WO2011008312A2 - Dérivés indole et indoline et leurs procédés d’utilisation - Google Patents

Dérivés indole et indoline et leurs procédés d’utilisation Download PDF

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Publication number
WO2011008312A2
WO2011008312A2 PCT/US2010/027931 US2010027931W WO2011008312A2 WO 2011008312 A2 WO2011008312 A2 WO 2011008312A2 US 2010027931 W US2010027931 W US 2010027931W WO 2011008312 A2 WO2011008312 A2 WO 2011008312A2
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WIPO (PCT)
Prior art keywords
indole
hexahydro
ethyl
methyl
epiminocyclohepta
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PCT/US2010/027931
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English (en)
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WO2011008312A3 (fr
Inventor
Michael R. Schrimpf
Chih-Hung Lee
Tao Li
Gregory A. Gfesser
Kathleen H. Mortell
Ramin Faghih
Diana L. Nersesian
Kevin B. Sippy
William H. Bunnelle
Marc Scanio
Lei Shi
Murali Gopalakrishnan
Diana L. Donnelly-Roberts
Min Hu
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Abbott Laboratories
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Priority claimed from US12/568,085 external-priority patent/US9063126B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2011008312A2 publication Critical patent/WO2011008312A2/fr
Publication of WO2011008312A3 publication Critical patent/WO2011008312A3/fr

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    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the present invention relates to indole and indoline derivatives, compositions comprising these indole and indoline derivatives, methods of preventing or treating disease conditions such as neurodegeneration or neuropsychiatric disorders using such compounds and compositions, and processes for preparing such compounds and compositions.
  • Alzheimer's disease is the most common form of dementia, wherein loss of memory and other intellectual abilities are serious enough to interfere with daily living.
  • Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive loss of memory accompanied with cholinergic neurodegeneration (Kar, S.;
  • AD Alzheimer's disease
  • senile plaques composed of ⁇ -amyloid peptide 1-42 A ⁇ i_ 42
  • NFTs neurofibrillary tangles formed by abnormal polymerization of microtubule-associated protein tau
  • pathological assemblies of A ⁇ i_ 42 cause diverse forms of AD and that tau plays a role including in mechanisms leading to A ⁇ i_42-induced neurodegeneration.
  • tau pathology exacerbates neurodegenerative and cognitive processes in the presence of A ⁇ i_4 2 (Oddo, S.; Caccamo, A.; et al. Temporal Profile of Amyloid- ⁇ (A ⁇ ) Oligomerization in an in Vivo Model of Alzheimer Disease: a link between A ⁇ and tau pathology. J. Biol. Chem. 2006, 281(3), 1599-1604.).
  • a ⁇ i_4 2 Oddo, S.; Caccamo, A.; et al. Temporal Profile of Amyloid- ⁇ (A ⁇ ) Oligomerization in an in Vivo Model of Alzheimer Disease: a link between A ⁇ and tau pathology. J. Biol. Chem. 2006, 281(3), 1599-1604.
  • AD Alzheimer's Dis. Res. 2006, 259- 279.
  • Beal M. F. Mitochondria and neurodegeneration. Novartis Found. Symp. 2007, 287(Mitochondrial Biology), 183-196.
  • Mitochondria play major roles in bioenergetics and cell death/survival signaling of the mammalian cell as they are 'gatekeepers of life and death'. Mitochondrial dysfunction contributes to the pathogenesis of various neurodegenerative diseases with
  • MTP mitochondrial permeability transition pores
  • the pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with mechanisms for maintaining cellular calcium homeostasis.
  • a deficit in mitochondria is the earliest feature of neurodegenerative diseases.
  • One general characteristic of aging and neurodegeneration is an increase in the number of neuronal cells undergoing signs of apoptotic degeneration.
  • a key role for this apoptotic process is attributable to the mitochondrial permeability transition pore, which provides transport in and out of mitochondria for both calcium ions and compounds with low molecular weight.
  • MPTP is a multiprotein complex with the outer membrane fragment including porin (a voltage-dependent ion channel), anti-apoptotic proteins of the Bcl-2 family, and the peripheral benzodiazepine receptor.
  • the inner fragment of MPTP contains an adenine nucleotide translocator and cyclophilin, which may interact with proapoptotic proteins of the Bax family.
  • Inhibition of mitochondrial calcium uptake and/or blocking of MPTP may protect cells against the development of apoptosis in the presence of pathological factors such as excitotoxins and anti-oxidants.
  • dimebolin latrepirdine, 2,3,4,5-tetrahydro-2,8- dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-lH-pyrido[4,3- ⁇ ]indole
  • Dimebolin has been shown to inhibit neuronal death in models of AD and Huntington's disease, another neurodegenerative disease (Lermontova, N. N.; Lukoyanov, N. V.; et al. Dimebone improves learning in animals with experimental
  • Alzheimer's disease Bull. Exp. Biol. Med. 2000, 129(6), 544-546. Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 2001, 939 (Neuroprotective Agents), 425-435.). More recently, dimebolin has been shown to possess a clinically beneficial effect in cognition in patients with AD (Burns, A.; Jacoby, R. Dimebon in Alzheimer's disease: old drug for new
  • dimebolin-treated patients demonstrated a significant improvement over placebo in cognition, global function, activities of daily living and behavior.
  • a six-month open-label extension trial of dimebolin produced results similar to those in the preceding 12-month clinical trial (Cummings, J.; Doody, R.; Gavrilova, S.; Sano, M.; Aisen, P.; Seely, L.; Hung, D. 18-month data from an open-label extension of a one-year controlled trial of dimebon in patients with mild-to-moderate Alzheimer's disease.
  • Alzheimer's Disease ICAD
  • Dimebolin has been approved in Russia as a non-selective antihistamine. The drug was sold for many years before selective anti-histaminergic agents were developed.
  • dimebolin was initially thought to exert its cognitive enhancing effects through inhibition of butyryl-cholinesterase, acetyl cholinesterase, NMDA receptor or L-type calcium channels (Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 2001, 939 (Neuroprotective Agents), 425-435. Lermontova, N. N.; Redkozubov, A. E.; et al. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels. Bull. Exp. Biol. Med. 2001, 132(5), 1079-1083. Grigor'ev, V. V.; Dranyi, O. A.; et al.
  • Hung and coworkers Hung, D. Dimebon: A phase 3 investigational agent for
  • the present invention relates to compounds of having a formula of (I), (II), (III), (IV), (V), or (VI):
  • a is a single or double bond
  • U, V, W, and Y are each independently -(CH 2 ) P -;
  • p at each occurrence is independently 0, 1, or 2;
  • Z is -(CH 2 V;
  • q 1, 2, or 3;
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, halogen, cyano, -G 1 , -N(R b )(R 3a ), -N(R a )C(O)R la , -N(R a )C(O)O(R la ), -N(R a )C(O)N(R b )(R 3a ), -OR la , -SR la , - S(O) 2 R 23 , or haloalkyl; wherein
  • R a and R b are each independently hydrogen, alkyl, or haloalkyl;
  • R la and R 3a are each independently hydrogen, alkyl, haloalkyl,
  • R 2a at each occurrence, is independently alkyl, haloalkyl, G 1 , or -(CR 63 R 7 ⁇ n -G 1 ; n, at each occurrence, is independently 1, 2, 3, 4, or 5;
  • R 6a and R 7a are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • G 1 at each occurrence, is independently aryl, heteroaryl, heterocycle, or cycloalkyl, wherein each G 1 is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, cyano, oxo, -NO 2 , -0R lb ,
  • n is independently 1, 2, 3, 4, or 5;
  • R lb and R 3b are each independently hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, haloalkyl, heteroarylalkyl, or heterocyclealkyl;
  • R 2b at each occurrence, is independently alkyl or haloalkyl
  • R 4b and R 5b are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • R 5 is hydrogen, alkyl, -G 1 , -S(O) 2 R 2a , -S(O) 2 N(R b )(R 3a ), -C(O)R la , -C(O)OR la ,
  • R 4a and R 5a are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • R 6 is alkyl, -S(O) 2 R 2a , -C(O)R la , -C(O)OR la , -C(O)N(R b )(R 3a ), -(CR 4a R 5a ) m -NO 2 ,
  • G 2 is aryl, heteroaryl, heterocycle, or cycloalkyl unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, cyano, oxo, -NO 2 , - OR lb , -OC(O)R lb ,-OC(O)N(R b )(R 3b ), -SR lb , -S
  • R 7 is hydrogen, alkyl, -G 1 , -(CR 4a R 5a ) m -NO 2 , -(CR 4a R 5a ) m -OR la , -(CR 4a R 5a ) m -OC(O)R la , -(CR 4a R 5a ) m -OC(O)N(R b )(R 3a ), -(CR 4a R 5a ) m -SR la , -(CR 4a R 5a ) m -S(O) 2 R 2a , -(CR 4a R 5a ) m -S(O) 2 N(R b )(R 3a ), -(CR 4a R 5a ) m -C(O)R la , -(CR 4a R 5a ) m -C(O)OR la , -(CR 4a R 5a ) m -C(O)N(R
  • R 8 is -(CR 43 R 53 V-G 1 , -(CR ⁇ R'VG'-G 1 , or -CR ⁇ CR ⁇ -G 1 ; with the proviso that in a compound of formula (I),
  • R 1 , R 2 and R 4 are each hydrogen
  • R 3 is hydrogen or halogen
  • U is CH 2 ;
  • V, W, and Y are each -(CH 2 ) P -, wherein p is 0;
  • Z is -(CH 2 ) q -, wherein q is 2 or 3;
  • X is NR 6 ;
  • R 6 is alkyl, -G 1 , or -(CR 43 R 5 VG 1 , wherein m is 1, R 4a and R 5a are hydrogen and G 1 is phenyl unsubstituted or substituted with alkyl, halogen, hydroxy or -OR la wherein R la is alkyl;
  • R 5 is other than hydrogen, alkyl, -(CR 43 R 5 ⁇ 1n -G 1 , -C(O)R 13 , -(CR 4a R 53 ) m -OR la , or
  • V is -(CH 2 ) p -, wherein p is 0;
  • Y is -(CH 2 ) p -, wherein p is 2;
  • Z is -(CH 2 ) q -, wherein q is 1 ;
  • R 6 is other than alkyl, C(O)R la , -(CR 4a R 5a ) m OR la , -(CR 4a R 5a ) m C(O)R la ,
  • the present invention further provides processes of making the compounds of the present invention, and intermediates employed in the processes.
  • the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound(s) having a formula of (I), (II), (III), (IV), (V), or (VI) described above or pharmaceutically acceptable salts thereof, in combination with at least one pharmaceutically acceptable carrier.
  • the present invention relates to a method of preventing or treating a neurodegeneration disorder using a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • Such methods involves administering a therapeutically effective amount of at least one compound of formula (I), (II), (III), (IV), (V) or (VI) to a subject in need of treatment thereof.
  • neurodegeneration disorders are Alzheimer's disease (AD), mild cognitive impairment (MCI), age-associated memory impairment (AAMI), multiple sclerosis, Parkinson's disease, vascular dementia, senile dementia, AIDS dementia, Pick's disease, dementia caused by cerebrovascular disorders, corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, diminished CNS function associated with traumatic brain injury or any combinations thereof.
  • the above method also further comprises administering a cognitive enhancing drug to the subject.
  • the cognitive enhancing drug can be administered simultaneously or sequentially with the compound of formula (I), (II), (III), (IV), (V), or (VI).
  • the present invention relates to a method of preventing or treating a neuropsychiatry disorder using a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • Such methods involve administering a therapeutically effective amount of at least one compound of formula (I), (II), (III), (IV), (V) or (VI), to a subject in need of treatment thereof.
  • neuropsychiatric disorders are schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar and manic disorders, depression or any combinations thereof.
  • the above method also further comprises administering a cognitive enhancing drug to the subject.
  • the cognitive enhancing drug can be administered simultaneously or sequentially with the compound of formula (I), (II), (III), (IV), (V), or (VI).
  • the present invention relates to methods of preventing or treating a pain condition using a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • Such methods include administering a therapeutically effective amount of at least one compound of formula (I), (II), (III), (IV), (V) or (VI), to a subject in need of treatment thereof.
  • pain conditions includes neuropathic and nociceptive pain, chronic or acute, such as, without limitation, allodynia, inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post operative pain, post stroke pain, and menstrual pain.
  • allodynia inflammatory pain
  • inflammatory hyperalgesia post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain, cancer pain
  • the present invention can also include use of a compound of formula (I), (II), (III), (IV), (V), or (VI) as neuroprotective agent for the prevention or treatment of a neurological disorder or condition.
  • the method includes administering a therapeutically effective amount of at least one compound of formula (I), (II), (III), (IV), (V) or (VI), to a subject in need of treatment thereof.
  • the neurological disorder or condition can include, but is not limited to, neurodegeneration disorders, neuropsychiatric disorder and pain conditions, brain injuries, stroke and other acute and chronic neuronal injuries or degenerative conditions.
  • the neurological disorder or condition can include, for example, conditions associated, at least in part, with mitochondrial dysfunction and/or neuronal apoptosis in the central nervous system.
  • the present invention relates to the use of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of the neurodegeneration disorders described above, alone or in combination with at least one pharmaceutically acceptable carrier.
  • the present invention relates to a method of identifying one or more target compounds useful for treating a neurodegeneration disorder or a
  • the method comprises the steps of:
  • neuroblastoma cells or cell lines are neuroblastoma cells or cell lines.
  • the present invention relates to a method of identifying one or more target compounds useful for treating a neurodegeneration disorder or a
  • the method comprises the steps of:
  • compositions comprising these compounds, and methods for preventing or treating neurodegenerative or
  • neuropsychiatric disorders by administering these compounds or pharmaceutical
  • compositions are further described herein.
  • Figure 1 shows a graphical representation of the concentration-dependent effects of
  • Example 1 on the number of neuron- like cells in nerve growth factor-differentiated PC 12 cells.
  • Cells were treated with varying concentrations of the test compound (Example 1).
  • Analysis was conducted 24 hours post-treatment using high-content screen (HCS) microscopy analysis system after staining with ⁇ -tubulin and Hoechst 33342.
  • the X-axis represents the test concentrations, and the Y-axis represents percent effects, normalized to 10 ⁇ M dimebolin.
  • Figure 2 shows a graphical representation of the concentration-dependent
  • Example 5 neuroprotective effects of Example 5 on the percent increase of neurite outgrowth.
  • a 100% response represents the neurite outgrowth of untreated cells.
  • Cells (primary postnatal (PO) cortical cells) treated with A ⁇ i_4 2 peptide showed a reduction in neurite outgrowth.
  • Cells pretreated with varying concentrations of the test compound (Example 5) and then subsequently with test compounds and freshly prepared A ⁇ i_ 42 peptide showed neurite outgrowth levels similar to or enhanced relative to untreated control cells.
  • the X-axis represents test concentrations, and the Y-axis represents percent effects.
  • Figure 3 shows a graphical representation of the concentration-dependent
  • SK-N-SH cells were treated with varying concentrations of Example 5.
  • Cellular function was determined with a plate reader with an excitation and emission of 560 nM and 595 nM for red fluorescence and with an excitation and emission of 485 nM and 535 nM for green fluorescence to determine the final JC-I value taking the red to green fluorescence ratio.
  • the X-axis represents the test concentrations, and the Y-axis represents mitochondrial function relative to 10 ⁇ M dimebolin (100% response).
  • Figure 4 shows a graphical representation of the concentration-dependent improvement in mouse 24-hour recall inhibitory avoidance scores upon treatment with test compound (Example 5).
  • the X-axis represents the day of exposure to condition, and the Y- axis represents the latency to cross to the punished side.
  • Figure 5 shows a graphical representation of the concentration-dependent improvement in rat social recognition ratio scores upon treatment with test compound (Example 5).
  • the X-axis represents the test concentrations, and the Y-axis represents the recognition ratio (T2:T1).
  • Figure 6 shows a graphical representation of the concentration-dependent improvement in the treatment of neuropathic pain in rat with test compound (Example 2).
  • the X-axis represents the test concentrations, and the Y-axis represents the pressure applied to elicit a pain response.
  • the present invention relates to compounds having a formula (I), (II),
  • the present invention relates to composition
  • composition comprising compounds having a formula (I), (II), (III), (IV), (V), and (VI) as described above and at least one pharmaceutically acceptable carrier.
  • the present invention relates to methods for preventing and treating disease conditions, such as neurodegeneration disorders or neuropsychiatric disorders, using compounds having a formula of formula (I), (II), (III), (IV), (V), and (VI) as described above.
  • the present invention relates to the use of compounds having a formula (I), (II), (III), (IV), (V), and (VI) in the manufacture of a medicament for the prevention or treatment of the disease conditions, such as neurodegeneration disorders or neuropsychiatric disorders, described above, alone or in combination with at least one pharmaceutically acceptable carrier.
  • the present invention provides at least one variable that occurs more than one time in any substituent or in the compound of the present invention or any other formulae herein.
  • Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds, which can be isolated from a reaction mixture. a. Definitions
  • alkenyl as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
  • lower alkyl or “Ci_ 6 alkyl” means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms.
  • Ci_ 3 alkyl means a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene denotes a divalent group derived from a straight or branched chain hydrocarbon 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and
  • alkylsulfonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl as used herein, means phenyl or a bicyclic aryl.
  • the bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.
  • Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system.
  • aryl groups of the present invention can be unsubstituted or substituted.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • cyano as used herein, means a -CN group.
  • cyanoalkyl as used herein, means a cyano group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
  • cycloalkyl or "cycloalkane” as used herein, means a monocyclic, a bicyclic, or a tricyclic cycloalkyl.
  • the monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring, or a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • Tricyclic cycloalkyls are exemplified by a bicyclic cycloalkyl fused to a monocyclic cycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbon atoms of the ring systems are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.
  • Representative examples of tricyc lie-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 ]nonane (octahydro-2,5- methanopentalene or noradamantane), and tricyclo[3.3.1.1 3 ' 7 ]decane (adamantane).
  • the monocyclic, bicyclic, and tricyclic cycloalkyls can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.
  • halo or halogen as used herein, means Cl, Br, I, or F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro- 3-fluoropentyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four- membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the f ⁇ ve-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six- membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3- dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl, pyridin-2(lH)-onyl, pyrrolinyl, pyrroliny
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle ring system in which two non adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, 1 ,4-benzoxazinyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, azabicyclo[2.2.1]heptyl (including 2- azabicyclo[2.2. l]hept-2-yl), 2,3-dihydro-lH-indolyl, isoindolinyl,
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • tricyclic heterocycles include, but not limited to, octahydro-2,5- epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[ ⁇ ]furan, hexahydro-lH-1,4- methanocyclopenta[c]furan, aza-admantane (l-azatricyclo[3.3.1.1 3 ' 7 ]decane), and oxa- adamantane (2-oxatricyclo[3.3.1.1 3 ' 7 ]decane).
  • the monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • heterocyclealkyl means a heterocycle group appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heteroaryl as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a five- or six-membered ring.
  • the five-membered ring contains two double bonds.
  • the five-membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1 ,2-oxazolyl, 1,3- oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,
  • heteroarylalkyl means a heteroaryl group appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heteroatom as used herein, means a nitrogen, oxygen, or sulfur atom.
  • hydroxyl or "hydroxy” as used herein, means an -OH group.
  • pain is understood to mean nociceptive pain and neuropathic pain, both chronic and acute pain, including but not limited to, osteoarthritis or rheumatoid arthritis pain, ocular pain, pains associated with intestinal inflammation, pains associated with cardiac muscle inflammation, pains associated with multiple sclerosis, pains associated with neuritis, pains associated with carcinomas and sarcomas, pains associated with AIDS, pains associated with chemotherapy, amputation pain, trigeminus neuralgia, headaches, such as migraine cephalalgia, or neuropathic pains, such as post-herpes zoster neuralgia, post-injury pains and post-operative pains.
  • Compounds of the present invention have the formula (I), (II), (III), (IV), (V), or (VI) as described above.
  • variable groups in compounds of formula (I), (II), (III), (IV), (V), or (VI) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, halogen, cyano, -G 1 , -N(R b )(R 3a ), -N(R a )C(0)R la , -N(R a )C(0)0(R la ),
  • R a and R b at each occurrence, are each independently hydrogen, alkyl, or haloalkyl
  • R la and R 3a at each occurrence, are each independently hydrogen, alkyl, haloalkyl, G 1 , or -(CR 6a R 7a ) n -G 1
  • R 2a at each occurrence, is independently alkyl, haloalkyl, G 1 , or -(CR 6a R 7a ) n -G 1
  • R 6a and R 7a at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl
  • n at each occurrence, is independently 1, 2, 3, 4, or 5
  • G 1 is aryl, heteroaryl, heterocycle
  • R lb and R 3b are each independently hydrogen, alkoxyalkyl, and haloalkyl;
  • R lb and R 3b at each occurrence, are each independently hydrogen, alkoxyalkyl, and haloalkyl;
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, haloalkyl, halogen, -G 1 , -OR la , or -SO 2 R 2a .
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, haloalkyl, halogen, alkoxy, haloalkoxy, cyclopropyl, alkylsulfonyl, pyridyl, pyrazolyl, or aryl optionally substituted with halogen or haloalkyl.
  • R 1 , R 2 , and R 4 are hydrogen, and R 3 is alkyl.
  • R 1 , R 2 , and R 4 are hydrogen, and R 3 is halogen.
  • R 1 , R 2 , and R 4 are hydrogen, and R 3 is fluorine.
  • R 1 , R 2 , R 3 and R 4 are each hydrogen.
  • R 5 is hydrogen, alkyl, -G 1 , -S(O) 2 R 2a , -S(O) 2 N(R b )(R 3a ),
  • R la and R 3a at each occurrence, are independently hydrogen, alkyl, haloalkyl, G 1 , or -(CR 6a R 7a ) n - G 1 ;
  • R 2a at each occurrence, is independently alkyl, haloalkyl, G 1 , or -(CR 6a R 7a ) n -G 1 ;
  • R 4a , R 5a , R 6a and R 7a at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl; and
  • R a , R b , m, n, and G 1 are as disclosed in the Summary of the Invention and the embodiments described herein.
  • R 5 is hydrogen, alkyl, haloalkyl, -C(O)R la , C(O)R la or S(O) 2 R 2a .
  • R 5 is hydrogen
  • R 5 is -C(O)R la , C(O)OR la or S(O) 2 R 2a .
  • R 5 is -C(O)R la , wherein R la is phenyl optionally substituted with alkyl or halogen.
  • R 5 is -C(O)OR la , wherein R la is alkyl.
  • R 5 is S(O) 2 R 2*1 , wherein R 2a is phenyl optionally substituted with alkyl, halogen or haloalkyl.
  • R 5 is alkyl or haloalkyl.
  • X is NR 6 .
  • X 1 is CHR 8 , or NR 8 .
  • X 1 is CHR 8'
  • X 1 is NR 6 .
  • R 6 is alkyl, -S(O) 2 R 2a , -C(O)R la , -C(O)OR la , -C(O)N(R b )(R 3a ), -(CR 4a R 5a ) m -NO 2 , -(CR 4a R 5a ) m -OR la , -(CR 4a R 5a ) m -OC(O)R la , -(CR 4a R 5a ) m -OC(O)N(R b )(R 3a ), -(CR 4a R 5a ) m -SR la , -(CR 4a R 5a ) m -S(O) 2 R 2a , -(CR 4a R 5a ) m -S(O) 2 N(R b )(R 3a ), -(CR 4a R 5a ) m -C(O)R la ,
  • -CR 4a CR 5a -S(O) 2 R 2a
  • -CR 4a CR 5a -S(O) 2 N(R b )(R 3a )
  • -CR 4a CR 5a -C(O)R la
  • -CR 4a CR 5a -C(O)OR la
  • -CR 4a CR 5a -G 1 , -G 1 , -G 2 -G 1 ; cyanoalkyl, or haloalkyl, wherein R a , R la , R 2a , R 3a , R 4a , R 5a , R b , m, G 1 , and G 2 are as disclosed in the Summary of the Invention and the embodiments described herein.
  • R 6 is -(CR 4a R 5a ) m -G 1 , wherein R 4a and R 5a are each hydrogen; m is 1, 2 or 3; and G 1 is as disclosed in the Summary of the Invention and the embodiments described herein.
  • R 6 is -(CR 4a R 5a ) m -G 1 , wherein R 4a and R 5a are each hydrogen; m is 1 or 2; and G 1 is phenyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridazin- 3(2H)-one, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, lH-benzimidazol-2-yl, quinolin-8-yl, thiazolyl, l,2-oxazol-5-yl, l,4,5,6-tetrahydropyrimidin-5-yl, imidazo[l,2- ⁇ ]pyridazin-2-yl, or imidazo[l,2- ⁇ ]pyrimidin-2-yl; wherein G 1 is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting
  • R 6 is -(CR 4a R 5a ) m -G ⁇ wherein one of R 4a or R 5a is alkyl and the others of R 4a and R 5a are hydrogen; m is 1, 2 or 3; and G 1 is optionally substituted phenyl or pyridyl.
  • R 6 is -C ⁇ 2 C ⁇ 2 -(6-methylpyridin-3-yl).
  • R 6 is -CR ⁇ CR ⁇ -G 1 , wherein R 4a and R 5a are each hydrogen, and G 1 is as disclosed in the Summary of the Invention and the embodiments described herein.
  • R 6 is -(CR 4a R 5a ) m -G 2 -G 1 , wherein R 4a and R 5a are at each occurrence hydrogen; m is 1; and G 2 is oxazolyl, pyridyl, pyrimidinyl, or phenyl; and G 1 is oxadiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyridazin-3(2H)-onyl, or phenyl, optionally unsubstituted or substituted with 1, 2, or 3 alkyl, haloalkyl or halogen.
  • R 6 is -G 2 -G 1 , wherein G 2 is optionally substituted aryl or optionally substituted heteroaryl, and G 1 is as disclosed in the Summary of the Invention and the embodiments described herein.
  • R 6 is wherein G 2 is a pyridazinyl and G 1 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 6 is wherein G 2 is a pyridinyl and G 1 is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle.
  • R 6 is wherein G 2 is a phenyl, pyridinyl, or pyridazinyl, and G 1 is optionally substituted phenyl, pyrazolyl, pyridazin-3(2H)-onyl, morpholinyl, piperazinyl, or imidazolyl.
  • R 6 is wherein G 2 is a phenyl and G 1 is optionally substituted aryl, optionally substituted heterocycle, or optionally substituted heteroaryl.
  • R 6 is -C(O)R la , wherein R la is as disclosed in the Summary of the Invention.
  • R 6 is -C(O)R la , wherein R la is -(CR ⁇ R 7 VG 1 , wherein R 6a ,
  • R 7a , n and G 1 are as disclosed in the Summary of the Invention.
  • R 6 is -C(O)R la , wherein R la is -(CR 6a R 7a ) n -G 1 , wherein R 6a , R 7a are each hydrogen, n is 1, and G 1 is optionally substituted phenyl.
  • R 6 is G 1 , wherein G 1 is as disclosed in the Summary of the Invention.
  • R 6 is G 1 , wherein G 1 is optionally substituted aryl or heteroaryl.
  • R 6 is G 1 , wherein G 1 is optionally substituted quinazolinyl, quinoxalin-2(lH)-onyl, pyrido[l,2- ⁇ ]pyrimidinyl, pyrimidinyl, pyridyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinolinyl, quinoxalinyl, benzoxazinyl, phenyl, pyrido[l,2- ⁇ ]pyrimidinyl, quinolinyl, or pyrido[l,2- ⁇ ]pyrimidin-4-onyl.
  • R 6 is -(CR 4a R 5a ) m -OR la , wherein R la , R 4a , R 5a , and m are as disclosed in the Summary of the Invention.
  • R 6 is -(CR 4a R 5a ) m -OR la , wherein R 4a , R 5a , and m are as disclosed in the Summary of the Invention, and R la is G 1 , wherein G 1 is as described in the Summary of the Invention.
  • R 6 is -(CR 4a R 5a ) m -OR la , wherein R la is phenyl optionally substituted with alkyl, halogen, or OR lb , wherein R lb is alkyl or haloalkyl; R 4a and R 5a are hydrogen at each occurrence, and m is 1 or 2.
  • R 6 is -S(O) 2 R 2*1 , wherein R 2a is as described in the Summary of the Invention.
  • R 6 is -S(O) 2 R 2a , wherein R 2a is as G 1 , wherein G 1 is as described in the Summary of the Invention.
  • R 6 is -S(O) 2 R 2a , wherein R 2a is as G 1 , wherein G 1 is phenyl, or pyridyl, optionally substituted with alkyl, halogen, or haloalkyl.
  • R 6 is -(CR 4a R 5a ) m -C(O)OR la or -(CR 4a R 5a ) m -C(O)N(R b) (R 3a ), wherein R la , R 3a , R 4a , R 5a , m, and R b are as disclosed in the Summary of the Invention.
  • R 6 is -(CR 4a R 5a ) m -C(O)OR la or
  • R la and R 3a are each independently G 1 , wherein G 1 is as described in the Summary of the Invention, and R 4a , R 5a , m, and R b are as disclosed in the Summary of the Invention.
  • R 6 is -(CR 4a R 5a ) m -C(O)OR la , wherein R la is alkyl; R 4a and R 5a are hydrogen at each occurrence; and m is 1 or 2.
  • R 6 is -(CR 4a R 5a ) m -C(O)N(R b) (R 3a ), wherein R 3a is optionally substituted phenyl; R 4a and R 5a are hydrogen at each occurrence; m is 1 or 2; and R b is hydrogen.
  • R 6 is -(CR 4a R 5a ) m -G 2 -G ⁇ wherein R 4a , R 5a , m, G 1 , and G 2 are as disclosed in the Summary of the Invention.
  • R 6 is -(CR 4a R 5a ) m -G 2 -G 1 , wherein R 4a , R 5a , and m are as disclosed in the Summary of the Invention and G 1 and G 2 are independently optionally substituted aryl or heteroaryl.
  • R 7 is hydrogen, alkyl, -G 1 , -(CR 4a R 5a ) m -NO 2 , -(CR 4a R 5a ) m -OR la , -(CR 4a R 5a ) m -OC(O)R la , -(CR 4a R 5a ) m -OC(O)N(R b )(R 3a ), -(CR 4a R 5a ) m -SR la , -(CR 4a R 5a ) m -S(O) 2 R 2a , -(CR 4a R 5a ) m -S(O) 2 N(R b )(R 3a ), -(CR 4a R 5a ) m -C(O)R la , -(CR 4a R 5a ) m -C(O)OR la ,
  • R 7 is hydrogen, alkyl, or haloalkyl.
  • R 8 is -(CR 43 R 5 VG 1 .
  • Compounds of formula (I) can include, but are not limited to, compounds wherein a is a single or double bond.
  • compounds within formula (I) include compounds having the following formula (Ia) and (Ib) and pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , U, V, W, X, Y, and Z are as disclosed in the Summary of the Invention and the embodiments described herein.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U is -(CH 2 ) P -, wherein p is 1; V, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (I) can also include, but are not limited to, compounds wherein U is -(CH 2 ) P -, wherein p is 1; V, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; and Z is -(CH 2 ) q -, wherein q is 3.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, V, and W are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; Y is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U,
  • V, and W are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; Y is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, V, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; W is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, V, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; W is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; V is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; V is -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 3.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U,
  • V, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, V, and W are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; Y is -(CH 2 ) P -, wherein p is 2; and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein V and W are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; and U and Y are each -(CH 2 ) P -, wherein p is l;and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (I) can include, but are not limited to, compounds wherein U, V, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; and Z is -(CH 2 ) q -, wherein q is 3.
  • R 1 , R 2 and R 4 are each hydrogen; R 3 is hydrogen or halogen; U is CH 2 ; V, W, and Y are each -(CH 2 ) P -, wherein p is 0, i.e., a bond; Z is -(CH 2 ) q -, wherein q is 2 or 3; X is NR 6 ; and R 6 is alkyl, -G 1 , or
  • Compounds of formula (II) can include, but are not limited to, compounds wherein R 1 , R 2 , R 3 , R 4 , R 7 , W, X 1 , and Y are as disclosed in the Summary of the Invention and the embodiments described herein and pharmaceutically acceptable salts thereof.
  • Compounds of formula (II) can include, but are not limited to, compounds wherein one of W and Y is -(CH 2 ) P -, wherein p is 0, i.e., a bond and the other is -(CH 2 ) P -, wherein p is 1.
  • Compounds of formula (II) can include, but are not limited to, compounds wherein one of W and Y is -(CH 2 ) P -, wherein p is 0, i.e., a bond and the other is -(CH 2 ) P -, wherein p is 2.
  • Compounds of formula (III) can include, but are not limited to, compounds wherein R 1 , R 2 , R 3 , R 4 , X, and Z are as disclosed in the Summary of the Invention and the
  • Compounds of formula (IV) can include, but are not limited to, compounds wherein a is a single or double bond.
  • compounds within formula (IV) include compounds of the following formula (IVa) and (IVb) and pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , V, X, and Z are as disclosed in the Summary of the Invention and the embodiments described herein.
  • Compounds of formula (IVa) can include, but are not limited to, compounds wherein V and Y are each -(CH 2 ) P -, wherein p is 1 ; and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (IVa) can include, but are not limited to, compounds wherein
  • Compounds of formula (IVa) can include, but are not limited to, compounds wherein
  • V and Y are each -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 2.
  • Compounds of formula (IVa) can include, but are not limited to, compounds wherein
  • V is -(CH 2 ) p -, wherein p is 0, i.e., a bond; Y is -(CH 2 ) P -, wherein p is 2; and Z is -(CH 2 ) q -, wherein q is 1.
  • Compounds of formula (IVb) can include, but are not limited to, compounds wherein V, Y, and Z are each CH 2 .
  • Compounds of formula (IVb) can include, but are not limited to, compounds wherein
  • V and Y are each -(CH 2 ) P -, wherein p is 1; and Z is -(CH 2 ) q -, wherein q is 2.
  • V is -(CH 2 ) P -, wherein p is 0, i.e., a bond; Y is -(CH 2 ) P -, wherein p is 2; and Z is -(CH 2 ) q -, wherein q is 1;
  • R 6 is other than alkyl, C(O)R la , -(CR 4a R 5a ) m OR la , -(CR 4a R 5a ) m C(O)R la , -(CR 4a R 5a ) m -N(Rb)(R3a), -(CR 43 R 53 V-G 1 , -CR ⁇ CR ⁇ -G 1 , -G 1 , cyanoalkyl or haloalkyl.
  • Compounds of formula (IVb) can include, but are not limited to, compounds wherein
  • V and Z are each CH 2 ; and Y is CH 2 CH 2 .
  • Compounds of formula (V) can include, but are not limited to, compounds wherein R 1 , R 2 , R 3 , R 4 , and X are as disclosed in the Summary of the Invention and the embodiments described herein and pharmaceutically acceptable salts thereof.
  • Compounds of formula (VI) can include, but are not limited to, compounds wherein a is a single or double bond.
  • compounds within formula (VI) include compounds of the following formula (Via) and (VIb) and pharmaceutically acceptable salts thereof:
  • the present invention also features processes for the preparation of the compounds of the invention.
  • Compounds of formula (VIII) are representative of compounds of formula (I). The preparation of compounds of formula (VII) and (VIII) are described in the
  • Compounds of formula (X) are representative of compounds of formula (IV).
  • Compounds of formula (IX) and (X) are prepared as described in the Examples.
  • Compounds of formula (XII) are representative of compounds of formula (VI).
  • Compounds of formula (XI) and (XII) are prepared as described in the Examples.
  • Stereoisomers of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present application may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution which is well known to those of ordinary skill in the art.
  • Geometric isomers may exist in the compounds of the present invention.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group.
  • Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration.
  • Compounds of this invention can exist in an isotopic form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 11 C, 14 C, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • Compounds containing tritium ( 3 H) and 14 C radioisotopes are preferred in general for their ease in preparation and detectability for radiolabeled compounds.
  • Iso topically labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such Isotopically labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. c. Biological Data
  • DMEM Dulbecco's modified Eagle's medium
  • DMSO dimethyl sulfoxide
  • FBS fetal bovine serum
  • FLIPR fluorometric imaging plate reader
  • GFAP glial fibrillary acidic protein
  • HBSS Hank's balanced salt solution
  • NGF nerve growth factor
  • PBS phosphate buffered saline
  • TMRE tetramethylrhodamine ethyl ester perchlorate
  • TRITC tetramethylrhodamine isothiocyanate.
  • Effects on Neurite Outgrowth in Neurons and Neuronal Cell Lines Effects on cellular properties such as neurite outgrowth and neuronal or neuronal-like cell number, etc. can be measured either using rat or human neuronal/neuroblastoma cell lines (e.g., SH-SY5Y, PC12, IMR-32, etc.) or using primary cells (e.g., rat cortical neurons). For example, it has been reported that dimebolin can increase neurite outgrowth in primary rat cortical neurons, comparable to that evoked by Brain Derived Neurotrophic factor
  • BDNF Alzheimer's Disease
  • Rat cortical cells were cultured and prepared for high content microscopy analysis as previously described (Hu, M.; Schurdak, M. E.; et al. High content screen microscopy analysis of A ⁇ i_ 42-induced neurite outgrowth reduction in rat primary cortical neurons: Neuroprotective effects of ⁇ 7 neuronal nicotinic acetylcholine receptor ligands. Brain Res. 2007, 1151, 227- 235.). Briefly, cortical cell cultures were plated at density of 5xlO 5 cells/mL onto poly-D- lysine coated 96-well plates and maintained in a cell incubator at 37 0 C with 5% CO 2 .
  • mice were then incubated overnight at about 4 0 C with mouse anti-tubulin monoclonal antibody (1 : 100) for staining neurons and rabbit anti-GFAP (1 : 1000) for staining glia.
  • rabbit anti-GFAP (1 : 1000) for staining glia.
  • cells were incubated with FITC-labeled anti-mouse and TRITC-labeled anti-rabbit antibodies (1 : 1000) for about 1 hour at room temperature.
  • nuclei 360/400 nm excitation and 465/300 nm emission filters
  • neuron 475/350 nm excitation and 535/400 nm emission filters
  • glial cell 535 nm excitation and 610 nm emission filters
  • the Neurite Outgrowth module in the MetaMorph Imaging software was used to automatically count total cell number, number of neuron cells, and the extent of neurite outgrowth.
  • Example 5 treatment with Example 5 resulted in significant attenuation of the A ⁇ i_ 42 -induced reduction of neurite outgrowth in primary postnatal (PO) cortical cells.
  • PO primary postnatal
  • Exposure to A ⁇ i_4 2 produced a decrease in neurite outgrowth.
  • Treatment of cells with compounds prior to and concomitantly with A ⁇ i_4 2 gave a neuroprotective effect with neurite outgrowth maintained or enhanced relative to untreated cells.
  • Table 1 shows the maximum response at the noted test compound concentration relative to 300 nM dimebolin.
  • test compound(s) on A ⁇ i_4 2 induced tau phosphorylation can be assessed in a cell line such as PC12 as previously described (Hu, M.; Waring, J. F.; et al. Role of GSK-3 ⁇ activation and ⁇ 7 nAChRs in A ⁇ i_42-induced tau phosphorylation in PC 12 cells. J. Neurochem. 2008, 106(3), 1371-1377.).
  • PC 12 cells are plated on poly-D-lysine coated 96-well plates, cultured in Ham's F12K medium supplemented with 15% horse serum, 2.5% FBS, 2 mM L-glutamine, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin at 37 0 C with 5% CO 2 and differentiated with 100 ng/mL NGF for approximately 6 days.
  • Cells are pretreated with test compounds for 30 minutes at about 37 0 C. The medium is then replaced with that containing freshly prepared A ⁇ i_4 2 or control peptide in the absence or presence of the test compounds and the cells are incubated at 37 0 C for 24 hours.
  • Cells are fixed with 3.7% formaldehyde in PBS (pH 7.4) for about 1 hour at room temperature followed by permeabilization by three washes with 0.1% Triton-X 100 in PBS.
  • the fixed cells are incubated with blocking buffer for about 2 hours at room temperature followed by overnight incubation with primary antibodies AT8 (for phosphorylated tau), anti-human tau (for total Tau), or anti-GSK-3B..
  • the method also involves a high-throughput assay using serum-deprivation conditions involving neuronal cells to screen for compounds that increase or preserve mitochondrial membrane potential.
  • Mitochondrial-mediated apoptosis occurs in response to a wide range of apoptotic stimuli including p53, c-myc, DNA damage, prooxidants, chemotherapeutic agents, serum starvation and death receptor activation (Lin C- H., Lu Y-Z., Cheng, F-C, Chu L-F. and Hsueh C-M. Bax-regulated mitochondrial-mediated apoptosis is responsible for the in vitro ischemia induced neuronal cell death of Sprague Dawley rat. Neuroscience Lett. 2005, 387, 22-27).
  • Serum deprivation for 16-18 hours initiates the early stages of apoptosis (Chavier D, Lecoeur H, Langonne A, Borgne-Sanchez A, Mariani J.,Martinou J-C, Rebouillat D and Jacotot E. Upstream control of apoptosis by caspase-2 in serum-deprived neurons. Apoptosis 10:1243-1259, 2005) and induces stress on a cell before full commitment to cell death.
  • Mitochondria play a critical role in the cell for survival or death due to their regulation of both energy metabolism as well as apoptosis (Sullivan PG, Rabchevsky AG, Waldmeirer PC and Springer JE. Mitochondrial Permeability Transition in CNS Trauma: Cause or Effect of Neuronal Cell Death. J. Neuroscience Res. 2005, 79, 231-239).
  • One of the first major events to occur in apoptosis is the breakdown of the membranes of the mitochondria to release cytochrome c, activate caspases, change electron transport and cause a decrease in mitochondrial membrane potential ( ⁇ m ).
  • a change in ⁇ m therefore serves as a measure of mitochondrial function and indicator of cell health.
  • this stress inducer, serum deprivation, combined with monitoring changes in the mitochondrial membrane potential in a 96-well format allows for the establishment of an efficient high-throughput screen (HTS) in order to evaluate the ability of compounds to increase mitochondrial membrane potential in the presence of stress and preserve health of the cell.
  • HTS high-throughput screen
  • SK-N-SH human neuroblastoma cells obtained from American Type Culture Collection (Rockville, MD) were maintained in the log phase of growth in Minimal Essential Media (MEM), 10% heat inactivated fetal calf serum and 100 units/mL antibiotic- antimycotic (AA). Cells were cultured and maintained in a humidified incubator at 37 0 C under 5% CO 2 and 95% air. Cells were trypsinized (0.25%) and subcultured every 3 days and used from 15-18 passages. All cell culture supplies were obtained from Invitrogen (Carlsbad, CA).
  • MEM Minimal Essential Media
  • AA antibiotic- antimycotic
  • SK-N-SH cells were plated 2-3 days in advance at a concentration of 50,000 cells/well onto collagen coated black-walled 96 well plates (Becton-Dickinson, Bedford, MA) in a total volume of 200 ⁇ L.
  • the media containing serum was aspirated from each well and rinsed once with MEM/1%AA without serum.
  • the cells then were incubated overnight in 100 ⁇ L of MEM/ 1% AA (no serum) with and without dimebolin or novel chemical entities overnight for ⁇ 18 hours.
  • JC-I dye (5,5',6,6'- tetrachloro-l,l ⁇ 3,3'-tetraethylbenzimidazolcarbocyanide) was diluted 1 :10 into MEM media according to the JC-I Mitochondrial Membrane Potential Assay Kit: (Cayman Chemical Company, Ann Arbor, MI) and then 10 ⁇ L of the JC-I dye solution was added to each well. The plates were centrifuged for 5 minutes at 400 ⁇ g at room temperature followed by 35 minute incubation at 37 0 C. The plates were washed twice with 200 ⁇ L of provided Assay Buffer followed an addition of 100 ⁇ L of Assay Buffer to each well.
  • the plates were read with an excitation and emission of 560 nM and 595 nM for red fluorescence and with an excitation and emission of 485 nM and 535 nM for green fluorescence to determine the final JC-I value taking the red to green fluorescence ratio.
  • This assay is based on change in mitochondrial membrane potential (MMP) using this lipophilic cationic dye, JC-I, by monitoring the changes in the ratio of red to green fluorescence as the MMP depolarizes.
  • MMP mitochondrial membrane potential
  • JC-I this lipophilic cationic dye
  • Example 5 As shown in Figure 3, treatment of SK-N-SH cells with Example 5 maintained mitochondrial function in a dose dependent manner.
  • a range of animal models capturing diverse cognitive domains may be utilized for assessing procognitive effects of compounds. Examples of these models are provided in Bitner et al., (Bitner, R. S.; Bunnelle, W. H.; et al. Broad-spectrum efficacy across cognitive domains by ⁇ 7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J. Neurosci. 2007, 27(39), 10578-10587.).
  • Various transgenic animal models that are relevant of neurodegenerative diseases of interest may also be utilized to assess effects of test compounds (Goetz, J.; Ittner, L. M. Animal models of Alzheimer's disease and frontotemporal dementia. Nat. Rev. Neurosci. 2008, 9(7), 532- 544.).
  • the inhibitory avoidance task involves the uses of a two-compartment step through apparatus (Ugo Basile, Collegeville, PA) that measures the animal's ability to remember a brief noxious stimulus (foot shock), and is considered a measure of trial learning, and memory consolidation. Briefly, mice were placed in a lighted compartment of the apparatus where the latency to enter into the preferred dark compartment is recorded. Entry into a dark compartment resulted in the immediate delivery of a mild foot shock (0.2 mA, 1 -second duration). Retention testing was conducted 24 hours later with the animal again placed in the lighted compartment where its latency to reenter the dark side of the apparatus was measured (no shock).
  • the social recognition test measures short-term memory on the basis of olfactory cues, and depends on the hippocampus.
  • Adult (350-450 g) rats were allowed to interact with a juvenile(60-80 g) rat for a 5 minute interaction trial (Tl) in which the adult exhibits behaviors that included close following, grooming and/or sniffing of the juvenile for as much as 40-50% of the trial duration.
  • the juvenile rat was then removed and the adult rat immediately administered various doses of test compound.
  • a second 5 minute recognition trial (T2) was conducted 120 minutes later where interactive behavior of the adult rat was again monitored.
  • DMTS Titration in Monkey Studies can be conducted in Rhesus monkeys that were initially trained in the DMTS procedure
  • trial initiation consists of presentation of one of three colored stimuli (red, blue, or yellow rectangles) that remain in view (sample stimuli) until touched by subject. Following a delay interval, two choice rectangles are presented, one being the previous sample stimulus, in which correct (matching) choice-touch to the sample stimuli is food reinforced.
  • the duration for each delay interval is adjusted for each subject until three levels of performance accuracy were approximated: zero delay (85-100% of trials answered correctly); short delay interval (75-84% correct); medium delay interval (65-74% correct); and long delay interval (55-64% correct).
  • the titration version of the DMTS task used in the present studies requires the animals to perform a 96 trial session that begins with a 0 sec delay interval. If the trial is answered correctly, a 1 second delay interval is presented during the next trial presented. The 1 second incremental progression is maintained until the subject made an incorrect match. The delay interval for the trial after an incorrect match is always decreased by 1 second. After an incorrect match, if the next trial is answered correctly, then the subsequent trial presented a delay interval 1 second longer in duration.
  • Dependent variables include the overall % of trials answered correctly, the number of trials to reach the maximal delay interval attained, and the maximum and average delay interval attained (in seconds). Compounds are administered prior to DMTS testing.
  • Animals were prepared for testing, by use of a surgical procedure that induces neuropathic pain in one paw.
  • Male Sprague Dawley rats were purchased from Charles River (Portage, MI). Prior to surgery, animals were housed in groups and maintained in a temperature -regulated environment. Following nerve ligation surgery, animals were housed in groups, and had access to food and water ad libitum.
  • the L5 and L6 spinal nerves of anesthetized rats were tightly ligated in a manner described previously (see Kim and Chung, Pain (1992) vol. 50 pp. 355-363). An incision was made on the dorsal portion of the hip and the muscle was blunt-dissected to reveal the spinal processes. The L6 transverse process was removed, and the left side L5 and L6 spinal nerves were tightly ligated with 5.0 braided silk suture. The wound was cleaned, the membrane sewn with 4.0 dissolvable Vicryl suture and the skin closed with wound clips.
  • the paw affected by the surgical procedure develops an allodynic response, a hypersensitivity to mechanical and other stimuli; neuropathic pain is assessed as an increased sensitivity in the surgically affected (left) allodynic paw compared to the control paw on the right side, and measured by comparing the response of the (left side) allodynic paw to the response of the unaffected right side control paw.
  • Representative compounds of the invention administered intraperitoneally 30 minutes before testing, were able to reduce the symptoms of neuropathic pain and induce a dose-dependent increase in the withdrawal threshold for allodynic (left side) limb, up to a maximum effect of 15 g.
  • the efficacy of the compound in reducing neuropathic pain at different doses was determined by comparing response in the surgery-affected paw versus the response in the control paw. This was expressed as the MPE (maximum potential effect).
  • Example 2 the compound of Example 2 (9-methyl-6-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6- tetrahydro-lH-2,5-ethanoazepino[4,3- ⁇ ]indole) was very effective, producing a 58% reduction (**p ⁇ 0.01, ***p ⁇ 0.001 vs. vehicle) in the withdrawal threshold at a dose of 10 mg/kg, administered by intraperitoneal injection as shown in Figure 6.
  • Example 2 was dosed i.p. (1, 3, and 10 mg/kg, 2 mL/kg) in vehicle (10% dimethyl sulfoxide/ ⁇ BC). Gabapentin (100 mg/kg, 2.0 mL/kg) was used as an internal control. Test animals were used 2.5 weeks post-surgery. No complicating adverse effects were observed.
  • test compounds were assessed in mouse, rat, dog and monkey to obtain various parameters including clearance (CIp), volume of distribution and bioavailability.
  • CIp clearance
  • na ⁇ ve rats or mice can be dosed with the compounds i.p. and sacrificed at various time points post-dosing.
  • plasma concentrations blood was collected into heparinized tubes and then centrifuged, and the separated plasma is frozen at -20 0 C until analysis.
  • compounds were extracted from the samples via liquid-liquid extraction and quantified by liquid chromatography/mass spectroscopy. d.
  • the present invention provides a method for preventing or treating a disease condition in a subject in need of treatment thereof.
  • the subject in need of treatment thereof can be a mammal, such as, but not limited to, a human.
  • the disease condition is a neurodegeneration disorder.
  • neurodegeneration disorder refers to a type of neurological disease marked by the loss of nerve cells in the brain or central nervous system.
  • Examples of neurodegeneration disorders include, but are not limited to, Alzheimer's disease (AD), mild cognitive impairment (MCI), age-associated memory impairment (AAMI), multiple sclerosis, Parkinson's disease, vascular dementia, senile dementia, AIDS dementia, Pick's disease, dementia caused by AD.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • Parkinson's disease vascular dementia
  • senile dementia AIDS dementia
  • Pick's disease dementia caused by
  • ALS amyotrophic lateral sclerosis
  • CNS function associated with traumatic brain injury or any combinations thereof.
  • the disease condition is a neuropsychiatric disorder.
  • neuropsychiatric disorder is a behavioral or psychological problem associated with a known neurological condition, and typically defined as a cluster of symptoms that co-exist.
  • neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar and manic disorders, depression or any combinations thereof.
  • the present invention relates to methods of preventing or treating a pain including neuropathic and nociceptive pain, chronic or acute, such as, without limitation, allodynia, inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post operative pain, post stroke pain, and menstrual pain.
  • a pain including neuropathic and nociceptive pain, chronic or acute, such as, without limitation, allodynia, inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury
  • Cognitive deficits are recognized in various forms of neurodegeneration and neuropsychiatric disorders (such as, but not limited to, dementia, including Alzheimer's disease, (AD) and neuropsychiatric diseases, particularly schizophrenia and bipolar disorders).
  • AD Alzheimer's disease
  • current therapies offer modest efficacy, and therefore, there is need for an agent that offers a superior clinical benefit.
  • dimebolin has been shown to inhibit neuronal death in models of neurodegenerative diseases suggestive of modification of disease processes (Lermontova, N. N.; Lukoyanov, N. V.; et al. Dimebon improves learning in animals with experimental Alzheimer's disease. Bull. Exp. Biol. Med. 2000, 129(6), 544-546. Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 2001,
  • dimebolin has been reported to improve neuronal function by enhancing neuronal outgrowth and affecting mitochondrial function.
  • Hung and coworkers Hung, D. Dimebon: A phase 3 investigational agent for Alzheimer's disease with a novel mitochondrial mechanism of action. Presented at the International Conference on Alzheimer's Disease, Chicago, IL, USA, July 2008; paper S4-04-05.
  • dimebolin can protect cells from excitotoxic damage and improve neurite outgrowth in in vitro model systems.
  • Other mechanisms of action may also contribute to its beneficial effects of compounds with a "dimebolin-like" profile.
  • multi-targeted mechanisms have been proposed as viable approaches for treatment of diverse neurodegenerative diseases (Zhang, H.
  • Dimebolin is also thought to exert its cognitive enhancing effects also through inhibition of butyryl-cholinesterase, acetyl cholinesterase, NMDA receptor or L-type calcium channels (Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 2001, 939 (Neuroprotective Agents), 425-435. Lermontova, N. N.; Redkozubov, A. E.; et al. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels. Bull. Exp. Biol. Med. 2001, 132(5), 1079-1083. Grigor'ev, V. V.; Dranyi, O. A.; et al.
  • the method comprises administering to the subject in need of treatment thereof (e.g., a mammal, such as a human) a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one cognitive enhancing drug.
  • a "cognitive enhancing drug” is a drug that improves impaired human cognitive abilities of the brain (namely, thinking, learning, and memory).
  • Cognitive enhancing drugs work by altering the availability of neurochemicals (e.g., neurotransmitters, enzymes, and hormones), by improving oxygen supply, by stimulating nerve growth, or by inhibiting nerve damage.
  • Examples of cognitive enhancing drugs include a compound that increases the activity of acetylcholine such as, but not limited to, an acetylcholine receptor agonist (e.g., a nicotinic ⁇ -7 receptor agonist or allosteric modulator, an ⁇ 4 ⁇ 2 nicotinic receptor agonist or allosteric modulators), an acetylcholinesterase inhibitor (e.g., donepezil, rivastigmine, and galantamine), a
  • an acetylcholine receptor agonist e.g., a nicotinic ⁇ -7 receptor agonist or allosteric modulator, an ⁇ 4 ⁇ 2 nicotinic receptor agonist or allosteric modulators
  • butyrylcholinesterase inhibitor an N-methyl-D-aspartate (NMDA) receptor antagonist (e.g., memantine), an activity-dependent neuroprotective protein (ADNP) agonist, a serotonin 5- HTlA receptor agonist (e.g., xaliproden), a 5-HT 4 receptor agonist, a 5-HT 6 receptor antagonist, a serotonin IA receptor antagonist, a histamine H 3 receptor antagonist, a calpain inhibitor, a vascular endothelial growth factor (VEGF) protein or agonist, a trophic growth factor, an anti-apoptotic compound, an AMPA-type glutamate receptor activator, a L-type or N-type calcium channel blocker or modulator, a potassium channel blocker, a hypoxia inducible factor (HIF) activator, a HIF prolyl 4-hydroxylase inhibitor, an anti-inflammatory agent, an inhibitor of amyloid A ⁇ peptide or amyloid plaque, an inhibitor of tau
  • NMDA
  • a phosphodiesterase 5 inhibitor e.g., tadalafil, sildenafil
  • a phosphodiesterase 4 inhibitor e.g., a monoamine oxidase inhibitor, or pharmaceutically acceptable salt thereof.
  • cognitive enhancing drugs include, but are not limited to, cholinesterase inhibitors such as donepezil (Aricept ® ), rivastigmine (Exelon ® ), galanthamine (Reminyl ® ), N-methyl-D-aspartate antagonists such as memantine
  • At least one cognitive enhancing drug can be administered simultaneously with the compounds of the present invention or sequentially with the compounds of the present invention (and in any order). Additionally, it is believed that the combinations described herein may have additive or synergistic effects when used in the above-described treatment.
  • the present invention relates to a method for preventing (the development of) a disease condition, such as a neurodegeneration disorder or a neuropsychiatric disorder.
  • a disease condition such as a neurodegeneration disorder or a neuropsychiatric disorder.
  • the term "prevent" a disease condition, such as a neurodegenerative disorder or a neuropsychiatric disorder by administration of any of the compounds described herein means that the detectable physical characteristics or symptoms of the disease or condition do not develop following the administration of the compound described herein.
  • the method of the present invention comprises administering to the subject in need of treatment thereof (e.g., a mammal, such as a human) a mammal, such as a human) a mammal, such as a human.
  • the method comprises administering to the subject a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one cognitive enhancing drug.
  • the present invention relates to a method for preventing the progression (e.g., worsening) of a disease condition, such as a
  • the method comprises administering to the subject in need of treatment thereof (e.g., a mammal, such as a human) a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one cognitive enhancing drug.
  • biomarkers, diagnostic tests or combination of biomarkers and diagnostic tests known to those skilled the art can be used to determine whether or not (1) a subject is at risk of developing one or more of neurodegeneration disorders or neuropsychiatric disorders; or (2) the neurodegeneration disorders or neuropsychiatric disorders in the subject previously diagnosed with one or more of the aforementioned disorders is progressing (e.g., worsening).
  • biomarkers, diagnostic tests or combinations of biomarkers and diagnostic tests known in the art can be used to identify subjects who are at risk of developing a neurodegeneration disorder or a neuropsychiatric disorder.
  • one or more biomarkers, diagnostic tests or combinations of biomarkers and diagnostic tests known in the art can be used to determine the progression of the disease or condition of subjects who have been identified as suffering from a neurodegeneration disorder or a neuropsychiatric disorder.
  • Bio markers that can be examined include, but are not limited to, beta-amyloidi_42, tau, phosphorylated tau (ptau), plasma AB antibodies, ⁇ - antichymotrypsin, amyloid precursor protein, APP isoform ratio in platelets, ⁇ -secretase (also known as BACE), CD59, 8-hydroxy-deoxyguanine, glutamine synthetase, glial fibrillary acidic protein (GFAP), antibodies to GFAP, interleukin-6-receptor complex, kallikrein, melanotransferrin, neurofilament proteins, nitrotyrosine, oxysterols, sulphatides, synaptic markers, SlOOB, NPS, plasma signaling proteins, etc., or any combinations thereof (See, Shaw, L., e
  • compositions of the present invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular subject (e.g., a mammal, preferably, a human (patient)), compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • Compounds of the present invention can also be administered to a subject as a pharmaceutical composition comprising the compounds of interest in combination with at least one pharmaceutically acceptable carriers.
  • the phrase "therapeutically effective amount" of the compound of the present invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • compositions namely, a mammal, such as a human ranges from about 0.01 mg/kg body weight to about 100 mg/kg body weight. More preferable doses can be in the range of from about 0.01 mg/kg body weight to about 30 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. e. Pharmaceutical Compositions
  • the present invention provides pharmaceutical compositions.
  • the pharmaceutical compositions of the present invention comprise the compounds of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical compositions of the present invention comprise compounds of the present invention that can be formulated together with at least one non-toxic
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising compounds of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, alone or in combination with one or more compounds that are not the compounds of the present invention.
  • one or more compounds that can be combined with the compounds of the present invention in pharmaceutical compositions include, but are not limited to, one or more cognitive enhancing drugs.
  • compositions of this present invention can be administered to a subject (e.g., a mammal, such as a human) orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • a subject e.g., a mammal, such as a human
  • parenterally intracisternally
  • intravaginally intraperitoneally
  • topically as by powders, ointments or drops
  • bucally as an oral or nasal spray.
  • administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and
  • compositions of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • Dosage forms for topical administration of a compound of the present invention include powders, sprays, ointments and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
  • Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecan
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • suitable bases such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium,
  • esters can be prepared from substrates of formula (I), (II), (III), (IV), (V) or (VI) containing either a hydroxyl group or a carboxy group by general methods known to persons skilled in the art. The typical reactions of these compounds are substitutions replacing one of the heteroatoms by another atom, for example:
  • Amides can be prepared from substrates of formula (I), (II), (III), (IV), (V) or (VI) containing either an amino group or a carboxy group in similar fashion. Esters can also react with amines or ammonia to form amides. n t-9c-o-nr— ** n- tc-o-
  • Another way to make amides from compounds of formula (I) is to heat carboxylic acids and amines together.
  • the present invention also contemplates compounds of the present invention formed by synthetic means or formed by in vivo biotransformation of a prodrug.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates.
  • solvated forms including hydrated forms, such as hemi-hydrates.
  • pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
  • the present invention relates to methods for identifying one or more target compounds that can be used to prevent or treat a neurodegenerative disorder or a neuropsychiatry disorder in a subject in need of treatment thereof.
  • the methods of the present invention allow for the identification of one or more target compounds in a high throughput manner.
  • the method of the present invention involves providing a population of neuronal or neuroblastoma cells or neuronal or neuroblastoma cell lines.
  • Examples of neuronal or neuroblastoma cells or cell lines that can be used in this method include, but are not limited to, PC 12, SH-SY5Y, SK-N-SH, IMR-32, or dissociated cells from tissues such as neonatal rat cortex or hippocampus cells.
  • One or more target compounds are added to the population of neuronal or neuroblastoma cells or cell lines. If more then one target compound is being added, the target compounds can all be the same compounds but added in varying
  • the target compounds can all be different compounds.
  • the cells or cell lines are allowed to incubate for a period from at least one 1 hour to about 72 hours, preferably about 24 hours.
  • the neuronal number and neurite outgrowth can then be determined using routine techniques known in the art.
  • the cells or cell lines can be fixed and then stained using any stain known in the art, such as, for example, ⁇ -tubulin (green).
  • the total cell number and the extent of neurite outgrowth can be determined using the Neurite Outgrowth module in the MetaMorph Imaging software (Commercially available from Molecular Devices, Sunnyvale, CA).
  • Target compounds that cause an increase in neuronal number and/or neuronal outgrowth are selected for further testing for use in preventing or treating a
  • JC-I measures the change in mitochondria membrane potential by measuring red
  • the compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this class.
  • the compounds of the present invention wherein the groups a, R 1 , R 2 , R 3 , R 4 , R 5 , U, V, W, X, Y, and Z, have the meanings as set forth in the Summary of the Invention section unless otherwise noted, can be synthesized as shown in Schemes 1-18.
  • aryl hydrazines of formula (1-4) can be reacted with benzophenone in the presence of a catalyst such as ammonium chloride or sulfuric acid in a heated solvent such as water, methanol or ethanol to give compounds of formula (1-3).
  • Compounds of formula (2-2) can be treated with a base such as sodium hydride, sodium amide, lithium diisopropylamide or cesium carbonate and a compound of formula (2-3), wherein LG 1 is a suitable leaving group such as chlorine, bromine, iodine, /?-toluenesulfonate, or trifluoromethanesulfonate, in solvents such as N 1 N- dimethylformamide, tetrahydrofuran, toluene, or ether to furnish compounds of formula (2-5) which are representative of compounds of formula (I).
  • a base such as sodium hydride, sodium amide, lithium diisopropylamide or cesium carbonate
  • LG 1 is a suitable leaving group such as chlorine, bromine, iodine, /?-toluenesulfonate, or trifluoromethanesulfonate
  • solvents such as N 1 N- dimethylformamide, tetrahydrofuran, tol
  • compounds of formula (2-2) can be treated with a compound of formula (2-4) in the presence of sodium and hydroquinone in a heated (80-140 0 C) solvent such as dimethyl sulfoxide for 24-96 hours to give compounds of formula (2-5) which are representative of compounds of formula (I).
  • Compounds of formula (2-4) can be obtained commercially or synthesized by coupling potassium vinyltrifluoroborate with an aryl or heteroaryl halide in the presence of a catalyst such as palladium(II) chloride, a ligand such as triphenylphosphine, and a base such as cesium carbonate in a solvent such as a mixture of tetrahydrofuran and H 2 O heated at 70-90 0 C.
  • Anilines of formula (3-2) can be transformed to hydrazines of formula (3-3) as described in U.S. Patent No. 3409628. Specifically, anilines of formula (3-2) can be reacted with a vinylheteroaryl or vinylaryl compound in the presence of sodium. Treatment with sodium nitrite and reduction with zinc in acetic acid produces the disubstituted hydrazine (3-3). Subsequently, compounds of formula (3-3) can be transformed to compounds of formula (3-1) using the conditions in Scheme 1 for the conversion of compounds of formula (1-4) to compounds of formula (1-3).
  • Compounds of formula (3-3) can also be directly converted to compounds of formula (2-5) using the conditions previously described for the conversion of compounds of formula (3-1) to compounds of formula (2-5).
  • Compounds of formula (4-1), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , U, V, W, Y, and Z are as defined in formula (I), can be prepared as described in Scheme 4.
  • Compounds of formula (2- 5) can be treated with a solution of sodium in liquid ammonia/tetrahydrofuran to supply compounds of formula (4-1).
  • Compounds of formula (2-5) can also be transformed to compounds of formula (4-1) by treatment with borane-tetrahydrofuran complex in a trifluoroacetic acid solution (Berger, J.; Tahbaz, P.; McPhail, A. T.; Onan, K. D.
  • compounds of formula (2-5) can be converted to compounds of formula (4-1) by treatment with sodium cyanoborohydride in a mixture of trifluoroacetic acid and methanol.
  • Compounds of formula (4-1) are representative of compounds of formula (I).
  • Compounds of formula (7-2) can be converted to compounds of formula (2-2) by treatment with compounds of formula (2-1) in the presence of palladium(II) acetate and diazabicyclo[2.2.2]octane (DABCO) in solvent such as methanol (Chen, C; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676-2677). Compounds of formula (2-2) can then be employed as described in Scheme 2.
  • DABCO diazabicyclo[2.2.2]octane
  • compounds of formula (10-2) can be reacted with vinylaryl or vinylheteroaryl groups of formula (2-4) in the presence of sodium optionally in the presence of hydroquinone in solvents such as N,N- dimethylformamide or dimethyl sulfoxide to give compounds of formula (10-6).
  • Compounds of formula (10-2) can also be reacted with compounds of formula (10-3), wherein LG 1 is a suitable leaving group such as chlorine, bromine, iodine, /?-toluenesulfonate, or
  • Compounds of formula (11-2) can be arylated with compounds of formula (1-2) wherein Hal is a halogen limited to iodine or bromine, in the presence of palladium(II) acetate, tri-t-butyl phosphine in the presence of cesium carbonate in heated toluene (Kang, H. -M.; Shin, L-J.; Kim, H.-Y.; Cho, C-G. Org. Lett. 2006, 8, 2047-2050).
  • Hal is a halogen limited to iodine or bromine
  • compounds of formula (11-2) can be transformed to compounds of formula (10-6) by treatment with compounds of formula (1-2), wherein Hal is limited to iodine, in the presence of copper(II) acetate, cesium carbonate, and 1,10-phenanthroline.
  • Another alternative involves the reaction of compounds of formula (11-2) with compounds of formula (11-3) in the presence of a base such as triethylamine and a catalyst such as copper(II) acetate in optionally heated dichloromethane (Nara, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Synth. Commun. 2003, 33, 87098).
  • a base such as triethylamine
  • a catalyst such as copper(II) acetate in optionally heated dichloromethane
  • esters of formula (12-1) can be converted to compounds of formula (2-4) in a three step process.
  • esters of formula (12-1) can be first reduced with a reducing agent such as lithium aluminum hydride and then subsequently oxidized with a reagent such as manganese(II) oxide to supply the corresponding aldehyde.
  • aldehyde can then be reacted with methylene(triphenyl)phosphorane to furnish compounds of formula (2-4), wherein R 5a is hydrogen.
  • compounds of formula (2-4), wherein R 5a is hydrogen can be prepared from aryl bromides or heteroaryl bromides of formula (12-2). Accordingly compounds of formula (12-2) are reacted with either potassium
  • esters of formula (12-1) can also be converted to compounds of formula (10-4).
  • esters of formula (12-1) can be first reduced with a reducing agent such as lithium aluminum hydride and then oxidized with a reagent such as manganese(II) oxide to supply the corresponding aldehyde.
  • a reducing agent such as lithium aluminum hydride
  • a reagent such as manganese(II) oxide
  • Compounds of formula (10-3) can be prepared from either compounds of formula (2- 4) or compounds of formula (10-4).
  • Aldehydes of formula (10-4) can be reacted with a reducing agent such as sodium borohydride to supply the corresponding alcohol.
  • the alcohol can be converted to a leaving group by reaction with a sulfonyl chloride such as p- toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base such as triethylamine or diisopropylethylamine to furnish compounds of formula (10-3) wherein the leaving group, LG 1 , is a sulfonate.
  • Compounds of formula (2-4) can also be converted to compounds of formula (10-3).
  • compounds of formula (2-4) can be reacted with a dialkylborane such as disiamylborane or 9-borabicyclo[3.3.1]nonane (9-BBN) in the presence of iodine to give compounds of formula (10-3), wherein LG 1 is iodine.
  • a dialkylborane such as disiamylborane or 9-borabicyclo[3.3.1]nonane (9-BBN) in the presence of iodine to give compounds of formula (10-3), wherein LG 1 is iodine.
  • compounds of formula (2-4) can first be converted to the corresponding primary alcohols by hydroboration with a dialkylborane followed by treatment with sodium hydroperoxide.
  • the intermediate alcohols can then be converted to sulfonates of formula (10-3) as previously described giving compounds of formula (10-3), wherein LG 1 is/?- toluenesulfonate or methanesulfonate.
  • Compounds of formula (10-5) also can be prepared in more than one way.
  • One option is to convert compounds of formula (12-3) to compounds of formula (10-5) by treatment with trimethylsulfonium iodide in the presence of a base such as te/t-butoxide in a solvent such as te/t-butanol (Boa, A. N.; Canavan, S. P.; et al. Bioorg. Med. Chem. 2005, 13, 1945-1967).
  • compounds of formula (2-4) can be converted to the epoxides of formula (10-5) by treatment with m-chloroperoxybenzoic acid in the presence of a base such as sodium bicarbonate in a mixture of water and dichloromethane (Kamabe, M.; Miyazaki, T.; Hashimoto, K.; Shirahama, H. Heterocycles 2002, 56(1-2), 105-111).
  • a base such as sodium bicarbonate
  • Compounds of formula (13-1) can be treated with compounds of formula (13-2), wherein G 2 is pyridazinyl, pyrimidinyl or triazinyl and Hal is chlorine, bromine or iodine, in the presence of a base such as potassium tert-butoxide or sodium hydride in a heated solvent such as ⁇ /, ⁇ /-dimethylformamide to provide compounds of formula (13-3).
  • a base such as potassium tert-butoxide or sodium hydride
  • a heated solvent such as ⁇ /, ⁇ /-dimethylformamide
  • compounds of formula (13-1) can be reacted with compounds of formula (13-2) in a palladium-mediated cross- coupling reaction.
  • compounds of formulas (13-1) and (13-2) can be combined in the presence of a catalyst such as bis(tri-t-butylphosphine and a base such as sodium t- butoxide in a heated solvent such as dioxane. The heating may be either conventional or achieved with microwave irradiation.
  • Compounds of formula (13-4), wherein a, R 1 , R 2 , R 3 and R 4 are as defined in formulas (I), (II), (III), (IV), (V), and (VI), and b represents the optionally protected bicyclic, tricyclic, or spirocyclic ring systems of compounds of formulas (I), (II), (III), (IV), (V), and (VI), can be prepared as described in Scheme 13.
  • Compounds of formula (13-1) can be coupled with compounds of formula G A -Hal, wherein G A is aryl or heteroaryl and Hal is bromine or iodine, to provide compounds of formula (13-4). The coupling can be
  • a nucleophilic aromatic substitution reaction may be carried out on compounds of formula (13-1) when G A is aryl substituted with one or more electron withdrawing groups such as nitro or cyano and Hal is limited to fluorine. Accordingly, compounds of formula (13-1) an be combined with the arylfluoride in the presence of a base such as sodium hydride in an optionally heated solvent such as N,N-dimethylformamide to give compounds of formula (13-4).
  • Compounds of formula (13-1) can be sulfonylated with compounds of formula G A S ⁇ 2 Cl, wherein G A is aryl or heteroaryl, in the presence of a base such as potassium tert-butoxide in a solvent such as tetrahydrofuran to provide compounds of formula (13-5).
  • reaction conditions include n-butyllithium, a catalyst such as
  • compounds of formula (13-1) can be reacted with ethyl bromoacetate in the presence of a base such as potassium tert-butoxide in a solvent such as tetrahydrofuran at or near ambient temperature over 8 to 24 hours to supply compounds of formula (13-8).
  • a base such as potassium tert-butoxide
  • a solvent such as tetrahydrofuran
  • Compounds of formula (13-8) can be hydrolyzed to compounds of formula (13-9) in the presence of aqueous sodium hydroxide heated in a solvent such as ethanol.
  • Compounds of formula (13-9) can be coupled with an amine of formula G A NH 2 using amide bond forming conditions well known to one skilled in the art to provide compounds of formula (13-10).
  • One set of amide bond forming conditions include l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, hydroxybenzotriazole, 4-(dimethylamino)pyridine stirred in dichloromethane for 2 to 24 hours.
  • R 1 , R 2 , R 3 , R 4 , R 6 , a, U, V, W, Y, an Z are as defined in formulas (I) can be prepared from compounds of formula (14-1).
  • Compounds of formula (14-1) can be reacted with aldehydes of formula R A CHO under reductive amination conditions to provide compounds of formula (14-2).
  • R A can be alkyl, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, or heterocycle.
  • compounds of formula (14-1) can be treated with aldehydes of formula R A CHO in the presence of sodium cyanoborohydride in the presence of an acid such as acetic acid in methanol to provide compounds of formula (14-2).
  • Compounds of formula (14-1) can be reacted with sulfonates OfR 6 OSO 2 R 0 , wherein R B is alkyl or haloalkyl and R c is
  • Compounds of formula (14-1) can also be reacted with acid chlorides of formula C1C(O)R A or sulfonyl chlorides of formula C1SO2R A in the presence of a base such as triethylamine or diisopropylamine in a solvent such as dichloromethane at or near ambient temperature to provide compounds of formulas (14-5) and (14-6), respectively.
  • a base such as triethylamine or diisopropylamine
  • a solvent such as dichloromethane
  • R 2 or R 3 is R D
  • compounds of formula G B -B(OR E ) 2 wherein G B is aryl, heteroaryl or cyclopropyl and R E is hydrogen, alkyl or joined together with the atoms to which they are attached form a dioxoborolane.
  • bases include but are not limited to potassium carbonate, potassium tert-butoxidc, sodium carbonate, potassium phosphate, cesium carbonate, and cesium fluoride.
  • catalysts include but are not limited to tetrakis(triphenylphosphine)palladium(0), dichloro[l,l'-ferrocenylbis(diphenyl- phosphine)]palladium(II) dichloromethane, bis(dibenzylidene-acetone)palladium, palladium(II) acetate in the presence of a ligand such as tricyclohexylphosphine, and trans- dichlorobis(triphenylphosphine)palladium(II).
  • the reaction may be conducted in a solvent such as but not limited to water, dioxane, 1,2-dimethoxyethane, ⁇ /, ⁇ /-dimethylformamide, toluene, ethanol, 2-propanol, tetrahydrofuran and the like or mixtures thereof.
  • a solvent such as but not limited to water, dioxane, 1,2-dimethoxyethane, ⁇ /, ⁇ /-dimethylformamide, toluene, ethanol, 2-propanol, tetrahydrofuran and the like or mixtures thereof.
  • the reaction may be conducted at ambient or elevated temperatures.
  • R 1 , R 2 , R 3 and R 4 are as defined in formulas (I), (II), (III), (IV), (V), and (VI), and R F is aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • R F is aryl, heteroaryl, arylalkyl, or heteroarylalkyl
  • Carboxylic acids of formula R F CO 2 H can be coupled with anilines of formula (3-2) using standard amide bond forming reaction conditions well known to one skilled in the art to give compounds of formula (17-1).
  • An alternative for the production of compounds of (17-4) involves the alkylation of compounds of formula (1-4) with compounds of formula R 1 ⁇ CH 2 -LG 1 , wherein LG 1 is a suitable leaving group such as chlorine, bromine, iodine, /?-toluenesulfonate, or trifluoromethanesulfonate.
  • LG 1 is a suitable leaving group such as chlorine, bromine, iodine, /?-toluenesulfonate, or trifluoromethanesulfonate.
  • Compounds of formula (1-4) can be reacted with compounds of formula R 1 ⁇ CH 2 -LG 1 in the presence of a base such as triethylamine or diisopropylethylamine in a heated solution of ethanol to give compounds of formula (17-4).
  • compounds of formula (1-4) can be reacted with compounds of formula R 1 ⁇ CH 2 -LG 1 in the presence of a base such as sodium amide in a cooled solution of tetrahydrofuran to give compounds of formula (17-4).
  • a base such as sodium amide
  • Compounds of formula (17-4) can be substituted for compounds of formula (3-3) in Scheme 3.
  • reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions may be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • an optically active form of a compound of the invention when required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • an optically active starting material prepared, for example, by asymmetric induction of a suitable reaction step
  • resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • Example IB The individual enantiomers of the mixture of Example IB were separated by preparative chiral supercritical fluid chromatography (ChiralPak ® OD-H 5 ⁇ m 21x250 mm column; flow rate 40 niL/minute; gradient of 10-50% CH 3 OH/CO 2 containing 0.1% diethylamine, 20 minutes) to afford the free base of the title compound as the first-eluting enantiomer (0.104 g, 0.301 mmol). This material was dissolved in warm ethanol (2 mL) and treated with a solution of D-tartaric acid (0.045 g, 0.301 mmol) in warm ethanol (2 mL).
  • Example IB The individual enantiomers of the mixture of Example IB were separated by preparative chiral supercritical fluid chromatography (ChiralPak ® OD-H 5 ⁇ m 21x250 mm column; flow rate 40 niL/minute; gradient of 10-50% CH3OH/CO2 containing 0.1% diethylamine, 20 minute) to afford the free base of the title compound as the second-eluting enantiomer (0.104 g, 0.301 mmol). This material was dissolved in warm ethyl acetate (2 mL) and ethanol (0.5 mL) and treated with hydrogen chloride/dioxane (4 M; 0.158 ml, 0.632 mmol), added dropwise.
  • reaction mixture was reduced to dryness and the residue was purified by preparative HPLC [Waters XBridgeTM RP 18 column, 5 ⁇ m, 30x100 mm, flow rate 40 niL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium
  • Example IA The individual enantiomers of the mixture of Example IA were separated by preparative chiral HPLC (Chiralpak ® AD 50x400 mm column; flow rate 100 niL/minute; 60:20:20:0.2 hexane-ethanol-methanol-diethylamine, 25 0 C) to afford the title compound as the second-eluting peak.
  • a reaction tube with a septum cap was charged with 30% sodium metal dispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of 2,1 l-dimethyl-5,6,7,8,9,10- hexahydro-7,10-epiminocyclohepta[ ⁇ ]indole (0.112 g, 0.495 mmol; Example IA) in dimethyl sulfoxide (2 mL). The vessel was sealed, flushed with nitrogen, and stirred for 10 minutes.
  • Example IA The individual enantiomers of the mixture of Example IA were separated by preparative chiral HPLC (Chiralpak ® AD 50x400 mm column; flow rate 100 niL/minute; 60:20:20:0.2 hexane-ethanol-methanol-diethylamine, 25 0 C) to afford the title compound as the f ⁇ rst-eluting peak.

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Abstract

Cette invention concerne des dérivés indole et indoline de formule (I), (II), (III), (IV), (V) ou (VI), a, R1, R2, R3, R4, R5, U, V, W, X, Y et Z étant tels que définis dans la description. Cette invention concerne également des compositions comprenant ces composés, et des procédés de traitement de pathologies en utilisant ces composés et ces compositions, et des procédés d’identification de ces composés.
PCT/US2010/027931 2009-07-14 2010-03-19 Dérivés indole et indoline et leurs procédés d’utilisation WO2011008312A2 (fr)

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