1 H-benzotriazole-6-yl, 1-methyl-1 H-benzothazole-6-yl, 2- or 3-chromanyl, 2-or 3-furanyl, 5-trifluoromethyl-2-furanyl, 2-indanyl, tetrahydro-3- furanyl, 1 -Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl, 5-fluoro-1 -indanyl, 5- methyl-1 -indanyl, 5- or 6-chloro-1-indanyl, 6-fluoro-1 -indanyl, 6-trifluoromethyl- 1 -indanyl, 6-methyl-1 -indanyl, 5-fluoro-2-indanyl, 5-methoxy-2-indanyl, [1 ,2,4]oxadiazole-5-yl, 3-cyclopropyl-[1 ,2,4]oxadiazole-5-yl, 3-cyclobutyl- [1 ,2,4]oxadiazole-5-yl, 3-isopropyl-[1 ,2,4]oxadiazole-5-yl, phenoxy, 4- piperidinyl, 2- or 3-pyrrolidinyl, 3-methyl-[1 ,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl, 4-trifluoromethyl-2-pyhdinyl, 2-, 3- or 4-pyridinyl, 6- trifluoromethyl-2-pyhdinyl, 1 ,2,3,4-tetrahydro-naphthalen-1 -yl, 1 ,2,3,4- tetrahydro-naphthalen-2-yl, 1 -phenyl-3-azetidinyl, 4- or 5-thiazolyl, 2-methyl-
thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl,
Figure imgf000204_0002
, 5-methyl- isoxazole-3-yl.
19. A chemical entity as defined in claim 1 , wherein R6 and R7 are each independently -H, halo, -CF3, thiophene-3-yl, or N,N-dimethyl-formamidyl.
20. A chemical entity as defined in claim 1 , wherein R6 is -H or halo.
21. A chemical entity as defined in claim 1 , wherein R6 is -H or halo and R7 is -H, halo, -CF3, thiophene-3-yl, or N,N-dimethyl-formamidyl.
22. A chemical entity as defined in claim 1 , wherein X is C.
23. A chemical entity as defined in claim 1 , wherein X is N.
24. A chemical entity as defined in claim 1 , selected from the group consisting of:
3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine; 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -propyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -ethyl-azetidine;
3-[5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonithle;
3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-thfluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy]-azetidine; 3-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1 -methyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -ethyl-azetidine; 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -propyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine
3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine;
3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-nnethyl-thiazole;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-nnethyl-isoxazole;
3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-phenyl]-5-nnethyl- [1 ,2,4]oxadiazole;
3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile;
3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine;
3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine; 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile;
3-[2-(2,4-Bis-trifluoronnethyl-benzyloxy)-5-chloro-phenoxy]-azetidine; 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine; 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylic acid ethyl ester;
3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine; (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)- 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
(R)- 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)- 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine; 4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-piperidine;
4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine; 4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine;
(±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine;
(±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine;
(±)-3-[5-Chloro-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-pipeπdine;
3-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidine; 3-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidine;
3-(5-Bromo-2-cyclohexylnnethoxy-phenoxy)-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoronnethyl-furan-3- carboxylic acid;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoronnethyl-furan-3- carboxylic acid ethyl ester;
5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoronnethyl- furan-3-yl]-methanol;
3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylnnethoxy)-phenoxy]- azetidine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoronnethyl- pyridine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine; 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl]-2-trifluoroπnethyl-pyridine;
3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine;
6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole;
6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1 -nnethyl-1 H-benzotriazole; 3-[5-Chloro-2-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethoxy)-phenoxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-oxazole;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole;
3-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine; (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1 -methyl-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine; (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1 -methyl-pyrrolidine;
(±)-Methanesulfonic acid 3-[4-bromo-2-(1 -methyl-pyrrol id in-3-yloxy)- phenoxymethyl]-phenyl ester; (±)-Methanesulfonic acid 3-[2-(1 -methyl-pyrrolidin-3-yloxy)-phenoxymethyl]- phenyl ester;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl- azetidine;
(S)-1 -Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -isopropyl- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -cyclobutyl- azetidine; (±)-1 -Benzyl-3-[5-chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -methyl- azetidine; (±)-3-[5-Bronno-2-[1 -(3-trifluoronnethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-[1 -(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-[1 -(3-trifluoronnethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(R)-3-[5-Bromo-2-[1 -(3-trifluoronnethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; (±)-3-[5-Chloro-2-[1 -(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]- azetidine; (±)-3-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile; (±)-3-[5-Chloro-2-[1-(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole;
5-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole;
2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole;
5-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole; (R)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;
(±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine;
(±)-4-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine;
(±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine; (R,S)-3-[5-Chloro-2-[1 -((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- piperidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine;
(±)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine;
3-[5-Bromo-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-azetidine;
(±)-4-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-piperidine;
(±)-3-[5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol;
^-(Azetidin-S-yloxy^-chloro-phenoxyl-phenyl-acetic acid;
(±)-3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-chloro-indan-1 -yloxy)-phenoxy]-azetidine; (±)-3-[5-Bromo-2-(6-chloro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-fluoro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-nnethyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(6-nnethyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(6-trifluoronnethyl-indan-1 -yloxy)-phenoxy]-azetidine; (±)-3-[5-Chloro-2-(6-methyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-(6-chloro-indan-1 -yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-1 -yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(5-tert-butyl-indan-1 -yloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(chroman-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(chronnan-3-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylnnethoxy)-phenoxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1 ,3-dinnethyl-1 H-pyrazole; 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -phenyl-azetidine;
3-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1 -one oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1 -one O-methyl-oxime; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -phenyl-ethanone oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -phenyl-ethanone O-methyl-oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -(4-chloro-phenyl)-ethanone;
3-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-[1 -(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[1 -(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine; 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine;
3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine;
3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;
3-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 3-[5-Trifluoronnethyl-2-[1-(3-trifluoronnethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[2-(1 -Phenyl-ethoxy)-5-tnfluoromethyl-phenoxy]-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -methyl-azetidine; 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -isopropyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -cyclobutyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -propyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -ethyl-azetidine;
3-[5-Fluoro-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine; 3-[5-Fluoro-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-1 -isopropyl- azetidine;
3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine;
3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzannide;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-nnethyl-azetidine; 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine;
3-(5-Bromo-2-phenethyloxy-phenoxy)-3-nnethyl-azetidine;
3-[5-Bromo-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-azetidine; 3-(5-Bromo-2-phenoxy-phenoxy)-3-nnethyl-azetidine;
(±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine; cis-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine; trans-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine;
3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine; (±)-3-[5-Chloro-2-(trans-1 -benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -benzhydryl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine; 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -tert-butyl-azetidine;
1 -tert-Butyl-3-[5-chloro-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-azetidine 1 -tert-Butyl-3-[5-chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
3-[5-Bronno-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-benzyl]-azetidine;
3-[5-Bronno-2-(3-chloro-benzyloxy)-phenoxynnethyl]-azetidine; 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxynnethyl]-1 -nnethyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxynnethyl]-azetidin-3-ol;
3-[1 -[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol;
3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine;
3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine; 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-nnethyl-[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl-[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl-
[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl-[1 ,2,4]oxadiazole; 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1 ,2,4]oxadiazole;
3-(5-Bromo-2-phenoxy-phenoxy)-azetidine;
3-[5-Bromo-2-(3-bronno-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine;
3-(5-Bromo-2-nn-tolyloxy-phenoxy)-azetidine; 3-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(4-bronno-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 3-[5-Bromo-2-(3-trifluoronnethoxy-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(naphthalen-1 -yloxy)-phenoxy]-azetidine;
3-(5-Chloro-2-phenoxy-phenoxy)-azetidine;
3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidine;
3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine;
3-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1 ,8]naphthyridine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline;
4-(5-Chloro-2-phenoxy-phenoxy)-piperidine; (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1 -methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1 -methyl-pyrrol id ine;
(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1 -ethyl-pyrrol id ine;
2-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone; [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone;
[4-Bromo-2-(1 -methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-nnethanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone; [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-nnethanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone;
[4-Bromo-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1 ,3]dioxol-5-yl-methanone;
Benzo[1 ,3]dioxol-5-yl-[4-bromo-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]- methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-nnethanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone; [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone; [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1 ,3]dioxol-5-yl-methanone; Benzo[1 ,3]dioxol-5-yl-[4-chloro-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]- methanone; [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone; and [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone; and pharmaceutically acceptable salts thereof.
25. A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by 5HT7 receptor activity, comprising an effective amount of at least one chemical entity selected from compounds of Formula (I):
Figure imgf000215_0001
wherein
R1 is -H, -Ci-4alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1 , 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1 ; R2 and R3 are each independently -H or -Ci-4alkyl;
R4 is -H, F, Ci-4alkyl, or R4 is -OH when L is -CH2-, -CF2-, -CHF-, -OCH2-, or - OCH(CH3)-; L is -O-, -CH2-, -OCH2-, -OCH(CH3)-, -CH2O-, -CF2-, or -CHF-; Z is -O-, -C(O)-, -OCH(Rb)-, or -OCH2C(Rc)(Rd)-; where where Rb is -H; a -Ci-4alkyl group unsubstituted or substituted with OH or halo; -CO2Ci-4alkyl; or -CO2H; and Rc and Rd are each independently -H, -Ci-4alkyl, -O-Ci-4alkyl, or halo; or Rc and Rd taken together form an oxime, a Ci-4alkyl oxime, or a carbonyl group; or Rc and Rd taken together with the carbon to which they are attached form a C3-6cycloalkyl group; R5 is: i) a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R9 substituents; where each R9 substituent is selected from the group consisting of: -
Ci-6alkyl, -OH, -OCi-6alkyl, -CN, -NO2, -C(O)Ci -6alkyl, -S(O)0-2-Ci-6alkyl, -OS(O)0-2-Ci -6alkyl, -SO2CF3, -SCF3, halo, -CF3,
-OCF3, -CO2H, -CO2Ci -6alkyl, -CH2OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two R9 substituents taken together form -OCH2O-, -OCF2O-, or
-OCH2CH2O-; ii) a naphthyl group, unsubstituted or substituted with Ci-4alkyl or halo; iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R9 substituents; iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci-4alkyl or halo; v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: -Ci-4alkyl, -OCi-4alkyl, halo, -CF3, oxime, -Ci-4alkyl oxime, or phenyl; and vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; X is C or N, R6 or R7 are each independently -H, halo, -CF3, thiophene, or -C(O)N(Rx)Ry; wherein Rx and Ryare each independently -H or -Ci-4alkyl; and (b) pharmaceutically acceptable salts of the compounds of Formula (I), pharmaceutically acceptable prodrugs of the compounds of Formula (I), and pharmaceutically active metabolites of the compounds of Formula (I).
26. A pharmaceutical composition according to claim 25, wherein said at least one chemical entity is selected from the group consisting of: 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -propyl-azetidine; 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -ethyl-azetidine;
3-[5-Bronno-2-(3-trifluoronnethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-azetidine; 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonitrile;
3-[5-Bromo-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-trifluoronnethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-4-nnethoxy-benzyloxy)-phenoxy]-azetidine; 3-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1 -nnethyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -ethyl-azetidine; 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -propyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine
3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -cyclobutyl-azetidine; 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -isopropyl-azetidine;
3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole; 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-nnethyl-thiazole;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-nnethyl-isoxazole;
3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-phenyl]-5-nnethyl-
[1 ,2,4]oxadiazole;
3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile;
3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine;
3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine; 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile;
3-[2-(2,4-Bis-trifluoronnethyl-benzyloxy)-5-chloro-phenoxy]-azetidine; 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine;
3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylic acid ethyl ester;
3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine;
(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)- 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine; (R)- 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(R)- 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine;
4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine; 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-piperidine;
4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine;
4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine; (±)-3-[5-Chloro-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-piperidine;
(±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine;
(±)-3-[5-Chloro-2-(3-tnfluoromethyl-benzyloxy)-phenoxy]-pipendine;
3-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidine; 3-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidine;
3-(5-Bromo-2-cyclohexylnnethoxy-phenoxy)-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoronnethyl-furan-3- carboxylic acid;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoronnethyl-furan-3- carboxylic acid ethyl ester;
5-[4-Chloro-2-(1 -methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl- furan-3-yl]-methanol;
3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylnnethoxy)-phenoxy]- azetidine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine;
3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoronnethyl- pyridine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-pyridine; 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine;
6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole;
6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1 -methyl-1 H-benzotriazole;
3-[5-Chloro-2-(2,2-difluoro-benzo[1 ,3]dioxol-5-ylmethoxy)-phenoxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-oxazole; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole;
3-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;
(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1 -methyl-pyrrol idine;
(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;
(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1 -methyl-pyrrolidine; (±)-3-[5-Bronno-2-(3-fluoro-benzyloxy)-phenoxy]-1-nnethyl-pyrrolidine;
(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1 -methyl-pyrrol id ine;
(±)-Methanesulfonic acid 3-[4-bromo-2-(1 -methyl-pyrrol id in-3-yloxy)- phenoxymethyl]-phenyl ester; (±)-Methanesulfonic acid 3-[2-(1 -methyl-pyrrolidin-3-yloxy)-phenoxymethyl]- phenyl ester;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl- azetidine;
(S)-1 -Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -isopropyl- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -cyclobutyl- azetidine;
(±)-1 -Benzyl-3-[5-chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; (±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1 -methyl- azetidine;
(±)-3-[5-Bromo-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-[1 -(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; (R)-3-[5-Bromo-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; (±)-3-[5-Chloro-2-[1 -(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]- azetidine; (±)-3-[5-Chloro-2-[1 -(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile; (±)-3-[5-Chloro-2-[1 -(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole;
5-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole;
2-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole;
5-[1 -[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole;
(R)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine; (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine;
(±)-4-[5-Chloro-2-[1 -(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine;
(±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine;
(R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- piperidine; (±)-3-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine;
(±)-4-[5-Chloro-2-[1 -(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine;
3-[5-Bromo-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-azetidine;
(±)-4-[5-Chloro-2-(2-fluoro-1 -phenyl-ethoxy)-phenoxy]-piperidine; (±)-3-[5-Chloro-2-(1 -phenyl-ethoxy)-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol; [2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid;
(±)-3-[5-Chloro-2-(6-fluoro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-chloro-indan-1 -yloxy)-phenoxy]-azetidine; (±)-3-[5-Bromo-2-(6-chloro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-fluoro-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(5-nnethyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(6-nnethyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Bromo-2-(6-trifluoronnethyl-indan-1 -yloxy)-phenoxy]-azetidine; (±)-3-[5-Chloro-2-(6-methyl-indan-1 -yloxy)-phenoxy]-azetidine;
(±)-3-[5-Chloro-2-(6-chloro-indan-1 -yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(6-trifluoromethyl-indan-1 -yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-1 -yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(5-tert-butyl-indan-1 -yloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 ,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(chroman-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(chroman-3-ylnnethoxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylmethoxy)-phenoxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1 ,3-dinnethyl-1 H-pyrazole;
3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -phenyl-azetidine; 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine; 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1 -one oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1 -one O-methyl-oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -phenyl-ethanone oxime; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -phenyl-ethanone O-methyl-oxime;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1 -(4-chloro-phenyl)-ethanone;
3-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-[1 -(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[1 -(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;
3-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine;
3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine; 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine;
3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine;
3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Trifluoromethyl-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Trifluoromethyl-2-[1-(3-trifluoronnethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 3-[2-(1 -Phenyl-ethoxy)-5-trifluoromethyl-phenoxy]-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -methyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-isopropyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -cyclobutyl-azetidine; 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -propyl-azetidine;
3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1 -ethyl-azetidine;
3-[5-Fluoro-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Fluoro-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-1 -isopropyl- azetidine; 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine;
3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzannide;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-nnethyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine; 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine;
3-(5-Bronno-2-phenethyloxy-phenoxy)-3-nnethyl-azetidine;
3-[5-Bronno-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-azetidine; 3-(5-Bromo-2-phenoxy-phenoxy)-3-nnethyl-azetidine;
(±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine; cis-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine; trans-1 -Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-nnethyl-azetidine;
3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine; (±)-3-[5-Chloro-2-(trans-1 -benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -benzhydryl-azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -azetidin-3-ol)-phenoxy]-azetidine;
3-[5-Chloro-2-(1 -lsopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine; 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1 -tert-butyl-azetidine;
1 -tert-Butyl-3-[5-chloro-2-(3-trifluoronnethyl-benzyloxy)-phenoxy]-azetidine
1 -tert-Butyl-3-[5-chloro-2-[1 -(3-trifluoronnethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 3-[5-Bromo-2-(5-trifluoronnethyl-furan-2-ylnnethoxy)-benzyl]-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxynnethyl]-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxynnethyl]-1 -nnethyl-azetidine;
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxynnethyl]-azetidin-3-ol;
3-[1 -[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol; 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine;
3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-nnethyl-[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl-[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl- [1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl-[1 ,2,4]oxadiazole;
5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1 ,2,4]oxadiazole;
3-(5-Bromo-2-phenoxy-phenoxy)-azetidine; 3-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine;
3-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine;
3-[5-Bromo-2-(3-nnethoxy-phenoxy)-phenoxy]-azetidine; 3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(4-bronno-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(3-trifluoronnethoxy-phenoxy)-phenoxy]-azetidine; 3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine;
3-[5-Bromo-2-(naphthalen-1 -yloxy)-phenoxy]-azetidine;
3-(5-Chloro-2-phenoxy-phenoxy)-azetidine;
3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine;
3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidine; 3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine;
3-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole;
2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1 ,8]naphthyridine; 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline;
4-(5-Chloro-2-phenoxy-phenoxy)-piperidine;
(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;
(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1 -methyl-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;
(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;
(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;
(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;
(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine;
(±)-3-[5-Bromo-2-(4-bronno-phenoxy)-phenoxy]-1 -ethyl-pyrrol id ine;
2-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone; [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone;
[4-Bromo-2-(1 -methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-nnethanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-nnethanone; [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone;
[4-Bromo-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1 ,3]dioxol-5-yl-methanone;
Benzo[1 ,3]dioxol-5-yl-[4-bromo-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]- methanone; [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-nnethanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone;
[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone;
[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1 ,3]dioxol-5-yl-methanone; Benzo[1 ,3]dioxol-5-yl-[4-chloro-2-(1 -isopropyl-azetidin-3-yloxy)-phenyl]- methanone;
[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone; and
[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone; and pharmaceutically acceptable salts, prodrugs, and active metabolites thereof.
27. A pharmaceutical composition according to claim 25, further comprising: an active ingredient selected from the group consisting of an additional active ingredient selected from the group consisting of: Hi receptor antagonists, H2 receptor antagonists, H3 receptor antagonists, topiramate, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors, acetylcholinesterase inhibitors, modafinil, anti-psychotics, sedatives, monoamine oxidase inhibitors, and tricyclic antidepressants.
28. A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by 5HT7 activity, comprising administering to the subject an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I):
Figure imgf000227_0001
wherein
R1 is -H, -Ci-4alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1 , 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1 ; R2 and R3 are each independently -H or -Ci-4alkyl;
R4 is -H, F, Ci-4alkyl, or R4 is -OH when L is -CH2-, -CF2-, -CHF-, -OCH2-, or - OCH(CH3)-;
L is -O-, -CH2-, -OCH2-, -OCH(CH3)-, -CH2O-, -CF2-, or -CHF-; Z is -O-, -C(O)-, -OCH(Rb)-, or -OCH2C(Rc)(Rd)-; where where Rb is -H; a -Ci-4alkyl group unsubstituted or substituted with OH or halo; -CO2Ci-4alkyl; or -CO2H; and
Rc and Rd are each independently -H, -Ci-4alkyl, -O-Ci-4alkyl, or halo; or Rc and Rd taken together form an oxime, a Ci-4alkyl oxime, or a carbonyl group; or Rc and Rd taken together with the carbon to which they are attached form a C3-6cycloalkyl group; R5 is: i) a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R9 substituents; where each Rg substituent is selected from the group consisting of: - Ci-6alkyl, -OH, -OCi-6alkyl, -CN, -NO2, -C(O)Ci -6alkyl, -S(O)0-2-Ci-6alkyl, -OS(O)0-2-Ci -6alkyl, -SO2CF3, -SCF3, halo, -CF3, -OCF3, -CO2H, -CO2Ci -ealkyl, -CH2OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two Rg substituents taken together form -OCH2O-, -OCF2O-, or
-OCH2CH2O-; ii) a naphthyl group, unsubstituted or substituted with Ci-4alkyl or halo; iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three Rg substituents; iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with Ci-4alkyl or halo; v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: -Ci-4alkyl, -OCi-4alkyl, halo, -CF3, oxime, -Ci-4alkyl oxime, or phenyl; and vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; X is C or N, R6 or R7 are each independently -H, halo, -CF3, thiophene, or -C(O)N(Rx)Ry; wherein Rx and Ryare each independently -H or -Ci-4alkyl; and (b) pharmaceutically acceptable salts of the compounds of Formula (I), pharmaceutically acceptable prodrugs of the compounds of Formula (I), and pharmaceutically active metabolites of the compounds of Formula (I).
29. A method according to claim 28, wherein the disease, disorder, or condition is selected from the group consisting of: sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive- compulsive disorder, mood disorders, post-traumatic stress and other stress- related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flushes associated with menopause, alcohol abuse, drug abuse, addictive disorders including drug addiction and alcohol addiction, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities.
30. A method according to claim 28, wherein the disease, disorder, or condition is is selected from the group consisting of: hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, and urinary incontinence.
31. The method according to claim 28, wherein the disease, disorder, or medical condition is selected from the group consisting of: glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.
PCT/US2009/062627 2008-10-30 2009-10-29 Serotonin receptor modulators WO2010059393A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US13/126,223 US8642583B2 (en) 2008-10-30 2009-10-29 Serotonin receptor modulators
US14/051,199 US20140038943A1 (en) 2008-10-30 2013-10-10 Serotonin receptor modulator
US14/925,835 US9981909B2 (en) 2008-10-30 2015-10-28 Serotonin receptor modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10990308P 2008-10-30 2008-10-30
US61/109,903 2008-10-30

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/126,223 A-371-Of-International US8642583B2 (en) 2008-10-30 2009-10-29 Serotonin receptor modulators
US14/051,199 Division US20140038943A1 (en) 2008-10-30 2013-10-10 Serotonin receptor modulator

Publications (1)

Publication Number Publication Date
WO2010059393A1 true WO2010059393A1 (en) 2010-05-27

Family

ID=41557680

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/062627 WO2010059393A1 (en) 2008-10-30 2009-10-29 Serotonin receptor modulators

Country Status (2)

Country Link
US (3) US8642583B2 (en)
WO (1) WO2010059393A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102976993A (en) * 2012-11-08 2013-03-20 杭州澳赛诺化工有限公司 Synthetic method of 3-hydroxyazetidine hydrochloride
EP2754653A2 (en) * 2011-09-05 2014-07-16 Korea Institute of Science and Technology Azetidine derivative and antidepressant composition containing same
JP2014527996A (en) * 2011-09-27 2014-10-23 ジェンフィットＧｅｎｆｉｔ Derivatives of 6-substituted triazolopyridazines as Rev-erb agonists
CN105308037A (en) * 2013-06-04 2016-02-03 阿克图拉姆生命科学股份公司 Triazole compounds and their use as gamma secretase modulators
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2023088285A1 (en) * 2021-11-16 2023-05-25 深圳湾实验室 Small molecule inhibitor against nasopharyngeal carcinoma, preparation method for compound and application thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010059393A1 (en) 2008-10-30 2010-05-27 Janssen Pharmaceutica Nv Serotonin receptor modulators
WO2010059390A1 (en) 2008-10-30 2010-05-27 Janssen Pharmaceutica Nv Modulators of serotonin receptor
WO2023240267A2 (en) * 2022-06-10 2023-12-14 Sionna Therapeutics Compounds, compositions, and methods of using thereof
CN116082131B (en) * 2022-06-26 2024-04-05 苏州华道生物药业股份有限公司 Method for synthesizing 1-indanone compound by one-pot method

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1964510A1 (en) * 1968-12-23 1970-07-09 Robins Co Inc A H 1-substituted-3-substituted phenoxypyrrolidines and processes for their preparation
DE2737630A1 (en) * 1977-08-20 1979-03-01 Boehringer Mannheim Gmbh 3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors
JPH03264583A (en) * 1990-03-14 1991-11-25 Dai Ichi Seiyaku Co Ltd Piperidine derivative and production of intermediate thereof
EP0600717A1 (en) * 1992-11-30 1994-06-08 Sankyo Company Limited Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis
WO2002018333A1 (en) * 2000-08-31 2002-03-07 Pfizer Limited Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors
WO2005047246A1 (en) * 2003-11-10 2005-05-26 Merck Sharp & Dohme Limited Novel 1, 3-disubstituted azetidine deivatives for use as 5ht2a receptor ligands
WO2007072150A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Piperidine derivatives
WO2008023258A1 (en) * 2006-08-23 2008-02-28 Pfizer Products Inc. Piperidine derivatives

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146630A (en) 1976-11-12 1979-03-27 Boehringer Mannheim Gmbh Blood pressure lowering and adrenergic β-receptor inhibiting 3-(4-phenoxymethylpiperidino)-propyl-phenyl ethers
US5130309A (en) * 1991-04-12 1992-07-14 A. H. Robins Company, Incorporated Aryloxy and aryloxyalklazetidines as antiarrhythmic and anticonvulsant agents
JP3264583B2 (en) 1994-05-27 2002-03-11 トヨタ自動車株式会社 Mounting method of vehicle floor carpet and wire harness and harness clamp
US5629325A (en) * 1996-06-06 1997-05-13 Abbott Laboratories 3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission
DK0863136T3 (en) 1997-02-25 2004-02-02 Akzo Nobel Nv Azetidine and pyrrolidine derivatives
US6110937A (en) * 1997-04-03 2000-08-29 Syntex Usa, Inc. Phenoxymethyl piperidine derivatives for the treatment of neuropathic pain
CO5011067A1 (en) 1997-11-03 2001-02-28 Novartis Ag DERIVATIVES OF BIFENYL AS PHARMACEUTICAL PRODUCTS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP1638939A2 (en) 2003-06-24 2006-03-29 Neurosearch A/S Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
JP2008001596A (en) 2004-09-03 2008-01-10 Astellas Pharma Inc Sodium channel inhibitor
WO2007038459A2 (en) 2005-09-27 2007-04-05 Novartis Ag Carboxyamine compounds and their use in the treatment of hdac dependent diseases
GB0607196D0 (en) 2006-04-11 2006-05-17 Prosidion Ltd G-protein coupled receptor agonists
DE102006033794B3 (en) 2006-07-19 2008-03-06 BEGO Bremer Goldschlägerei Wilh. Herbst GmbH & Co. KG Set of elements for the production of a dental prosthesis, system for the production of a dental prosthesis or a set of elements and corresponding manufacturing methods
WO2008023720A1 (en) 2006-08-23 2008-02-28 Astellas Pharma Inc. Urea compound or salt thereof
EP1938690B1 (en) 2006-12-22 2013-10-23 Preentec AG Sterilising and preserving fluids
RU2010142937A (en) * 2008-03-20 2012-04-27 Форест Лабораториес Холдингс Лимитед (Bm) NEW PIPERIDINE DERIVATIVES AS STEAROIL-COA DESATURASE INHIBITORS
WO2010059393A1 (en) 2008-10-30 2010-05-27 Janssen Pharmaceutica Nv Serotonin receptor modulators
WO2010059390A1 (en) 2008-10-30 2010-05-27 Janssen Pharmaceutica Nv Modulators of serotonin receptor

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1964510A1 (en) * 1968-12-23 1970-07-09 Robins Co Inc A H 1-substituted-3-substituted phenoxypyrrolidines and processes for their preparation
DE2737630A1 (en) * 1977-08-20 1979-03-01 Boehringer Mannheim Gmbh 3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors
JPH03264583A (en) * 1990-03-14 1991-11-25 Dai Ichi Seiyaku Co Ltd Piperidine derivative and production of intermediate thereof
EP0600717A1 (en) * 1992-11-30 1994-06-08 Sankyo Company Limited Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis
WO2002018333A1 (en) * 2000-08-31 2002-03-07 Pfizer Limited Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors
WO2005047246A1 (en) * 2003-11-10 2005-05-26 Merck Sharp & Dohme Limited Novel 1, 3-disubstituted azetidine deivatives for use as 5ht2a receptor ligands
WO2007072150A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Piperidine derivatives
WO2008023258A1 (en) * 2006-08-23 2008-02-28 Pfizer Products Inc. Piperidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARRAK ET AL.: "The First Synthesis of Spiro (1,4-Benzodioxin-2,4'-Piperidines) and Spiro (1,4-Benzodioxin-2,3'-Pyrrolidines)", SYNLETT, no. 6, 5 May 2003 (2003-05-05), pages 813 - 816, XP002574322 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2754653A2 (en) * 2011-09-05 2014-07-16 Korea Institute of Science and Technology Azetidine derivative and antidepressant composition containing same
EP2754653A4 (en) * 2011-09-05 2015-02-18 Korea Inst Sci & Tech Azetidine derivative and antidepressant composition containing same
US9120771B2 (en) 2011-09-05 2015-09-01 Korea Institute Of Science And Technology Azetidine derivative and antidepressant composition including the same
JP2014527996A (en) * 2011-09-27 2014-10-23 ジェンフィットＧｅｎｆｉｔ Derivatives of 6-substituted triazolopyridazines as Rev-erb agonists
CN102976993A (en) * 2012-11-08 2013-03-20 杭州澳赛诺化工有限公司 Synthetic method of 3-hydroxyazetidine hydrochloride
CN105308037A (en) * 2013-06-04 2016-02-03 阿克图拉姆生命科学股份公司 Triazole compounds and their use as gamma secretase modulators
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
US12037342B2 (en) 2019-05-23 2024-07-16 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2023088285A1 (en) * 2021-11-16 2023-05-25 深圳湾实验室 Small molecule inhibitor against nasopharyngeal carcinoma, preparation method for compound and application thereof

Also Published As

Publication number Publication date
US9981909B2 (en) 2018-05-29
US8642583B2 (en) 2014-02-04
US20160046574A1 (en) 2016-02-18
US20140038943A1 (en) 2014-02-06
US20110207714A1 (en) 2011-08-25

Similar Documents

Publication Publication Date Title
US9981909B2 (en) Serotonin receptor modulators
CN114805139B (en) Prodrugs of ketamine, compositions and uses thereof
EP1831173B1 (en) Tetrahydroisoquinoline compounds for treatment of cns disorders
EP1943216B1 (en) Prolinamide derivatives as sodium channel modulators
AU2014374043B2 (en) TRPA1 modulators
NZ566023A (en) Carboxamide derivatives as muscarinic receptor antagonists
EP2129655A1 (en) Prolinamide derivatives as modulators of voltage-gated sodium channels
CN101321726A (en) Novel fused pyrrole derivative
CN114874209B (en) Oxadiazole transient receptor potential channel inhibitors
EP3828174A1 (en) Pyridazinone derivative
CN111183138A (en) Isochroman compounds and uses
JP2023513373A (en) P2X3 modulators
CN101410116A (en) Urotensin II receptor antagonists
US8957059B2 (en) Modulators of serotonin receptors
KR20100052507A (en) Novel heterocyclic compounds as mglu5 antagonists
WO2023232135A1 (en) Pde4b inhibitor and use thereof
WO2016126869A1 (en) 3,3-difluoro-piperidine derivatives as nr2b nmda receptor antagonists
EP2546255A1 (en) Benzazepine compound
EA023020B1 (en) SPIROHETEROCYCLIC COMPOUNDS AND USE THEREOF AS mGlu5 ANTAGONISTS
AU2014365915B2 (en) Tetrahydro-tetrazolo[1,5-a]pyrazines as ROR-gamma inhibitors
WO2010053825A1 (en) 2-aminopyrimidine compounds as serotonin receptor modulators
EP4313313A1 (en) Aryl heterocyclic compounds as kv1.3 potassium shaker channel blockers
BRPI0415273B1 (en) MORPHOLINE DERIVATIVES AS NOREPINEPHRINE REABSORATION INHIBITORS, ITS CHLORIDRATE SALT, ITS USE, INTERMEDIARIES AND PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITION
CN117881664A (en) Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as NAV1.8 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09760040

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13126223

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09760040

Country of ref document: EP

Kind code of ref document: A1