WO2004052348A2 - Treatment of diseases with combinations of alpha 7 nicotinic acetylcholine receptor agonists and other compounds - Google Patents

Treatment of diseases with combinations of alpha 7 nicotinic acetylcholine receptor agonists and other compounds Download PDF

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Publication number
WO2004052348A2
WO2004052348A2 PCT/IB2003/005525 IB0305525W WO2004052348A2 WO 2004052348 A2 WO2004052348 A2 WO 2004052348A2 IB 0305525 W IB0305525 W IB 0305525W WO 2004052348 A2 WO2004052348 A2 WO 2004052348A2
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substituted
azabicyclo
carboxamide
alkyl
oct
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PCT/IB2003/005525
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French (fr)
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WO2004052348A3 (en
Inventor
Jeffrey Wayne Corbett
Vincent Edward Groppi, Jr.
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Pharmacia & Upjohn Company Llc
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Priority to JP2004558917A priority Critical patent/JP2006510662A/en
Priority to CA002508004A priority patent/CA2508004A1/en
Priority to BR0317110-8A priority patent/BR0317110A/en
Priority to MXPA05005666A priority patent/MXPA05005666A/en
Priority to AU2003279492A priority patent/AU2003279492A1/en
Priority to EP03772599A priority patent/EP1572205A2/en
Publication of WO2004052348A2 publication Critical patent/WO2004052348A2/en
Publication of WO2004052348A3 publication Critical patent/WO2004052348A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compositions and methods to treat diseases or condition with a Nicotinic acetylcholine receptors (liAChRs) full agonist relative to nicotine plus either an inhibitor of cholinesterase, and/or a beta secretase inhibitor, and/or a gamma secretase inhibitor collectively referred to as "inhibitors.”
  • a Nicotinic acetylcholine receptors liAChRs
  • the al nAChR is one receptor system that has proved to be a difficult target for testing. Native al nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68(5):2140-51). Another feature that makes functional assays of ⁇ 7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
  • Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the al nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT 3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity.
  • Eisele et al. used the N-terminus of the avian (chick) form of the ⁇ 7 nAChR receptor and the C-terminus of the mouse form of the 5-HT 3 gene.
  • the al nAChR is a calcium channel while the 5-HT 3 R is a sodium and potassium chamiel.
  • Eisele et al. teaches that the chicken al nAChR/ mouse 5-HT 3 R behaves quite differently than the native al nAChR with the pore element not conducting calcium but actually being blocked by calcium ions.
  • WO 00/73431 A2 reports on assay conditions under which the 5-HT R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
  • AD Alzheimer's disease
  • a beta amyloid
  • Beta-amyloid is a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Deposition of A beta in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A beta, also sometimes designated betaA4). A beta peptide is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-42 amino acids. Several proteases called secretases are involved in the processing of APP.
  • APP amyloid precursor protein
  • Cleavage of APP at the N-terminus of the A beta peptide by beta-secretase and at the C-terminus by one or more gamma-secretases constitutes the beta- amyloidogenic pathway, i.e. the pathway by which A beta is formed.
  • Cleavage of APP by alpha-secretase produces alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation. This alternate pathway precludes the formation of A beta peptide.
  • a description of the proteolytic processing fragments of APP is found, for example, in U.S. Patent Nos. 5,441,870; 5,721,130; and 5,942,400.
  • beta-secretase An aspartyl protease has been identified as the enzyme responsible for processing of APP at the beta-secretase cleavage site.
  • the beta-secretase enzyme has been disclosed using varied nomenclature, including BACE, Asp, and Memapsin. See, for example, Sinha etal., 1999, Nature 402:537-554 (p501) and published PCT application WO00/17369.
  • Several lines of evidence indicate that progressive cerebral deposition of beta- amyloid peptide (A beta) plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991, Neuron 6:487.
  • a beta peptide accumulates as a result of APP processing by beta secretase and or gamma secretase thus inhibition of either enzymes' activity maybe desirable for the treatment of AD.
  • In vivo processing of APP at the beta-secretase cleavage site is thought to be a rate-limiting step in A beta production, and it, thus, may be a good therapeutic target for the treatment of AD. See for example, Sabbagh, M., et al., 1997, Ah. Dis. Rev. 3, 1-19.
  • Cognitive disorders including Alzheimer's disease, are generally accompanied by symptoms of forgetfulness, confusion, memory loss and other symptoms resulting from aging, brain injury, or disease.
  • the concomitant decrease in cognitive function during the aging process has been documented in various mammals, including humans.
  • presenile and senile primary degenerative dementia appear to be common causes of mental deterioration among the elderly.
  • the symptoms of cognitive disorder appear to be associated with decreased acetylcholine synthesis as well as impairment of the ACh receptive neurons.
  • choline acetyltransferase which catalyzes the synthesis of acetylcholine from choline and acetyl coenzyme A
  • Cholinergic acetylcholme releasing nerve endings in the hippocampus.
  • alpha 7 nAChRs are generally intact. The cholinergic neurotransmission are thus recognized as critically important to memory function.
  • the first approach is to enhance cholinergic neurons by excessive exposure to a form of choline. Such attempts have been mildly successful, but only in the early stages of Alzheimer's disease.
  • the second approach involves postsynaptic direct stimulation of alpha 7 nAChRs.
  • the third approach involves the inhibition of acetylcholinesterase, the enzyme that metabolizes acetylcholine. Accordingly, new compositions and methods for treating diseases resulting from cholinergic hypofunction are desired.
  • the present invention is useful for the treatment of, or preparation of a medicament for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR receptor is implicated, including any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
  • diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's
  • Alzheimer's disease diseases to be treated within the scope of the present invention, including Alzheimer's disease, are chronic neurodegenerative disorders. Acetylcholine- synthesizing neurons in the basal forebrain region and their cortical synaptic connections exliibit a well-characterized degeneration in Alzheimer's disease. The symptoms of this degeneration and can be treated with the drug combinations described herein.
  • Embodiments of the invention may include one or more or combination of the following.
  • the present invention claims the method of treating the diseases discussed herein or preparing a medicament to so treat, using any compound that is a full agonist to an al Nicotinic Acetylcholme Receptor (nAChR) or al nAChR full agonists, described either herein or elsewhere to be administered with either: I) a cholinesterase inhibitor, II) a beta secretase inhibitor, III) a gamma secretase inhibitor or any combination of one, two, or three of the different inhibitors in combination with a al nAChR full agonists.
  • nAChR al Nicotinic Acetylcholme Receptor
  • al nAChR full agonist is used interchangeably with ⁇ 7 nAChR agonists when discussing the compounds of the present invention.
  • Another aspect of the present invention includes al nAChR full agonists as described for example, but not by way of limitation, in any one or more of the following patents and published applications: WO 01/60821 Al, WO 01/36417A1, WO 02/100857A1, WO 03/042210A1, and WO 03/029252A1, all of which are incorporated herein by reference.
  • some al nAChR full agonist are the compounds of Formula I as described herein.
  • the present invention also includes pharmaceutical compositions containing the active compounds, and methods to treat the identified diseases.
  • the present invention is useful for the treatment of, or preparation of a medicament for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR is implicated, including any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
  • diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease
  • Another aspect of the present invention includes the method or use of a compound of Formula I, where Azabicyclo is any one or more of I, II, III, IN, N, NI, or NIL
  • Another aspect of the present invention includes the method or use of a compound of Formula I, where W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H).
  • W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H).
  • W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H)
  • W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H), wherein the variables within each has any definition allowed.
  • W includes any one or more of the following: 4-chlorobenz-l- yl; dibenzo[b,d]thiophene-2-yl; isoquinoline-3-yl; furo[2,3-c]pyridine-5-yl; 1,3- benzodioxole-5-yl; 2,3-dihydro-l ,4-benzodioxine-6-yl; 1 ,3-benzoxazole-5-yl; thieno[2,3-c]pyridine-5-yl; thieno[3,2-c]pyridine-6-yl; [l]benzothieno[3,2-c]pyridine-
  • 6-yl pyrrolo[l,2-a]pyrazine-3-yl; lH-indole-6-yl; pyrazino[l,2-a]indole-3-yl; 1,3- benzothiazole-6-yl; [l]benzofuiO[2,3-c]pyridine-3-yl; [l]benzofuro[2,3-c]pyridine-3- yl; 2H-chromene-6-yl; indolizine-6-yl; and [l,3]dioxolo[4,5-c]pyridine-6-yl; any of which is optionally substituted as allowed in formula I.
  • the compounds of Formula I (Azabicyclo is I) have asymmetric centers on the quinuclidine ring.
  • the compounds of the present invention include quinuclidines having 3R configuration, 2S, 3R configuration, or 3S configuration and also include racemic mixtures and compositions of varying degrees of streochemical purities.
  • embodiments of the present invention include compounds of Formula I having the following stereospecificity and substitution:
  • Azabicyclo (i) is a racemic mixture
  • the compounds of Formula I (Azabicyclo is III) have asymmetric centers on the 7-azabicyclo[2.2.1]heptane ring which can exhibit a number of stereochemical configurations.
  • exo and endo are stereochemical prefixes that describe the relative configuration of a substituent on a bridge (not a bridgehead) of a bicyclic system. If a substituent is oriented toward the larger of the other bridges, it is endo. If a substituent is oriented toward the smaller bridge it is exo. Depending on the substitution on the carbon atoms, the endo and exo orientations can give rise to different stereoisomers.
  • the endo orientation gives rise to the possibility of a pair of enantiomers: either the IS, 2S, 4R isomer or its enantiomer, the IR, 2R, 4S isomer.
  • the exo orientation gives rise to the possibility of another pair of stereoisomers which are diastereomeric and C-2 epimeric with respect to the endo isomers: either the IR, 2S, 4S isomer or its enantiomer, the IS, 2R, 4R isomer.
  • the compounds of this invention exist in the exo orientation.
  • the absolute stereochemistry is exo-(lS, 2R, 4R).
  • the compounds of the present invention have the exo orientation at the C-2 carbon and S configuration at the C-l carbon and the R configuration at the C-2 and the C-4 carbons of the 7-azabicyclo[2.2.1]heptane ring.
  • the inventive compounds exhibit much higher activity relative to compounds lacking the exo 2R, stereochemistry.
  • the ratio of activities for compounds having the exo 2R configuration to other stereochemical configurations may be greater than about 100: 1. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required.
  • compositions can include one or more compounds, each having an exo 2R configuration, or mixtures of compounds having exo 2R and other configurations, hi mixtxires of compounds, those species possessing stereochemical configurations other than exo 2R act as diluents and tend to lower the activity of the pharmaceutical composition.
  • pharmaceutical compositions including mixtures of compounds possess a larger percentage of species having the exo 2R configuration relative to other configurations.
  • the compounds of Formula I (Azabicyclo is II) have asymmetric center(s) on the [2.2.1] azabicyclic ring at C3 and C4.
  • the scope of this invention includes the separate stereoisomers of Formula I being endo-AS, endo-AR, exo-4S, exo-AR:
  • the endo isomer is the isomer where the non-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges.
  • the exo isomer is the isomer where the non-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges.
  • Some embodiments of compounds of Formula I for when Azabicyclo is II include racemic mixtures where R is absent (k 2 is 0) or is at C2 or C6; or Azabicyclo II has the exo-A(S) stereochemistry and R has any definition discussed herein and is bonded at any carbon discussed herein.
  • the compounds of Formula I (Azabicyclo III) have asymmetric center(s) on the [2.2.1] azabicyclic ring at CI, C4 and C5.
  • the scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being (1R,AR,5S), (1R,AR,5R), (1S,AS,5R), (1S,AS,5S)
  • the endo isomer is the isomer where the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges.
  • the exo isomer is the isomer where the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges.
  • Another group of compounds of Formula I includes R 2 - 3 is absent, or is present and either at C3 or bonds to any carbon with sufficient valancy.
  • the compounds of Formula I (Azabicyclo IN) have asymmetric center(s) on the [2.2.1] azabicyclic ring at CI, C4 and C6.
  • the scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being exo-(lS,AR,6S), exo-(lR,AS,6R), endo-(lS,AR,6R), and e7--fo-(lR,4S,6S):
  • the endo isomer is the isomer where the non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges.
  • the exo isomer is the isomer where the non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges.
  • Another group of compounds of Formula I (Azabicyclco IN) includes R 2 - 3 is H, or is other than H and bonded at C3 or is bonded to any carbon with sufficient valancy.
  • the compounds of Formula I have asymmetric center(s) on the [3.2.1] azabicyclic ring at C3 and C5.
  • the scope of this invention includes the separate stereoisomers of Formula I being endo-3S, 5R, endo-3R, 5S, e o-3R, 5R, e o-3S, 5S:
  • Azabicyclo N Another group of compounds of Formula I (Azabicyclo N) includes compounds where Azabicyclo N moiety has the stereochemistry of 3R, 5R, or is a racemic mixture and the moiety is either not substituted with R (each is absent) or has one to two substituents being at either C2 and/or C4.
  • the preferred substituents for substitution at C2 are alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl; and for substitution at C4 are F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl.
  • the compounds of Formula I (Azabicyclo is NI) have asymmetric centers on the [3.2.2] azabicyclic ring with one center being at C3 when R 2 is absent.
  • the scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being 3(S) and 3(R):
  • Azabicyclo NI Another group of compounds of Formula I (Azabicyclo NI) includes compounds where Azabicyclo NI moiety is either not substituted with R 2 (each is absent) or has one to two substituents with one being at either C2 or C4 or when two are present, one being at each C2 and C4.
  • the preferred substituents for substitution at C2 are alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl
  • substitution at C4 are F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl.
  • Stereoselective syntheses and/or subjecting the reaction product to appropriate purification steps produce substantially enantiomerically pure materials.
  • Suitable stereoselective synthetic procedures for producing enantiomerically pure materials are well known in the art, as are procedures for purifying racemic mixtures into enantiomerically pure fractions.
  • the compounds of the present invention having the specified stereochemistry above have different levels of activity and that for a given set of values for the variable substituruents one isomer may be preferred over the other isomers. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. It is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially enantiomerically pure materials. Suitable stereoselective synthetic procedures for producing enantiomerically pure materials are well known in the art, as are procedures for purifying racemic mixtures into enantiomerically pure fractions.
  • the present invention comprises a method of administering to a mammal an amount of at least one acetylcholinesterase inhibitor, beta secretase inhibitor, or gamma secretase inhibitor, collectively referred to as "an inhibitor," and an alpha 7 nAChR full agonist.
  • the method would be used to treat diseases or conditions in a mammal, wherein the mammal experiences cholinergic hypofunction.
  • central and peripheral nervous system disorders involving cholinergic hypofunction include, but are not limited to, dementias, amnesias, cerebral insufficiencies, and psychiatric disturbances in the central nervous system and neuronal and smooth muscle dysfunction of the gut, skeletal muscle dysfunction for breathing, bladder, and secretory glands in the peripheral nervous system.
  • the acetylcholinesterase inhibitor and alpha 7 nAChR full agonist(s) can be administered together as a composition, or may be administered separately.
  • the method would be used to treat diseases or conditions in a mammal, wherein the mammal experiences neurodegeneration leading to cholinergic hypofunction and concomitant central nervous system dysfunction.
  • the central nervous system disorders involving cholinergic hypofunction include, but are not limited to, dementias, amnesias.
  • the acetylcholinesterase inhibitor and alpha 7 nAChR full agonist(s) can be administered together as a composition, or may be administered separately.
  • compositions of the invention can be administered using art-recognized techniques.
  • the inhibitor and the alpha 7 nAChR full agonist are administered orally, or parenterally.
  • the compositions of the invention can be administered using the same art-recognized techniques used for administration of acetylcholinesterase inhibitors and alpha 7 nAChR full agonists. Accordingly, techniques of administration need not be repeated here.
  • beta secretase inhibitors are more preferred and are described here in detail.
  • beta secretase inhibitors what is meant are compounds that are effective inhibitors of beta-secretase, that inhibit beta-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce amyloid beta deposits or plaques.
  • beta-secretase mediated treatments suggested for the treatment and prevention of disease characterized by amyloid beta deposits or plaques, such as AD are included in the term beta-secretase inhibitors as used herein. Illustrations of and non limiting examples of beta-secretase inhibitors are disclosed in the following references and by specific mention here are meant to be made part of this application, as if copied herein in whole, and intended to be incorporated herein by reference. These references and examples below are not intended to limit in any way the definition of a beta-secretase inhibitor discovered either before or after the filing of this application for patent.
  • Beta secretase inhibitors include the compounds disclosed in the following published patent applications and granted patents (incorporated herein by reference):
  • gamma secretase inhibitors By gamma secretase inhibitors what is meant are compounds that are effective inhibitors of gamma-secretase, that inhibit gamma-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce amyloid beta deposits or plaques. All gamma-secretase mediated treatments suggested for the treatment and prevention of disease characterized by amyloid beta deposits or plaques, such as AD are included in the term gamma-secretase inhibitors as used herein.
  • the invention provides pharmaceutical compositions comprising a composition according to the invention and a pharmaceutically acceptable carrier or diluent and optionally other adjuvants.
  • the alpha 7 agonist and the inhibitor(s) can be administered simultaneously or at separate intervals.
  • the alpha 7 agonist and the inhibitor(s) can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition.
  • two or more separate compositions i.e., one containing alpha 7 agonist and the other(s) containing the inhibitor(s), can be administered simultaneously.
  • a pharmaceutical combination therapy composition can include therapeutically effective amounts of the alpha 7 agonist, noted herein, and therapeutically effective amount of the inhibitor(s).
  • the combined administration of the alpha 7 agonist and the inhibitor(s) is expected to require less of the generally- prescribed dose for any of agents when used alone and or is expected to result in less frequent administration of either, both or all agents.
  • These compositions maybe formulated with common excipients, diluents or carriers, and compressed into tablets, or fonnulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes.
  • the compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
  • compositions containing alpha 7 agonist and the inhibitor(s) are administered on a different schedule.
  • One may be administered before the other as long as the time between the administrations falls within a therapeutically effective interval.
  • a therapeutically effective interval is a period of time beginning when one of either (a) the alpha 7 agonist, or (b) one to three of the inhibitor(s) is(are) administered to a mammal and ending at the limit of the beneficial effect in the treatment of the disease or condition to be treated from the combination of (a) and (b).
  • the methods of administration of the alpha 7 agonist and the inhibitor(s) may vary. Thus, any of the agents may be administered rectally, topically, orally, sublingually, or parenterally.
  • al nAChR full agonists combined with either acetylcholinesterase inhibitors, beta secretase inliibitors and/or gamma secretase inhibitors can be used to treat any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
  • diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Hunt
  • Alpha 7 nAChR full agonists within the scope of the present invention include compounds of Formula I.
  • the present invention comprises a method of administering the alpha 7 agonist to a mammal with an effective amount of at least one of the following acetylcholinesterase inhibitor, beta secretase inhibitor, or gamma secretase inhibitor, collectively referred to as "an inhibitor," and an alpha 7 nAChR full agonist.
  • an inhibitor an alpha 7 nAChR full agonist.
  • acetylcholinesterase inhibitors, beta secretase inhibitors, and gamma secretase inhibitors is discussed herein.
  • the invention provides pharmaceutical compositions comprising a composition according to the invention and a phannaceutically acceptable carrier or diluent and optionally other adjuvants.
  • Acceptable carriers, diluents, and adjuvants are any of those commercially used in the art, in particular, those used in pharmaceutical compositions of acetyleholinesterase inhibitors and alpha 7 nAChR full agonists. Accordingly, such carriers, diluents, and adjuvants need not be repeated here.
  • a pharmaceutical combination therapy composition can include therapeutically effective amounts of the compounds of Formula I, noted herein, and a therapeutically effective amount of the inhibitor.
  • compositions may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes.
  • the compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
  • Alpha 7 nAChR full agonists of the present invention include, but are not limited to compounds of Formula I as described herein.
  • the present invention includes the administration of an alpha 7 nAChR full agonists in combination with a cholinesterase, and/or a beta secretase inhibitor, and/or a gamma secretase inhibitor, including a combination of all three inhibitors administered with the al nAChR full agonist.
  • Non-limiting examples of al nAChR full agonists include compounds of Formula I:
  • R 0 is H, lower alkyl, substituted lower alkyl, or lower haloalkyl
  • Each Ri is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
  • Each R 2 is independently F, CI, Br, I, alkyl, substituted alkyl, haloalkyl, cycloalkyl, aryl, or R 2 is absent provided that k ⁇ - 2 , k ⁇ - 6 , k 2 , k 5 , k 6 , or k is 0; k ⁇ - is 0 or 1; k ⁇ - 6 is 0 or 1, provided that the sum of k ⁇ - 2 and k ⁇ - 6 is one; k 2 is 0 or l; k is 0, 1, or 2; k 6 is 0, 1, or 2; k 7 is 0 or 1 ;
  • R 2 - 3 is H, F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl; Each R 3 is independently H, alkyl, or substituted alkyl;
  • R 4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, CI, Br, I, -OH, -CN, -NH 2 , -NH(alkyl), or -N(alkyl) 2 ;
  • Lower alkyl is both straight- and branched-chain moieties having from 1-4 carbon atoms;
  • Lower haloalkyl is lower alkyl having 1 to (2n+l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety;
  • Lower substituted alkyl is lower alkyl having 0-3 substituents independently selected from F, CI, Br, or I and further having 1 substituent selected from R 5 , R 6 , -CN, -NO , -ORg, -SR 8 , -N(Rg) 2 , -C(O)R 8 , -C(O)OR 8 , -C(S)R 8 , -C(O)N(R 8 ) 2 , -NR 8 C(O)N(R 8 ) 2 , -NR 8 C(O)R 8 , -S(O)R 8 , -S(O) 2 R 8 , -OS(O) 2 R 8 , -S(O) 2 N(R 8 ) 2 , -NR 8 S(O) 2 R 8 , phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, CI, Br, or I; Alkyl is
  • Haloalkyl is alkyl having 1 to (2n+l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkyl is alkyl having 0-3 substituents independently selected from
  • Alkenyl is straight- and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond;
  • Haloalkenyl is alkenyl having 1 to (2n-l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkenyl is alkenyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R 5 , R 6 , -CN, -NO 2 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)OR 8 , -C(S)R 8 , -C(O)N(R 8 ) 2 , -NR 8 C(O)N(R 8 ) 2 , -NR 8 C(O)R 8 , -S(O)R 8 , -S(O) 2 R 8 , -OS(O) 2 R 8 , -S(O) 2 N(R 8 ) 2 ,
  • Alkynyl is straight- and branched-chained moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond;
  • Haloalkynyl is alkynyl having 1 to (2n-3) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkynyl is alkynyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R 5 , R 6 , -CN, -NO 2 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)OR 8 , -C(S)R 8 , -C(O)N(R 8 ) 2 , -NR 8 C(O)N(R 8 ) 2 , -NR 8 C(O)R 8 , -S(O)R 8 , -S(O) 2 R 8 , -OS(O) 2 R 8 , -S(O) 2 N(R 8 )
  • Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms
  • Halocycloalkyl is cycloalkyl having 1-4 substituents independently selected from F, or CI; Substituted cycloalkyl is cycloalkyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R 5 , R 6 , -CN, -NO 2 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)OR 8 , -C(S)R 8 , -C(O)N(R 8 ) 2 , -NR 8 C(O)N(R 8 ) 2 , -NR 8 C(O)R 8 , -S(O)R 8 , -S(O) 2 R 8 , -OS(O) 2 R 8 , -S(O) 2 N(R 8 ) 2 , -NR 8 S(O) R 8 , phenyl, or phen
  • Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R ⁇ o)-, or -O-;
  • Haloheterocycloalkyl is heterocycloalkyl having 1-4 substituents independently selected from F, or CI;
  • Substituted heterocycloalkyl is heterocycloalkylhaving 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R 5 , R 6 , -CN, -NO 2 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)OR 8 , -C(S)R 8 , -C(O)N(R 8 ) 2 , -NR 8 C(O)N(R 8 ) 2 , -NR 8 C(O)R 8 , -S(O)R 8 , -S(O) 2 R 8 , -OS(O) 2 R 8 , -S(O) 2 N(R 8 ) 2 , -NR 8 S(O) 2 R 8 , phenyl, or phenyl having 1 substituent selected from R 9 and further having 0-3 substituents independently selected from F, CI,
  • Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;
  • Substituted phenyl is a phenyl either having 1-4 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from Rn and 0-3 substituents independently selected from F, CI, Br, or I;
  • Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from R ⁇ and 0-3 substituents independently selected from F, CI, Br, or I, where the substitution can be independently on either only one ring or both rings of said naphthalene moiety;
  • Substituted phenoxy is a phenoxy either having 1-3 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from R ⁇ and 0-2 substituents independently selected from F, CI, Br, or I;
  • R 5 is 9-membered fused- ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula
  • Li is O, S, or NR; 10.
  • L is CR ⁇ 2 or N
  • L 2 and L 3 are independently selected from CR 12 , C(R ⁇ 2 ) , O, S, N, or NR 10 , provided that both L 2 and L 3 are not simultaneously O, simultaneously S, or simultaneously O and S, or
  • L is CR ⁇ 2 or N
  • L 2 and L are independently selected from CR ⁇ 2 , O, S, N, or NRio
  • each 9-membered fused-ring moiety having 0-1 substituent selected from R and further having 0-3 substituent(s) independently selected from F, CI, Br, or I, wherein the R 5 moiety attaches to other substituents as defined in fonnula I at any position as valency allows;
  • R 7 is alkyl, substituted alkyl, haloalkyl, -ORn, -CN, -NO 2 , -N(R 8 ) 2 ;
  • Each Rg is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R ⁇ 3 , cycloalkyl substituted with 1 substituent selected from R ⁇ , heterocycloalkyl substituted with 1 substituent selected from R ⁇ 3 , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • R 9 is alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, -OR i4 , -SR i4 , -N(R ⁇ 4 ) 2 , -C(O)R ⁇ 4 , -C(O)N(R ⁇ 4 ) 2 , -CN, -NR ⁇ 4 C(O)R ⁇ 4 , -S(O) 2 N(R ⁇ 4 ) 2 , -NR ⁇ 4 S(O) 2 R 14 , -NO 2 , alkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or R ⁇ 3 , cycloalkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or R ⁇ , or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or R ⁇
  • Rio is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R 7 and further having 0-3 substituents independently selected from F, CI, Br, or I;
  • Each Rn is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • Each R ⁇ is independently H, F, CI, Br, I, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -CN, -NO 2 , -OR ⁇ 4 , -SR ⁇ , -N(R J ) 2 ,
  • -C(O)R 14 -C(O)N(R ⁇ 4 ) 2 , -NR ⁇ 4 C(O)R 14 , -S(O) 2 N(R 14 ) 2 , -NR ⁇ 4 S(O) 2 RR 14 , or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that where valency allows the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -OR ⁇ , -SR 1 , -N(R i4 ) 2 , -C(O)R M , -NO 2 , -C(O)N(R 14
  • Each Ri 4 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl; wherein W is (A):
  • R A - I3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, -R 5 , R 6 , -OR A .
  • R A -ib is -O-R A -3, -S-R A - 3 , -S(O)-R A - , -C(O)-R A - , and alkyl substituted on the ⁇ carbon with R A - 7 where said ⁇ carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the phenyl ring attached to the core molecule and the ⁇ carbon being the carbon furthest from said C-1 carbon;
  • Each R A - 3 is independently selected from H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or substituted phenyl;
  • R ⁇ - . is selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, or substituted heterocycloalkyl;
  • Each R A - 5 is independently selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or substituted phenyl;
  • Each R A _ 6 is independently selected from alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or substituted phenyl; R A - 7 is selected from aryl, R 5 , or R 6 ;
  • W is (B): wherein B° is -O-, -S-, or -N(R B -o)-;
  • R B - I is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limited substituted alkyl, limited substituted alkenyl, limited substituted alkynyl, aryl, -OR B - 2 , -OR B - 3 , -SR B - 2 , -SR B - 3 , F, CI, Br, I, -N(R B - 2 ) 2 , -N(R B - 3 ) 2 , -C(O)R B - 2 , -C(O)R B - 3 , -C(O)
  • Each R B - is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or substituted phenyl;
  • Each R B - 3 is independently H, alkyl, haloalkyl, limited substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl;
  • R B - is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • (C) is a six-membered heterocyclic ring system having 1-2 nitrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nitrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six- six-fused-ring system, and further having 1-2 substitutents independently selected
  • Each Rc-i is independently H, F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, substituted phenyl, -NO 2 , -CN, -OR c - 2 , -SR C - 2 , -SOR C - 2 , -SO 2 R c - 2 , -NR c - C(O)R c - 3 , -NRc- 2 C(O)R c - 2 , -NRc- 2 C(O)R
  • Each Rc- 2 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rc- 5 , cycloalkyl substituted with 1 substituent selected from Rc- 5 , heterocycloalkyl substituted with 1 substituent selected from Rc- 5 , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • Each Rc- 3 is independently H, alkyl, or substituted alkyl
  • Rc- 4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, CI, Br, I, -OH, -CN, -NH 2 , -NH(alkyl), or -N(alkyl) 2 ;
  • Rc-5 is -CN, -CF 3 , -NO 2 , -OR C - 6 , -SR C - 6 , -N(R C - 6 ) 2 , -C(O)R C - 6 , -SOR c - 6 , -SO 2 RR C - 6 , -C(O)N(R C - 6 ) 2 , -NR c - 6 C(O)R c - 6 , -S(O) 2 N(R c - 6 ) 2 , or -NR c - 6 S(O) 2 R c - 6 ;
  • Each Rc- 6 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • D°, D 1 , D 2 , and D 3 are N or C(R D - ⁇ ) provided that up to one of D°, D 1 , D 2 , or D 3 is N and the others are C(R D - I ), further provided that when the core molecule is attached at D 2 and D° or D 1 is N, D 3 is C(H), and further provided that there is only one attachment to the core molecule;
  • Each R D - ⁇ is independently H, F, Br, I, CI, -CN, -CF 3 , -OR D - 5 , -SR D - 5 , -N(R D - 5 ) 2 , or a bond to -C(X)- provided that only one of R D - I , R D - 3 , and R D - 4 is said bond;
  • Each Rp- 2 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , or R 6 ;
  • Each Rp- 3 is independently H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO 2 , -ORD-IO, -C(O)N(RD-II) 2 .
  • R D - is independently H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO 2 , -OR D - ⁇ 0 , -
  • D 7 is O, S, or N(R D - 2 );
  • D 8 and D 9 are C(Ro- ⁇ ), provided that when the molecule is attached to the phenyl moiety at D 9 , D 8 is CH;
  • Each R D - ⁇ o is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
  • Each R D - ⁇ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R ⁇ , cycloalkyl substituted with 1 substituent selected from R ⁇ 3 , heterocycloalkyl substituted with 1 substituent selected from R , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • R D - 12 is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
  • E° is CH or N
  • R E - O is H, F, CI, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, R 5 , R 6 , -OR E - 3 , -OR E - , -SR E - 3 , -SR E . 5 .
  • E 1 is O, CRE-I-I, or C(R E - ⁇ - ⁇ ) 2 , provided that when E 1 is CR E - ⁇ - ⁇ , one R E - ⁇ is a bond to CR E - ⁇ _ ⁇ , and further provided that at least one of E 1 or E 2 is O;
  • Each RE-I-1 is independently H, F, Br, CI, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -OR E , or -N(R E ) 2 , provided that at least one R E - ⁇ - ⁇ is H when E 1 is C(R E - ⁇ _ ⁇ ) 2 ;
  • Each R E - ⁇ is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E 1 provided that E 1 is CR E - ⁇ - ⁇ ;
  • E 2 is O, CR E - - 2 - or C(R E - 2 - ) 2 , provided that when E 2 is CRE- 2 -2 .
  • one R E . 2 is a bond to CRE-2-2, and further provided that at least one of E 1 or E 2 is O;
  • Each R E - 2 - 2 is independently H, F, Br, CI, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -OR E , or -N(R E ) 2 , provided that at least one R E -2-2 is H
  • Each R B - is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E 2 provided that E 2 is CR E - 2 - ;
  • Each R E is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • Each R E - 3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or phenyl having 1 substituent selected from R 9 and further having 0-3 substituents independently selected from F, CI, Br, or I or substituted phenyl;
  • R E - 4 is H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or substituted phenyl;
  • Each R E - is independently H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , or R 6;
  • Each R E - 6 is independently alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , R 6 , phenyl, or phenyl having 1 substituent selected from R 9 and further having 0-3 substituents independently selected from F, CI, Br, or i;
  • F 4 is N(R F - 7 ), O, or S;
  • R F _ ! is H, F, CI, Br, I, -CN, -CF 3 , -OR F . 8 , -SR F - 8 , or -N(R F . 8 ) 2 ;
  • R F - is H, F, alkyl, haloalkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R 5 , R 6 , ⁇ N(R F - )-aryl,
  • R F - 3 is H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO 2 , -OR F - 8 , -C(O)N(R F .
  • R F - is H, or alkyl
  • Each R F - 5 is independently F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, -CF 3 , -OR F - 8 , -C(O)NH 2 , -NHR F - 8 , -SR F - 8 , -CO 2 R F - 8 , aryl, phenoxy, substituted phenoxy, heteroaryl, -N(R F - 4 )-aryl, or -O-substituted aryl;
  • R F . 6 is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, F, Br, CI, I, -O F - S , -C(O)NH 2 , -NHRF- 8 , -SR F -8, -CO R F - 8 , aryl, R 5 , or R 6 , and each of the other two R F - 6 is independently selected from alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, F, Br, Cl, I, -OR F - S , -C(O)NH 2 , -NHR F - 8
  • R F - is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R 9 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
  • R F -s is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
  • R F - 9 is aryl, R 5 , or R 6 ;
  • G 1 is N or CH;
  • Each G 2 is N or C(R G -I), provided that no more than one G 2 is N;
  • Each R G - I is independently H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, -NO 2 , F, Br, Cl, I, -C(O)N(R G .
  • R G - 65 aryl, R 5 , R 6 , or two R G - ⁇ on adjacent carbon atoms may combine for W to be a 6-5-6 fused-tricyclic-heteroaromatic-ring system optionally substituted on the newly fonned ring where valency allows with 1-2 substitutents independently selected from F, Cl, Br, I, and R G - 2 ;
  • R G - 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -OR G - 8 , -SR G - 8 , -S(O) 2 R G - 8 , -S(O)R G - 8 , -OS(O) 2 R G - 8 , -N(R G - 8 ) 2 , -C(O)R G - 8 , -C(S)R G - 8 , -C(O)OR G - 8 , -CN, -C(O)N(R G - 8 ) 2 , -NR G - 8 C(O)R G - 8 , -S(O) 2 N(R G - 8 ) 2 , -NR
  • Each R G - 3 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R G - 4 , cycloalkyl substituted with 1 substituent selected from R G - 4 , heterocycloalkyl substituted with 1 substituent selected from R G - 4 , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • R C M is -OR G - 5 , -SR G - 5 , -N(R G . 5 ) 2 , -C(O)R G - 5 , -SOR G - 5 , -SO 2 R G - 5 , -C(O)N(R G - 5 ) 2 , -CN, -CF 3 , -NR G . 5 C(O)R G . 5 , -S(O) 2 N(R G - 5 ) 2 , -NR G - 5 S(O) 2 R G . 5 , or -NO 2 ;
  • Each R G - 5 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • R G - 6 is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 0-4 substituents independently selected from F, Cl, Br, I, and R G - 7 ;
  • R G - 7 is alkyl, substituted alkyl, haloalkyl, -OR G - 5 , -CN, -NO , -N(R G - 3 ) 2 ;
  • Each R G - 8 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or R G - 7 ;
  • H' is N or CH
  • Each RH-I is independently F, Cl, Br, I, -CN, -NO 2 , alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocyclcoalkyl, aryl, R 5 , R 6 , -OR 8 , -SR 8 , -SOR 8 , -SO 2 R 8 , -SCN, -S(O)N(R 8 ) 2 , -S(O) 2 N(R 8 ) 2 , -C(O)R 8 , -C(O) 2 R 8 , -C(O)N(R
  • n H 0, 1, or 2;
  • R H - 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORH- 3 , -SR H - 3 , -S(O) 2 R H -3, -S(O)RH- 3 , -OS(O) 2 RH- 3 , -N(RH- 3 )2, -C(O)R H -3, -C(S)R H - 3 , -C(O)OR H .
  • Each R H - 3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or R 7 ; or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof.
  • the present invention is useful in the treatment of, or preparation of medicament(s) for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR is implicated, including cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
  • diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular de
  • AChR refers to acetylcholine receptor.
  • nAChR refers to nicotinic acetylcholine receptor.
  • Pre-senile dementia is also known as mild cognitive impairment.
  • 5HT 3 R refers to the serotonin-type 3 receptor.
  • ⁇ -btx refers to ⁇ -bungarotoxin.
  • FLIP R refers to a device marketed by Molecular Devices, Inc. designed to precisely measure cellular fluorescence in a high throughput whole-cell assay. (Schroeder et. al., J Biomolecular Screening, 1(2), p 75-80, 1996).
  • TLC thin-layer chromatography
  • HPLC high pressure liquid chromatography
  • MeOH refers to methanol
  • EtOH refers to ethanol
  • IPA refers to isopropyl alcohol.
  • THF refers to tetrahydrofuran.
  • DMSO refers to dimethylsulfoxide.
  • DMF refers to N,N-dimethylformamide.
  • EtOAc refers to ethyl acetate.
  • TMS refers to tetramethylsilane.
  • TEA triethylamine
  • DIEA refers to NN-diisopropylethylamine
  • MLA refers to methyllycaconitine
  • Ether refers to diethyl ether.
  • HATU refers to O-(7-azabenzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', N'-tetramethyluronium hexafluorophosphate.
  • CDI refers to carbonyl diimidazole.
  • NMO refers to N-methylmorpholine-N-oxide.
  • TPAP refers to tetrapropylammonium perruthenate.
  • Na 2 SO refers to sodium sulfate.
  • K 2 CO 3 refers to potassium carbonate.
  • MgSO refers to magnesium sulfate.
  • acetylcholinesterase inhibitor or “beta secretase inhibitor” include their respective pharmaceutically acceptable salts, such as hydrochlorides, tartrates, and the like.
  • Halogen is F, Cl, Br, or I.
  • C ⁇ - 6 alkyl refers to alkyl of one to six carbon atoms.
  • Non-inclusive examples of heteroaryl compounds that fall within the definition of R 5 and R 6 include, but are not limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl
  • heterocycloalkyl examples include, but are not limited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazine, azetidino, azetidinono, oxindolo, dihydroimidazolo, and pyrrolidinono
  • Amino protecting group includes, but is not limited to, carbobenzyloxy (CBz), tert butoxy carbonyl (BOC) and the like. Examples of other suitable amino protecting groups are known to person skilled in the art and can be found in "Protective Groups in Organic synthesis," 3rd Edition, authored by Theodora Greene and Peter Wuts.
  • Alkyl substituted on an ⁇ carbon with R - 7 is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the W moiety and the co carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon. Therefore, when determining the ⁇ carbon, the C-1 carbon will be the carbon attached, as valency allows, to the W moiety and the ⁇ carbon will be the carbon furthest from said C-1 carbon.
  • Mammal denotes human and other mammals.
  • Brine refers to an aqueous saturated sodium chloride solution. Equ means molar equivalents.
  • IR refers to infrared spectroscopy.
  • Lv refers to leaving groups within a molecule, including Cl, OH, or mixed anhydride.
  • NMR nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • MS refers to mass spectrometry expressed as m/e or mass/charge unit.
  • HRMS refers to high resolution mass spectrometry expressed as m/e or mass/charge unit.
  • [M+H] + refers to an ion composed of the parent plus a proton.
  • [M-H] " refers to an ion composed of the parent minus a proton.
  • M+Na] + refers to an ion composed of the parent plus a sodium ion.
  • [M+K] + refers to an ion composed of the parent plus a potassium ion.
  • El refers to electron impact.
  • ESI refers to electrospray ionization.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • compositions of the present invention maybe in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases, and salts prepared from inorganic acids, and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N, N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like.
  • cyclic amines such as arginine, betaine, caffeine, choline, N, N
  • Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic acids include salts of C ⁇ - 6 alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid, and aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
  • an effective amount of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired therapeutic effect.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound(s) used, the mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
  • compositions use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients.
  • carrier material or excipient means any substance, not itself a therapeutic agent, used as a carrier and or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a confrolled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl-methyl cellulose, or other methods known to those skilled in the art.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition.
  • compositions of the present invention may be administered by any suitable route, e.g., parenterally, bucal, intravaginal, and rectal, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • routes of administration are well known to those skilled in the art.
  • the compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly.
  • saline solution, dextrose solution, or water may be used as a suitable carrier.
  • Formulations for parenteral admimstration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the serotonin type 3 receptor is a member of a superfamily of ligand- gated ion channels, which includes the muscle and neuronal nAChR, the glycine receptor, and the ⁇ -aminobutyric acid type A receptor. Like the other members of this receptor superfamily, the 5HT 3 R exhibits a large degree of sequence homology with al nAChR but functionally the two ligand-gated ion channels are very different. For example, ⁇ 7 nAChR is rapidly inactivated, is highly permeable to calcium and is activated by acetylcholine and nicotine.
  • 5HT 3 R is inactivated slowly, is relatively impermeable to calcium and is activated by serotonin.
  • 7 nAChR and5HT 3 R proteins have some degree of homology, but function very differently. Indeed the pharmacology of the channels is very different.
  • Ondansefron a highly selective 5HT 3 R antagonist, has little activity at the al nAChR.
  • GTS -21 a highly selective ⁇ 7 nAChR full agonist, has little activity at the 5HT 3 R.
  • al nAChR is a ligand-gated Ca ++ channel formed by a homopentamer of ⁇ 7 subunits.
  • al nAChR binds selectively to this homopetameric, al nAChR subtype, and that al nAChR has a high affinity binding site for both ⁇ -btx and methyllycaconitine (MLA).
  • al nAChR is expressed at high levels in the hippocampus, ventral tegmental area and ascending cholinergic projections from nucleus basilis to thalamocortical areas.
  • ⁇ 7 nAChR full agonists increase neurotransmitter release, and increase cognition, arousal, attention, learning and memory.
  • Selective al nACliR full agonists may be found using a functional assay on FLIPR (see WO 00/73431 A2).
  • FLIPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes. This assay may be used to accurately measure the functional pharmacology of ⁇ 7 nAChR and 5HT 3 R.
  • To conduct such an assay one uses cell lines that expressed functional forms of the al nAChR using the ⁇ 7/5-HT 3 channel as the drug target and cell lines that expressed functional 5HT 3 R. In both cases, the ligand-gated ion channel was expressed in SH-EP1 cells. Both ion channels can produce robust signal in the FLIPR assay.
  • the compounds of the present invention are al nAChR full agonists. Therefore, as another aspect of the present invention, the compounds of the present invention may be used to treat a variety of diseases including cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (also known as mild cognitive impairment), and senile dementia.
  • diseases including cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (also known as mild cognitive impairment), and senile dementia.
  • Alzheimer's disease has many aspects, including cognitive and attention deficits.
  • these deficits are treated with cholinesterase inhibitors. These inhibitors slow the break down of acetylcholine, and thereby provide a general nonspecific increase in the activity of the cholinergic nervous system. Since the drugs are nonspecific, they have a wide variety of side effects.
  • Neurodegeneration is a common problem associated with diseases such as
  • Alzheimer's disease While the current drugs treat some of the symptoms of this disease, they do not control the underlying pathology of the disease. Accordingly, it would be desirable to provide a drug that can slow the progress of Alzheimer's disease.
  • Pre-senile dementia (mild cognitive impairment) concerns memory impainnent rather than attention deficit problems and otherwise unimpaired cognitive functioning. Mild cognitive impairment is distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. There cunently is no medication specifically identified for treatment of mild cognitive impairment, due somewhat to the newness of identifying the disease. Therefore, there is a need for a drug to treat the memory problems associated with mild cognitive impairment.
  • Senile dementia is not a single disease state. However, the conditions classified under this name frequently include cognitive and attention deficits.
  • the compounds of the present invention are ⁇ 7 nAChR full agonists. Therefore, yet other diseases to be treated with compounds of the present invention include treating the cognitive and attention deficits as well as the neurodegeneration associated with any one or more or combination of the following: amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
  • Amyotrophic lateral sclerosis also known as Lou Gehrig's disease, belongs to a class of disorders known as motor neuron diseases wherein specific nerve cells in the brain and spinal cord gradually degenerate to negatively affect the control of voluntary movement.
  • motor neuron diseases wherein specific nerve cells in the brain and spinal cord gradually degenerate to negatively affect the control of voluntary movement.
  • amyotrophic lateral sclerosis although patients may receive treatment from some of their symptoms and although Riluzole has been shown to prolong the survival of patients. Therefore, there is a need for a pharmaceutical agent to treat this disease.
  • Brain tumors are abnormal growths of tissue found inside of the skull. Symptoms of brain tumors include behavioral and cognitive problems. Surgery, radiation, and chemotherapy are used to treat the tumor, but other agents are necessary to address associated symptoms. Therefore, there is a need to address the symptoms of behavioral and cognitive problems.
  • AIDS Acquired immune deficiency syndrome
  • HAV human immunodeficiency virus
  • This virus attacks selected cells and impairs the proper function of the immune, nervous, and other systems. HIV infection can cause other problems such as, but not limited to, difficulties in thinking, otherwise known as AIDS dementia complex. Therefore, there is a need to drugs to relieve the confusion and mental decline of persons with AIDS.
  • Persons with Down's syndrome have in all or at least some of their cells an extra, critical portion of the number 21 chromosome.
  • Adults who have Down's syndrome are known to be at risk for Alzheimer-type dementia. Currently, there is no proven treatment for Down's syndrome. Therefore, there is a need to address the dementia associated with Down's syndrome.
  • Dementia with Lewy Bodies is a neurodegenerative disorder involving abnormal structures known as Lewy bodies found in certain areas of the brain. Symptoms of dementia with Lewy bodies include, but are not limited to, fluctuating cognitive impairment with episodic delirium. Currently, treatment concerns addressing the parkinsonian and psychiatric symptoms. However, medicine to control tremors or loss of muscle movement may actually accentuate the underlying disease of dementia with Lewy bodies. Therefore, there is a need of a pharmaceutical agent to treat dementia with Lewy bodies.
  • Huntington's disease Genetically programmed degeneration of neurons in certain areas of the brain cause Huntington's disease. Early symptoms of Huntington's disease include mood swings, or trouble learning new things or remembering a fact. Most drugs used to treat the symptoms of Huntington's disease have side effects such as fatigue, restlessness, or hyperexcitability. Currently, there is no treatment to stop or reverse the progression of Huntington's disease. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
  • Parkinson's disease is a neurological disorder characterized by tremor, hypokinesia, and muscular rigidity. Cunently, there is no treatment to stop the progression of the disease. Therefore, there is a need of a phannaceutical agent to address Parkinson's.
  • Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. "Peptides" pp.
  • Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. "Peptides” pp. 39-91, San Diego, CA, Academic Press, (1995), and include, but are not limited to, agents such as carbodiimides, phosphonium and uronium salts (such as HATU).
  • the carboxylic acid is activated with a uronium salt, preferably HATU (see J. Am. Chem. Soc, 4397 (1993)), in the presence of the Azabicyclico moiety and a base such as DIEA in DMF to afford the desired amides.
  • a uronium salt preferably HATU (see J. Am. Chem. Soc, 4397 (1993)
  • the carboxylic acid is converted to the acyl azide by using DPP A; the appropriate amine precursor is added to a solution of the appropriate anhydride or azide to give the desired final compounds.
  • the ester (Lv being OMe or OEt) may be reacted directly with the amine precursor in refluxing methanol or ethanol to give the compounds of Formula I.
  • 6-substituted-[2.2.2]-3-amines (Azabicyclo I) are known in the art. The preparation of compounds where R 2 is present is described in Ada Pol. Pharm. 179-85 (1981). Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared by reduction of an oxime or an imine of the conesponding 6-substituted-3- quinuclidinone by methods l ⁇ iown to one of ordinary skill in the art (see J. Labelled Compds. Radiopharm., 53-60 (1995), J Med. Chem. 988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)).
  • the 6-substituted-[2.2.2]-3-amine can be prepared from a 6-substituted-3- hydroxyquinuclidine by Mitsunobu reaction followed by deprotection as described in Synth. Commun. 1895-1911 (1995).
  • the 6-substituted-[2.2.2]-3-amine can be prepared by conversion of a 6-substituted-3-hydroxyquinuclidine into the conesponding mesylate or tosylate, followed by displacement with sodium azide and reduction as described in J Med. Chem. 587-593 (1975).
  • the oximes can be prepared by treatment of the 3-quinuclidinones with hydroxylamine hydrochloride in the presence of base.
  • the imines can be prepared by treatment of the 3-quinuclidinones with a primary amine under dehydrating conditions.
  • the 3-hydroxyquinuclidines can be prepared by reduction of the 3- quinuclidinones.
  • the 6-substituted-3-quinuclidinones can be prepared by known procedures (see J Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perl ⁇ n Trans. /409-420 (1991), J. Org. Chem. 3982-3996 (2000)).
  • Compounds for Azabicyclo II where R 2 is present can also be prepared by modification of intermediates described in the synthesis of exo-3 -amino- 1- azabicyclo[2.2. ljheptane as the bis(hydro para-toluenesulfonate) salt, described in detail herein.
  • hit 6 can be oxidized to the aldehyde and treated with an organometallic reagent to provide hit 20 using procedures described in Tetrahedron (1999), 55, p 13899.
  • frit 20 can be converted into the amine using methods described for the synthesis of exo-3-amino-l-azabicyclo[2.2. ljheptane as the bis(hydro para- toluenesulfonate) salt.
  • the desired salt can be made using standard procedures.
  • the oximes can be prepared by treatment of the N-2-azabicyclo[2.2.1 jheptanones with hydroxylamine hydrochloride in the presence of a base.
  • the imines can be prepared by treatment of the N-2- azabicyclo[2.2.1J-heptanones with a primary amine under dehydrating conditions.
  • the N-2-azabicyclo[2.2.1 jheptanones can be prepared by known procedures (see Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191 (1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).
  • exo- and era o-l-azabicyclo[3.2.1Joctan-3-amines are prepared from 1- azabicyclic[3.2.1Joctan-3-one (Thill, B. P., Aaron, H. S., J. Org. Chem., 4376-4380 (1968)) according to the general procedure as discussed in Lewin, A.H., et al., J. Med. Chem., 988-995 (1998).
  • Benzoyl chloride (14.9 mL, 128 mmol) is added to a stined solution of nifroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). The solution is refluxed for 24 hr and then concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (80:20) affords hit 1 as a white solid (68% yield): 1H NMR (CDC1 3 ) ⁇ 8.0, 7.6, 7.4, 4.9, 4.8.
  • Step B Preparation of ethyl E-4-(benzylamino)-2-butenoate (Int 2).
  • Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is added to a stined solution of benzylamine (16 mL, 146 mmol) in CH 2 C1 2 (200 mL) at rt.
  • the reaction mixture stirs for 15 min, and is diluted with ether (1 L).
  • the mixture is washed with saturated aqueous NaHCO 3 solution (3x) and water, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • the residue is purified by flash chromatography on silica gel.
  • Step C Preparation of tra..5 , -4-nitro-l-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int 3).
  • hit 1 (6.81 g, 34.9 mmol) and hit 2 (7.65 g, 34.9 mmol) in EtOH (70 mL) stirs at rt for 15 h and is then concentrated in vacuo.
  • the residue is diluted with ether (100 mL) and saturated aqueous NaHCO 3 solution (100 mL).
  • the organic layer is separated and dried (Na SO ), filtered and concentrated in vacuo.
  • the crude product is purified by flash chromatography on silica gel.
  • Step D Preparation of trot -s-4-amino- 1 -(phenylmethyl)-3 -pyrrolidineacetic acid ethyl ester (Int 4).
  • hit 3 A mixture of hit 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH (100 mL) is placed in a Pan bottle and hydrogenated for 4 h under an atmosphere of hydrogen (46 psi) at rt. The mixture is filtered through a pad of Celite, and the solvent is removed in vacuo to afford hit 4 as a clear oil (100% yield): 1H MR (300 MHz, CDC1 3 ) ⁇ 7.3- 7.2, 4.1, 3.6, 3.2, 3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.
  • Step E Preparation of tr ⁇ n-.-4-(l,l-dimethylethoxycarbonylamido)-l-
  • Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to a stirred solution of Int 4 (2.94 g, 11.2 mmol) in CH 2 C1 2 (30 mL) cooled in an ice bath. The reaction is allowed to warm to rt and stirred overnight. The mixture is concentrated in vacuo. The crude product is purified by flash chromatography on silica gel.
  • Int 6 is a racemic mixture that can be resolved via chromatography using a
  • Step G Preparation of exo 3-(tert-butoxycarbonylamino)-l- azabicyclo[2.2. ljheptane (Int 7).
  • TEA 8.0 g, 78.9 mml
  • CH 2 C1 2 50 mL
  • CH 3 SO 2 Cl 5.5 g, 47.8 mmol
  • the resulting yellow mixture is diluted with saturated aqueous NaHCO 3 solution, extracted with CH 2 C1 2 several times until no product remains in the aqueous layer by TLC.
  • the organic layers are combined, washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue is dissolved in EtOH (85 mL) and is heated to reflux for 16 h.
  • the reaction mixture is allowed to cool to rt, transfened to a Pan bottle and treated with 10% Pd/C catalyst (1.25 g).
  • the bottle is placed under an atmosphere of hydrogen (53 psi) for 16 h.
  • the mixture is filtered through Celite, and fresh catalyst (10% Pd/C, 1.25 g) is added. Hydrogenolysis continues overnight. The process is repeated three more times until the hydrogenolysis is complete.
  • the final mixture is filtered through Celite and concentrated in vacuo.
  • the residue is purified by flash chromatography on silica gel.
  • Step H Preparation of exo-3-ami ⁇ o-l-azabicyclo[2.2. ljheptane bis(hydro- p ⁇ r ⁇ -toluenesulfonate) .
  • Step I Preparation of ethyl 5-hydroxy-6-oxo- 1 ,2,3 ,6-tetrahydiOpyridine-4- carboxylate (Int 10).
  • Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanically stined suspension of potassium ethoxide (33.2 g, 395 mmol) in dry toluene (0.470 L).
  • 2-pynolidinone (33.6 g, 395 mmol) is added, and then a solution of diethyl oxalate (53.1 mL, 390 mmol) in toluene (98 mL) is added via an addition funnel.
  • toluene (118 mL) and EtOH (78 mL) are added sequentially.
  • the mixture is heated to reflux for 18 h.
  • Step K Preparation of cis- 4-(hydroxymethyl)piperidin-3-ol (h t 12).
  • Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portions to a stined solution of LiAlH in THF (80 mL of a 1.0 M solution) in an ice-water bath.
  • the mixture is warmed to rt, and then the reaction is heated to reflux for 48 h.
  • the mixture is cooled in an ice-water bath before water (3.0 mL, 170 mmol) is added dropwise, followed by the sequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water (9.0 mL, 500 mmol).
  • Excess K CO 3 is added, and the mixture is stined vigorously for 15 min.
  • Step L Preparation of benzyl cis -3 -hydroxy-4-(hydroxymethyl)piperidine- 1 - carboxylate ( it 13).
  • N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is added to a stined solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueous ⁇ aHCO 3 (15 mL) at rt. The mixture is stined at rt for 18 h. The organic and aqueous layers are separated. The aqueous layer is extracted with ether (3X).
  • Step M Preparation of benzyl e.s-3-hydroxy-4-[(4-methylphenyl)sulfonyl oxymethylJpiperidine-1 -carboxylate (Int 14).
  • R ⁇ r ⁇ -toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to a stirred solution of it 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a -15°C bath. The mixture is stined for 4 h, followed by addition of HCl (4.5 mL of a 6.0 M solution). CH 2 C1 2 (5 mL) is added. The organic and aqueous layers are separated. The aqueous layer is extracted with CH 2 C .
  • a mixture of hit 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500 mg) in EtOH (50 mL) is placed under an atmosphere of hydrogen. The mixture is shaken for 16 h. The mixture is filtered through Celite. Solid NaHCO 3 (1.1 g, 13 mmol) is added to the filtrate, and the mixture is heated in an oil bath at 50°C for 5 h. The solvent is removed in vacuo. The residue is dissolved in saturated aqueous K 2 CO 3 solution.
  • the pH of the aqueous layer is adjusted to 9 with 50% aqueous NaOH solution.
  • the aqueous layer is extracted with CH 2 C1 2 (3X), and the combined organic layers are washed with brine, dried (Na 2 SO ), filtered and concentrated in vacuo.
  • the crude product is purified by flash chromatography on silica gel. Elution with CHCVMeOH-NH OH (92:7:1) affords Int 16 as a colorless oil (41% yield): 1H NMR (CDC1 3 ) ⁇ 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.
  • Step P Preparation of e.?-fo-3-amino-l-azabicyclo[2.2. ljheptane bis(hydro- p ⁇ r ⁇ -toluenesulfonate) .
  • Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen.
  • the solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT.
  • the acetone is removed under reduced pressure (25°C, bath temperature) to provide a gray slurry.
  • the slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue.
  • Methyl-3-bromo-propiolate (83.7 g, 0.513 mole) is added to N-t-butyloxy- pyrrole (430 ml, 2.57 mole) under nitrogen.
  • the dark mixture is warmed in a 90 °C bath for 30 h, is cooled, and the bulk of the excess N-t-butyloxy-pyrrole is removed in vacuo using a dry ice/acetone condenser.
  • the dark oily residue is chromatographed over 1 kg silica gel (230-400 mesh) eluting with 0-15% EtOAc/hexane.
  • (+/-)Endo-l -tert-butyl 2-methyl 7-azabicyclo[2.2.1Jheptane-2,7-dicarboxylate (72.8 g, 0.285 mole) is dissolved in 1000 ml dry MeOH in a dried flask under nitrogen.
  • the solution is treated with solid NaOMe (38.5 g, 0.713 mole) neat, in a single lot and the reaction is warmed to reflux for 4h.
  • the mixture is cooled to 0°C, is treated with 400 ml water, and the reaction is stined lh as it warms to RT.
  • the mixture is concentrated in vacuo to about 400 ml and the pH of the aqueous residue is adjusted to 4.5 with 12N HCl.
  • (+/-)Exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2. ljheptane- 2-carboxylic acid (32.5 g, 0.135 mole) is combined with TEA (24.4 ml, 0.175 mole) in 560 ml dry toluene in a dry flask under nitrogen.
  • the solution is treated drop-wise with diphenylphosphoryl azide (37.7 ml, 0.175 mole), and is allowed to stir for 20 min at RT.
  • the mixture is treated with benzyl alcohol (18.1 ml, 0.175 mole), and the reaction is stirred overnight at 50°C.
  • the mixture is cooled, is extracted successively with 2 x 250 ml 5% citric acid, 2 x 200 ml water, 2 x 200 ml saturated sodium bicarbonate, and 2 x 100 ml saturated NaCl.
  • the organic layer is dried (MgSO ) and concentrated in vacuo to an amber oil.
  • the crude material was chromatographed over 800 g silica gel (230-400 mesh), eluting with 15-50% EtOAc/hexane.
  • the 2R enantiomer is triturated with 12 ml ether followed by 12 ml hexane (to remove lingering diastereo and enantiomeric impurities) and is dried to afford 9.5 g (43%) of purified exo-tert-butyl (IS, 2R, 4R)-(+)-2 ⁇ [(benzyloxy)carbonylJamino ⁇ -7- azabicyclo[2.2.1]heptane-7-carboxylate with 99% enantiomeric excess.
  • MS (El) for C ⁇ 9 H 26 N 2 O 4 , m/z: 346 (M) + . [ocJ 25 D 22, (c 0.42, chloroform).
  • tert-Butyl 4-(2-oxopropylidene)piperidine-l -carboxylate (Int 101): Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is washed with pentane (3X) and suspended in dry THF (40 mL). The solution is cooled to 0°C before diethyl (2-oxopropyl)phosphonate (9.75 g, 50.2 mmol) is added dropwise. After complete addition, the solution is warmed to rt and stined for 30 min.
  • tert- Butyl 4-oxo-l-piperidinecarboxylate (5.0g, 25.1 mmol) is added in portions over 10 min, followed by stirring at rt for 2 h. A saturated aqueous solution of ammonium chloride is added, followed by dilution with ether. The organic layer is exfracted with water. The organic layer is dried (MgSO 4 ), filtered and concentrated to a yellow oil. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-ether (60:40) gave 4.5 g (75%)of Int 101 as a white solid: ! H NMR (CDC1 3 ) ⁇ 6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.
  • hit 101 (4.5 g, 19 mmol) and 10% palladium on activated carbon (450mg) in EtOH (150 mL) is placed in a Pan bottle and hydrogenated for 5 h at 50 psi. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo to afford 4.3 g (94%) of hit 102 as a clear oil: 1H NMR (CDC1 3 ) ⁇ 4.1, 2.8, 2.4, 2.2, 2.0, 1.7, 1.5, 1.1.
  • tert-Butyl 4-(3-biOmo-2-oxopropyl)piperidine-l -carboxylate hit 103: To a stined solution lithium hexamethyldisilylamide in THF (20. 0 mL, 1.0 M) in a -78 °C bath is added chlorotrimethylsilane (11.0 mL, 86.4 mmol) dropwise. The mixture is stined at -78 °C for 20 min, followed by addition of Int 102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL) dropwise. After complete addition, the mixture is stined at -78 °C for 30 min.
  • the amine can be coupled to form the appropriate amides or thioamides as a racemic mixture.
  • the racemic mixture can then be resolved by chromatography using chiral columns or chiral HPLC, techniques widely known in the art, to provide the requisite resolved enantiomers 3(R) and 3(5) of said amides.
  • the free base can also be prepared directly from n-butyl furo[2,3- cJpyridine-5-carboxylate by direct condensation using at least 1.5 molar equivalents of (R)-3-aminoquinuclidine and heating in ethanol or n-butyl alcohol.
  • 2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO 3 (19.5g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask.
  • the flask is placed in an oil bath at 90°C, and after 5 min, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3 x 8 mL, then 2.2 mL all at 90-min intervals and then the final 2.3 mL after the reaction stirs for 15 h at 90°C.
  • the reaction is stined at 90°C for another 4 h and then cooled by placing the flask in an ice bath.
  • the pH of the reaction is then adjusted to 1 using 6N HCl.
  • the reaction is stirred for 1.5 h in an ice bath allowing an undesired solid to form.
  • the undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc.
  • the mixture is stined until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stined over the weekend at rt.
  • the pH of the mixture is adjusted to 3 with 2N NaHSO 4 , and the mixture is extracted with 4 x 50 mL EtOAc.
  • the combined organic layer is dried (MgSO 4 ), is filtered .! and the filtrate is concentrated in vacuo to a yellow solid.
  • I-2-D (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL, 68 mmol), bis(triphenylphosphine) palladium dichloride (1.02 g, 1.46 mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl 3 /40 mL THF under N 2 .
  • TEA 21 mL, 151 mmol
  • the reaction is stined 3 h at rt and is diluted with 200 mL CHCI 3 .
  • the crude material is chromatographed over 300 g silica gel (230-400 mesh) eluting with 30-40% EtOAc/hexane. Two sets of fractions with two different desired compounds are identified by TLC/UN. The two compounds eluted separately.
  • the early-eluting pool of fractions is combined and concentrated to afford [7-chloro-2- (trimethylsilyl)furo[2,3-cJpyridin-5-ylJmethanol (1-5 -D) as a white solid (46% yield).
  • the later-eluting pool of fractions is combined and concentrated to provide (7- chloiOfuro[2,3-c]pyridin-5-yl)methanol (I-4-D) as a white solid (27% yield).
  • I-4-D (32.0 g, 174 mmol) is combined with zinc powder (34.2 g, 523 mmol) in absolute EtOH (900 mL), using an overhead stirrer.
  • the mixture is heated to 70°C, HCl (87.2 mL, 1.05 mol) is added slowly drop-wise, and the mixture is heated to reflux for 1 h.
  • the mixture is cooled slightly, filtered to remove the metallic zinc and concentrated to near-dryness.
  • the yellow oil is diluted with H 2 O (150 mL) and EtOAc (950 mL) and is treated slowly drop-wise with 20% Na CO 3 (310 mL) as the mixture is warmed to reflux.
  • the vigorously stined (using overhead stiner) mixture is refluxed for 1 h, cooled slightly and the organics removed via cannula under reduced pressure.
  • Additional EtOAc (600 mL) is added, the mixture is heated to reflux for 1 h, cooled slightly and the organics removed as above.
  • More EtOAc (600 mL) is added, the mixture is stined at rt overnight then heated to reflux for 1 h, cooled slightly and most of the organics removed as above.
  • the remaining mixture is filtered tlirough celite, rinsed with EtOAc until no additional product elutes, and the layers separated.
  • the aqueous layer is further exfracted with EtOAc (2 X 400 mL).
  • Oxalyl chloride (685 ⁇ L, 7.8 mmol) is dissolved in 30 mL CH 2 C1 2 in a dry flask under N 2 . The flask is placed in a dry-ice/acetone bath, DMSO (1.11 mL, 15.6 mmol) in 5 mL CH 2 CI2 is added drop-wise, and the mixture is stined for 20 min.
  • 3-Bromofuran (8.99 mL, 100.0 mmol) is dissolved in DMF (8.5 mL), cooled to 0°C, treated dropwise with POCl 3 (9.79 mL, 105.0 mmol), stined for 1 h at RT and then heated to 80°C for 2 h. The mixture is cooled to RT, poured over ice (1 kg) and neutralized to pH 9 with solid K 2 CO 3 . The mixture is stined for 1 h, extracted with Et O (3 X 500 mL), dried (K CO 3 ) and concentrated to a dark brown oil.
  • 3-Bromo-2-furaldehyde (14.22 g, 81.3 mmol) is combined with ethylene glycol (6.55 mL, 117.4 mmol) and / ? ⁇ r -toluene sulfonic acid monohydrate (772 mg, 4.06 mmol) in benzene (200 mL) and heated to reflux with a Dean-Stark trap for 5 h. Additional ethylene glycol (1.64 mL, 29.41 mmol) and benzene (150 mL) are added and the solution is heated for an additional 2 h. The mixture is cooled to RT, treated with saturated NaHCO and stined for 0.5 h.
  • 2-(l,3-Dioxolan-2-yl)-3-furaldehyde (2.91 g, 17.31 mmol) is combined with formic acid (17 mL, 451 mmol) and water (4.25 mL) and stined at RT for 18 h.
  • the mixture is slowly transfened into a solution of NaHCO 3 (45 g, 541 mmol) in water (600 mL), then strined for 0.5 h.
  • EtOAc 200 mL
  • the combined organics are dried (Na 2 SO ) and concentrated to a yellow oil (3.28 g).
  • Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) is dissolved in CHC1 3 (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stined for 5 min then added dropwise to a 0°C solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHC1 3 (80 mL).
  • the mixture is stined for 2.5 h as the cooling bath expires then 5.5 h at RT and finally 24 h at 50°C.
  • the mixture is concentrated in vacuo to a yellow oily-solid (6.66 g).
  • Methyl furo[3,2-cJpyridine-6-carboxylate (1.55 g, 8.74 mmol) is dissolved in MeOH (30 mL) and H 2 O (15 mL), treated with 3 N NaOH (6.4 mL) and stirred at RT for 7 h.
  • the mixture is concentrated to dryness, dissolved in H O (10 mL) and acidified to pH 2 with concentrated HCl.
  • the solution is concentrated to dryness, suspended in a smaller amount of water (7 mL) and the resulting solid collected via filtration (lot A).
  • the filtrate is concentrated, triturated with water (3 mL) and the resulting solid collected via filtration (lot B).
  • Oxalyl chloride (3.1 mL, 35 mmol) is dissolved in 200 mL CH 2 C1 2 in a dried flask under N 2 .
  • the flask is placed in a dry-ice/acetone bath at -78°C, DMSO (4.95 mL, 70 mmol) in 10 mL CH 2 C1 2 is added drop-wise, and the mixture is stirred for 20 min.
  • (7-Chlorofuro[2,3-cJpyridin-5-yl)methanol (I-4-D (5.5 g, 30 mmol) in 10 mL CH C1 2 is added, and the reaction is stirred 30 min at -78°C.
  • TEA (21.3 mL, 153 mmol) is then added.
  • I-6-D (3.0 g, 16.5 mmol) is dissolved in 40 mL DMSO.
  • KH 2 PO 4 (561 mg, 4.1 mmol) in 6.5 mL H 2 O is added and then NaClO 2 (2.6 g, 23.1 mmol) in 24 mL H 2 O is added, and the reaction is stined overnight at rt.
  • the reaction is diluted with 200 mL H 2 O, the pH is adjusted to 9 with 2N NaOH, and any remaining aldehyde is extracted into 3 x 50 L ether.
  • the pH of the aqueous layer is adjusted to 3 with 10% aqueous HCl and is extracted with 4 x 50 mL EtOAc.
  • Oxalyl chloride (869 ⁇ L, 9.9 mmol) is dissolved in 50 mL CH 2 C1 2 in a dry flask under N 2 .
  • the flask is placed in a dry-ice/acetone bath at -78°C, DMSO (1.41 mL, 19.8 mmol) in 5 mL CH 2 C1 2 is added drop-wise, and the mixture is stined for 20 min. 1-21-D (1.53 g, 8.5 mmol) in 5 mL CH C1 2 is then added, and the reaction is stined 30 min at -78°C.
  • TEA (5.9 mL, 42.5 mmol) is added and the reaction is stirred 20 min at -78°C.
  • 1-22-D (1.35 g, 7.62 mmol) is dissolved in 40 mL THF, 20 mL t-butanol, and 20 mL H 2 O.
  • KH 2 PO 4 (3.1 lg, 22.9 mmol) and NaClO 2 (2.58 g, 22.9 mmol) are added, and the reaction is stined over the weekend at rt.
  • the reaction is concentrated in vacuo to a residue.
  • the residue is partitioned between 20 mL water and CH 2 C1 2 (2 x 50 mL).
  • I-24-D (2.0 g, 10.8 mmol) is added to 500 mg 10% Pd/C catalyst in 25 mL EtOH in a 250 mL Pan shaker bottle. 2N NaOH (6 mL, 12 mmol) is added, and the reaction is hydrogenated at 20 PSI for 6 h. The catalyst is removed by filtration, and the filtrate is concentrated in vacuo to an aqueous residue. The residue is partitioned between 50 mL 50% saturated NaCl and 30 mL CH 2 C1 2 . The organic layer is dried (K 2 CO ), filtered, and then concentrated in vacuo to afford (2-methylfuro[2,3- c]pyridin-5-yl)methanol (I-25-D (77% yield).
  • the mixture is concenfrated to dryness, dissolved in IN NaOH (75 mL), and extracted with CH 2 CI 2 (4 x 50 mL). The combined organic layer is dried (K 2 CO 3 ), filtered, and concenfrated to a white solid (2.0 g). The crude material is adsorbed onto silica gel (4 g) and chromatographed over a standard 40 g Biotage column, eluting with 90%
  • Oxalyl chloride (1.16 mL, 13.2 mmol) is added to CH 2 C1 2 (30 mL) in a dry flask under N 2 and in a dry-ice/acetone bath at -78°C.
  • DMSO (18.80 mL, 26.5 mmol) is slowly added.
  • the solution is stined for 20 min, and I-54-D (1.88 g, 11.5 mmol) is added.
  • the mixture is stined for 1 h at -78°C, then 30 min at 0-5°C.
  • the material is washed with saturated NaHCO 3 (75 mL), dried (K 2 CO 3 ), filtered, and concentrated in vacuo to a yellow solid (3.23 g).
  • the layers are separated and the residual aldehyde extracted with additional ether.
  • the aqueous layer is acidified to pH 3 with concentrated HCl, then extracted with CH 2 ⁇ 2 (4 X). Large amounts of acid remained in the aqueous layer, so the aqueous layer is concentrated to dryness.
  • the solid is triturated with CHC1 3 (4 X), and then 10% MeOH/CH 2 Cl 2 (4 X) to extract much of the acid into the supernatant.
  • the combined organic layer is dried (Na 2 SO 4 ), filtered, and concentrated to a tan solid (1.69 g, greater than 100% isolated yield).
  • the solid is diluted with CHC1 3 and is heated to reflux for 3 h.
  • Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 min) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) under N 2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stined for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes. The reaction is warmed to 65°C for 15h in an oil bath.
  • 2-Nitrothiophene (33.76 g, 261.4 mmol) is suspended in concentrated HCl (175 mL) and heated to 50°C.
  • Stannous chloride (118.05 g, 523.2 mmol) is added portionwise, maintaining the reaction temperature between 45-50°C with an ice bath, that is removed after the addition.
  • the solution is allowed to cool slowly to 30°C over an hour.
  • the solution is then cooled in an ice bath and filtered.
  • the cake is washed with concentrated HCl (20 mL), dried in a stream of air, and washed with ether (50 mL) to afford the hexachlorostannate salt of 2-aminothiophene as a brown solid (26% yield).
  • 3,3-Dimethyl-2-formyl propionitrile sodium (3.33 g, 20.2 mmol) can readily be prepared from the method described by Bertz, S.H., et al., J. Org. Chem., Al, 2216- 2217 (1982).
  • 3,3-Dimethyl-2-formyl propionitrile sodium is dissolved in MeOH (40 mL), and concentrated HCl (4 mL) and the hexachlorostannate salt of 2- aminothiophene (10.04 g, 19.1 mmol) in MeOH (130 mL) is slowly added drop-wise to the mixture.
  • 4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stining in lOOOmL 1:1 saturated NaHCO 3 /ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2 x 175 mL), and the combined organic layer is dried (MgSO ), filtered, and concentrated to an oil. THF (300 mL) is chilled to -70°C in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6mL.
  • I-150-D (11.6 g, 51.5 mmol) is dissolved in absolute MeOH (120 mL) and chilled in an ice bath. Concentrated sulfuric acid (2.0 mL) is carefully added drop- wise. The ice bath is allowed to expire as the solution stined for 2 days. The reaction is quenched by pouring onto a mixture of 500 g ice with saturated NaHCO solution (400 mL).
  • I-151-D (11.76 g, 46.4 mmol) is dissolved in toluene (50 mL) under N 2 and heated to 70°C.
  • Phosphorous trichloride (23.2 mL, 46.4 mmol) is added drop-wise via syringe, and the solution is stined for 18 h at 70°C.
  • Trimethyl phosphite (5.47 mL, 46.4 mmol) is then added drop-wise, and stirring continued for an additional 2 h at 70°C.
  • the mixture is concentrated in vacuo to an oil, and the crude material is dissolved in EtOAc (100 mL) and washed with saturated NaHCO 3 (3 x 50 mL).
  • 2,3-Thiophene dicarboxaldehyde (1.40 g, 9.99 mmol) is dissolved in CH 2 C1 2 (100 mL) and the flask is placed in an ice bath.
  • 1-152-D (2.63 g, 11.0 mmol) is dissolved in CH 2 C1 2 (50 mL), l,8-diazabicyclo[5.4.0Jundec-7-ene (1.65 mL, 11.0 mmol) is added, and this solution is added drop-wise to the chilled thiophene solution.
  • the reaction mixture is stined for 1 h while the flask is in an ice bath and then over night at rt.
  • the reaction is concentrated in vacuo, and the crude material is chromatographed over 300 g slurry-packed silica eluting with 50% EtOAc/hexane. The fractions were collected in two different groups to obtain the desired compounds. Each group of fractions is combined and concentrated separately. The first group of fractions affords methyl thieno[2,3-cJpyridine-5-carboxylate (I-154-D) as a white solid (41%) yield), and the second group of fractions affords methyl thieno[3,2- cJpyridine-6-carboxylate (I-155-D) as a yellow solid (38% yield).
  • Methyl thieno[3,2-cJpyridine-6-carboxylate (I-155-D) (678 mg, 3.5 mmol) is dissolved in MeOH (16 mL) and H 2 O (2 mL).
  • 2M NaOH (1.8 mL, 3.6 mmol) is added drop-wise, and the solution stirred at rt. After 2 days (complete disappearance of ester by TLC), the solution is concentrated in vacuo. The residue is dissolved in H 2 O (12 mL), and the pH is adjusted to 3.5 with 10% HCl.
  • 2,4-Lutidine (51.4 mL, 0.445 mole) is added drop-wise to 250 mL fuming sulfuric acid in a flask under N 2 in an ice bath.
  • the solution is treated portionwise with potassium nitrate (89.9 g, 0.889 mole) over a 15 min period.
  • the reaction is stined lh in an ice bath, 2 h at rt, is gradually warmed in a 100°C oil bath for 5 h, and then in a 130°C oil bath for 4 h.
  • the mixture is cooled, is poured into 1000 mL ice, and the mixture is neutralized with NaHCO 3 (1,100 g, 13.1 mole).
  • I-174-D (500 mg, 3.42 mmol) is dissolved in 1.5 mL fonnic acid. The solution is cooled in an ice bath, 30% aqueous hydrogen peroxide (722 ⁇ L, 6.8 mmol) is added drop-wise, and the reaction is stined 1 h in an ice bath, and allowed to stand overnight at 5°C. The mixture is diluted with H 2 O, the solid is collected, washed with H 2 O and is dried to give 522 mg of an off-white solid. The formate salt is added to 7 mL H 2 O, 3 mL 2N NaOH is added, and the pH is adjusted to 3 with 5% aqueous HCl.
  • I-175-D (920 mg, 4.5 mmol) is dissolved in 25 mL 10% aqueous acetonitrile in a flask.
  • p-Toluene sulfonic acid (630 mg, 3.3 mmol) is added, and the mixture is heated to 90°C for 8 h. The mixture is cooled to rt, concentrated in vacuo, and the residue is partitioned between 15 mL saturated NaHCO 3 and CH 2 C1 2 (4 x 10 mL).
  • Furo[2,3-c]pyridin-5-ylmethyl acetate (5.17 g, 27.05 mmol) is dissolved in CH 2 C1 2 (130 mL), layered with saturated NaHCO 3 (220 mL), treated with Br 2 (8.36 mL, 162.3 mmol) and stined very slowly for 4.5 h at rt.
  • the mixture is stined vigorously for 30 min, is diluted with CH 2 Cl 2 (100 mL) and the layers separated.
  • the aqueous layer is exfracted with CH 2 C1 2 (2 x 100 mL) and the combined organics are concenfrated to a small volume under a stream of nitrogen.
  • the solution is diluted with EtOH (200 mL), treated with K 2 CO 3 (22.13 g, 160.1 mmol) and stirred for 2.5 days at rt.
  • the mixture is concentrated to dryness, partitioned between 50% saturated NaCl (200 mL) and CH 2 C1 2 (5 x 200 mL), dried (Na 2 SO ) and concentrated in vacuo to a yellow solid (6.07 g).
  • the crude material is adsorbed onto silica gel (12 g) and chromatographed over 250 g slurry-packed silica gel, eluting with a gradient of 50% EtOAc / hexane to 100% EtOAc.
  • Oxalyl chloride (1.77 mL, 20.1 mmol) is combined with CH 2 C1 2 (60 L) in a dried flask under nitrogen, cooled to -78°C, treated dropwise with DMSO (2.86 mL, 40.25 mmol) and stined for 20 min.
  • the cooled solution is treated drop-wise with a solution of (3-bromofuro[2,3-c]pyridin-5-yl)methanol (4.0 mg, 17.5 mmol) in THF (50 mL), stined for 1 h, then treated drop-wise with Et 3 N (12.2 mL, 87.5 mmol).
  • the mixture is stirred for 30 min at -78°C, then 30 min at 0°C.
  • 3-Bromofuro[2,3-cJpyridine-5-carbaldehyde (3.26 g, 14.42 mmol) is dissolved in THF (100 mL)/t-BuOH (50 mL)/H 2 O (50 mL), treated with a single portion of NaOCl 2 (4.89 g, 43.3 mmol) and KH 2 PO 4 (3.92 g, 28.8 mmol) and stined at rt for 18 h.
  • the white solid is collected via filtration and the filtrate is concentrated in vacuo to dryness.
  • the residue is suspended in water (25 mL), acidified to pH 2 with concentrated HCl and the resulting solid collected via filtration.
  • Furo[2,3-c]pyridin-5-ylmethyl acetate (956 mg, 5 mmol) is dissolved in CH 2 C1 2 (40 mL) and cooled to 0°C. Chlorine gas is bubbled through the solution for 15 min, the cooling bath is immediately removed and the mixture stined for 2 h. The mixture is re-cooled to 0°C, saturated with chlorine gas, the cooling bath removed and the solution warmed to rt. The solution is layered with saturated NaHCO 3 (20 mL), stined gently for 2 h then stined vigorously for 15 min.
  • the mixture is diluted with saturated NaHCO 3 (50 mL), exfracted with CH 2 C1 2 (1 x 40 mL then 1 x 20 mL), dried (K 2 CO 3 ) and concentrated to a volume of 20 mL under a stream of nitrogen.
  • the solution is diluted with EtOH (35 mL), treated with K 2 CO 3 (4.09 g, 29.6 mmol) and stined for 18 h at rt. Water (7 mL) is added and the mixture stined for 2 days.
  • Oxalyl chloride (231 ⁇ L, 2.6 mmol) is combined with CH 2 C1 2 (10 mL), cooled to -78°C, treated dropwise with DMSO (373 ⁇ L, 5.3 mmol) and stined for 20 min.
  • the cooled solution is treated dropwise with a solution of (3-chlorofuro[2,3-cJpyridin- 5-yl)methanol (420 mg, 2.3 mmol) in THF (5 mL) / CH 2 C1 2 (5 mL), stined for 1 h, then treated dropwise with Et 3 N (1.59 mL, 11.45 mmol).
  • the mixture is stined for 30 min at -78°C, then 30 min at 0°C.
  • 3-CMorofuro[2,3-cJpyridine-5-carbaldehyde (317 mg, 1.74 mmol) is dissolved in THF (10 mL)/t-BuOH (5 mL)/H 2 O (5 mL), treated with a single portion of sodium chlorite (592 mg, 5.24 mmol) and KH 2 PO 4 (473 mg, 3.48 mmol) and stined at rt for 18 h.
  • the reaction mixture is concentrated in vacuo to dryness, suspended in water (10 mL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h.
  • N-butyl lithium (150.6 ml, 241 mmol) is added dropwise to ether (100 ml) at -20°C under N 2 .
  • 3-Bromothianaphthene (10.5 ml, 80.3 mmol) is dissolved in ether (50 ml) and also added dropwise to the chilled solution, stirring cold for 0.5 h.
  • DMF (16.3 ml, 210 mmol) is dissolved in ether (75 ml) and added dropwise, and the solution stined an additional 15 h at -20°C.
  • the reaction is quenched onto ice (300 g) in 10% H 2 SO 4 (200 ml) and stined until both layers turn yellow in color.
  • Methyl (acetylamino)(dimethoxyphosphoryl) acetate (1-152-D) (2.63 g, 11.0 mmol) is dissolved in CH 2 C1 2 (50 ml) and added to l,8-diazabicyclo[5.4.0Jundec-7-ene (1.65 ml, 11.0 mmol), stirring for 5 minutes. This solution is added dropwise to the chilled thiophene solution. The reaction mixture is stined in the ice bath for 1 h and then over night at rt.
  • 3,4-Dibromothiophene (12.5 ml, 113 mmol) is combined with CuCN (30.4 g, 339 mmol) in DMF (40 ml) in a dry flask under nitrogen utilizing an over-head stiner.
  • the reaction is allowed to reflux at 180°C for 5 h.
  • the dark mixture is then poured into a solution of FeCl 3 (113.6 g, 700 mmol) in 1.7M HCl (200 ml) and heated at 65°C for 0.5 h, again using the over-head stiner.
  • the reaction is cooled to rt and extracted with CH 2 C1 2 (7 x 300 ml).
  • 3,4-Dicyanothiophene (5.0 g, 37.2 mmol) is suspended in benzene (150 ml) in a dry flask under nitrogen utilizing an over-head stiner.
  • Diisobutyl aluminum hydride (1.0M in toluene) (82.0 ml, 82.0 mmol) is added dropwise, and the reaction stined at rt for 2 h. The reaction is then carefully quenched with MeOH (5 ml) and poured onto 30% H 2 SO 4 (60 ml) with ice (200 g). The slurry is stined until all lumps are dissolved, and the layers are allowed to separate.
  • Methyl (acetylamino)(dimethoxyphosphoryl)acetate (1.88 g, 7.85 mmol) is dissolved in CH 2 C1 2 (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). This solution is added dropwise to the chilled thiophene solution after stirring for 5 min. The reaction mixture is stirred at 0°C for 1 h and then overnight at rt. The volatiles are removed in vacuo and the crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane. The appropriate fractions are combined and concentrated to yield 2.09 g of the carbinol intermediate as a white foam.
  • Methyl thieno[3,4-c]pyridine-6-carboxylate (250 mg, 1.3 mmol) is dissolved in MeOH (7 ml) and water (1 ml). 2M NaOH (0.72 ml, 1.43 mmol) is added drop- wise. The reaction is stirred overnight at rt and is monitored by TLC. The volatiles are removed in vacuo and the residue is dissolved in water (2 ml). 10% HCl is used to adjust the pH to 3, and the reaction again stined overnight at rt. The aqueous solution is extracted repeatedly with EtOAc (20 x 10 ml). The combined organics are dried (MgSO 4 ), filtered, and concentrated to a yellow solid.
  • the organic layer is extracted several times with Vi saturated aqueous sodium carbonate solution.
  • the organic layer is washed with water, dried (MgSO ), filtered, and concentrated in vacuo to give a mixture (92%) of recovered starting material methyl 2,3-dihydrobenzofuran- 5-carboxylate and methyl benzofuran-5-carboxylate in a ratio of 1 :3.
  • the crude product is purified by preparative HPLC using a Chiralcel O J column.
  • a stined mixture of methyl benzofuran-5-carboxylate (1.3 g, 7.38 mmol) in MeOH (51 mL) and sodium hydroxide (41 mL of a 5 % aqueous solution) is heated to 65°C for 4 h.
  • the mixture is cooled to rt, and MeOH was removed in vacuo.
  • the remaining aqueous layer is exfracted with CH 2 C1 2 .
  • the aqueous layer is extracted with CHC1 3 .
  • Acid A can be prepared from ethyl 4,5-dihydroxypyridine-2-carboxylate (see Z.
  • R E - I or R E - 2 where E° is CH and E 1 and E 2 are each Oais described in Taniguchi, Eiji, et al., Biosci. Biotech. Biochem., 56 (4), 630-635, 1992. See also Henning, R.; Lattrell, R.; Gerhards, H. J.; Leven, M.;
  • E° is N
  • at least one R E - I and/or at least one R E - 2 is other than H and is not a bond
  • the compounds can be obtained using methods described herein for where E° is CH.
  • a suspension of calcium ethoxide (816mg, 6.3mmol), butene oxide (5.2mL, 93mmol) and 2,4-diiodophenol (2.17g, 6.3n ⁇ mol) is heated in a sealed flask at 80°C for 18 h.
  • the reaction mixture is allowed to cool, poured into IN ⁇ C1 and extracted three times with C ⁇ 2 C1 2 .
  • the combined organic extracts are dried (Na 2 SO ), filtered and concentrated in vacuo.
  • Intennediate E4 is obtained following the procedures discussed for Intermediate E3, making non-critical changes, and starting with [(2S)-7-bromo-2,3- dihydro- 1 ,4-benzodioxin-2-ylJmethanol
  • Ada. Chemica. Scandinavica 1999, 53, 258] (1.9 g, 10.0 mmol) and anhydrous K 2 CO 3 (2.7 g, 19.5 mmol) in acetone (30 mL) is added allyl bromide (1.7 mL, 19.8 mmol). The mixture is heated in a 60°C oil bath for 2 h.
  • the flask After stirring in the 90°C bath for an additional 4 h, the flask is placed in ice bath, and the contents are treated with 100 ml of crushed ice, acidified with 39 ml of 6 N HCl to pH 1 , and the precipitated material is stined for 1.5 h in an ice bath. The undesired solid is removed by filtration, and the filtrate is exfracted seven times with EtOAc.
  • 2-Chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (5.7 g, 20 mmol) is combined with bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) in 50 ml DMF under nitrogen.
  • the mixture is treated with tetravinyl tin, is warmed to 60°C for 6 h followed by 50°C for 18 h, and at rt for 72 h.
  • the mixture is diluted with 250 ml EtOAc and is extracted with 4 x 100 ml 2:1 :1 water/saturated NaCl/saturated NaHCO 3 .
  • the organic layer is dried (MgSO ) and is concentrated in vacuo to a yellow oil.
  • Oxalyl chloride (452 ⁇ L, 5.1 mmol) is dissolved in 15 ml CH 2 C1 2 under nitrogen at -78°C. The solution is treated drop-wise with DMSO (729 ⁇ L, 10.3 mmol) in 5 ml CH 2 C1 2 and the mixture is stined 30 min at -78°C.
  • DMSO 7.29 ⁇ L, 10.3 mmol
  • 3,4-Dihydro-2H- pyrano[2,3-c]pyridin-6-ylmethanol (731 mg, 4.4 mmol) is added drop-wise to the reaction mixture in 5 ml CH C1 2 and the reaction is stined 30 min at -78°C.
  • the mixture is treated with TEA (3.08 ml, 22.1 mmol), is stirred 30 min at -78°C and 2 h at 0°C.
  • the mixture is washed with 1 x 10 ml saturated NaHCO 3 , is dried (K 2 CO 3 ), and is concentrated in vacuo.
  • the crude intermediate is chromatographed over 25 g SiO 2 (230-400 mesh) eluting with 35% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 685 mg (95%) of the aldehyde as an off-white solid.
  • the aldehyde (685 mg, 4.2 mmol) is combined with NaClO 2 (80%, 1.42 g,
  • 2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO 3 (19.5g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask.
  • the flask is placed in an oil bath at 90°C, and after 5 minutes, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3 8 mL, then 2.2 mL all at 90-minute intervals and then the final 2.3 mL after the reaction had stined for 15 h at 90°C.
  • the reaction is stined at 90°C for another 4 h and then is cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stined for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc.
  • the mixture is stined until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt.
  • the pH of the mixture is adjusted to 3 with 2N NaHSO 4 , and the mixture is extracted with 4 x 50 mL EtOAc.
  • the combined organic layer is dried (MgSO 4 ), is filtered ⁇ and the filtrate is concenfrated in vacuo to a yellow solid.
  • I-13-F maybe oxidized to 4-(benzylamino)-2-chloro-3-hydroxypyridine-6- carboxaldehyde (I-14-F) under a wide variety of conditions (e.g., TPAP andNMO in CH 2 C1 ).
  • I-14-F may be oxidized to produce the conesponding carboxylic acid I-l 5-F using an oxidizing reagent such as NaClO 2 and KH 2 PO 4 in DMSO/H O or Ag 2 O, or hydrogen peroxide or ruthenium tetroxide.
  • Removal of the benzyl group and the chloro group of Acid I-l 5-F may be accomplished by utilizing hydrogen or a hydrogen source (e.g., cyclohexene, cyclohexadiene, ammonium formate, hydrazine, etc.) in the presence of Pd C or other catalyst, under a variety of conditions and in various solvents, to produce 4-amino-5- hydroxypyridine-2-carboxylic acid (Acid I-16-F).
  • hydrogen or a hydrogen source e.g., cyclohexene, cyclohexadiene, ammonium formate, hydrazine, etc.
  • Cyclocondensation of Acid I-16-F with trimethyl orthoformate in the presence of catalytic j? ⁇ r ⁇ -toluenesulfonic acid may be conducted to produce [l,3]oxazolo[5,4- cJpyridine-6-carboxylic acid.
  • Intermediate F7 can be made by the saponification of the methyl ester I-20-E, which can be made pursuant to Wynberg, Hans, et al., Reel. Trav. Chim. Pays-Bas (1968), 87(10), 1006-1010.
  • a solution of sodium sulfide anohydrate (1.15 g, 4.9 mmol) in methanol- water (ca. 10 mL, 1 : 1) is warmed on a hot plate.
  • elemental sulfur 150 mg, 4.6 mmol. Heating is continued for 15 min before the solution is poured into a separate solution of 1.0 g (4.6 mmol) of methyl 4-chloro-3- nifrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48, 837.) in MeOH (5.0 mL).
  • the mixture is heated in a 65°C oil bath for 30 min, followed by cooling to RT.
  • the mixture is diluted with water and extracted with hexanes-ether (1:1).
  • the aqueous layer is exfracted with ether.
  • the ethereal layer is dried (MgSO 4 ), filtered and concenfrated in vacuo to a yellow powder for 1,3- benzothiazole-5-carboxylic acid (260 mg, 98%): 1H NMR (400 MHz, DMSO-d 6 ) ⁇ 13-12.5, 9.5, 8.6, 8.3, 8.0.
  • Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) / CHC1 3 (40 mL) in a dry flask, under nitrogen.
  • TEA (8.14 mL ⁇ 58.4 mmol) is added and the mixture is heated to 50°C for 4 h.
  • Methyl 4-acetyl-3-hydroxybenzoate (350 mg, 1.8 mmole) is combined with 5 ml absolute EtOH. The solution is treated with hydroxylamine hydrochloride (125 mg, 1.8 mmole) dissolved in 0.9 ml 2N aqueous NaOH, and the reaction is stined overnight at rt. The volatiles are removed in vacuo and the residue is washed with H 2 O, collected, and dried to give 294 mg (78%) of methyl 3-hydroxy-4-[N- hydroxyethanimidoyljbenzoate as a tan solid. MS (El) m/z : 209 (M + ).
  • carboxylic acids can be synthesized by known procedures, or modification thereof, some of which are described herein.
  • 3-(pyrrolo[l,2-c]pyrimidine)carboxylic acid can be synthesized from the conesponding pyrrole-2-carboxaldehyde by reaction with an isocyanoacetate in the presence of base as described inJ. Org. Chem. 1999, 64, 7788 andJ Org. Chem. 1976, 41, 1482 or by methods described in Liebigs Ann. Chem. 1987, 491.
  • Scheme 1G depicts this transformation.
  • the pynolo[l,2-a]pyrazine acid fragment can be prepared using the methods shown in Scheme 2G.
  • the ester intermediate can be prepared using methods described in Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993, 49, 8139-46, whereby the requisite pyrrole-2-carboxaldehyde is reacted with aminoester diethylacetal to form the imine.
  • the imine can then be cyclized under acidic conditions to afford the desired bicyclic core.
  • the resulting ester can be hydrolyzed under typical hydrolysis procedures well known in the art to afford the requisite pynolo [ 1 ,2-a]pyrazine acids .
  • the pynole-2-carboxaldehydes can be obtained from commercial sources or can be synthesized by known procedures.
  • pynole-2-carboxaldehyde can be converted into 4-halo, 5-halo and 4,5-dihalopyrrole-2-carboxaldehydes as described in Bull. Soc. Chim. Fr. 1973, 351. See Examples 12-22.
  • substituted pyrroles can be converted into pyrrole carboxaldehydes by Nilsmeier formylation using procedures well known in the art (see J. Het. Chem. 1991, 28, 2053, Synth. Commun. 1994, 24, 1389 ox Synthesis, 1995, 1480.
  • Scheme 3G depicts these transfonnations.
  • Ethyl pynolo[l,2-c]pyrimidine-3-carboxylate (4.1g, 21.2mmol) is dissolved/suspended in lOOmL concentrated HCl. The mixture is heated under reflux.
  • Methyl nicotinate 1 -oxide (Coperet, C; Adolfsson, H.; Khuong, T-A. V.; Yudin, A. K.; Sharpless, K. B. J. Org. Chem. 1998, 63, 1740-41.) (5.0 g, 32.2 mmol) and dimethylsulfate (3.2 ml, 33.2 mmol) are placed in a 100 ml flask and heated to 65- 70°C for 2 h. Upon cooling a salt precipitates. The resulting precipitate is dissolved in water (12 ml).
  • the reaction mixture is heated to 35°C with an oil bath for 1 h.
  • the reaction mixture is cooled to 0°C in an ice-bath and neutralized with ammonium hydroxide at such a rate that the temperature did not rise above 5°C.
  • Pyrrolofl -2-a1pyrazine-3-carboxylic acid hydrochloride Procedure E: Pyrrole-2-carboxaldehyde (recrystallized from EtOAc/hexanes prior to use) (3.67 g, 38.6 mmol) is added to a solution of ethyl 3-ethoxy-O-ethylserinate (7.95 g, 38.6 mmol) in freshly distilled THF or CH 2 C1 2 (100 mL) in an oven dried 250 mL flask.
  • Procedure E Pyrrole-2-carboxaldehyde (recrystallized from EtOAc/hexanes prior to use) (3.67 g, 38.6 mmol) is added to a solution of ethyl 3-ethoxy-O-ethylserinate (7.95 g, 38.6 mmol) in freshly distilled THF or CH 2 C1 2 (100 mL) in an oven dried 250
  • Pyrrolo[l,2-aJpyrazine-3-carboxylic acid hydrochloride is prepared from ethyl pyrrolo[l,2-a]pyrazine-3-carboxylate, using Procedure B to give a pale brown solid. Yield 90%.
  • HRMS (FAB) calcd for C 8 H 6 O 2 N 2 +H 163.0508, found 163.0513,
  • Ethyl 9H-beta-carboline-3-carboxylate and ethyl pyrazino[l,2-a]indole-3- carboxylate are prepared according to Dekhane, M., et al, Tetrahedron, 49, 1993, 8139-46, to give a dark colored solid that is purified with silica gel chromatography (20% to 75% EtOAc/hexanes as the eluent) to give the ethyl 9H-beta-carboline-3- carboxylate as a brown solid (yield 16%) and the ethyl pyrazino[l,2-a]indole-3- carboxylate as a brown soild (yield 35%).
  • Phenyl chloroformate (0.75mL, 6. Ommol) is added dropwise to a solution of 4- iodopyrazole (1.05g, 5.4mmol) and TEA (0.9mL, 6.5mmol) in 15mL CH 2 C1 2 .
  • the reaction is stined at RT. After 60h, water is added.
  • the mixture is extracted with CH 2 C1 2 , dried (MgSO 4 ), filtered and concenfrated. Hexane is added and the solvent is removed in vacuo. A white solid forms on standing to provide 1.6g (95%) of phenyl 4-iodo-lH-pyrazole-l -carboxylate.
  • Phenyl 4-iodo-lH-pyrazole-l -carboxylate (1.6g, 5.2mmol) and (R)-(+)-3- aminoquinuclidine dihydrochloride (l.Og, 5.2mmol) are suspended in lOmL DMF.
  • DIEA (2.7mL, 15.5mmol) is added dropwise. After 36 h, the solvent is removed and the residue is taken up in IN NaOH and CHC1 3 . The aqueous layer is extracted with CHC1 3 , dried (MgSO ), filtered and concentrated.
  • Example 4(H) (0.142 g, 20 %) as a white solid: HRMS (ESI) calcd for CnH ⁇ 5 ⁇ 4 OI (MH+) 347.0370, found 347.0370. Anal. Calcd for CnHi 5 IN 4 O: C, 38.17; H, 4.37; N, 16.18. Found: C, 38.43; H, 4.42; N, 16.11. Materials and Methods for identifying binding constants: Membrane Preparation.
  • mice Male Sprague-Dawley rats (300-350g) are sacrificed by decapitation and the brains (whole brain minus cerebellum) are dissected quickly, weighed and homogenized in 9 volumes/g wet weight of ice-cold 0.32 M sucrose using a rotating pestle on setting 50 (10 up and down strokes). The homogenate is centrifuged at 1,000 x g for 10 minutes at 4 °C. The supernatant is collected and centrifuged at 20,000 x g for 20 minutes at 4 °C. The resulting pellet is resuspended to a protein concentration of 1 -8 mg/mL. Aliquots of 5 mL homogenate are frozen at -80 °C until needed for the assay.
  • 0.4 mL homogenate are added to test tubes containing buffer and various concenfrations of radioligand, and are incubated in a final volume of 0.5 mL for 1 hour at 25 °C.
  • Nonspecific binding was determined in tissues incubated in parallel in the presence of 0.05 ml MLA for a final concentration of 1 ⁇ M MLA, added before the radioligand.
  • drugs are added in increasing concentrations to the test tubes before addition of 0.05 ml [ 3 H]-MLA for a final concentration of 3.0 to 4.0 nM [ 3 H]-MLA.
  • the incubations are terminated by rapid vacuum filtration through Whatman GF/B glass filter paper mounted on a 48 well Brandel cell harvester.
  • Filters are pre-soaked in 50 mM Tris HCl pH 7.0 - 0.05 % polyethylenimine. The filters are rapidly washed two times with 5 mL aliquots of cold 0.9% saline and then counted for radioactivity by liquid scintillation spectrometry.
  • Pharmacokinetics of the compounds of formula I can be evaluated in mice to determine the ability of each compound to penetrate the blood-brain barrier. Each mouse receives a single intravenous administration at 5 mg/kg. Blood samples are collected by serial sacrifice at 5 min (IN only), 0.5, 1, 2, 4, and 8 h after dosing with two mice per collection time. Blood was placed into tubes containing heparin and centrifuged for plasma. Brain samples were also collected at 0.5 and 1 h increments from the same mouse used for blood collection. Plasma and brain samples were analyzed for drug concentrations using a LC-MS/MMS method.
  • nAChR al Nicotinic Acetylcholine Receptor
  • nAChR full agonist examples provided above.
  • three drugs are used in combination it is prefened that one be an al nAChR full agonist.
  • the combinations of drugs may be administered either at the same or different times, either in the same or different form, hi one embodiment they may be given a month apart or they may be given in a co-administration where the two or three drugs are given on or about the same time in the same manner.
  • the combination refers to administration such that the patients blood contains the two, three or four drugs at the same time at some point during freatment.

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Abstract

The present invention relates to compositions and methods to treat diseases or condition with an α nAChR full agonist and an inhibitor of cholinesterase, and or beta secretase and or gamma secretase.

Description

TREATMENT OF DISEASES WITH COMBINATIONS OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONISTS AND OTHER COMPOUNDS
FIELD OF INVENTION
The present invention relates to compositions and methods to treat diseases or condition with a Nicotinic acetylcholine receptors (liAChRs) full agonist relative to nicotine plus either an inhibitor of cholinesterase, and/or a beta secretase inhibitor, and/or a gamma secretase inhibitor collectively referred to as "inhibitors."
BACKGROUND OF THE INVENTION
The al nAChR is one receptor system that has proved to be a difficult target for testing. Native al nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68(5):2140-51). Another feature that makes functional assays of α7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the al nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the α7 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the al nAChR is a calcium channel while the 5-HT3R is a sodium and potassium chamiel. Indeed, Eisele et al. teaches that the chicken al nAChR/ mouse 5-HT3R behaves quite differently than the native al nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years. Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and beta amyloid (or neuritic) plaques, comprised predominantly of an aggregate of a peptide fragment know as A beta. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders. On autopsy, large numbers of these lesions are generally found in areas of the human brain important for memory and cognition.
Beta-amyloid is a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Deposition of A beta in areas of the brain responsible for cognitive activities is a major factor in the development of AD. Beta-amyloid plaques are predominantly composed of amyloid beta peptide (A beta, also sometimes designated betaA4). A beta peptide is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-42 amino acids. Several proteases called secretases are involved in the processing of APP.
Cleavage of APP at the N-terminus of the A beta peptide by beta-secretase and at the C-terminus by one or more gamma-secretases constitutes the beta- amyloidogenic pathway, i.e. the pathway by which A beta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation. This alternate pathway precludes the formation of A beta peptide. A description of the proteolytic processing fragments of APP is found, for example, in U.S. Patent Nos. 5,441,870; 5,721,130; and 5,942,400.
An aspartyl protease has been identified as the enzyme responsible for processing of APP at the beta-secretase cleavage site. The beta-secretase enzyme has been disclosed using varied nomenclature, including BACE, Asp, and Memapsin. See, for example, Sinha etal., 1999, Nature 402:537-554 (p501) and published PCT application WO00/17369. Several lines of evidence indicate that progressive cerebral deposition of beta- amyloid peptide (A beta) plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, 1991, Neuron 6:487. It has been proposed that A beta peptide accumulates as a result of APP processing by beta secretase and or gamma secretase thus inhibition of either enzymes' activity maybe desirable for the treatment of AD. In vivo processing of APP at the beta-secretase cleavage site is thought to be a rate-limiting step in A beta production, and it, thus, may be a good therapeutic target for the treatment of AD. See for example, Sabbagh, M., et al., 1997, Ah. Dis. Rev. 3, 1-19.
Cognitive disorders, including Alzheimer's disease, are generally accompanied by symptoms of forgetfulness, confusion, memory loss and other symptoms resulting from aging, brain injury, or disease. The concomitant decrease in cognitive function during the aging process has been documented in various mammals, including humans. In particular, presenile and senile primary degenerative dementia appear to be common causes of mental deterioration among the elderly. The symptoms of cognitive disorder appear to be associated with decreased acetylcholine synthesis as well as impairment of the ACh receptive neurons. The activity of the enzyme choline acetyltransferase (ChAT), which catalyzes the synthesis of acetylcholine from choline and acetyl coenzyme A, can be severely reduced as reflected by the loss of cholinergic (acetylcholme releasing) nerve endings in the hippocampus. Conversely, alpha 7 nAChRs are generally intact. The cholinergic neurotransmission are thus recognized as critically important to memory function.
Presently, there are three general approaches to enhance cholinergic transmission in the central nervous system. The first approach is to enhance cholinergic neurons by excessive exposure to a form of choline. Such attempts have been mildly successful, but only in the early stages of Alzheimer's disease.
The second approach involves postsynaptic direct stimulation of alpha 7 nAChRs. The third approach involves the inhibition of acetylcholinesterase, the enzyme that metabolizes acetylcholine. Accordingly, new compositions and methods for treating diseases resulting from cholinergic hypofunction are desired. SUMMARY OF THE INVENTION
The present invention is useful for the treatment of, or preparation of a medicament for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR receptor is implicated, including any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
Diseases to be treated within the scope of the present invention, including Alzheimer's disease, are chronic neurodegenerative disorders. Acetylcholine- synthesizing neurons in the basal forebrain region and their cortical synaptic connections exliibit a well-characterized degeneration in Alzheimer's disease. The symptoms of this degeneration and can be treated with the drug combinations described herein.
Embodiments of the invention may include one or more or combination of the following. The present invention claims the method of treating the diseases discussed herein or preparing a medicament to so treat, using any compound that is a full agonist to an al Nicotinic Acetylcholme Receptor (nAChR) or al nAChR full agonists, described either herein or elsewhere to be administered with either: I) a cholinesterase inhibitor, II) a beta secretase inhibitor, III) a gamma secretase inhibitor or any combination of one, two, or three of the different inhibitors in combination with a al nAChR full agonists. The use of the term al nAChR full agonist is used interchangeably with α7 nAChR agonists when discussing the compounds of the present invention. Another aspect of the present invention includes al nAChR full agonists as described for example, but not by way of limitation, in any one or more of the following patents and published applications: WO 01/60821 Al, WO 01/36417A1, WO 02/100857A1, WO 03/042210A1, and WO 03/029252A1, all of which are incorporated herein by reference. In particular, by way of example and not limitation, some al nAChR full agonist are the compounds of Formula I as described herein. The method or use of a compound of Formula I, where X is O, or X is S, and where the other variables of Formula I have any definition discussed herein.
The method or use of a compound of Formula I, where Azabicyclo is any one or more of I, II, III, IN, N, NI, or NIL The method or use of a compound of Formula I, where W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H).
The present invention also includes pharmaceutical compositions containing the active compounds, and methods to treat the identified diseases.
The present invention is useful for the treatment of, or preparation of a medicament for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR is implicated, including any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
Another aspect of the present invention includes the method or use of a compound of Formula I, where Azabicyclo is any one or more of I, II, III, IN, N, NI, or NIL The method or use of a compound of Formula I, where Ri is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl; each R2 is independently F, CI, Br, I, alkyl, substituted alkyl, haloalkyl, cycloalkyl, aryl, or R2 is absent provided that kι-2, kι-6, k2, k5, k6, or k7 is 0; and R2.3 is H, F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl. The method or use of a compound of Formula I, where the variables of formula I have any definition discussed herein.
Another aspect of the present invention includes the method or use of a compound of Formula I, where W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H). The method or use of a compound of Formula I, where W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H). The method or use of a compound of Formula I, where W is any one or more of (A), (B), (C), (D), (E), (F), (G), or (H), wherein the variables within each has any definition allowed. For example, and not by way of limitation, W includes any one or more of the following: 4-chlorobenz-l- yl; dibenzo[b,d]thiophene-2-yl; isoquinoline-3-yl; furo[2,3-c]pyridine-5-yl; 1,3- benzodioxole-5-yl; 2,3-dihydro-l ,4-benzodioxine-6-yl; 1 ,3-benzoxazole-5-yl; thieno[2,3-c]pyridine-5-yl; thieno[3,2-c]pyridine-6-yl; [l]benzothieno[3,2-c]pyridine-
3-yl; l,3-benzothiazole-6-yl; thieno[3,4-c]pyridine-6-yl; 2,3-dihydro-l-benzofuran-5- yl; l-benzofuran-5-yl; furo[3,2-c]pyridine-6-yl; [l]benzothieno[2,3-c]pyridine-3-yl; dibenzo[b,d]furan-2-yl; l-benzofuran-6-yl; 2-naphthyl; lH-indole-6-yl; pyrrolo[l,2- c]pyrimidine-3-yl; l-benzothiophene-5-yl; l-benzothiophene-5-yl; 1-benzothiophene-
6-yl; pyrrolo[l,2-a]pyrazine-3-yl; lH-indole-6-yl; pyrazino[l,2-a]indole-3-yl; 1,3- benzothiazole-6-yl; [l]benzofuiO[2,3-c]pyridine-3-yl; [l]benzofuro[2,3-c]pyridine-3- yl; 2H-chromene-6-yl; indolizine-6-yl; and [l,3]dioxolo[4,5-c]pyridine-6-yl; any of which is optionally substituted as allowed in formula I. One of ordinary skill in the art will recognize how the variables are defined by comparing the named radicals with the different values for W. When W is (D), it is preferred that one of RD-ι is the bond to C(X). Specific compounds within the scope of this invention include any one or more of the following as the free base or as a pharmaceutically acceptable salt thereof:
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]dibenzo[b,d]thiophene-2-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]isoquinoline-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzodioxole-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;
N- [( 1 S ,2R,4R)-7-azabicyclo [2.2.1 ]hept-2-yl] isoquinoline-3 -carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-methylfuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzoxazole-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methyl-l,3-benzoxazole-5-carboxamide;
N-[(l S,2R,4R)-7-azabicyclo[2.2.1 ]hept-2-yl]thieno[2,3-c]pyridine-5-carboxamide; N-[(l S,2R,4R)-7-azabicyclo[2.2. l]hept-2-yl]thieno[3,2-c]pyridine-6-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-isopropylfuro[2,3-c]pyridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]tbieno[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6-carboxamide;
5-{[(2R)-7-azoniabicyclo[2.2.1]hept-2-ylamino]carbonyl}-3-ethylfuro[2,3-c]pyridin-
6-ium dichloride; 5-{[(2R)-7-azoniabicyclo[2.2.1]hept-2-ylamino]carbonyl}-3-isopropylfuro[2,3- c]pyridin-6-ium dicliloride;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N- 1 -azabicyclo[2.2.2]oct-3-yl[ 1 ]benzothieno[3,2-c]pyridine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzothiazole-6-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-chlorofuro[2,3-c]pyridine-5-carboxamide;
N-l-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,4-c]pyridine-6-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-3-methylfuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,3-dihydro-l-benzofuran-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]thieno[2,3-c]pyridine-5-carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzofixran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]thieno[3,2-c]pyridine-6-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-ethylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-isopropylfuro[2,3-c]pyridine-5- carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-chlorofuro[2,3-c]pyridine-5- carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-chlorofuro[2,3-c]pyridine-5-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)- 1 -azabicyclo[3.2.1 ]oct-3-yl]-4-chlorobenzamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]thieno[3,4-c]pyridine-6-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]dibenzo[b,d]thiophene-2-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l]benzothieno[2,3-c]pyridine-3-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl][l]benzothieno[2,3-c]pyridine-3- carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-l-benzofuran-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]heρt-2-yl]dibenzo[b,d]furan-2-carboxamide; N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-.uro[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-l-benzofirran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-bromofuro[2,3-c]pyridine-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-biOmofuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-2-naphthamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]pyrrolo[ 1 ,2-c]pyrimidine-3 -carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]thieno[2,3-c]pyridine-5-carboxamide; N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]thieno[3,2-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-lH-indole-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]thieno[2,3-c]pyridine-5- carboxamide; 3-methyl-N-[(2S,3R)-2-ιnethyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide;
N-[(2S,3R)-2-methyl- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6- carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]ρyrrolo[l,2-c]pyrimidine-3- carboxamide;
N-[(2S,3R)-2-methyl- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 ,3-benzothiazole-6-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]pyrrolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] - 1 -benzothiophene-5 -carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]pyrrolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]pyrrolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-3-bromofuro[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-l,3-benzodioxole-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-bromo-l-benzofuran-5-carboxamide;
N-[(l S,2R,4R)-7-azabicyclo[2.2. l]heρt-2-yl]-3-bromo-l -benzofuran-5 -carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-bromothieno[253-c]pyridine-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-bromothieno[2,3-c]pyridine-5- carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-l-benzothiophene-5-carboxamide;
N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-methyl-l-benzofuran-5-carboxamide;
N-[(l S,2R,4R)-7-azabicyclo[2.2.1 ]hept-2-yl]-3-methyl- 1 -benzofuran-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methyl-l-benzofuran-6-carboxamide;
N-[(3R,5R)- 1 -azabicyclo[3.2. l]oct-3-yl]- 1 -benzofuran-6-carboxamide;
N-[(2S53R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-l-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-l-benzothiophene-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l-benzothiophene-6-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]pyrrolo[l,2-a]pyrazine-3-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-l-benzothiophene-6-carboxamide;
N- [(3R)- 1 -azabicyclo[2.2.2] oct-3 -yl] - 1 -methyl- 1 H-indole-6-carboxamide;
N-[(3 S)- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-l-benzofuran-5-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]heρt-2-yl]-3-isopropyl-l-benzofuran-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethynylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] - 1 H-indazole-6-carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-2 -methyl- 1 -benzofuran-5-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-methyl-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]pyrazino[l,2-a]indole-3-carboxamide;
3-bromo-N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]pyrrolo[l,2-a]pyrazine-3-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-7-methoxy-2-naphthamide;
N-[(l S52R,4R)-7-azabicyclo[2.2.1 ]hept-2-yl]pyrrolo[l ,2-a]pyrazine-3-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-l,3-benzothiazole-6-carboxamide;
N-[(3R,4S)- 1 -azabicyclo [2.2.1 ]hept-3-yl]-3-bromo- 1 -benzofuran-6-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l]beιιz;o-mo[2,3-c]pyridine-3-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl][l]benzofuro[2,3-c]pyridine-3- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-l-benzofuran-5-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-ethynyl-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2H-cl omene-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-prop-l-ynyl-l-benzofuran-5-carboxaιrιide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-phenyl-l,3-benzodioxole-5-carboxamide;
N-[(3R)-1 -azabicyclo[2.2.2]oct-3-yl]-6-bromopyrrolo[ 1 ,2-a]pyrazine-3-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-prop-l-ynylfuro[2,3-c]pyridine-5- carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]pyrrolo[l,2-a]pyrazine-3- carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2] oct-3 -yl]indolizine-6-carboxamide; 2-amino-N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzothiazole-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-6-ethynylpyrrolo[l,2-a]pyrazine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-8-methoxy-2-naphthamide;
N- [(2 S ,3R)-2-methyl- 1 -azabicyclo [2.2.2] oct-3 -yl] mdolizine-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l,3]dioxolo[4,5-c]pyridine-6-carboxamide; N-[(l S,2R,4R)-7-azabicyclo[2.2. l]hept-2-yl][l,3]dioxolo[4,5-c]pyridine-6- carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-3-cyano- 1 -benzofuran-5-carboxamide;
N-[(3R54S)-l-azabicyclo[2.2.1]hept-3-yl][l,3]dioxolo[4,5-c]pyridine-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro-l,4-benzodioxine-6- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-7-hydroxy-2-naphthamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-ethynylfuro[2,3-c]pyridine-5- carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-6-chloroisoquinoline-3-carboxamide; N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro- 1 ,4-benzodioxine-6- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro-l,4-benzodioxine-6- carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-6-methylisoquinoline-3-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-6-methylisoquinoline-3-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-cyanofuro[2,3-c]pyridine-5-carboxamide; N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-2-naphthamide; and N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]dibenzo[b,d]furan-2-carboxamide.
The compounds of Formula I (Azabicyclo is I) have asymmetric centers on the quinuclidine ring. The compounds of the present invention include quinuclidines having 3R configuration, 2S, 3R configuration, or 3S configuration and also include racemic mixtures and compositions of varying degrees of streochemical purities. For example, and not by limitation, embodiments of the present invention include compounds of Formula I having the following stereospecificity and substitution:
Figure imgf000012_0001
wherein the Azabicyclo (i) is a racemic mixture;
(ii) has the stereochemistry of 3R at C3;
(iii) has the 3R,2S stereochemistry at C3 and C2, respectively;
(iv) has the stereochemistry of 3S at C3; or
(v) is a racemic mixture; and for (iii) and (v), R2 has any definition or specific value discussed herein.
The compounds of Formula I (Azabicyclo is III) have asymmetric centers on the 7-azabicyclo[2.2.1]heptane ring which can exhibit a number of stereochemical configurations.
Figure imgf000012_0002
The terms exo and endo are stereochemical prefixes that describe the relative configuration of a substituent on a bridge (not a bridgehead) of a bicyclic system. If a substituent is oriented toward the larger of the other bridges, it is endo. If a substituent is oriented toward the smaller bridge it is exo. Depending on the substitution on the carbon atoms, the endo and exo orientations can give rise to different stereoisomers. For instance, when carbons 1 and 4 are substituted with hydrogen and carbon 2 is bonded to a nitrogen-containing species, the endo orientation gives rise to the possibility of a pair of enantiomers: either the IS, 2S, 4R isomer or its enantiomer, the IR, 2R, 4S isomer. Likewise, the exo orientation gives rise to the possibility of another pair of stereoisomers which are diastereomeric and C-2 epimeric with respect to the endo isomers: either the IR, 2S, 4S isomer or its enantiomer, the IS, 2R, 4R isomer. The compounds of this invention exist in the exo orientation. For example, when R2 is absent (C3 is -CH -) and R3 = H, the absolute stereochemistry is exo-(lS, 2R, 4R). The compounds of the present invention have the exo orientation at the C-2 carbon and S configuration at the C-l carbon and the R configuration at the C-2 and the C-4 carbons of the 7-azabicyclo[2.2.1]heptane ring. Unexpectedly, the inventive compounds exhibit much higher activity relative to compounds lacking the exo 2R, stereochemistry. For example, the ratio of activities for compounds having the exo 2R configuration to other stereochemical configurations may be greater than about 100: 1. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. For example, pharmaceutical compositions can include one or more compounds, each having an exo 2R configuration, or mixtures of compounds having exo 2R and other configurations, hi mixtxires of compounds, those species possessing stereochemical configurations other than exo 2R act as diluents and tend to lower the activity of the pharmaceutical composition. Typically, pharmaceutical compositions including mixtures of compounds possess a larger percentage of species having the exo 2R configuration relative to other configurations.
The compounds of Formula I (Azabicyclo is II) have asymmetric center(s) on the [2.2.1] azabicyclic ring at C3 and C4. The scope of this invention includes the separate stereoisomers of Formula I being endo-AS, endo-AR, exo-4S, exo-AR:
Figure imgf000013_0001
endo-AS endo-AR exo-AS exo-AR
The endo isomer is the isomer where the non-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges.
The exo isomer is the isomer where the non-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges. Thus, there can be four separate isomers: exo-A(R), exo-A(S), endo-A(R), and endo- A(S). Some embodiments of compounds of Formula I for when Azabicyclo is II include racemic mixtures where R is absent (k2 is 0) or is at C2 or C6; or Azabicyclo II has the exo-A(S) stereochemistry and R has any definition discussed herein and is bonded at any carbon discussed herein.
The compounds of Formula I (Azabicyclo III) have asymmetric center(s) on the [2.2.1] azabicyclic ring at CI, C4 and C5. The scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being (1R,AR,5S), (1R,AR,5R), (1S,AS,5R), (1S,AS,5S)
Figure imgf000014_0001
endo-lR,AR,5R endo-lS,AS,5S exo-lR,AR,5S exo-lS,AS,5R
The endo isomer is the isomer where the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges. The exo isomer is the isomer where the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges. Thus, there can be four separate isomers: exo-(lR,AR,5S), exo-(lS,AS,5R), endo- (1S,AS,5S), endo-(lR,AR,5R). Another group of compounds of Formula I (Azabicyclo III) includes R2-3 is absent, or is present and either at C3 or bonds to any carbon with sufficient valancy. The compounds of Formula I (Azabicyclo IN) have asymmetric center(s) on the [2.2.1] azabicyclic ring at CI, C4 and C6. The scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being exo-(lS,AR,6S), exo-(lR,AS,6R), endo-(lS,AR,6R), and e7--fo-(lR,4S,6S):
Figure imgf000014_0002
endo-lR,AS,6S endo-lS,AR,6R exo-lR,AS,6R exo-lS,AR,6S
The endo isomer is the isomer where the non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected toward the larger of the two remaining bridges. The exo isomer is the isomer where the non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected toward the smaller of the two remaining bridges. Thus, there can be four separate isomers: exo-(lS,AR,6S), exo-(lR,AS,6R), endo- (1S,4R,6R), and endo-(lR,AS,6S). Another group of compounds of Formula I (Azabicyclco IN) includes R2-3 is H, or is other than H and bonded at C3 or is bonded to any carbon with sufficient valancy.
The compounds of Formula I have asymmetric center(s) on the [3.2.1] azabicyclic ring at C3 and C5. The scope of this invention includes the separate stereoisomers of Formula I being endo-3S, 5R, endo-3R, 5S, e o-3R, 5R, e o-3S, 5S:
Figure imgf000015_0001
endo-3S, 5R endo-3R, 5S exo-3R, 5R exo-3S, 5S
Another group of compounds of Formula I (Azabicyclo N) includes compounds where Azabicyclo N moiety has the stereochemistry of 3R, 5R, or is a racemic mixture and the moiety is either not substituted with R (each is absent) or has one to two substituents being at either C2 and/or C4. When the moiety is substituted, the preferred substituents for substitution at C2 are alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl; and for substitution at C4 are F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl.
The compounds of Formula I (Azabicyclo is NI) have asymmetric centers on the [3.2.2] azabicyclic ring with one center being at C3 when R2 is absent. The scope of this invention includes racemic mixtures and the separate stereoisomers of Formula I being 3(S) and 3(R):
Figure imgf000015_0002
3(5) 3(R)
Another group of compounds of Formula I (Azabicyclo NI) includes compounds where Azabicyclo NI moiety is either not substituted with R2 (each is absent) or has one to two substituents with one being at either C2 or C4 or when two are present, one being at each C2 and C4. When the moiety is substituted, the preferred substituents for substitution at C2 are alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl; and for substitution at C4 are F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl. Stereoselective syntheses and/or subjecting the reaction product to appropriate purification steps produce substantially enantiomerically pure materials. Suitable stereoselective synthetic procedures for producing enantiomerically pure materials are well known in the art, as are procedures for purifying racemic mixtures into enantiomerically pure fractions.
The compounds of the present invention having the specified stereochemistry above have different levels of activity and that for a given set of values for the variable substituruents one isomer may be preferred over the other isomers. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. It is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially enantiomerically pure materials. Suitable stereoselective synthetic procedures for producing enantiomerically pure materials are well known in the art, as are procedures for purifying racemic mixtures into enantiomerically pure fractions.
i another aspect, the present invention comprises a method of administering to a mammal an amount of at least one acetylcholinesterase inhibitor, beta secretase inhibitor, or gamma secretase inhibitor, collectively referred to as "an inhibitor," and an alpha 7 nAChR full agonist. Acetylcholinesterase Inhibitors
When the inhibitor is an acetylcholinesterase inhibitor, the method would be used to treat diseases or conditions in a mammal, wherein the mammal experiences cholinergic hypofunction. As used herein, central and peripheral nervous system disorders involving cholinergic hypofunction include, but are not limited to, dementias, amnesias, cerebral insufficiencies, and psychiatric disturbances in the central nervous system and neuronal and smooth muscle dysfunction of the gut, skeletal muscle dysfunction for breathing, bladder, and secretory glands in the peripheral nervous system. The acetylcholinesterase inhibitor and alpha 7 nAChR full agonist(s) can be administered together as a composition, or may be administered separately. They may be administered at the same or different times, but at some time point in the treatment both drugs should be in the patients bloodstream at the same time. The method would be used to treat diseases or conditions in a mammal, wherein the mammal experiences neurodegeneration leading to cholinergic hypofunction and concomitant central nervous system dysfunction. The central nervous system disorders involving cholinergic hypofunction include, but are not limited to, dementias, amnesias. The acetylcholinesterase inhibitor and alpha 7 nAChR full agonist(s) can be administered together as a composition, or may be administered separately.
The compositions of the invention can be administered using art-recognized techniques. Preferably, the inhibitor and the alpha 7 nAChR full agonist are administered orally, or parenterally. In general, however, the compositions of the invention can be administered using the same art-recognized techniques used for administration of acetylcholinesterase inhibitors and alpha 7 nAChR full agonists. Accordingly, techniques of administration need not be repeated here.
Acetylcholinesterase inhibitors including physostigmine, aricept, rivastigamine, galantamine, monoamine acridines and their derivatives (e.g., US Patent A, 816,456), piperidinyl-alkanoyl heterocyclic compounds (e.g., EP 487 071), N-benzyl-piperidine derivatives (e.g., US Patent 5,106,856), 4-(l-benzylpiperidyl)- substituted fused quinoline derivatives (e.g., EP 481 429), cyclic amide derivatives (e.g., EP 468 187), and other typical acetylcholinesterase inhibitors such as carbonic acid derivatives (e.g., US Patent 5,602,176). Beta Secretase Inhibitors
Narious pharmaceutical agents have been proposed for the treatment of Alzheimer's disease but without any real success. Here we have determined that two classes of compounds maybe especially effective in the treatment of Alzheimer's disease when combined with an alpha 7 nAChR full agonist. These are selective beta secretase inhibitors and selective gamma secretase inhibitors. Beta secretase inhibitors are more preferred and are described here in detail. By beta secretase inhibitors what is meant are compounds that are effective inhibitors of beta-secretase, that inhibit beta-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce amyloid beta deposits or plaques. All beta-secretase mediated treatments suggested for the treatment and prevention of disease characterized by amyloid beta deposits or plaques, such as AD are included in the term beta-secretase inhibitors as used herein. Illustrations of and non limiting examples of beta-secretase inhibitors are disclosed in the following references and by specific mention here are meant to be made part of this application, as if copied herein in whole, and intended to be incorporated herein by reference. These references and examples below are not intended to limit in any way the definition of a beta-secretase inhibitor discovered either before or after the filing of this application for patent.
Beta secretase inhibitors include the compounds disclosed in the following published patent applications and granted patents (incorporated herein by reference):
1. US 5,981,168, issued 9 November 1999, inventors P. B. Reiner and B.P. Connop. The compounds described in this publication, in particular the compounds disclosed on col. 4-8 and col.15-22. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
2. US 2002/0143177 Al, publication date 3 October 2002, inventors J. P. Beck, et al. The compounds described in this publication, in particular the compounds disclosed on pages 3^40, 46-63, and 68-107. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
3. US 2002/0128255 Al, published 12 September 2002, inventors J. P. Beck, et al. The compounds described in this publication, in particular the compounds disclosed on pages 3-38, and 43-265. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
4. US 2002/0115616 Al, published 22 August 2002, inventors J. G. Boyd and D.H Singleton. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
5. US 2002/0019403 Al, published 14 February 2002, inventors R. Horn, et al. The compounds described in this publication, in particular the compounds disclosed on pages 1-44, and 48-128. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
6. WO 00/77030 Al, published 21 December 2000, inventors J. Varghese, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-6, 9-37 and 45-61. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
7. WO 01/70672 A2, published 27 September 2001, inventors R. Horn, et al. The compounds described in this publication, in particular the compounds described on pages 4-119, 137-178, and 189-234. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
8. WO 01/34639 A2, published 17 May 2001, inventors J. E. Audia, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-5, 7-35 and 52-56. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
9. WO 01/34571 Al, published 17 May 2001, inventors J. E. Audia, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-6, 8-43 and 60-66. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
10. WO 02/100856 Al, published 19 December 2002, inventors SR Pulley, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-25, 34-53, 79-108, 118-160. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
11. WO 02/100820 Al, published 19 December 2002, inventors M. Maillard and JA Tucker. The compounds described in this publication, in particular the compounds disclosed on pages 4-99, 122-199. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein. 12. WO 02/100818 A2, published 19 December 2002, inventors H. J.
Schostarez and R.A. Chrusciel. The compounds described in this publication, in particular the compounds disclosed on pages 4-36, 46-52, 77-155, 164-205. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein. 13. WO 02/100399 Al, published 19 December 2002, inventors S. R. Pulley.
The compounds described in this publication, in particular the compounds disclosed on pages 4-25, 35-53, 78-169. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
14. WO 02/98849 A2, published 12 December 2002, inventors J. Freskos, et al. The compounds described in this publication, in particular the compounds disclosed on pages 5-142, 164-182, 201-353. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein. 15. WO 02/94985 A2, published 28 November 2002, inventors J. E. Bruce, et al. All compounds described or claimed in this publication are copied into this document and incoφorated by reference herein.
16. WO 02/94768 A2, published 28 November 2002, inventors H. Schostarez, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-36, 44-107, 124-206, 223-287. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
17. WO 02/88101 A2, published 7 November 2002, inventors G. R. Bhisetti, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-7, 18-21, 32-88 and 98-200. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
18. WO 02/48150 A2, published 20 June 2002, inventors N. H. Greig, et al. The compounds described in this publication, in particular the compounds disclosed on pages 6-37, 48-50, 65-70 and 89-128. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
19. WO 02/02520 A2, published 10 January 2002, inventors J. P. Beck, et al. The compounds described in this publication, in particular the compounds disclosed on pages 8-98, 115-118, 122-158, and pages 166-284. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
20. WO 02/02518 A2, published 10 January 2002, inventors J. P. Beck, et al. The compounds described in this publication, in particular the compounds disclosed on page 8-99, 115-118, 122-158, and 166-284. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
21. WO 02/02512 A2, published 10 January 2002, inventors M. Maillaird, et al. The compounds described in this publication, in particular the compounds disclosed on pages 8-96, 111-339, and 347-649. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
22. WO 02/02506 A2, published 10 January 2002, inventors L. Y. Fang and J. Varhese. The compounds described in this publication, in particular the compounds disclosed on pages 7-84, 100-103, 106-113, and 122-433. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
23. WO 02/02505 A2, published 10 January 2002, inventors L. Y. Fang, et al. The compounds described in this publication, in particular the compounds disclosed on pages 5-28, 29-61, 77-80, 83-92, and 100-135. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
24. WO 03/6453 Al, published 23 January 2003, inventors H.J. Schostarez and R.A. Chrusciel. The compounds described in this publication, in particular the compounds disclosed on pages 4-39, 47-55, 82-179. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
25. WO 03/6021 Al, published 23 January 2003, inventors H.J. Schostarez and R.A. Chrusciel. The compounds described in this publication, in particular the compounds disclosed on pages 4-38, 74-92, 102-130. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
26. WO 03/6013 Al, published 23 January 2003, inventors H.J. Schostarez and R.A. Chrusciel. The compounds described in this publication, in particular the compounds disclosed on pages 4-30, 38-45, 70-134, 143-170. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
27. WO 03/2122 Al, published 09 January 2003, inventorsJ. Varghese, et al. The compounds described in this publication, in particular the compounds disclosed on pages 4-24, 59-87. All compounds described or claimed in this publication are copied into this document and incorporated by reference herein.
Gamma Secretase Inhibitors
By gamma secretase inhibitors what is meant are compounds that are effective inhibitors of gamma-secretase, that inhibit gamma-secretase-mediated cleavage of APP, that are effective inhibitors of A beta production, and/or are effective to reduce amyloid beta deposits or plaques. All gamma-secretase mediated treatments suggested for the treatment and prevention of disease characterized by amyloid beta deposits or plaques, such as AD are included in the term gamma-secretase inhibitors as used herein. another aspect, the invention provides pharmaceutical compositions comprising a composition according to the invention and a pharmaceutically acceptable carrier or diluent and optionally other adjuvants. Acceptable carriers, diluents, and adjuvants are any of those commercially used in the art, in particular, those used in pharmaceutical compositions of acetyleholinesterase inhibitors and alpha 7 nAChR full agonists. Accordingly, such carriers, diluents, and adjuvants need not be repeated here. In a combination therapy to treat the diseases or conditions discussed herein, the alpha 7 agonist and the inhibitor(s) can be administered simultaneously or at separate intervals. When administered simultaneously the alpha 7 agonist and the inhibitor(s) can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition. Alternatively, two or more separate compositions, i.e., one containing alpha 7 agonist and the other(s) containing the inhibitor(s), can be administered simultaneously.
A pharmaceutical combination therapy composition can include therapeutically effective amounts of the alpha 7 agonist, noted herein, and therapeutically effective amount of the inhibitor(s). The combined administration of the alpha 7 agonist and the inhibitor(s) is expected to require less of the generally- prescribed dose for any of agents when used alone and or is expected to result in less frequent administration of either, both or all agents. These compositions maybe formulated with common excipients, diluents or carriers, and compressed into tablets, or fonnulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes. The compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
When separately administered, therapeutically effective amounts of compositions containing alpha 7 agonist and the inhibitor(s) are administered on a different schedule. One may be administered before the other as long as the time between the administrations falls within a therapeutically effective interval. A therapeutically effective interval is a period of time beginning when one of either (a) the alpha 7 agonist, or (b) one to three of the inhibitor(s) is(are) administered to a mammal and ending at the limit of the beneficial effect in the treatment of the disease or condition to be treated from the combination of (a) and (b). The methods of administration of the alpha 7 agonist and the inhibitor(s) may vary. Thus, any of the agents may be administered rectally, topically, orally, sublingually, or parenterally. Further aspects and embodiments of the invention may become apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the examples and the appended claims. While the invention is susceptible of embodiments in various forms, described hereafter are specific embodiments of the invention with the understanding that the present disclosure is intended as illustrative, and is not intended to limit the invention to the specific embodiments described herein.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, we have found that al nAChR full agonists combined with either acetylcholinesterase inhibitors, beta secretase inliibitors and/or gamma secretase inhibitors can be used to treat any one or more of the following: cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration. Alpha 7 nAChR full agonists within the scope of the present invention include compounds of Formula I. In another aspect, the present invention comprises a method of administering the alpha 7 agonist to a mammal with an effective amount of at least one of the following acetylcholinesterase inhibitor, beta secretase inhibitor, or gamma secretase inhibitor, collectively referred to as "an inhibitor," and an alpha 7 nAChR full agonist. What is meant by acetylcholinesterase inhibitors, beta secretase inhibitors, and gamma secretase inhibitors is discussed herein.
In another aspect, the invention provides pharmaceutical compositions comprising a composition according to the invention and a phannaceutically acceptable carrier or diluent and optionally other adjuvants. Acceptable carriers, diluents, and adjuvants are any of those commercially used in the art, in particular, those used in pharmaceutical compositions of acetyleholinesterase inhibitors and alpha 7 nAChR full agonists. Accordingly, such carriers, diluents, and adjuvants need not be repeated here. A pharmaceutical combination therapy composition can include therapeutically effective amounts of the compounds of Formula I, noted herein, and a therapeutically effective amount of the inhibitor. The combined administration of the compounds of Formula I and the inhibitor is expected to require less of the generally- prescribed dose for either agent when used alone and or is expected to result in less frequent administration of either, both or all agents. These compositions may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes. The compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
The present invention claims any compound that is a full agonists relative to nicotine of an al Nicotinic Acetylcholine Receptors (nAChRs) or al nAChR full agonists, described either herein or elsewhere. Alpha 7 nAChR full agonists of the present invention include, but are not limited to compounds of Formula I as described herein. The present invention includes the administration of an alpha 7 nAChR full agonists in combination with a cholinesterase, and/or a beta secretase inhibitor, and/or a gamma secretase inhibitor, including a combination of all three inhibitors administered with the al nAChR full agonist. Non-limiting examples of al nAChR full agonists include compounds of Formula I:
Figure imgf000024_0001
Formula I wherein Azabicyclo is
Figure imgf000024_0002
Figure imgf000025_0001
VII wherein X is O, or S;
R0 is H, lower alkyl, substituted lower alkyl, or lower haloalkyl;
Each Ri is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
Each R2 is independently F, CI, Br, I, alkyl, substituted alkyl, haloalkyl, cycloalkyl, aryl, or R2 is absent provided that kι-2, kι-6, k2, k5, k6, or k is 0; kι- is 0 or 1; kι-6 is 0 or 1, provided that the sum of kι-2 and kι-6 is one; k2 is 0 or l; k is 0, 1, or 2; k6 is 0, 1, or 2; k7 is 0 or 1 ;
R2-3 is H, F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl; Each R3 is independently H, alkyl, or substituted alkyl;
R4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, CI, Br, I, -OH, -CN, -NH2, -NH(alkyl), or -N(alkyl)2;
Lower alkyl is both straight- and branched-chain moieties having from 1-4 carbon atoms; Lower haloalkyl is lower alkyl having 1 to (2n+l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety;
Lower substituted alkyl is lower alkyl having 0-3 substituents independently selected from F, CI, Br, or I and further having 1 substituent selected from R5, R6, -CN, -NO , -ORg, -SR8, -N(Rg)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O)2R8, phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, CI, Br, or I; Alkyl is both straight- and branched-chain moieties having from 1-6 carbon atoms;
Haloalkyl is alkyl having 1 to (2n+l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkyl is alkyl having 0-3 substituents independently selected from
F, CI, Br, or I and further having 1 substituent selected from R5, R6, -CN, -NO2, -OR8, -SR8, -N(R8)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O)2R8, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I;
Alkenyl is straight- and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond;
Haloalkenyl is alkenyl having 1 to (2n-l) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkenyl is alkenyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R5, R6, -CN, -NO2, -OR8, -SR8, -N(R8)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O)2R8, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I;
Alkynyl is straight- and branched-chained moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond;
Haloalkynyl is alkynyl having 1 to (2n-3) substituent(s) independently selected from F, CI, Br, or I where n is the maximum number of carbon atoms in the moiety; Substituted alkynyl is alkynyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R5, R6, -CN, -NO2, -OR8, -SR8, -N(R8)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O)2R8, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I;
Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;
Halocycloalkyl is cycloalkyl having 1-4 substituents independently selected from F, or CI; Substituted cycloalkyl is cycloalkyl having 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R5, R6, -CN, -NO2, -OR8, -SR8, -N(R8)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O) R8, phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, CI, Br, or I;
Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being -S-, -N(Rιo)-, or -O-;
Haloheterocycloalkyl is heterocycloalkyl having 1-4 substituents independently selected from F, or CI;
Substituted heterocycloalkyl is heterocycloalkylhaving 0-3 substituents independently selected from F, or CI, and further having 1 substituent selected from R5, R6, -CN, -NO2, -OR8, -SR8, -N(R8)2, -C(O)R8, -C(O)OR8, -C(S)R8, -C(O)N(R8)2, -NR8C(O)N(R8)2, -NR8C(O)R8, -S(O)R8, -S(O)2R8, -OS(O)2R8, -S(O)2N(R8)2, -NR8S(O)2R8, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I;
Lactam heterocycloalkyl is a cyclic moiety having from 4-7 atoms with one atom being only nitrogen with the bond to the lactam heterocycloalkyl thru said atom being only nitrogen and having a =O on a carbon adjacent to said nitrogen, and having up to 1 additional ring atom being oxygen, sulfur, or nitrogen and further having 0-2 substituents selected from F, CI, Br, I, or R where valency allows;
Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;
Substituted phenyl is a phenyl either having 1-4 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from Rn and 0-3 substituents independently selected from F, CI, Br, or I;
Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from Rπ and 0-3 substituents independently selected from F, CI, Br, or I, where the substitution can be independently on either only one ring or both rings of said naphthalene moiety;
Substituted phenoxy is a phenoxy either having 1-3 substituents independently selected from F, CI, Br, or I, or having 1 substituent selected from Rπ and 0-2 substituents independently selected from F, CI, Br, or I; R5 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of -O-, =N-, -N(Ri0)-, and -S-, and having 0-1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I, or R5 is 9-membered fused- ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula
Figure imgf000028_0001
wherein Li is O, S, or NR; 10.
Figure imgf000028_0002
wherein L is CRι2 or N, L2 and L3 are independently selected from CR12, C(Rι2) , O, S, N, or NR10, provided that both L2 and L3 are not simultaneously O, simultaneously S, or simultaneously O and S, or
Figure imgf000028_0003
wherein L is CRι2 or N, and L2 and L are independently selected from CRι2, O, S, N, or NRio, and each 9-membered fused-ring moiety having 0-1 substituent selected from R and further having 0-3 substituent(s) independently selected from F, CI, Br, or I, wherein the R5 moiety attaches to other substituents as defined in fonnula I at any position as valency allows;
R6 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from =N- and having 0-1 substituent selected from R and 0-3 substituent(s) independently selected from F, CI, Br, or I, or R6 is 10- membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from =N-, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R and 0-3 substituent(s) independently selected from F, CI, Br, or I, wherein the R6 moiety attaches to other substituents as defined in formula I at any position as valency allows;
R7 is alkyl, substituted alkyl, haloalkyl, -ORn, -CN, -NO2, -N(R8)2; Each Rg is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rι3, cycloalkyl substituted with 1 substituent selected from Rι , heterocycloalkyl substituted with 1 substituent selected from Rι3, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
R9 is alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, -ORi4, -SRi4, -N(Rι4)2, -C(O)Rι4, -C(O)N(Rι4)2, -CN, -NRι4C(O)Rι4, -S(O)2N(Rι4)2, -NRι4S(O)2R14, -NO2, alkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or Rι3, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or Rπ, or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or Rι3;
Rio is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R7 and further having 0-3 substituents independently selected from F, CI, Br, or I;
Each Rn is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
Each Rι is independently H, F, CI, Br, I, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -CN, -NO2, -ORι4, -SRι , -N(RJ )2,
-C(O)R14, -C(O)N(Rι4)2, -NRι4C(O)R14, -S(O)2N(R14)2, -NRι4S(O)2RR14, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that where valency allows the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -ORι , -SR1 , -N(Ri4)2, -C(O)RM, -NO2, -C(O)N(R14)2, -CN, -NR14C(O)R14, -S(O)2N(RM)2, or -NRι4S(O)2Rι4, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, CI, Br, or I; Ri3 is -ORi4, -SR14, -N(Rι4)2, -C(O)R14, -C(O)N(Rι4)2, -CN, -CF3,
-NR14C(O)R14, -S(O)2N(R14)2, -NR14S(O)2R14, or -NO2;
Each Ri4 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl; wherein W is (A):
Figure imgf000030_0001
(A-1) (A-2) wherein RA-I3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, -R5, R6, -ORA.3, -ORA-4, -SRA-3, F, CI, Br, I, -N(RA-3)2, -N(RA-5)2, -C(O)RA-3, -C(O)RA-5, -CN, -C(O)N(RA-3)2, -C(O)N(RA-6)2, -NRA.3C(O)RA-3, -S(O)RA-3, -OS(O)2RA_3, -NRA-3S(O)2RA-3, -NO2, and -N(H)C(O)N(H)RA-3;
RA-ib is -O-RA-3, -S-RA-3, -S(O)-RA- , -C(O)-RA- , and alkyl substituted on the ω carbon with RA-7 where said ω carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the phenyl ring attached to the core molecule and the ω carbon being the carbon furthest from said C-1 carbon;
Each RA-3 is independently selected from H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl; RΛ- . is selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, or substituted heterocycloalkyl;
Each RA-5 is independently selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl;
Each RA_6 is independently selected from alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl; RA-7 is selected from aryl, R5, or R6;
wherein W is (B):
Figure imgf000031_0001
wherein B° is -O-, -S-, or -N(RB-o)-;
B1 and B2 are independently selected from =N-, or =C(RB-ι)-; B3 is =N-, or =CH-, provided that when both B1 and B2 are =C(RB-ι)- and B3 is =CH-, only one =C(RB-I)- can be =CH-, and further provided that when B° is -O-, B2 is =C(RB-ι)~ and B3 is =C(H)-, B1 cannot be =N-,
RB-O is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, limited substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, or aryl, and provided that when B is (B-2) and B is =N- and B is N(RB-O), RB-O cannot be phenyl or substituted phenyl;
RB-I is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limited substituted alkyl, limited substituted alkenyl, limited substituted alkynyl, aryl, -ORB-2, -ORB-3, -SRB-2, -SRB-3, F, CI, Br, I, -N(RB-2)2, -N(RB-3)2, -C(O)RB-2, -C(O)RB-3, -C(O)N(RB-2)2, -C(O)N(RB-3)2, -CN, -NRB.2C(O)RB-4, -S(O)2N(RB-2)2, -OS(O)2RB-4, -S(O)2RB-2, -S(O)2RB-3, -NRB.2S(O)2RB-2, ~N(H)C(O)N(H)RB-2, -NO2, R5, and R6;
Each RB- is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl;
Each RB-3 is independently H, alkyl, haloalkyl, limited substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl; RB- is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
wherein W is (C):
(C) is a six-membered heterocyclic ring system having 1-2 nitrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nitrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six- six-fused-ring system, and further having 1-2 substitutents independently selected
Each Rc-i is independently H, F, CI, Br, I, alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, substituted phenyl, -NO2, -CN, -ORc-2, -SRC-2, -SORC-2, -SO2Rc-2, -NRc- C(O)Rc-3, -NRc-2C(O)Rc-2, -NRc-2C(O)Rc.4, -N(RC.2)2, -C(O)RC-2, -C(O)2Rc-2, -C(O)N(Rc-2)2, -SCN, -NRc-2C(O)Rc-2, -S(O)N(RC-2)2, -S(O)2N(Rc-2)2, -NRc-2S(O)2Rc-2, R5, or R6;
Each Rc-2 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rc-5, cycloalkyl substituted with 1 substituent selected from Rc-5, heterocycloalkyl substituted with 1 substituent selected from Rc-5, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
Each Rc-3 is independently H, alkyl, or substituted alkyl;
Rc-4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, CI, Br, I, -OH, -CN, -NH2, -NH(alkyl), or -N(alkyl)2;
Rc-5 is -CN, -CF3, -NO2, -ORC-6, -SRC-6, -N(RC-6)2, -C(O)RC-6, -SORc-6, -SO2RRC-6, -C(O)N(RC-6)2, -NRc-6C(O)Rc-6, -S(O)2N(Rc-6)2, or -NRc-6S(O)2Rc-6;
Each Rc-6 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
wherein W is (D):
Figure imgf000032_0001
provided that the bond between the -C(=X)- group and the W group may be attached at any available carbon atom within the D group as provided in RD-I, RD-3, and RD-4; D°, D1, D2, and D3 are N or C(RD-ι) provided that up to one of D°, D1, D2, or D3 is N and the others are C(RD-I), further provided that when the core molecule is attached at D2 and D° or D1 is N, D3 is C(H), and further provided that there is only one attachment to the core molecule;
D4— D5— D6 is selected from
Figure imgf000033_0001
N=C(RD-3)-C(RD-4)2, C(RD-3)=C(RD-3)-N(RD.2), C(RD-3)2-N(RD-2)-C(RD-3)2, C(RD-4)2-C(RD-3)=N, N(RD-2)-C(RD-3)2-C(RD-3)2, C(RD-3)2-C(RD-3)2-N(RD-2), O-C(RD-3)=C(RD-3),
O-C(RD-3)2-C(RD-3)2, C(RD-3)2-O-C(RD-3)2, C(RD-3)=C(RD-3)-O, C(RD-3)2-C(RD.3)2-O, S-C(RD-3)=C(RD-3), S-C(RD-3)2-C(RD-3)2, C(RD-3)2-S-C(RD-3)2, C(RD-3)=C(RD.3)-S, or C(RD-3)2-C(RD-3)2-S; provided that when C(X) is attached to W at D2 and D6 is O, N(RD.2), or S, D4— D5 is not CH=CH; and further provided that when C(X) is attached to W at D2 and D4 is O, N(RD-2), or S, D5— D6 is not CH=CH;
Each RD-ι is independently H, F, Br, I, CI, -CN, -CF3, -ORD-5, -SRD-5, -N(RD-5)2, or a bond to -C(X)- provided that only one of RD-I, RD-3, and RD-4 is said bond;
Each Rp-2 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, or R6;
Each Rp-3 is independently H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORD-IO, -C(O)N(RD-II)2. -NRD-ι0CORD-12, ~N(RD-10)2, -SRD-ι0, -S(O)2RD-10, -C(O)Ro-ι2, -CO2RD-IO, aryl, R5, R6, a bond to -C(X)- provided that only one of RD-ι, Ro-3, and RQ-4 is said bond; Each RD- is independently H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORD-ι0, -C(O)N(RD-ιι)2, -NRD.ιoCORD-12, -N(RD-π)2, -SRD-ι0, -CO2RD-10, aryl, R5, R6, a bond to -C(X)- provided that only one of RD-ι, Rp-3, and Ro-4 is said bond; Each Rp-5 is independently H, Cι-3 alkyl, or C2-4 alkenyl;
D7 is O, S, or N(RD-2);
D8 and D9 are C(Ro-ι), provided that when the molecule is attached to the phenyl moiety at D9, D8 is CH; Each RD-ιo is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
Each RD-Π is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rι , cycloalkyl substituted with 1 substituent selected from Rι3, heterocycloalkyl substituted with 1 substituent selected from R , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
RD-12 is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
wherein W is (E):
Figure imgf000034_0001
E° is CH or N;
RE-O is H, F, CI, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, R5, R6, -ORE-3, -ORE- , -SRE-3, -SRE.5. -N(RE-3)2, -NRE-3RE-6. -N(RE-6)2, -C(O)RE-3, -CN, -C(O)N(RE-3)2, -NRE-3C(O)RE-3, -S(O)RE_3, -S(O)RE-5, -OS(O)2RE-3, -NRE-3S(O)2RE-3, -NO2, or -N(H)C(O)N(H)RE-3; E1 is O, CRE-I-I, or C(RE-ι-ι)2, provided that when E1 is CRE-ι-ι, one RE-ι is a bond to CRE-ι_ι, and further provided that at least one of E1 or E2 is O;
Each RE-I-1 is independently H, F, Br, CI, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -ORE, or -N(RE)2, provided that at least one RE-ι-ι is H when E1 is C(RE-ι_ι)2; Each RE-ι is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E1 provided that E1 is CRE-ι-ι;
E2 is O, CRE- -2- or C(RE-2- )2, provided that when E2 is CRE-2-2. one RE.2 is a bond to CRE-2-2, and further provided that at least one of E1 or E2 is O; Each RE-2-2 is independently H, F, Br, CI, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -ORE, or -N(RE)2, provided that at least one RE-2-2 is H
Figure imgf000035_0001
Each RB- is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E2 provided that E2 is CRE-2- ;
Each RE is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
Each RE-3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or I or substituted phenyl;
RE-4 is H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl;
Each RE- is independently H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, or R6;
Each RE-6 is independently alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, CI, Br, or i;
wherein W is (F):
Figure imgf000035_0002
(F-1 ) (F-2)
F° is C(H) wherein F1— F2— F3 is selected from O-C(RF-2)=N,
O-C(RF.3XRF-2)-N(RF-4), O-C(RF-3)(RF-2)-S, O-N=C(RF-3), O-C(RF_2)(RF.5)-O,
O-C(RF.2)(RF-3)-O, S-C(RF.2)=N, S-C(RF-3)(RF-2)-N(RF-4), S-N=C(RF-3), N=C(RF-2)-O, N=C(RF.2)-S, N=C(RF-2)-N(RF-4), N(RF-4)-N=C(RF-3), N(RF-4)-C(RF-3)(RF-2)-O, N(RF-4)-C(RF.3)(RF-2)-S, N(RF-4)-C(RF.3)(RF-2)-N(RF-4), C(RF-3)2-O-N(RF-4), C(RF-3)2-N(RF-4)-O, C(RF-3)2-N(RF-4)-S, C(RF-3)=N-O, C(RF-3)=N-S, C(RF-3)=N-N(RF-4), C(RF-3)(RF-6)-C(RF.2)(RF-6)-C(RF.3)(RF-6), or C(RF-3)2-C(RF.2)(RF-3)-C(RF-3)2; F° is N wherein F1— F2— F3 is selected from O-C(RF-2)=N,
O-C(RF-3)(RF.2)-N(RF-4), O-C(RF-3)(RF-2)-S, O-N-C(RF_3) O-C(RF-2)(RF.3)-O, S-C(RF-2)=N, S-C(RF-3)(RF-2)-N(RF-4), S-N=C(RF-3), N=C(RF-2)-O, N=C(RF-2)-S, N=C(RF.2)-N(RF.4), N(RF-4)-N=C(RF-3), N(RF-4)-C(RF.3)(RF-2)-O, N(RF-4)-C(RF-3)(RF-2)-S, N(RF-4)-C(RF-3)(RF-2)-N(RF_4), C(RF-3)2-O-N(RF-4), C(RF-3)2-N(RF-4)-O, C(RF-3)2-N(RF-4)-S, C(RF-3)=N-O, C(RF-3)=N-S,
C(RF-3)=N-N(RF-4), C(RF-3)=C(RF-2)-C(RF-3)2, or C(RF-3)2-C(RF-2)(RF-3)-C(RF.3)2; F4 is N(RF-7), O, or S;
RF_! is H, F, CI, Br, I, -CN, -CF3, -ORF.8, -SRF-8, or -N(RF.8)2; RF- is H, F, alkyl, haloalkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R5, R6, ~N(RF- )-aryl,
-N(RF-4)-substituted phenyl, -N(RF. )-substituted naphthyl, -O-substituted phenyl, -O-substituted naphthyl, -S-substituted phenyl, -S-substituted naphthyl, or alkyl substituted on the CO carbon with RF-9 where said ω carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to W and the ω carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
RF-3 is H, F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORF-8, -C(O)N(RF.8)2, -NHRF* -NRF-8CORF-8, -N(RF-8)2, -SRF-8, -C(O)RF-8, -CO2RF-8, aryl, R5, or R6;
RF- is H, or alkyl;
Each RF-5 is independently F, Br, CI, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, -CF3, -ORF-8, -C(O)NH2, -NHRF-8, -SRF-8, -CO2RF-8, aryl, phenoxy, substituted phenoxy, heteroaryl, -N(RF-4)-aryl, or -O-substituted aryl;
One of RF.6 is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, F, Br, CI, I, -O F-S, -C(O)NH2, -NHRF-8, -SRF-8, -CO RF-8, aryl, R5, or R6, and each of the other two RF-6 is independently selected from alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, F, Br, Cl, I, -ORF-S, -C(O)NH2, -NHRF-8, -SRF-8, -CO2RF.8, aryl, R5, or R6; RF- is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R9 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
RF-s is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl; RF-9 is aryl, R5, or R6;
wherein W is (G):
Figure imgf000037_0001
G1 is N or CH; Each G2 is N or C(RG-I), provided that no more than one G2 is N;
Each RG-I is independently H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, -NO2, F, Br, Cl, I, -C(O)N(RG.3)2, -N(RG-3)2, -SRG-6, -S(O)2RG-6, -ORG-6, -C(O)RG-6, -CO2RG-65 aryl, R5, R6, or two RG-ι on adjacent carbon atoms may combine for W to be a 6-5-6 fused-tricyclic-heteroaromatic-ring system optionally substituted on the newly fonned ring where valency allows with 1-2 substitutents independently selected from F, Cl, Br, I, and RG-2;
RG-2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORG-8, -SRG-8, -S(O)2RG-8, -S(O)RG-8, -OS(O)2RG-8, -N(RG-8)2, -C(O)RG-8, -C(S)RG-8, -C(O)ORG-8, -CN, -C(O)N(RG-8)2, -NRG-8C(O)RG-8, -S(O)2N(RG-8)2, -NRG-8S(O)2RG-8, -NO2, -N(RG-g)C(O)N(RG-8)2, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, phenyl having 0-4 substituents independently selected from F, Cl, Br, I and RG- , naphthyl, or naphthyl having 0-4 substituents independently selected from F, Cl, Br, I, or RG-7; provided that whenG2 adjacent to the bridge N is C(RG-ι) and the other G2 are CH, that RG-ι is other than H, F, Cl, I, alkyl, substituted alkyl or alkynyl;
Each RG-3 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from RG-4, cycloalkyl substituted with 1 substituent selected from RG-4, heterocycloalkyl substituted with 1 substituent selected from RG-4, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
RCM is -ORG-5, -SRG-5, -N(RG.5)2, -C(O)RG-5, -SORG-5, -SO2RG-5, -C(O)N(RG-5)2, -CN, -CF3, -NRG.5C(O)RG.5, -S(O)2N(RG-5)2, -NRG-5S(O)2RG.5, or -NO2;
Each RG-5 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
RG-6 is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 0-4 substituents independently selected from F, Cl, Br, I, and RG-7;
RG-7 is alkyl, substituted alkyl, haloalkyl, -ORG-5, -CN, -NO , -N(RG-3)2;
Each RG-8 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or RG-7;
whereinW is (H)
Figure imgf000038_0001
H' is N or CH;
Each RH-I is independently F, Cl, Br, I, -CN, -NO2, alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocyclcoalkyl, aryl, R5, R6, -OR8, -SR8, -SOR8, -SO2R8, -SCN, -S(O)N(R8)2, -S(O)2N(R8)2, -C(O)R8, -C(O)2R8, -C(O)N(R8)2, C(R8)=N-OR8, -NC(O)R5, -NC(O)RH-3, -NC(O)R6, -N(R8)2, -NR8C(O)R8, -NR8S(O)2R8, or two RH-ι on adjacent carbon atoms may fuse to form a 6-membered ring to give a 5-6 fused, bicyclic moiety where the 6-membered ring is optionally substituted with 1-3 substitutents selected
mH is 0, 1, or 2;
RH-2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORH-3, -SRH-3, -S(O)2RH-3, -S(O)RH-3, -OS(O)2RH-3, -N(RH-3)2, -C(O)RH-3, -C(S)RH-3, -C(O)ORH.3, -CN, -C(O)N(RH-3)2- -NRH-3C(O)RH-3, -S(O)2N(RH.3)2, -NRH-3S(O)2RH-3, -NO2, -N(RH-3)C(O)N(RH-3)2, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, phenyl having 0-4 substituents independently selected from F, Cl, Br, I and R7, naphthyl, naphthyl having 0-4 substituents independently selected from F, Cl, Br, I, or R7, or two RH-2 on adjacent carbon atoms may combine to form a three-ring-fused-5- 6-6 system optionally substituted with up to 3 substituents independently selected from Br, Cl, F, I, -CN, -NO2, -CF3, -N(RH-3) 5 -N(RH-3)C(O)RH-3, alkyl, alkenyl, and alkynyl;
Each RH-3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or R7; or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof.
The present invention is useful in the treatment of, or preparation of medicament(s) for the treatment of, a wide variety of disease and disorders where the alpha 7 nAChR is implicated, including cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" or "hr" for hour or hours, "min" for minute or minutes, and "rt" for room temperature).
All temperatures are in degrees Centigrade. Room temperature is within the range of 15-25 degrees Celsius.
AChR refers to acetylcholine receptor. nAChR refers to nicotinic acetylcholine receptor.
Pre-senile dementia is also known as mild cognitive impairment.
5HT3R refers to the serotonin-type 3 receptor. α-btx refers to α-bungarotoxin.
FLIP R refers to a device marketed by Molecular Devices, Inc. designed to precisely measure cellular fluorescence in a high throughput whole-cell assay. (Schroeder et. al., J Biomolecular Screening, 1(2), p 75-80, 1996).
TLC refers to thin-layer chromatography. HPLC refers to high pressure liquid chromatography.
MeOH refers to methanol.
EtOH refers to ethanol.
IPA refers to isopropyl alcohol.
THF refers to tetrahydrofuran. DMSO refers to dimethylsulfoxide.
DMF refers to N,N-dimethylformamide.
EtOAc refers to ethyl acetate.
TMS refers to tetramethylsilane.
TEA refers to triethylamine. DIEA refers to NN-diisopropylethylamine.
MLA refers to methyllycaconitine.
Ether refers to diethyl ether.
HATU refers to O-(7-azabenzotriazol-l-yl)-Ν,Ν,Ν', N'-tetramethyluronium hexafluorophosphate. CDI refers to carbonyl diimidazole.
NMO refers to N-methylmorpholine-N-oxide.
TPAP refers to tetrapropylammonium perruthenate.
Na2SO refers to sodium sulfate. K2CO3 refers to potassium carbonate.
MgSO refers to magnesium sulfate.
When Na2SO4, K CO3, or MgSO4 is used as a drying agent, it is anhydrous.
As used herein, "acetylcholinesterase inhibitor," or "beta secretase inhibitor" include their respective pharmaceutically acceptable salts, such as hydrochlorides, tartrates, and the like.
Halogen is F, Cl, Br, or I.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Q-j indicates a moiety of the integer 'i" to the integer "j" carbon atoms, inclusive. Thus, for example, Cι-6 alkyl refers to alkyl of one to six carbon atoms.
Non-inclusive examples of heteroaryl compounds that fall within the definition of R5 and R6 include, but are not limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and furopyridinyl.
Non-inclusive examples of heterocycloalkyl include, but are not limited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazine, azetidino, azetidinono, oxindolo, dihydroimidazolo, and pyrrolidinono
Some of the amines described herein require the use of an amine-protecting group to ensure functionalization of the desired nitrogen. One of ordinary skill in the art would appreciate where, within the synthetic scheme to use said protecting group. Amino protecting group includes, but is not limited to, carbobenzyloxy (CBz), tert butoxy carbonyl (BOC) and the like. Examples of other suitable amino protecting groups are known to person skilled in the art and can be found in "Protective Groups in Organic synthesis," 3rd Edition, authored by Theodora Greene and Peter Wuts.
Alkyl substituted on an ω carbon with R -7 is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the W moiety and the co carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon. Therefore, when determining the ω carbon, the C-1 carbon will be the carbon attached, as valency allows, to the W moiety and the ω carbon will be the carbon furthest from said C-1 carbon. The core molecule is Azabicyclo-N(Rι)-C(=X)-:
Bond to core molecule
"core molecule"
Figure imgf000042_0001
Mammal denotes human and other mammals. Brine refers to an aqueous saturated sodium chloride solution. Equ means molar equivalents. IR refers to infrared spectroscopy.
Lv refers to leaving groups within a molecule, including Cl, OH, or mixed anhydride.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from TMS. MS refers to mass spectrometry expressed as m/e or mass/charge unit. HRMS refers to high resolution mass spectrometry expressed as m/e or mass/charge unit. [M+H]+ refers to an ion composed of the parent plus a proton. [M-H]" refers to an ion composed of the parent minus a proton. [M+Na]+ refers to an ion composed of the parent plus a sodium ion. [M+K]+ refers to an ion composed of the parent plus a potassium ion. El refers to electron impact. ESI refers to electrospray ionization. CI refers to chemical ionization. FAB refers to fast atom bombardment.
Compounds of the present invention maybe in the form of pharmaceutically acceptable salts. The tenn "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases, and salts prepared from inorganic acids, and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N, N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like. Salts derived from pharmaceutically acceptable organic non-toxic acids include salts of Cι-6 alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid, and aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
By the term "effective amount" of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired therapeutic effect. As pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound(s) used, the mode of administration, and the like. Thus, it is not possible to specify an exact "effective amount." However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
In addition to the compound(s) of Formula I, the compositions use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed., 1975). The term "carrier" material or "excipient" herein means any substance, not itself a therapeutic agent, used as a carrier and or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a confrolled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl-methyl cellulose, or other methods known to those skilled in the art. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition.
In addition to the oral dosing, noted above, the compositions of the present invention may be administered by any suitable route, e.g., parenterally, bucal, intravaginal, and rectal, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Such routes of administration are well known to those skilled in the art. The compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly. For parenteral administration, saline solution, dextrose solution, or water may be used as a suitable carrier. Formulations for parenteral admimstration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The serotonin type 3 receptor (5HT R) is a member of a superfamily of ligand- gated ion channels, which includes the muscle and neuronal nAChR, the glycine receptor, and the γ-aminobutyric acid type A receptor. Like the other members of this receptor superfamily, the 5HT3R exhibits a large degree of sequence homology with al nAChR but functionally the two ligand-gated ion channels are very different. For example, α7 nAChR is rapidly inactivated, is highly permeable to calcium and is activated by acetylcholine and nicotine. On the other hand, 5HT3R is inactivated slowly, is relatively impermeable to calcium and is activated by serotonin. These experiments suggest that the 7 nAChR and5HT3R proteins have some degree of homology, but function very differently. Indeed the pharmacology of the channels is very different. For example, Ondansefron, a highly selective 5HT3R antagonist, has little activity at the al nAChR. The converse is also true. For example, GTS -21, a highly selective α7 nAChR full agonist, has little activity at the 5HT3R. al nAChR is a ligand-gated Ca++ channel formed by a homopentamer of α7 subunits. Previous studies have established that α-bungarotoxin ( -btx) binds selectively to this homopetameric, al nAChR subtype, and that al nAChR has a high affinity binding site for both α-btx and methyllycaconitine (MLA). al nAChR is expressed at high levels in the hippocampus, ventral tegmental area and ascending cholinergic projections from nucleus basilis to thalamocortical areas. α7 nAChR full agonists increase neurotransmitter release, and increase cognition, arousal, attention, learning and memory. Data from human and animal pharmacological studies establish that nicotinic cholinergic neuronal pathways control many important aspects of cognitive function including attention, learning and memory (Levin, E.D., Psychopharmacology, 108:417-31, 1992; Levin, E.D. and Simon B.B., Psychopharmacology, 138:217-30, 1998). For example, it is well known that nicotine increases cognition and attention in humans. ABT-418, a compound that activates α4β2 and α7 nAChR, improves cognition and attention in clinical trials of Alzheimer's disease and attention-deficit disorders (Potter, A. et. al, Psychopharmacology (Berl)., 142(4):334-42, Mar. 1999; Wilens, T. E. et. al., Am. J. Psychiatry, 156(12):1931-7, Dec. 1999). It is also clear that nicotine and selective but weak al nAChR full agonists increase cognition and attention in rodents and non-human primates.
Selective al nACliR full agonists may be found using a functional assay on FLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes. This assay may be used to accurately measure the functional pharmacology of α7 nAChR and 5HT3R. To conduct such an assay, one uses cell lines that expressed functional forms of the al nAChR using the α7/5-HT3 channel as the drug target and cell lines that expressed functional 5HT3R. In both cases, the ligand-gated ion channel was expressed in SH-EP1 cells. Both ion channels can produce robust signal in the FLIPR assay.
As discussed, the compounds of the present invention are al nAChR full agonists. Therefore, as another aspect of the present invention, the compounds of the present invention may be used to treat a variety of diseases including cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (also known as mild cognitive impairment), and senile dementia.
Alzheimer's disease has many aspects, including cognitive and attention deficits. Currently, these deficits are treated with cholinesterase inhibitors. These inhibitors slow the break down of acetylcholine, and thereby provide a general nonspecific increase in the activity of the cholinergic nervous system. Since the drugs are nonspecific, they have a wide variety of side effects. Thus, there is a need for a drug that stimulates a portion of the cholinergic pathways and thereby provides improvement in the cognitive and attention deficits associated with Alzheimer's disease without the side effects created by nonspecific stimulation of the cholinergic pathways.
Neurodegeneration is a common problem associated with diseases such as
Alzheimer's disease. While the current drugs treat some of the symptoms of this disease, they do not control the underlying pathology of the disease. Accordingly, it would be desirable to provide a drug that can slow the progress of Alzheimer's disease.
Pre-senile dementia (mild cognitive impairment) concerns memory impainnent rather than attention deficit problems and otherwise unimpaired cognitive functioning. Mild cognitive impairment is distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. There cunently is no medication specifically identified for treatment of mild cognitive impairment, due somewhat to the newness of identifying the disease. Therefore, there is a need for a drug to treat the memory problems associated with mild cognitive impairment.
Senile dementia is not a single disease state. However, the conditions classified under this name frequently include cognitive and attention deficits.
Generally, these deficits are not treated. Accordingly, there is a need for a drug that provides improvement in the cognitive and attention deficits associated with senile dementia.
As discussed, the compounds of the present invention are α7 nAChR full agonists. Therefore, yet other diseases to be treated with compounds of the present invention include treating the cognitive and attention deficits as well as the neurodegeneration associated with any one or more or combination of the following: amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, belongs to a class of disorders known as motor neuron diseases wherein specific nerve cells in the brain and spinal cord gradually degenerate to negatively affect the control of voluntary movement. Currently, there is no cure for amyotrophic lateral sclerosis although patients may receive treatment from some of their symptoms and although Riluzole has been shown to prolong the survival of patients. Therefore, there is a need for a pharmaceutical agent to treat this disease.
Traumatic brain injury occurs when the brain is damaged from a sudden physical assault on the head. Symptoms of the traumatic brain injury include confusion and other cognitive problems. Therefore, there is a need to address the symptoms of confusion and other cognitive problems.
Brain tumors are abnormal growths of tissue found inside of the skull. Symptoms of brain tumors include behavioral and cognitive problems. Surgery, radiation, and chemotherapy are used to treat the tumor, but other agents are necessary to address associated symptoms. Therefore, there is a need to address the symptoms of behavioral and cognitive problems.
Acquired immune deficiency syndrome (AIDS) results from an infection with the human immunodeficiency virus (HIV). This virus attacks selected cells and impairs the proper function of the immune, nervous, and other systems. HIV infection can cause other problems such as, but not limited to, difficulties in thinking, otherwise known as AIDS dementia complex. Therefore, there is a need to drugs to relieve the confusion and mental decline of persons with AIDS. Persons with Down's syndrome have in all or at least some of their cells an extra, critical portion of the number 21 chromosome. Adults who have Down's syndrome are known to be at risk for Alzheimer-type dementia. Currently, there is no proven treatment for Down's syndrome. Therefore, there is a need to address the dementia associated with Down's syndrome.
Dementia with Lewy Bodies is a neurodegenerative disorder involving abnormal structures known as Lewy bodies found in certain areas of the brain. Symptoms of dementia with Lewy bodies include, but are not limited to, fluctuating cognitive impairment with episodic delirium. Currently, treatment concerns addressing the parkinsonian and psychiatric symptoms. However, medicine to control tremors or loss of muscle movement may actually accentuate the underlying disease of dementia with Lewy bodies. Therefore, there is a need of a pharmaceutical agent to treat dementia with Lewy bodies.
Genetically programmed degeneration of neurons in certain areas of the brain cause Huntington's disease. Early symptoms of Huntington's disease include mood swings, or trouble learning new things or remembering a fact. Most drugs used to treat the symptoms of Huntington's disease have side effects such as fatigue, restlessness, or hyperexcitability. Currently, there is no treatment to stop or reverse the progression of Huntington's disease. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
Parkinson's disease is a neurological disorder characterized by tremor, hypokinesia, and muscular rigidity. Cunently, there is no treatment to stop the progression of the disease. Therefore, there is a need of a phannaceutical agent to address Parkinson's. The key step in the preparation of this class of compounds is the coupling of the Azabicyclo moiety with the requisite acid chloride (Lv = Cl), mixed anhydride (e.g., Lv = diphenyl phosphoryl, bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formula of O-C(O)-RLV, where RLV includes phenyl or t-butyl), or carboxylic acid (Lv =OH) in the presence of an activating reagent. Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. "Peptides" pp. 39-91, San Diego, CA, Academic Press, (1995), and include, but are not limited to, agents such as carbodiimides, phosphonium and uronium salts (such as HATU). Compounds of Formula I can be prepared as shown in Scheme 1. The key step in the preparation of this class of compounds is the coupling of an azabicyclic moiety with the requisite acid chloride (Lv = Cl), mixed anhydride (e.g., Lv = diphenyl phosphoryl, bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formula of O-C(O)-RLv, where R v includes phenyl or t-butyl), or carboxylic acid (Lv =OH) in the presence of an activating reagent. Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. "Peptides" pp. 39-91, San Diego, CA, Academic Press, (1995), and include, but are not limited to, agents such as carbodiimides, phosphonium and uronium salts (such as HATU). Scheme 1
Azabicyclo-NH2 + Lv-C(=O)-W -» Azabicyclo-NH-C(=O)-W
Generally, the carboxylic acid is activated with a uronium salt, preferably HATU (see J. Am. Chem. Soc, 4397 (1993)), in the presence of the Azabicyclico moiety and a base such as DIEA in DMF to afford the desired amides. Alternatively, the carboxylic acid is converted to the acyl azide by using DPP A; the appropriate amine precursor is added to a solution of the appropriate anhydride or azide to give the desired final compounds. In some cases, the ester (Lv being OMe or OEt) may be reacted directly with the amine precursor in refluxing methanol or ethanol to give the compounds of Formula I.
Certain 6-substituted-[2.2.2]-3-amines (Azabicyclo I) are known in the art. The preparation of compounds where R2 is present is described in Ada Pol. Pharm. 179-85 (1981). Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared by reduction of an oxime or an imine of the conesponding 6-substituted-3- quinuclidinone by methods lαiown to one of ordinary skill in the art (see J. Labelled Compds. Radiopharm., 53-60 (1995), J Med. Chem. 988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)). Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared from a 6-substituted-3- hydroxyquinuclidine by Mitsunobu reaction followed by deprotection as described in Synth. Commun. 1895-1911 (1995). Alternatively, the 6-substituted-[2.2.2]-3-amine can be prepared by conversion of a 6-substituted-3-hydroxyquinuclidine into the conesponding mesylate or tosylate, followed by displacement with sodium azide and reduction as described in J Med. Chem. 587-593 (1975).
Figure imgf000050_0001
The oximes can be prepared by treatment of the 3-quinuclidinones with hydroxylamine hydrochloride in the presence of base. The imines can be prepared by treatment of the 3-quinuclidinones with a primary amine under dehydrating conditions. The 3-hydroxyquinuclidines can be prepared by reduction of the 3- quinuclidinones. The 6-substituted-3-quinuclidinones can be prepared by known procedures (see J Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perlάn Trans. /409-420 (1991), J. Org. Chem. 3982-3996 (2000)).
One of ordinary skill in the art will recognize that the methods described for the reaction of the unsubstituted 3-amino-l~azabicyclo[2.2. ljheptane (R2=absent) are equally applicable to substituted compounds (R2 ≠ H). For where Azabicyclo is II, compounds where R2 is present can be prepared from appropriately substituted nitro alcohols using procedures described in Tetrahedron (1997), 53, p. 11121 as shown below. Methods to synthesize nitro alcohols are well known in the art (see J. Am. Chem. Soc. (1947), 69, p 2608). The scheme below is a modification of the synthesis of exo-3-amino-l-azabicyclo[2.2. ljheptane as the bis(hydro para-toluenesulfonate) salt, described in detail herein, to show how to obtain these amine precursors. The desired salt can be made using standard procedures.
Figure imgf000051_0001
exo-2-sub-[2.2.1]-3-Amine
Compounds for Azabicyclo II where R2 is present can also be prepared by modification of intermediates described in the synthesis of exo-3 -amino- 1- azabicyclo[2.2. ljheptane as the bis(hydro para-toluenesulfonate) salt, described in detail herein. For example, hit 6 can be oxidized to the aldehyde and treated with an organometallic reagent to provide hit 20 using procedures described in Tetrahedron (1999), 55, p 13899. frit 20 can be converted into the amine using methods described for the synthesis of exo-3-amino-l-azabicyclo[2.2. ljheptane as the bis(hydro para- toluenesulfonate) salt. Once the amine is obtained, the desired salt can be made using standard procedures.
Figure imgf000051_0002
The schemes used are for making ex -3-amino-l-azabicyclo[2.2. ljheptane. However, the modifications discussed are applicable to make the endo isomer also.
There are several methods by which the amine precursor for Azabicyclo III and Azabicyclo IN can be obtained:
Figure imgf000051_0003
n-5-amine [2.2.1]-5-Amine
Figure imgf000051_0004
2-azabicyclo[2.2.1]heptan-6-amine [2.2.1]-6-Amine where Lv can be -CH2Ph, -CH(Me)Ph, -OH, -OMe, or -OCH2Ph. The respective amine precursors for Azabicyclo III and Azabicyclo IN can be prepared by reduction of an oxime or an imine of the conesponding N-2-azabicyclo[2.2.1J- heptanone by methods known to one skilled in the art (see J. Labelled Compds. Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth. Commun. 1895- 1911 (1992), Synth. Commun. 2009-2015 (1996)). The oximes can be prepared by treatment of the N-2-azabicyclo[2.2.1 jheptanones with hydroxylamine hydrochloride in the presence of a base. The imines can be prepared by treatment of the N-2- azabicyclo[2.2.1J-heptanones with a primary amine under dehydrating conditions. The N-2-azabicyclo[2.2.1 jheptanones can be prepared by known procedures (see Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191 (1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).
The exo- and era o-l-azabicyclo[3.2.1Joctan-3-amines are prepared from 1- azabicyclic[3.2.1Joctan-3-one (Thill, B. P., Aaron, H. S., J. Org. Chem., 4376-4380 (1968)) according to the general procedure as discussed in Lewin, A.H., et al., J. Med. Chem., 988-995 (1998).
Figure imgf000052_0001
One of ordinary skill in the art will also recognize that the methods described for the reaction of the unsubstituted l-azabicyclo[3.2.1Joctan-3-amine or 1- azabicyclo[3.2.2]nonan-3-amine (R2=absent) are equally applicable to substituted compounds (R2 present). The R2 substituent may be introduced as known to one skilled in the art through standard alkylation chemistry. Exposure of 1- azabicyclo[3.2.1Joctan-3-one or l-azabicyclo[3.2.2]nonan-3-one to a hindered base such as LDA (lithium diisopropylamide) in a solvent such as THF or ether between 0°C to -78°C followed by the addition of an alkylating agent (R2LV, where Lv = Cl, Br, I, OTs, etc.) will, after being allowed to wann to about 0°C to rt followed by an aqueous workup, provide the desired compound as a mixture of isomers. Chromatographic resolution (flash, HPLC, or chiral HPLC) will provided the desired purified alkylated ketones. From there, formation of the oxime and subsequent reduction will provide the desired endo or exo isomers. AMINES
Preparation of N-(2S,3R)-2-methyl- 1 -azabicyclo[2.2.2Joctan-3-amine dihydiOchloride (2S-methyl-2.2.2-Amine): See, e.g., US 20020042428 Al.
Preparation of the l-azabicyclo-2.2.1 Amines:
Synthesis of exo-3-amino- 1 -azabicyclo[2.2.1 Jheptane as the bis(hydro para-toluenesulfonate) salt (exø-[2.2.1J-Amine):
Figure imgf000053_0001
exo-[2.2.1]-Amine Step A. Preparation of 2-(benzoyloxy)-l-nitroethane (Int 1).
Benzoyl chloride (14.9 mL, 128 mmol) is added to a stined solution of nifroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). The solution is refluxed for 24 hr and then concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (80:20) affords hit 1 as a white solid (68% yield): 1H NMR (CDC13) δ 8.0, 7.6, 7.4, 4.9, 4.8.
Step B. Preparation of ethyl E-4-(benzylamino)-2-butenoate (Int 2).
Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is added to a stined solution of benzylamine (16 mL, 146 mmol) in CH2C12 (200 mL) at rt. The reaction mixture stirs for 15 min, and is diluted with ether (1 L). The mixture is washed with saturated aqueous NaHCO3 solution (3x) and water, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (70:30) affords Int 2 as a clear oil (62% yield): 1H NMR (CDC13) δ 7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4, 2.1-1.8, 1.3.
Step C. Preparation of tra..5,-4-nitro-l-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int 3).
A solution of hit 1 (6.81 g, 34.9 mmol) and hit 2 (7.65 g, 34.9 mmol) in EtOH (70 mL) stirs at rt for 15 h and is then concentrated in vacuo. The residue is diluted with ether (100 mL) and saturated aqueous NaHCO3 solution (100 mL). The organic layer is separated and dried (Na SO ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes- EtOAc (85:15) affords hit 3 as a clear oil (76% yield): 1H NMR (CDC13) δ 7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0, 2.7-2.6, 2.4-2.3, 1.2.
Step D . Preparation of trot -s-4-amino- 1 -(phenylmethyl)-3 -pyrrolidineacetic acid ethyl ester (Int 4).
A mixture of hit 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH (100 mL) is placed in a Pan bottle and hydrogenated for 4 h under an atmosphere of hydrogen (46 psi) at rt. The mixture is filtered through a pad of Celite, and the solvent is removed in vacuo to afford hit 4 as a clear oil (100% yield): 1H MR (300 MHz, CDC13) δ 7.3- 7.2, 4.1, 3.6, 3.2, 3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.
Step E. Preparation of trαn-.-4-(l,l-dimethylethoxycarbonylamido)-l-
(phenylmethyl)-3-pynolidineacetic acid ethyl ester (hit 5).
Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to a stirred solution of Int 4 (2.94 g, 11.2 mmol) in CH2C12 (30 mL) cooled in an ice bath. The reaction is allowed to warm to rt and stirred overnight. The mixture is concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (80:20) affords Int 5 as a white solid (77% yield): 1H NMR (300 MHz, CDC13) δ 7.4-7.2, 5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4, 1.3.
Step F. Preparation of trans (tert-butoxycarbonylamino)-4-(2-hydroxyethyl)- 1 -
(N-phenylmethyl) pyrrolidine (Int 6). LiAlH4 powder (627 mg, 16.5 mmol) is added in small portions to a stirred solution of h t 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) in a -5°C bath. The mixture is stined for 20 min in a -5°C bath, then quenched by the sequential addition of water (0.6 mL), 15% (w/v) aqueous NaOH (0.6 mL) and water (1.8 mL). Excess anhydrous K2CO3 is added, and the mixture is stined for 1 h, then filtered. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel. Elution with EtOAc affords Int 6 as a white solid (94% yield): 1H NMR (CDC13) δ 7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7, 3.3-3.2, 2.8-2.7, 2.3-2.1, 1.7, 1.5.
Int 6 is a racemic mixture that can be resolved via chromatography using a
Diacel chiral pack AD column. From the two enantiomers thus obtained, the (+)-enantiomer, [OCJ25 D +35 (c 1.0, MeOH), gives rise to the conesponding enantiomerically pure exo-A-S final compounds, whereas the (-)-enantiomer, [αJ25o - 34 (c 0.98, MeOH), gives rise to enantiomerically pure exo-A-R final compounds. The methods described herein use the (+)-enantiomer of Int 6 to obtain the enantiomerically pure exo-4-S final compounds. However, the methods used are equally applicable to the (-)-enantiomer of Int 6, making non-critical changes to the methods provided herein to obtain the enantiomerically pure exo-A-R final compounds.
Step G. Preparation of exo 3-(tert-butoxycarbonylamino)-l- azabicyclo[2.2. ljheptane (Int 7).
TEA (8.0 g, 78.9 mml) is added to a stined solution of Int 6 (2.5 g, 7.8 mmol) in CH2C12 (50 mL), and the reaction is cooled in an ice-water bath. CH3SO2Cl (5.5 g, 47.8 mmol) is then added dropwise, and the mixture is stined for 10 min in an ice- water bath. The resulting yellow mixture is diluted with saturated aqueous NaHCO3 solution, extracted with CH2C12 several times until no product remains in the aqueous layer by TLC. The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is dissolved in EtOH (85 mL) and is heated to reflux for 16 h. The reaction mixture is allowed to cool to rt, transfened to a Pan bottle and treated with 10% Pd/C catalyst (1.25 g). The bottle is placed under an atmosphere of hydrogen (53 psi) for 16 h. The mixture is filtered through Celite, and fresh catalyst (10% Pd/C, 1.25 g) is added. Hydrogenolysis continues overnight. The process is repeated three more times until the hydrogenolysis is complete. The final mixture is filtered through Celite and concentrated in vacuo. The residue is purified by flash chromatography on silica gel. Elution with CHCl3-MeOH-NH OH (90:9.5:0.5) affords hit 7 as a white solid (46% yield): H NMR (CDC13) δ 5.6-5.5, 3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8, 1.7-1.5, 1.5.
Step H. Preparation of exo-3-amiηo-l-azabicyclo[2.2. ljheptane bis(hydro- p αrα-toluenesulfonate) .
Rαra-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) is added to a stined solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50 mL). The reaction mixture is heated to reflux for 10 h, followed by cooling to rt. The precipitate is collected by vacuum filtration and washed with cold EtOH to give exo-[2.2.1]-Amine as a white solid (84% yield): 1H MR (CD3OD) δ 7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4, 2.3-2.2, 1.9-1.8.
Synthesis of endo-3-axnm.o-l -azabicyclo[2.2.1 Jheptane as the bis(hydro para-toluenesulfonate) salt (e..<io-[2.2.1]-Amine):
Figure imgf000056_0001
e/-cto-[2.2.1]-Amine
Step I. Preparation of ethyl 5-hydroxy-6-oxo- 1 ,2,3 ,6-tetrahydiOpyridine-4- carboxylate (Int 10).
Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanically stined suspension of potassium ethoxide (33.2 g, 395 mmol) in dry toluene (0.470 L). When the mixture is homogeneous, 2-pynolidinone (33.6 g, 395 mmol) is added, and then a solution of diethyl oxalate (53.1 mL, 390 mmol) in toluene (98 mL) is added via an addition funnel. After complete addition, toluene (118 mL) and EtOH (78 mL) are added sequentially. The mixture is heated to reflux for 18 h. The mixture is cooled to rt and aqueous HCl (150 mL of a 6.0 M solution) is added. The mixture is mechanically stined for 15 min. The aqueous layer is extracted with CH C1 , and the combined organic layers are dried (MgSO ), filtered and concentrated in vacuo to a yellow residue. The residue is recrystallized from EtOAc to afford it 10 as a yellow solid (38% yield): 1H NMR (CDC13) δ 11.4, 7.4, 4.3, 3.4, 2.6, 1.3.
Step J. Preparation of ethyl c/---3-hydroxy-2-oxopiperidine-4-carboxylate (Int
ID-
A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0 g) in glacial acetic acid is placed under an atmosphere of hydrogen (52 psi). The mixture is shaken for 72 h. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo to afford Int 11 as a white solid (98% yield): 1H NMR (CDC13) δ 6.3, 4.2, 4.0-3.8, 3.4, 3.3-3.2, 2.2, 1.3.
Step K. Preparation of cis- 4-(hydroxymethyl)piperidin-3-ol (h t 12).
Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portions to a stined solution of LiAlH in THF (80 mL of a 1.0 M solution) in an ice-water bath. The mixture is warmed to rt, and then the reaction is heated to reflux for 48 h. The mixture is cooled in an ice-water bath before water (3.0 mL, 170 mmol) is added dropwise, followed by the sequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water (9.0 mL, 500 mmol). Excess K CO3 is added, and the mixture is stined vigorously for 15 min. The mixture is filtered, and the filtrate is concentrated in vacuo to afford Int 12 as a yellow powder (70% yield): 1H NMR (OMSO-d6) δ 4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5-2.3, 1.5, 1.3.
Step L. Preparation of benzyl cis -3 -hydroxy-4-(hydroxymethyl)piperidine- 1 - carboxylate ( it 13).
N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is added to a stined solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueous ΝaHCO3 (15 mL) at rt. The mixture is stined at rt for 18 h. The organic and aqueous layers are separated. The aqueous layer is extracted with ether (3X). The combined organic layers are dried (K2CO3), filtered and concentrated in vacuo to afford it 13 as a yellow oil (99% yield): 1H NMR (CDC13) δ 7.4-7.3, 5.2, 4.3, 4.1, 3.8-3.7, 3.0-2.8, 2.1, 1.9-1.7, 1.4.
Step M. Preparation of benzyl e.s-3-hydroxy-4-[(4-methylphenyl)sulfonyl oxymethylJpiperidine-1 -carboxylate (Int 14).
Rαrα-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to a stirred solution of it 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a -15°C bath. The mixture is stined for 4 h, followed by addition of HCl (4.5 mL of a 6.0 M solution). CH2C12 (5 mL) is added. The organic and aqueous layers are separated. The aqueous layer is extracted with CH2C . The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford hit 14 as a colorless oil (78% yield): 1H NMR (CDC13) δ 7.8, 7.4-7.2, 5.1, 4.3-4.2, 4.1, 3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.
Step . Preparation of exo-l-azabicyclo[2.2.1]heptan-3-ol (Int 15).
A mixture of hit 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500 mg) in EtOH (50 mL) is placed under an atmosphere of hydrogen. The mixture is shaken for 16 h. The mixture is filtered through Celite. Solid NaHCO3 (1.1 g, 13 mmol) is added to the filtrate, and the mixture is heated in an oil bath at 50°C for 5 h. The solvent is removed in vacuo. The residue is dissolved in saturated aqueous K2CO3 solution. Continuous extraction of the aqueous layer using a liquid-liquid extraction apparatus (18 h), followed by drying the organic layer over anhydrous K2CO3 and removal of the solvent in vacuo affords Int 15 as a white solid (91% yield): 1H NMR δ 3.8, 3.0-2.8, 2.6-2.5, 2.4-2.3, 1.7, 1.1.
Step O. Preparation of e-7 o-3-azido-l-azabicyclo[2.2. ljheptane (h t 16).
To a mixture of hit 15 (1.0 g, 8.9 mmol) and triphenyl phosphine (3.0 g, 11.5 mmol) in toluene-THF (50 mL, 3:2) in an ice-water bath are added sequentially a solution of hydrazoic acid in toluene (15 mL of ca. 2 M solution) and a solution of diethyl azadicarboxylate (1.8 mL, 11.5 mmol) in toluene (20 mL). The mixture is allowed to warm to rt and stir for 18 h. The mixture is extracted with aqueous 1.0M HCl solution. The aqueous layer is extracted with EtOAc, and the combined organic layers are discarded. The pH of the aqueous layer is adjusted to 9 with 50% aqueous NaOH solution. The aqueous layer is extracted with CH2C12 (3X), and the combined organic layers are washed with brine, dried (Na2SO ), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with CHCVMeOH-NH OH (92:7:1) affords Int 16 as a colorless oil (41% yield): 1H NMR (CDC13) δ 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.
Step P. Preparation of e.?-fo-3-amino-l-azabicyclo[2.2. ljheptane bis(hydro- p αrα-toluenesulfonate) .
A mixture of t 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst (12 mg) in EtOH (10 mL) is placed under an atmosphere of hydrogen (15 psi). The mixture is stined for 1 h at rt. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo. The residue is dissolved in EtOH (10 mL) and^αra- toluenesulfonic acid monohydrate (690 mg, 3.7 mmol) is added. The mixture is stined for 30 min, and the precipitate is filtered. The precipitate is washed sequentially with cold EtOH and ether. The precipitate is dried in vacuo to afford e/. o-[2.2.1]-Amine as a white solid (85% yield): 1H MR (CD3OD) δ 7.7, 7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.
Preparation of exo-tert-butyl (IS, 2R, 4R)-(+)-2-amino-7- azabicyclo[2.2.1]heptane-7-carboxylate (7-aza-[2.2.1]-Amine):
Figure imgf000059_0001
7-aza-[2.2.1]-Amine
Preparation of methyl-3-bromo-propiolate:
Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25°C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65 °C, about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal, calc'd for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
Preparation of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1 Jhepta-2,5- diene-2,7-dicarboxylate.
Methyl-3-bromo-propiolate (83.7 g, 0.513 mole) is added to N-t-butyloxy- pyrrole (430 ml, 2.57 mole) under nitrogen. The dark mixture is warmed in a 90 °C bath for 30 h, is cooled, and the bulk of the excess N-t-butyloxy-pyrrole is removed in vacuo using a dry ice/acetone condenser. The dark oily residue is chromatographed over 1 kg silica gel (230-400 mesh) eluting with 0-15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 97 g (57%) of 1 -tert- butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a dark yellow oil. HRMS (FAB) calc'd for Cι3Hι6BrΝO4+H: 330.0341, found 330.0335 (M+H)+.
Preparation of (+/-) E« o-7-tert-butyl 2-methyl 7-azabicyclo[2.2.1Jheptane- 2,7-dicarboxylate.
7-tert-Butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1 Jhepta-2,5-diene-2,7- dicarboxylate (97 g, 0.294 mole) is added tol0% Pd/C (6.8g) in 900 ml absolute
ΕtOH in a PARR bottle. The suspension is diluted with a solution of NaHCO3 (25 g, 0.301 mole) in 250 ml water and the mixture is hydrogenated at 50 PSI for 2.5 h. The catalyst is removed by filtration, is washed with fresh ΕtOH, and the filtrate is concentrated in vacuo to give a residue. The residue is partitioned between 1 x 200 ml saturated NaHCO3 and CH2C12 (4 x 100 ml). The combined organic layer is dried (1:1 K2CO3/ MgSO ) and concentrated in vacuo to afford 72.8 g (98%) of (+/-) endo- 1 -tert-butyl 2-methyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. MS (ΕI) for Cι4H22O4, m/z: 255 (M)+.
Preparation of (+/-) exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1 Jheptane-
2-carboxylic acid.
(+/-)Endo-l -tert-butyl 2-methyl 7-azabicyclo[2.2.1Jheptane-2,7-dicarboxylate (72.8 g, 0.285 mole) is dissolved in 1000 ml dry MeOH in a dried flask under nitrogen. The solution is treated with solid NaOMe (38.5 g, 0.713 mole) neat, in a single lot and the reaction is warmed to reflux for 4h. The mixture is cooled to 0°C, is treated with 400 ml water, and the reaction is stined lh as it warms to RT. The mixture is concentrated in vacuo to about 400 ml and the pH of the aqueous residue is adjusted to 4.5 with 12N HCl. The precipitate is collected and dried. The tan, slightly tacky solid is washed with 2 x 100 ml 60% ether in hexane and is dried to provide 47 g (68%) of exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1Jheptane-2-carboxylic acid as an off-white powder. HRMS (FAB) calc'd for Cι2Hι9NO4+H: 242.1392, found
242.1390 (M+H)+.
Preparation of (+/-) exo-tert-butyl 2-{[(benzyloxy)carbonyl]amino}-7- azabicyclo [2.2.1 Jheptane-7-carboxylate.
(+/-)Exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2. ljheptane- 2-carboxylic acid (32.5 g, 0.135 mole) is combined with TEA (24.4 ml, 0.175 mole) in 560 ml dry toluene in a dry flask under nitrogen. The solution is treated drop-wise with diphenylphosphoryl azide (37.7 ml, 0.175 mole), and is allowed to stir for 20 min at RT. The mixture is treated with benzyl alcohol (18.1 ml, 0.175 mole), and the reaction is stirred overnight at 50°C. The mixture is cooled, is extracted successively with 2 x 250 ml 5% citric acid, 2 x 200 ml water, 2 x 200 ml saturated sodium bicarbonate, and 2 x 100 ml saturated NaCl. The organic layer is dried (MgSO ) and concentrated in vacuo to an amber oil. The crude material was chromatographed over 800 g silica gel (230-400 mesh), eluting with 15-50% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 44 g (94%) of (+/-) exo-tert-butyl 2- {[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1Jheptane-7-carboxylate as a pale oil. 1H NMR (CDCl3) δ 1.29-1.60, 1.44, 1.62-2.01, 3.76-3.88, 4.10, 4.24, 5.10, 7.36 ppm.
Preparation of exo-tert-butyl (IS, 2R, 4R)-(+)-2{[(benzyloxy)carbonyl]amino}-
7-azabicyclo[2.2.1]heptane-7-carboxylate and exo-tert-butyl (IR, 2S, 4S)-(-)-
2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1Jheptane-7-carboxylate. The isolated (+/-) exo-tert-butyl 2- {[(benzyloxy)carbonyl]amino} -7- azabicyclo[2.2.1]heptane-7-carboxylate is resolved via preparative chiral HPLC
(50x500 mm Chiralcel OJ column, 30 deg. C, 70 mL/min. 10/90 (v/v) isopropanol/heptane). The resolution affords 10.5 g of exo-tert-butyl (IS, 2R, 4R)-(+)-
2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate and 15.5 g of exσ-tert-butyl-(lR, 2S, 4S)(-)-2{[(benzyloxy)carbonylJamino}-7- azabicyclo[2.2.1Jheptane-7-carboxylate.
The 2R enantiomer is triturated with 12 ml ether followed by 12 ml hexane (to remove lingering diastereo and enantiomeric impurities) and is dried to afford 9.5 g (43%) of purified exo-tert-butyl (IS, 2R, 4R)-(+)-2 {[(benzyloxy)carbonylJamino}-7- azabicyclo[2.2.1]heptane-7-carboxylate with 99% enantiomeric excess. MS (El) for Cι9H26N2O4, m/z: 346 (M)+. [ocJ25 D = 22, (c 0.42, chloroform).
The 2S enantiomer is triturated with 20 ml ether followed by 20 ml hexane to give 14 g (64%) of purified exo-tert-butyl (IR, 2S, 4S)-(-)- 2{[(benzyloxy)carbonylJamino}-7-azabicyclo[2.2.1]heptane-7-carboxylate with 99% enantiomeric excess. MS (El) for Cι9H26N2O4! m/z: 346 (M)+. [ J25 D = -23, (c 0.39, chloroform).
Preparation of exo-tert-butyl-(lS, 2R, 4R)-(+)-2-amino-7- azabicyclo[2.2.1Jheptane-7-carboxylate (7-aza-[2.2.1J-Amine). Exo-tert-butyl (IS, 2R, 4R)-(+)-2 {[(benzyloxy)carbonyl]amino}-7- azabicyclo[2.2.1]heptane-7-carboxylate (9.5 g, 27.4 mmol) is combined with 950 mg 10% Pd/C in 75 ml absolute ΕtOH in a 500 ml Pan bottle. The reaction mixture is hydrogenated at 50 PSI for 3h, the catalyst is removed by filtration, and the filter cake was washed with MeOH. The filtrate is concentrated in vacuo to give 6.4 g of a residue. The crude material is chromatographed over 200 g silica gel (230-400 mesh) eluting with 7% CH3OH/CHCl3 containing 1% cone. NH OH. The appropriate fractions are combined and concentrated to give 5.61 g (96%) of exo-tert-butyl-(lS, 2R, 4R)-(+)-2-amino-7-azabicyclo[2.2.1Jheptane-7-carboxylate as a pale oil. MS (ΕI) for CnH2oN2θ2) m/z: 212 (M)+. [αJ25D = 9, (c 0.61, chloroform).
Preparation of l-azabicyclo[3.2.1]octan-3-amine: Preparation of the 3R,5R-[3.2.1]-Amine:
(3S)-l-[(S)-l-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid: According to the literature procedure (Nielsen et al. J. Med. Chem 1990, 70-
77), a mixture of itaconic acid (123.17 g, 946.7 mmol) and (S)-(-)-α-methyl benzylamine (122.0 mL, 946.4 mmol) were heated (neat) in a 160°C oil bath for 4 h. Upon cooling, MeOH (-200 L) was added and the resulting solid collected by filtration. The solid was treated with EtOH (-700 mL) and warmed using a steam bath until -450 mL solvent remained. After cooling to rt, the solid was collected and dried to afford 83.2 g as a white crystalline solid: [α]25 D = -80 (c 0.97, DMSO). MS (El) m/z 233 (M+). The lack of a resonance 3.59 indicates a single diastereomer. The other diastereomer can be retrieved from the initial MeOH triturant. Attempts to crystallize this material generally led to small quantities of (3RS)-l-[(S)-l-phenethylJ-5-oxo-3- pyrrolidine-carboxylic acid.
(3S)-l-[(S)-l-PhenethyI]-3-(hydroxymethyl)pyrrolidine:
A suspension (3S)-l-[(S)-l-phenethylJ-5-oxo-3-pynolidine-carboxylic acid (82.30 g, 352.8 mmol) in Et O (200 mL) was added in small portions to a slurry of LiAlH4 (17.41 g, 458.6 mmol) in Et2O (700 mL). The mixture began to reflux during the addition. The addition funnel containing the suspension was rinsed with Et2O (2 x 50 mL), and the mixture was heated in a 50 °C oil bath for an additional 2 h and first allowed to cool to rt and then further cooled using an ice bath. The mixture was carefully treated with H2O (62 mL). The resulting precipitate was filtered, rinsed with Et2O, and discarded. The filtrate was concentrated to a yellow oil. When EtOAc was added to the oil, a solid began to form. Hexane was then added and removed by filtration and dried to afford 43.3 g as a white solid. [αJ25 D = -71 (c 0.94, CHC13). MS (El) m/z 205 (M+).
(3R)-l-[(S)-l-Phenethyl]-3-(cyanomethyl)pyrrolidine:
A solution of (3S)-l-[(S)-l-phenethyl]-3-(hydroxymethyl)pyrrolidine (42.75 g, 208.23 mmol) in chloroform (350 mL) was heated to reflux under N2. The solution was treated with a solution of thionyl chloride (41.8 mL, 573 mmol) in chloroform (40 mL) dropwise over 45 min. The mixture stined for an additional 30 min, was cooled and concentrated. The residue was diluted with H2O (-200 mL), 1 N NaOH was added until a pH - 8 (pH paper). A small portion (-50 mL) of sat. NaHCO3 was added and the basic mixture was extracted with EtOAc (3 x 400 mL), washed with brine, dried (MgSO ), filtered and concentrated to give 46.51 g of a red-orange oil for (3S)-l-[(S)-l-phenethylJ-3-(chloromethyl)pynolidine: Rf: 0.50 (EtOAc-hexane 1:1); MS (ESI+) m/z 224.2 (Mtt). The chloride (46.35 g, 208.0 mmol) was transfened to a flask, dimethyl sulfoxide (200 mL) was added, and the solution was treated with NaCN (17.84 g, 363.9 mmol). The mixture was heated under N2 in a 100°C oil bath overnight and was cooled. The brown mixture was poured into H O (300 mL) and extracted with EtOAc (1000 mL in portions). The combined organic layer was washed with H2O (6 x -50 mL), brine (-100 mL), dried (MgSO4), filtered and concentrated to give 40.61 g as an orange-red oil: R/. 0.40 (EtOAc-PhCH3 1:1). MS (ESI+) for m/z 215.2 (M+H+).
(3R)-Methyl l-[(S)-l-phenylethly]pyrrolidine-3-acetate: Acetyl chloride (270 mL, 3.8 mol) was carefully added to a flask containing chilled (0°C) methanol (1100 mL). After the addition was complete, the acidic solution stined for 45 min (0 °C) and then (3R)-l-[(S)-l-phenethylJ-3- (cyanomethyl)pyrrolidine (40.50 g, 189.0 mmol) in methanol (200 mL) was added. The ice bath was removed and the mixture stined for 100 h at rt. The resulting suspension was concentrated. Water (-600 mL) was added, the mixture stined for 45 min and then the pH was adjusted (made basic) through the addition of -700 mL sat. aq. NaHCO3. The mixture was extracted with EtOAc (3 x 300 mL). The combined organics were washed with brine, dried (MgSO4), filtered through celite and concentrated to give 36.86 g as an orange-red oil. MS (ESI+) m/z 248.2 (M+H+).
(5R)-l-Azabicyclo[3.2.1]octan-3-one hydrochloride:
A solution of (3R)-methyl l-[(S)-l-phenylethly]pynolidine-3 -acetate (25.72g, 104.0 mmol) in THF (265 mL) was cooled under N2 in a CO2/acetone bath. Next, ICH2C1 (22.7 mL, 312.0 mmol) was added, and the mixture stined for 30 min. A solution of 2.0M lithium diisopropylamide (heptane/THF/ethylbenzene, 156 mL, 312 mmol) was added slowly over 30 min. The internal temperature reached a maximum of-40°C during this addition. After 1 h, sat. NH4C1 (100 mL) was added and the mixture was allowed to warm to rt. The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting red-brown foam was chromatographed (300 g SiO2, CHCl3-MeOH-NH4OH (89:10:1) followed by CHCl3-MeOH (3:1). The product fractions were pooled and concentrated to afford (5R)~3-oxo-l-[(lS)-l-phenylethylJ-l- azoniabicyclo[3.2.1Joctane chloride (10.12g) as a tan foam (MS (ESI+) m/z 230.1 (M+ff). This foam (10.1 g, 38 mmol) was taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) added and the mixture was hydrogenated (45 psi) overnight. The mixture was filtered and re-subjected to the reduction conditions (9.1 g, 10% Pd C, 50 psi). After 5 h, TLC indicated the consumption of the (5R)-3-oxo-l-[(lS)-l-phenylethylJ-l- azoniabicyclo[3.2.1Joctane chloride. The mixture was filtered, concentrated and triturated (minimal tPrOH) to give 3.73 g in two crops, as an off-white solid: [αJ25 D = 33 (c 0.97, DMSO). MS (El) m/z 125 (M ).
(3R,5R)-l-azabicyclo[3.2.1]octan-3-amine dihydrochloride:
Figure imgf000065_0001
• HCl
(3R, 5/?)-[3.2.1]-Amine To a flask containing (5R)-l-azabicyclo[3.2.1]octan-3-one hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol), and ethanol (130 mL) was added sodium acetate trihydrate (9.23 g, 67.8 mmol). The mixture stined for 3 h and was filtered and concentrated. The resulting white solid was taken up in n- propanol (100 mL) and sodium (-13.6 g, 618 mmol) was added over 20-25 portions. The reaction spontaneously began to reflux, and the reaction was heated in an oil bath (100°C). The addition was complete in -20 min and the mixture had solidified after -40 min. The oil bath was removed and /.-propanol (2 x 25 mL) was added dissolving the remaining sodium metal. The mixture was carefully quenched through the dropwise addition of H2O (100 mL). Saturated aq. NaCl (20 mL) was added, and the layers were separated. The organic layer was dried (MgSO4), filtered, treated with freshly prepared MeOH/HCl, and concentrated. The resulting solid was triturated with 30 mL EtOH, filtered and dried in vaccuo to afford 3.51 g as a white solid: [αJ25 D - -3 (c 0.94, DMSO). MS (FAB) m/z 127 (MH+).
Preparation of e/.rfo-l-azabicyclo[3.2.1]octan-3-amine dihydrochloride
(en</o-[3.2.1]-Amine):
Figure imgf000065_0002
A mixture of l-azabicyclo[3.2.1Joctan-3-one hydrochloride (2.80 g, 17.3 mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g, 22.4 mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). The mixture is stirred for 3 h and evaporated in vacuo. The residue is diluted with CH2C12, treated with charcoal, filtered and evaporated. The resulting oxime (3.1 mmol) is treated with acetic acid (30 mL) and hydrogenated at 50 psi over PtO (50 mg) for 12 h. The mixture is then filtered and evaporated. The residue is taken up in a minimal amount of water (6 mL) and the pH is adjusted to >12 using solid NaOH. The mixture is then extracted with ethyl acetate (4 X 25 mL), dried (MgSO ), filtered, treated with ethereal HCl, and evaporated to give the give e-._fo-[3.2.1]-Amine.
Preparation of the 3.2.2 Amines:
Figure imgf000066_0001
tert-Butyl 4-(2-oxopropylidene)piperidine-l -carboxylate (Int 101): Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is washed with pentane (3X) and suspended in dry THF (40 mL). The solution is cooled to 0°C before diethyl (2-oxopropyl)phosphonate (9.75 g, 50.2 mmol) is added dropwise. After complete addition, the solution is warmed to rt and stined for 30 min. tert- Butyl 4-oxo-l-piperidinecarboxylate (5.0g, 25.1 mmol) is added in portions over 10 min, followed by stirring at rt for 2 h. A saturated aqueous solution of ammonium chloride is added, followed by dilution with ether. The organic layer is exfracted with water. The organic layer is dried (MgSO4), filtered and concentrated to a yellow oil. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-ether (60:40) gave 4.5 g (75%)of Int 101 as a white solid: !H NMR (CDC13) δ 6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.
Preparation of tert-butyl 4-(2-oxopropyl)piperidine- 1 -carboxylate (hit 102) :
A mixture of hit 101 (4.5 g, 19 mmol) and 10% palladium on activated carbon (450mg) in EtOH (150 mL) is placed in a Pan bottle and hydrogenated for 5 h at 50 psi. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo to afford 4.3 g (94%) of hit 102 as a clear oil: 1H NMR (CDC13) δ 4.1, 2.8, 2.4, 2.2, 2.0, 1.7, 1.5, 1.1.
tert-Butyl 4-(3-biOmo-2-oxopropyl)piperidine-l -carboxylate (hit 103): To a stined solution lithium hexamethyldisilylamide in THF (20. 0 mL, 1.0 M) in a -78 °C bath is added chlorotrimethylsilane (11.0 mL, 86.4 mmol) dropwise. The mixture is stined at -78 °C for 20 min, followed by addition of Int 102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL) dropwise. After complete addition, the mixture is stined at -78 °C for 30 min. The mixture is warmed to 0°C in an ice- water bath and phenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) is added. The mixture is stined in an ice-bath for 30 min, followed by the addition of water and ether. The aqueous layer is washed with ether, and the combined organic layers are washed with saturated aqueous sodium thiosulfate solution. The organic layer is dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-ether (60:40) gave 2.2 g (52%) of Int 103 as a It. yellow oil: 1H NMR (CDC13) δ 4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1- 2.0, 1.7, 1.5, 1.2-1.1.2.
l-Bromo-3-piperidin-4-ylacetone trifluoroacetate (Int 104): To a stined solution of hit 103 (2.2 g, 6.9 mmol) in CH2C12 (30 mL) in an ice- water bath is added trifluoroacetic acid (10 mL, 130 mmol). The mixture is stined at 0°C for 30 min. The volatiles are removed in vacuo to afford 2.0 g (87%) of Int 104 as a yellow residue: MS (ESI) for C8Hι5BrNO [M+HJ m/e 220.
l-Azabicyclo[3.2.2Jnonan-3-one (Int 105):
To a stined solution of DIEA (13 mL) in acetonilfrile (680 mL) at reflux temperature is added a solution of hit 104 (2.0 g, 6.0 mmol) in acetonitrile (125 mL) over a 4 h period via syringe pump. The mixture is kept at reflux temperature overnight. The mixture is concentrated in vacuo and the remaining residue is partitioned between a saturated aqueous potassium carbonate solution and CHC1 - MeOH (90:10). The aqueous layer is extracted with CHCl3-MeOH (90:10), and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on silica gel. Elution with CHCl3-MeOH-NH4OH (95:4.5:0.5) gives 600 mg (72%) of hit 105 as a clear solid: 1HNMR (CDC13) δ 3.7, 3.3-3.2, 3.1-3.0, 2.7, 2.3, 2.0-1.8.
l-Azabicyclo[3.2.2]nonan-3-amine bis(4-methylbenzenesulfonate) ([3.2.2]- Amine):
To a stirred mixture of hit 105 (330 mg, 2.4 mmol) and sodium acetate^trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) is added hydroxylamine«hydrochloride (200 mg, 2.8 mmol). The mixture is stined at rt for 10 h. The mixture is filtered and the filtrate is concentrated in vacuo to a yellow solid. To a solution of the solid (350 mg, 2.3 mmol) in n-propanol (30 mL) at reflux temperature is added sodium metal (2.0 g, 87 mmol) in small portions over 30 min. Heating at reflux is continued for 2 h. The solution is cooled to rt and brine is added. The mixture is extracted with n-propanol, and the combined organic layers are concentrated in vacuo. The residue is taken up in CHC1 and the remaining solids are filtered. The filtrate is dried (MgSO4), filtered and concentrated in vacuo to a clear solid. To a stirred solution of the solid (320 mg, 2.3 mmol) in EtOH (4 mL) is added p -toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). The solution is warmed in a water bath to 45°C for 30 min, followed by concentration of the solvent to afford 710 mg (62%) of [3.2.2J-Amine as a white solid: 1H NMR (CD3OD) δ 7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4, 2.2-2.1, 2.1-2.0, 1.9.
Resolution of stereoisomers:
The amine can be coupled to form the appropriate amides or thioamides as a racemic mixture. The racemic mixture can then be resolved by chromatography using chiral columns or chiral HPLC, techniques widely known in the art, to provide the requisite resolved enantiomers 3(R) and 3(5) of said amides.
Coupling procedures using the Azabicyclo moieties discussed herein with various W moieties discussed herein to prepare compounds of formula I are discussed in the following, all of which are incorporated herein by reference: US 6,492,386; US 6,500,840; US 6,562,816; US 2003/0045540A1; US 2003/0055043A1; US 2003/0069296A1; US 2003/0073707A1; US 2003/015089A1; US 2003/0130305A1; US 2003/0153595A1; WO 03/037896; WO 03/40147; WO 03/070728; WO 03/070731; WO 03/070732. Although the compounds made therein maybe for one specific Azabicyclo moiety, the procedures discussed, or slight non-critical changes thereof, can be used to make the compounds of formula I.
The intermediates providing the W of formula I either are commercially available or prepared using known procedures, making non-critical changes.
Compounds of Fonnula I where W is (D) are made using the coupling procedures discussed herein and in the literature, making non-critical changes to obtain the desired compounds. The following intermediates to provide W as (D) of formula I are for exemplification only and are not intended to limit the scope of the present invention. Other intermediates within the scope of the present invention can be obtained using known procedures or by making slight modifications to known procedures.
Intermediate Dl: furof2,3-c1pyridine-5-carboxylic acid There are many routes for obtaining the carboxylic acid including the preparation of the acid discussed herein and also from hydrolyzing the ester, the preparation of which is discussed in US 6,265,580. n-Butyl furo[2,3-cJpyridine-5- carboxylate is hydrolyzed to the corresponding carboxylate salt on treatment with sodium or potassium hydroxide in aqueous methanol or acetonitrile-methanol mixtures. Acidification to pH 2.5-3.5 generates the carboxylic acid, which is isolated as a solid. The free base can also be prepared directly from n-butyl furo[2,3- cJpyridine-5-carboxylate by direct condensation using at least 1.5 molar equivalents of (R)-3-aminoquinuclidine and heating in ethanol or n-butyl alcohol.
2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO3 (19.5g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask. The flask is placed in an oil bath at 90°C, and after 5 min, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3 x 8 mL, then 2.2 mL all at 90-min intervals and then the final 2.3 mL after the reaction stirs for 15 h at 90°C. The reaction is stined at 90°C for another 4 h and then cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stirred for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc. The combined organic extracts are concentrated in vacuo, toluene is added to the flask and removed in vacuo to azeotrope water, and then CH2θ2 is added and removed in vacuo to obtain 2-chloro-6-(hydroxymethyl)-3-pyridinol (I-l-D) as a pale yellow solid (81% yield) sufficiently pure for subsequent reaction. MS (El) for C6H6ClNO2, m/z: 159 (M)+. I-l-D (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL H2O. The mixture is stined until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stined over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4 x 50 mL EtOAc. The combined organic layer is dried (MgSO4), is filtered.! and the filtrate is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-2-D) as an off- white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2 hexane/acetic acid to afford additional pure I-2-D (12% yield). MS (El) for C6H5ClINO2, m/z: 285(M)+.
I-2-D (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL, 68 mmol), bis(triphenylphosphine) palladium dichloride (1.02 g, 1.46 mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl3/40 mL THF under N2. TEA (21 mL, 151 mmol) is added, and the reaction is stined 3 h at rt and is diluted with 200 mL CHCI3. The mixture is washed with 2 x 150 mL 5% HCl and the combined aqueous layers are extracted with 2 x 50 mL CHC13. The combined organic layer is washed with 100 mL 50% saturated NaCl, is dried (MgSO4), and concentrated in vacuo to an amber oil. The crude material is chromatographed over 350 g silica gel (230-400 mesh), eluting with 35% EtOAc/hexane to afford 2-chloro-6- (hydroxymethyl)-4-[(trimethylsilyl)ethynylJ-3-pyridinol (I-3-D) as a golden solid (92% yield). MS (El) for CnHι4ClNO2Si, m/z: 255(M)+.
1-3 -D (7.9 g, 31.2 mmol) and cuprous iodide (297 mg, 1.6 mmol) in 60 mL EtOH/60 mL TEA are added to a flask. The reaction is placed in an oil bath at 70°C for 3.5h, is cooled to rt, and concentrated in vacuo. The residue is partitioned between 100 mL 5% HCl and CH2C12 (4 x 50 mL). The combined organic layer is dried (MgSO ), filtered, and concentrated in vacuo to give 6.5 g of a crude amber solid. The crude material is chromatographed over 300 g silica gel (230-400 mesh) eluting with 30-40% EtOAc/hexane. Two sets of fractions with two different desired compounds are identified by TLC/UN. The two compounds eluted separately. The early-eluting pool of fractions is combined and concentrated to afford [7-chloro-2- (trimethylsilyl)furo[2,3-cJpyridin-5-ylJmethanol (1-5 -D) as a white solid (46% yield). The later-eluting pool of fractions is combined and concentrated to provide (7- chloiOfuro[2,3-c]pyridin-5-yl)methanol (I-4-D) as a white solid (27% yield). MS (El) for C8H6ClΝO2, m/z: 183 (M)+ for I-4-D. HRMS (FAB) calculated for CnHι ClNO2Si w/ : 255.0482, found 255.0481 for I-5-D.
I-5-D (1.05 g, 4.1 mmol) and 10% Pd/C catalyst (1.05 g) are placed in 20 mL absolute EtOH. Cyclohexene (4 mL, 40.1 mmol) is added, and the reaction is refluxed for 2.5h, and then filtered through celite. The filter cake is washed with 1 :1 EtOH/CH2Cl2, and the filtrate is concentrated to a pale yellow solid. The residue is partitioned between 40 mL saturated NaHCO3 and extracted with CH2C12 (4 x 20 mL). The combined organic layer is dried (MgSO4), filtered, and then concentrated in vacuo to a pale oil (1.04 g). The pale oil is chromatographed over 50 g silica gel (230- 400 mesh) eluting with 50-70% EtOAc hexane to afford 5-hydroxymethyl-2- trimethylsilyl-furo[2,3-c]pyridine (I-14-D) as a white solid (90% yield). MS (El) for CnHi5NO2Si, m/z: 221(M)+.
I-14-D (770 mg, 3.48 mmol) is dissolved in 10 mL MeOH. 2N NaOH (3 mL, 6 mmol) is added, and the reaction is stined for 1.5 h at rt. The solution is concentrated in vacuo to a residue. Water (20 mL) is added to the residue and extracted with 4 10 mL CH2θ2. The combined organic layer is dried (K2CO3), filtered, and concentrated in vacuo to afford furo[2,3-c]pyridin-5-yl methanol (I-16-D) as a white solid (90% yield). Analysis calculated for C8H7NO2: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.60; H, 4.56; N, 9.44. Alternatively, 1-3 -D is used to obtain I-16-D with fewer steps: 1-3 -D (44.6 g,
174.4 mmol) is combined with cuprous iodide (1.66 g, 8.72 mmol) and diisopropylamine (44 ml, 300 mmol) in 300 ml methanol under nitrogen. The reaction is warmed to 45-50°C for 6 h, is cooled to rt and treated with 100 ml saturated NaHCO3 followed by 100 ml 2N NaOH. The dark mixture is stined overnight, filtered through celite, the volatiles removed in vacuo and the residue is partitioned between 1 x 500 ml water and 4 x 200 ml CH2CI2 (some filtrations is required to effect good separation). The combined organic layer is dried (MgSO4) and concentrated in vacuo to afford I-4-D (25.25g, 79%) as a pale orange solid. Anal. Calcd for C8H6ClNO2: C,52.34; H,3.29; N,7.63. Found: C,52.27; H,3.23; N,7.57.
I-4-D (32.0 g, 174 mmol) is combined with zinc powder (34.2 g, 523 mmol) in absolute EtOH (900 mL), using an overhead stirrer. The mixture is heated to 70°C, HCl (87.2 mL, 1.05 mol) is added slowly drop-wise, and the mixture is heated to reflux for 1 h. The mixture is cooled slightly, filtered to remove the metallic zinc and concentrated to near-dryness. The yellow oil is diluted with H2O (150 mL) and EtOAc (950 mL) and is treated slowly drop-wise with 20% Na CO3 (310 mL) as the mixture is warmed to reflux. The vigorously stined (using overhead stiner) mixture is refluxed for 1 h, cooled slightly and the organics removed via cannula under reduced pressure. Additional EtOAc (600 mL) is added, the mixture is heated to reflux for 1 h, cooled slightly and the organics removed as above. More EtOAc (600 mL) is added, the mixture is stined at rt overnight then heated to reflux for 1 h, cooled slightly and most of the organics removed as above. The remaining mixture is filtered tlirough celite, rinsed with EtOAc until no additional product elutes, and the layers separated. The aqueous layer is further exfracted with EtOAc (2 X 400 mL). The combined organics are dried (MgSO ) and concentrated to a dark yellow solid (23.6 g). The crude material is chromatographed over 900 g slurry-packed silica gel, eluting with 60% EtOAc / hexane (3 L), 70% EtOAc / hexane (2 L), and finally 100% EtOAc. The appropriate fractions are combined and concentrated in vacuo to afford I-16-D (19.5 g, 75%) as a white solid. Anal. Calcd for C8H7NO2: C,64.42; H,4.73; N,9.39; Found: C,64.60; H,4.56; N.9.44.
Oxalyl chloride (685μL, 7.8 mmol) is dissolved in 30 mL CH2C12 in a dry flask under N2. The flask is placed in a dry-ice/acetone bath, DMSO (1.11 mL, 15.6 mmol) in 5 mL CH2CI2 is added drop-wise, and the mixture is stined for 20 min.
I-16-D (1.0 g, 6.7 mmol) in 10 mL CH2C12 is added, and the reaction is stined 30 min at -78°C. TEA (4.7 mL, 33.5 mmol) is added, the reaction is allowed to warm to rt, is stined lh, and washed with 25 mL saturated NaHCO3. The organic layer is dried (K2CO3), filtered, and concentrated in vacuo to an orange solid. The crude material is chromatographed over 50 g silica gel (230-400 mesh) eluting with 33% EtOAc/ hexane to provide furo[2,3-cJpyridine-5-carbaldehyde (I-17-D as a white solid (86% yield). MS (El) for C8H5NO2, m/z: 147 (M)+. I-17-D (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO. KH2PO4 (221 mg, 1.6 mmol) in 3 mL H2O is added and then NaClO2 (920 mg, 8.2 mmol) in 7 mL H2O is added, and the reaction is stined 3 h at rt. The reaction is diluted with 25 mL water, the pH is adjusted to 10 with 2N NaOH, and the mixture is extracted with 3 x 20 mL ether. The combined ether layer is discarded. The pH of the aqueous layer is adjusted to 3.5 with 10% aqueous HCl and is extracted with 13 x 10 mL 10% MeOH/CH2Cl2. The MeOH/CH2Cl2 organic layer is dried (Na2SO4), filtered, and concentrated in vacuo to a pale oil. The residual DMSO is removed under a stream of N at rt to provide a white paste. The paste is dissolved in MeOH and concentrated to dryness. The white solid is washed with ether and dried to afford crude furo[2,3-c]pyridine-5- carboxylic acid (I-18-D) (94% yield). MS (ESI) for C8H5NO3, 162.8 (M-H)".
Intermediate D2: Furof3,2-clpyridine-6-carboxyIic acid
3-Bromofuran (8.99 mL, 100.0 mmol) is dissolved in DMF (8.5 mL), cooled to 0°C, treated dropwise with POCl3 (9.79 mL, 105.0 mmol), stined for 1 h at RT and then heated to 80°C for 2 h. The mixture is cooled to RT, poured over ice (1 kg) and neutralized to pH 9 with solid K2CO3. The mixture is stined for 1 h, extracted with Et O (3 X 500 mL), dried (K CO3) and concentrated to a dark brown oil. The crude material is chromatographed over 600 g slurry-packed silica gel, eluting with 6% EtOAc/hexane (4L), 8% EtOAc/hexane (2L), 10% EtOAc/hexane (IL), and finally 20% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 14.22 g (81%) of 3-bromo-2-furaldehyde as a yellow oil. MS (El) m/z: 11 A (M+).
3-Bromo-2-furaldehyde (14.22 g, 81.3 mmol) is combined with ethylene glycol (6.55 mL, 117.4 mmol) and/?Ωr -toluene sulfonic acid monohydrate (772 mg, 4.06 mmol) in benzene (200 mL) and heated to reflux with a Dean-Stark trap for 5 h. Additional ethylene glycol (1.64 mL, 29.41 mmol) and benzene (150 mL) are added and the solution is heated for an additional 2 h. The mixture is cooled to RT, treated with saturated NaHCO and stined for 0.5 h. The layers are separated and the organics are dried (Na2SO4) and concentrated to a brown oil (18.8 g). The crude material is chromatographed over 700 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 16.45 g (92%) of 2-(3-bromo-2-furyl)-l,3-dioxolane as a yellow-orange oil. MS (EI) w/ : 218 (M+).
2-(3-Bromo-2-furyl)-l,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in a dry flask under nitrogen, cooled to -78°C, treated dropwise with tert- butyllithium (2.59 mL, 4.4 mmol) and stined for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at -78°C, then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to RT over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1 X 20 mL). The organics are dried (Na2SO ) and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(l,3-dioxolan-2- yl)-3-furaldehyde as a pale yellow oil. MS (El) m/z: 168 (M+). 2-(l,3-Dioxolan-2-yl)-3-furaldehyde (2.91 g, 17.31 mmol) is combined with formic acid (17 mL, 451 mmol) and water (4.25 mL) and stined at RT for 18 h. The mixture is slowly transfened into a solution of NaHCO3 (45 g, 541 mmol) in water (600 mL), then strined for 0.5 h. EtOAc (200 mL) is added, the layers separated and the aqueous layer extracted with EtOAc (2 X 200 mL). The combined organics are dried (Na2SO ) and concentrated to a yellow oil (3.28 g). The crude material is chromatographed over 90 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 2.45 g of furan-2,3- dicarbaldehyde slightly contaminated with ethylene glycol diformate as a yellow oil. 1H NMR (CDC13): δ 7.00 (d, J= 2 Hz, 1 H), 7.67 (d, J= 2 Hz, 1 H), 10.07 (s, 1 H), 10.49 (s, 1 H) ppm.
Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) is dissolved in CHC13 (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stined for 5 min then added dropwise to a 0°C solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHC13 (80 mL). The mixture is stined for 2.5 h as the cooling bath expires then 5.5 h at RT and finally 24 h at 50°C. The mixture is concentrated in vacuo to a yellow oily-solid (6.66 g). The crude material is chromatographed over a standard lOOg slurry-packed silica gel, eluting with 65% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 1.30 g (82%) of methyl furo[3,2- cJpyridine-6-carboxylate as a yellow solid. MS (El) m/z: 111 (M+).
Methyl furo[3,2-cJpyridine-6-carboxylate (1.55 g, 8.74 mmol) is dissolved in MeOH (30 mL) and H2O (15 mL), treated with 3 N NaOH (6.4 mL) and stirred at RT for 7 h. The mixture is concentrated to dryness, dissolved in H O (10 mL) and acidified to pH 2 with concentrated HCl. The solution is concentrated to dryness, suspended in a smaller amount of water (7 mL) and the resulting solid collected via filtration (lot A). The filtrate is concentrated, triturated with water (3 mL) and the resulting solid collected via filtration (lot B). The filtrate from lot B is concentrated and carried on without further purification as an acid/salt mixture (lot C). Both lots A and B are dried in a vacuum oven at 50°C for 18 h to afford 690 mg (48%) for lot A and 591 mg (42%) for lot B of furo[3,2-cJpyridine-6-carboxylic acid as yellow solids. MS (CI) -?./ : 164 (M + H+).
Intermediate D3: 7-Chlorofurof2,3-c1pyridine-5-carboxylic acid
Oxalyl chloride (3.1 mL, 35 mmol) is dissolved in 200 mL CH2C12 in a dried flask under N2. The flask is placed in a dry-ice/acetone bath at -78°C, DMSO (4.95 mL, 70 mmol) in 10 mL CH2C12 is added drop-wise, and the mixture is stirred for 20 min. (7-Chlorofuro[2,3-cJpyridin-5-yl)methanol (I-4-D (5.5 g, 30 mmol) in 10 mL CH C12 is added, and the reaction is stirred 30 min at -78°C. TEA (21.3 mL, 153 mmol) is then added. The reaction is stirred 30 min in the dry-ice/acetone bath, an ice bath replaces the dry-ice/acetone bath, and the reaction is stined 1 h and is washed with 100 mL 1:1 saturated NaCl/NaHCO3. The organic layer is dried (K2CO3), filtered, and concentrated in vacuo to afford 7-chlorofuro[2,3-cJpyridine-5- carbaldehyde (I-6-D as a pale yellow solid (97% yield). MS (El) for C8H4ClNO2 m/z: 181 (M)+.
I-6-D (3.0 g, 16.5 mmol) is dissolved in 40 mL DMSO. KH2PO4 (561 mg, 4.1 mmol) in 6.5 mL H2O is added and then NaClO2 (2.6 g, 23.1 mmol) in 24 mL H2O is added, and the reaction is stined overnight at rt. The reaction is diluted with 200 mL H2O, the pH is adjusted to 9 with 2N NaOH, and any remaining aldehyde is extracted into 3 x 50 L ether. The pH of the aqueous layer is adjusted to 3 with 10% aqueous HCl and is extracted with 4 x 50 mL EtOAc. The combined organic layer is dried (MgSO4), filtered, and concentrated in vacuo to a white solid. The solid is washed with ether and dried to afford 7-chlorofuro[2,3-cJpyridme-5-carboxylic acid (I-7-D) (55% yield). MS (CI) for C8H4ClNO3, m/z: 198 (M+H).
Intermediate D4: 2,3-Dihydrofurof2,3-c1pyridine-5-carboxyIic acid I-7-D (980 mg, 4.98 mmol) is dissolved in 75 mL MeOH containing 500 mg
20% palladium hydroxide on carbon in a 250 mL Pan shaker bottle. The reaction mixture is hydrogenated at 20 PSI for 24 h. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to a white solid. The solid is dissolved in MeOH and is loaded onto 20 mL Dowex 50W-X2 ion exchange resin (hydrogen form) which had been prewashed with MeOH. The column is eluted with 50 mL MeOH followed by 150 mL 5% TEA in MeOH to afford 2,3-dihydrofuro[2,3-cJpyridine-5-carboxylic acid q-8-D) (74% yield). HRMS (FAB) calculated for C8H7NO3+H: 166.0504, found 166.0498 (M+H).
Intermediate D5: 3,3-Dimethyl-2,3-dihydrofuro[2.3-clpyri ine-5-carboxylic acid
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-2-D) (6.3 g, 22 mmol) is dissolved in 30 mL DMF in a dry flask under N2. The flask is placed in an ice bath, and 60% sodium hydride in mineral oil (880 mg, 22 mmol) is added. The reaction is stirred 30 min while the flask is kept in an ice bath. The ice bath is removed for 30 min and then the flask is placed back into the ice bath to cool the reaction. 3-Bromo- 2-methylpropene (23.1 mmol) is added, and the reaction is stined overnight at rt. The reaction is diluted with 150 mL EtOAc and is washed with 4 x 50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried (Na2SO4), filtered, and then concentrated in vacuo to a pale oil which is crystallized from hexanes to afford (6- chloro-4-iodo-5-[(2-methyl-2-propenyl)oxy]-2-pyridinyl)methanol (I-19-D) (86% yield). HRMS (FAB) calculated for C10HπClINθ2+H: 339.9603, found 339.9604 (M+H).
I-19-D (6.3 g, 18.9 mmol), sodium formate (1.49 g, 21.8 mmol), TEA (8 mL, 57.2 mmol), palladium acetate (202 mg, 0.9 mmol) and terra (n-butyl)ammonium chloride (5.25 g, 18.9 mmol) are added to 30 mL DMF in a dry flask under N2. The reaction is warmed to 60°C for 5h, is poured into 150 mL EtOAc, and is washed with 4 x 50 mL 50% saturated 1 :1 NaCl/NaHCO3. The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo to a pale oil. The crude material is chromatographed over 40 g silica gel (Biotage), eluting with 30% EtOAc/hexane to afford (7-chloro-3 , 3 -dimethyl-2,3 -dihydrofuro[2 , 3 -cJpyridin-5-yl)methanol (I-20-D) (54% yield). MS (El) for Cι0Hι2ClNO2, m/z: 213 (M)+.
I-20-D (2.11 g, 9.9 mmol) and 600 mg 10% Pd C catalyst are placed in 30 mL EtOH in a 250 mL Pan shaker bottle. 2N NaOH (5 mL, 10 mmol) is then added and the mixture is hydrogenated at 20 PSI for 2.5 h. The catalyst is removed by filtration, and the filtrate is concentrated in vacuo to an aqueous residue. Saturated NaHCO3 (20 mL) is added to the residue and extracted with 4 x 20 mL CH2C12. The combined organic layer is dried (K2CO3), filtered, and concentrated in vacuo to afford (3,3- dimethyl-2,3-dihydrofuro[2,3-cJpyridin-5-yl)methanol fI-21-D (92% yield). MS (El) for Ci0Hi3NO2, m/z: 179 (M)+.
Oxalyl chloride (869 μL, 9.9 mmol) is dissolved in 50 mL CH2C12 in a dry flask under N2. The flask is placed in a dry-ice/acetone bath at -78°C, DMSO (1.41 mL, 19.8 mmol) in 5 mL CH2C12 is added drop-wise, and the mixture is stined for 20 min. 1-21-D (1.53 g, 8.5 mmol) in 5 mL CH C12 is then added, and the reaction is stined 30 min at -78°C. TEA (5.9 mL, 42.5 mmol) is added and the reaction is stirred 20 min at -78°C. The dry-ice/acetone bath is removed, the reaction is stined lh, and the reaction is washed with 25 mL saturated NaHCO . The organic layer is dried (K2CO3), filtered, and then concentrated in vacuo to an orange solid. The crude material is chromatographed over 40 g silica gel (Biotage) eluting with 25%
EtOAc/hexane to afford 3,3-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (1-22-D) (92% yield). MS (El) for Cι0HnNO2, m/z: 111 (M)+.
1-22-D (1.35 g, 7.62 mmol) is dissolved in 40 mL THF, 20 mL t-butanol, and 20 mL H2O. KH2PO4 (3.1 lg, 22.9 mmol) and NaClO2 (2.58 g, 22.9 mmol) are added, and the reaction is stined over the weekend at rt. The reaction is concentrated in vacuo to a residue. The residue is partitioned between 20 mL water and CH2C12 (2 x 50 mL). The combined organic layer is dried (Na2SO4), filtered, and then concentrated in vacuo to afford crude 3,3-dimethyl-2,3-dihychofuro[2,3-cJpyridine-5- carboxylic acid (I-23-D) (99% yield). HRMS (FAB) calculated for Cι0HnNO3+H: 194.0817, found 194.0808 (M+H).
Intermediate D6: 2-Methylfuro[2,3-c1pyridine-5-carboxylic acid 2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-2-D) (4.6 g, 16 mmol), propargyl trimethylsilane (2 g, 17.8 mmol), bis(triphenylphosphine) palladium dichloride (156 mg, 0.21 mmol), cuprous iodide (122 mg, 0.64 mmol), and piperidine (3.52 mL, 26.6 mmol) are added to 25 mL DMF in a dry flask under N2. The mixture is warmed to 45°C for 7 h, is stirred overnight at rt, and is diluted with 150 mL EtOAc. The mixture is washed with 4 x 50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried (Na2SO ), filtered, and then concentrated in vacuo to an amber oil. The crude material is chromatographed over 40 g silica gel (230-400 mesh) eluting with 35% EtOAc/hexane to afford (7-chloro-2-methylfuro[2,3- c]pyridin-5-yl)methanol (I-24-D (44% yield). MS (CI) for C9H8ClNO2, m/z: 198 (M+H).
I-24-D (2.0 g, 10.8 mmol) is added to 500 mg 10% Pd/C catalyst in 25 mL EtOH in a 250 mL Pan shaker bottle. 2N NaOH (6 mL, 12 mmol) is added, and the reaction is hydrogenated at 20 PSI for 6 h. The catalyst is removed by filtration, and the filtrate is concentrated in vacuo to an aqueous residue. The residue is partitioned between 50 mL 50% saturated NaCl and 30 mL CH2C12. The organic layer is dried (K2CO ), filtered, and then concentrated in vacuo to afford (2-methylfuro[2,3- c]pyridin-5-yl)methanol (I-25-D (77% yield). MS (CI) for C9H9NO2, m/z: 164 (M+H). Oxalyl chloride (784 μL, 8.9 mmol) is dissolved in 25 mL CH2C12 in a dry flask under N2. The flask is placed in a dry-ice/acetone bath at -78°C, and DMSO (1.26 mL, 17.8 mmol) in 5 mL CH C12 is added. The mixture is stirred for 20 min and I-25-D (1.53 g, 8.5 mmol) in 5 mL CH2C12 is added. The reaction is stined 1 h, TEA (5.9 mL, 42.5 mmol) is added, and the reaction is stined 30 min at -78°C. The flask is placed in an ice bath, and the reaction is stined 1 h. The reaction is washed with 50 mL saturated NaHCO3. The organic layer is dried (K2CO3), filtered, and then concentrated in vacuo to a tan solid. The crude material is chromatographed over 40 g silica gel (Biotage) eluting with 25% EtOAc/hexane to afford 2-methylfuro[2,3- cJpyridine-5-carbaldehyde (I-26-D) (99% yield). MS (El) for C9H7NO2, m/z: 161 (M)+.
I-26-D (1.15 g, 7.1 mmol) is dissolved in 40 mL THF, 20 mL t-butanol, and 20 mL H2O. 2-Methyl-2-butene (6.5 mL, 57.4 mmol) is added, and then KH2PO4 (3.1 lg, 22.9 mmol) and NaClO (2.58 g, 22.9 mmol) are added. The reaction is stined 6 h at rt. The reaction is concentrated in vacuo. Water (20 ml) is added to the residue, a white solid remained. The white solid is collected, washed with water and then with ether, and is dried to afford 2-methylfuro[2,3-c]pyridine-5-carboxylic acid (I-27-D (70% yield). MS (El) for C9H7NO3, m/z 111 (M)+.
Intermediate D7: 3-Methylfuror2,3-clpyridine-5-carboxyIic acid
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-2-D) (7.14 g, 25.0 mmol) is dissolved in DMF (50 mL) in a dry flask under N2, sodium hydride (60% dispersion in mineral oil) (1.0 g, 25.0 mmol) is added, and the reaction is stined for 1 h at rt. Allyl bromide (2.38 mL, 27.5 mmol) is added, and the reaction mixture is stined 48h at rt. The mixture is diluted with EtOAc (50 mL) and washed 4 x 25 mL of a 50% saturated solution of 1 :1 NaCl/NaHCO3. The organic layer is dried (MgSO ), filtered and concentrated in vacuo to a white solid. The solid is washed with hexane and dried to afford 3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodopyridine (I-50-D) as a white solid (68% yield). MS (El) for C9H9ClINO2, m/z: 325 (M)+.
1-50-D (5.51 g, 16.9 mmol) is suspended in benzene (30 mL) in a dry flask under N2. Azo(bis)isobutyryl nitrile (289 mg, 1.8 mmol) is added, the mixture is rapidly heated to reflux, and tributyltin hydride (4.91 mL, 18.2 mmol) in benzene (10 mL) is added. The solution is refluxed for 1.5 h, allowed to cool to rt and concentrated in vacuo. The resulting residue is chromatographed over 125 g slurry- packed silica gel, eluting with a gradient of EtOAc/hexane (20% - 60%) to afford (7- chloro-3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (1-51-D) as a white solid (89% yield). MS (ESI) for C9Hι0ClNO2+H, m/z: 200.1 (M+H).
1-51-D (3.00 g, 15.0 mmol) is added to 20% palladium hydroxide on carbon (800 mg) and 2N NaOH (9.2 mL, 18.2 mmol) in a Parr shaker bottle. The mixture is hydrogenated at 20 PSI for 3 h, is filtered through celite and concentrated in vacuo to a residue. The resulting residue is partitioned between H2O (50 mL) and CH2C12 (4 x 30 mL). The combined organic layer is dried (MgSO ), filtered, and concentrated to a colorless oil which solidified upon standing to afford 2.50 g (greater than 100% yield) of (3-methyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)methanol (1-52-D) as a white crystalline solid. MS (El) for C9HnNO2, m/z: 165 (M)+.
1-52-D (2.48 g, 15.03 mmol) is dissolved in pyridine (15 mL), and acetic anhydride (4.18 mL, 45.09 mmol) is added and stined for 16 h at rt under N2. The reaction is concenfrated in vacuo, and the residue is diluted with EtOAc (75 mL), washed with 50% saturated NaHCO3 (4 x 30 mL), and dried (MgSO4). The organic layer is filtered and concenfrated in vacuo to afford (3-methyl-2,3-dihydrofuro[2,3- cJpyridin-5-yl)methyl acetate (1-53-D) as a colorless oil (92% yield). MS (El) for CnHι3NO3, m/z: 207 (M)+.
1-53-D (2.85 g, 13.8 mmol) is dissolved in dioxane (100 mL), 2,3,5,6- tertachlorobenzoquinone (3.72 g, 15.1 mmol) is added, and the reaction is heated to reflux for 17 h. The reaction is concenfrated in vacuo. The resulting brown solid is washed with 1 : 1 EtO Ac/ether (50 mL), and the insoluble material filtered off. The filtrate is concentrated to a brown solid, dissolved in MeOH (50 mL), treated with 2N NaOH (16 mL, 32 mmol), and stined at rt for 1 h. The mixture is concenfrated to dryness, dissolved in IN NaOH (75 mL), and extracted with CH2CI2 (4 x 50 mL). The combined organic layer is dried (K2CO3), filtered, and concenfrated to a white solid (2.0 g). The crude material is adsorbed onto silica gel (4 g) and chromatographed over a standard 40 g Biotage column, eluting with 90%
EtOAc/hexane to afford (3-methylfuro[2,3-cJpyridin-5-yl)methanol (I-54-D) as a white solid (84% yield). MS (El) for C9H9NO2, m/z: 163 (M)+.
Oxalyl chloride (1.16 mL, 13.2 mmol) is added to CH2C12 (30 mL) in a dry flask under N2 and in a dry-ice/acetone bath at -78°C. DMSO (18.80 mL, 26.5 mmol) is slowly added. The solution is stined for 20 min, and I-54-D (1.88 g, 11.5 mmol) is added. The mixture is stined for 1 h at -78°C, then 30 min at 0-5°C. The material is washed with saturated NaHCO3 (75 mL), dried (K2CO3), filtered, and concentrated in vacuo to a yellow solid (3.23 g). The crude material is adsorbed onto silica gel (6 g) and chromatographed over a standard 40 g Biotage column, eluting with 25% EtOAc/hexane to afford 3-methylfuro[2,3-cJpyridine-5-carbaldehyde (I-55-D) as a white solid (72% yield). MS (El) for C9H7NO2, m/z: 161 (M)+.
I-55-D (1.33 g, 8.28 mmol) is dissolved in THF (50 mL), tert-butylalcohol (25 mL) and H2O (25 mL), under N2, and NaClO2 (2.81 g, 24.84 mmol) and KH2PO4 (2.25 g, 16.56 mmol) are added. The reaction mixture is stined overnight at rt, concentrated to dryness, dissolved in 50% saturated brine (60 mL) and extracted with ether (3 X). TLC of extracts indicates acid as well as residual aldehyde, so the organic and aqueous layers are combined and basified to pH 10 with NH4OH. The layers are separated and the residual aldehyde extracted with additional ether. The aqueous layer is acidified to pH 3 with concentrated HCl, then extracted with CH2θ2 (4 X). Large amounts of acid remained in the aqueous layer, so the aqueous layer is concentrated to dryness. The solid is triturated with CHC13 (4 X), and then 10% MeOH/CH2Cl2 (4 X) to extract much of the acid into the supernatant. The combined organic layer is dried (Na2SO4), filtered, and concentrated to a tan solid (1.69 g, greater than 100% isolated yield). The solid is diluted with CHC13 and is heated to reflux for 3 h. The flask is removed from heat, allowed to cool slightly, then filtered. The filtrate is concenfrated to a tan solid (1.02 g). The solid is triturated with ether, filtered and dried to afford 3- methylfuro[2,3-c]pyridine-5-carboxylic acid (1-56-D as a light tan solid (51% yield). MS (CI) for C9H7NO3, m/z 178 (M+H).
Intermediate D8: 3-Ethylfuro[2,3-clpyridine-5-carboxylic acid
From l-chloro-2-butene and 2-chloro-6-(hydiOxymethyl)-4-iodo-3-pyridinol (I-2-D , the conesponding 3-ethylfuro[2,3-c]pyridine-5-carboxylic acid (I-60-D) was prepared. HRMS (FAB) calculated for Cι0H9NO3+H: 192.0661, found 192.0659 (M+H).
Intermediate DIP: Furo[2,3-b1pyridine-2-carboxyIic
Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 min) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stined for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes. The reaction is warmed to 65°C for 15h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in H2O (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHC13 (4 x 400 mL). The combined organic layer is dried (MgSO4), filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (L 40-D as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate. Recrystallization in ether a second time afforded I-40-D as a pale yellow solid (7.3% yield). MS (El) for Cι0H9NO4, m/z: 207 (M)+. I-40-D (207 mg, 1.0 mmol) is added to TEA (139 μL, 1.0 mmol) in CH2C12 (5 mL) at rt and 2-[N,N-bis(frifluoromethylsulfonyl)aminoJ-5-chloropyridine (393 mg, 1.0 mmol) is added. The solution is stined for 1 h at rt, diluted with EtOAc (25 mL) and washed with 50% saturated brine (2 x 15 mL). The organic layer is dried (Νa2SO ), filtered, and concenfrated to a yellow oil which solidified upon standing. The crude material is adsorbed onto silica gel (1.2 g) and chromatographed over 25 g slurry-packed silica gel, eluting with 20% EtOAc/hexane to afford ethyl 3- ([(trifluoromethyl)sulfonyl]oxy)furo[2,3-b]pyridine-2-carboxylate ( 1-41-D) as a white crystalline solid (98% yield). Analysis calculated for CnH8F3NO6S: C, 38.94; H, 2.38; N, 4.13, found: C, 38.84; H, 2.29; N, 4.11.
1-41 -D (1.36 g, 4.0 mmol) is added to 10% Pd/C catalyst (68 mg) and NaHCO3 (336 mg, 4.0 mmol) in EtOH (100 mL)/H2O (5 mL) in a 250 mL Pan shaker bottle. The mixture is hydrogenated at 10 PSI for 5 h, filtered and concentrated to a residue. The residue is partitioned between 50% saturated NaHCO3 (80 mL) and EtOAc (80 mL). The organic layer is dried (Na SO ), filtered, and concentrated in vacuo to a colorless oil which solidified upon standing (793 mg). The crude material is chromatographed over 40 g slurry-packed silica gel, eluting with 25% EtOAc/hexane to afford ethyl furo[2,3-b]pyridine-2-carboxylate (1-42-D) as a white solid (90% yield). MS (El) for Cι0H9NO3, m/z: 191 (M)+. 1-42-D (758 mg, 3.96 mmol) is dissolved in MeOH (20 mL) and lithium hydroxide monohydrate (366 mg, 8.7 mmol) in 6mL H2O is added under N2. The reaction is stirred at rt for 2 h, concentrated to near-dryness, diluted with H2O (5 mL) and acidified to pH 3 with 10% HCl. The resulting solid is collected by filtration, washed with additional water and dried to afford furo[2,3-b]pyridine-2-carboxylic acid (1-43-D) as a white solid (97% yield). MS (El) for C8H5NO3, m/z: 163 (M)+.
Intermediate Dll: 3-Isopropylfuro[2,3-clpyridine-5-carboxyIic acid
3-Isopropylfuro[2,3-c]pyridine-5-carboxylic acid (I-70-D) is obtained starting with l-chloro-3-methyl-2-butene and 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-2-D , using the method described for Intermediate C7, making non-critical changes. HRMS (FAB) calculated for CuHnNO3+H: 206.0817, found 206.0817 (M+H)+.
Intermediate D12: Thieno[2,3-blpyridine-2-carboxylic acid THF (200 mL) in a dry flask under N2 is chilled by placing the flask in a dry- ice/acetone bath at -78°C. Butyllithium (125 mL, 200 mmol) is added drop-wise, followed by the drop-wise addition of iodobenzene (11.19 mL, 100 mmol) in THF (10 mL). The solution is allowed to stir for 30 min at -78°C. Diisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and 2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) are added successively in a drop-wise manner, and the solution is stined for 1 h at - 40°C. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) is added drop-wise, and the solution is stined for 1 h at -40°C. The reaction is quenched with 40 mL 6N HCl, diluted with 250 mL ether, and a small amount of sodium thiosulfate solution is added to remove the iodine color. The solution is neutralized with saturated NaHCO3, filtered, and extracted with ether (3 x 150 mL). The combined organic layer is dried (Na2SO4), filtered, and concenfrated in vacuo. The crude material is chromatographed over 600 g slurry-packed silica, eluting with 20% EtOAc/hexane to afford 2- chloronicotinaldehyde (I-90-D) as a pale orange solid (54% yield). MS (El) for C6H4ClNO, m/z: 141 (M)+.
I-90-D (1.41 g, 10.01 mmol) is dissolved in DMF (lOmL) and H2O (1 mL) under N2. K2CO3 (1.56 g, 11.27 mmol) and methyl thioglycolate (1.00 mL, 11.25 mmol) are added portionwise. The reaction is stirred at 35°C for 24 h, quenched with cold H2O (75 mL), and placed in an ice bath to enhance precipitation. The precipitate is isolated by filtration, affording methyl-thieno[2,3-bJpyridine-2-carboxylate α-101-D) as an orange powder (40% yield). MS (El) for C9H7NO2S, m/z: 193 (M)+. I-101-D (0.700 g, 3.63 mmol) is dissolved in MeOH (15 mL) and 3 mL H2O. 2N NaOH (1.82 mL, 3.63 mmol) is added drop-wise, and the reaction is stined at rt for 24 h. The reaction is concentrated in vacuo, and H2O (40 mL) is added to dissolve the residue. The resulting solution is acidified to pH 4 using concentrated HCl, and the precipitate is isolated by filtration, yielding thieno[2,3-b]pyridine-2-carboxylic acid (1-102-D) as a white powder (85% yield). MS (El) for C8H5NO2S, m/z: 179 (M)+.
Intermediate D13: Thienof2,3-b1pyridine-5-carboxylic acid
2-Nitrothiophene (33.76 g, 261.4 mmol) is suspended in concentrated HCl (175 mL) and heated to 50°C. Stannous chloride (118.05 g, 523.2 mmol) is added portionwise, maintaining the reaction temperature between 45-50°C with an ice bath, that is removed after the addition. The solution is allowed to cool slowly to 30°C over an hour. The solution is then cooled in an ice bath and filtered. The cake is washed with concentrated HCl (20 mL), dried in a stream of air, and washed with ether (50 mL) to afford the hexachlorostannate salt of 2-aminothiophene as a brown solid (26% yield).
3,3-Dimethyl-2-formyl propionitrile sodium (3.33 g, 20.2 mmol) can readily be prepared from the method described by Bertz, S.H., et al., J. Org. Chem., Al, 2216- 2217 (1982). 3,3-Dimethyl-2-formyl propionitrile sodium is dissolved in MeOH (40 mL), and concentrated HCl (4 mL) and the hexachlorostannate salt of 2- aminothiophene (10.04 g, 19.1 mmol) in MeOH (130 mL) is slowly added drop-wise to the mixture. Following addition, the mixture is heated to reflux in an oil bath (80°C) for 4 h, and then MeOH (10 mL) and concentrated HCl (10 mL) are added. The reaction continued refluxing for another 20 h. The solution is cooled to rt, and the reaction is concentrated in vacuo. The purple residue is dissolved in H2O (60 L), and the slurry is filtered. The cake is pulverized and stined vigorously with 5% MeOH/CHCl3 (105 mL) while heating to 55°C. The mixture is cooled and filtered, and the organic layer is concentrated to a green oil. The crude material is chromatographed over 130 g slurry-packed silica, eluting with 30% EtOAc/hexane to afford thieno[2,3-bJpyridine-5-carbonitrile (I-105-D as a pale yellow solid (24% yield). HRMS (FAB) calculated for C8H4N2S+H: 161.0173, found 161.0173 (M+H). NaOH (0.138 g, 3.45 mmol) is added to a solution ofI-105-D (0.503 g, 3.14 mmol) dissolved in 70% EtOH/H2θ (12 L). The mixture is heated to reflux at 100°C for 3 h. The reaction is concentrated in vacuo, and the residue is dissolved in H2O (8 mL) and neutralized with concentrated HCl. The slurry is filtered and rinsed with ether. An initial NMR of the isolated material indicates the presence of the carboxamide intermediate, so the material is suspended in IM NaOH (6 mL) and stined overnight. Water (10 mL) is added, the solution is extracted with ether (3 x 10 mL), and the mixture is neutralized with concentrated HCl. The slurry is filtered and rinsed with ether, affording of thieno[2,3-b]pyridine-5-carboxylic acid (I-106-D) as an off-white solid (48% yield). MS (El) for C8H5NO2S, m/z: 179 (M)+.
Intermediate D14: Thieno[2,3-b1pyridine-6-carboxyIic acid 2-Nitrothiophene (12.9 g, 99.9 mmol) is dissolved in concentrated HCl (200 mL) and stirred vigorously at 30°C. Granular tin (25 g, 210 mmol) is slowly added portionwise. When the tin is completely dissolved, zinc chloride (6.1 g, 44.7 mmol) in EtOH (70 mL) is added drop-wise, the mixture is heated to 85°C, and malondialdehyde diethyl acetal (24 mL, 100 mmol) in EtOH (30 mL) is added. The solution continued stirring at 85°C for 1 h, and is quenched by pouring over ice (100 g). The mixture is adjusted to pH 10 with NH4OH, and the resulting slurry is carefully filtered through celite overnight. The liquor is exfracted with CHC13 (3 x 300 mL), and the combined organic layer is dried (MgSO4), filtered, and concentrated to a brown oil. The crude material is chromatographed over 250 g slurry-packed silica, eluting with 35% EtOAc/hexane to give thieno[2,3-bJ pyridine (I-110-D) as an orange oil (26% yield). MS (El) for C7H5NS, m/z: 135 (M)+.
I-110-D (3.47 g, 25.7 mmol) is dissolved in acetic acid (12 mL) and heated to 85°C. 30% Hydrogen peroxide (9 mL) is added drop-wise and the solution is allowed to stir overnight. The reaction is allowed to cool to rt and quenched with paraformaldehyde until a peroxide test proved negative using starch-iodine paper. The solution is diluted with H2O (100 mL) and neutralized with NaHCO , then extracted repeatedly with CHC13 (12 x 80 mL, 6 x 50 mL). The combined organic layer is dried (Na2SO ), filtered, and concentrated to a brown solid. The crude material is chromatographed over 70 g slurry-packed silica eluting with 3.5%
MeOH/CH2Cl2 to afford thieno[2,3-bJ pyridine-7-oxide (I-l 11-D) as a pale yellow solid (22% yield). MS (El) for C7H5NOS m/z: 151 (M)+.
A 0.5M solution ofl-l l l-D (5 mL, 2.5 mmol) in CH2C12 is diluted with 8 mL of CH2C1 under N2. Dimethyl carbamyl chloride (0.27 mL, 2.9 mmol) is added drop- wise, followed by the addition of trimethylsilyl cyanide (0.388 mL, 2.9 mmol) via syringe. The reaction is allowed to stir for 9 days and is quenched with 10% K2CO3 (10 mL). The layers are allowed to separate, the organic layer is isolated and dried (K2CO3), filtered, and concentrated to a brown solid. The crude material is chromatographed over 25 g slurry-packed silica, eluting with 35% EtOAc/hexane to afford thieno[2,3-bJpyridine-6-carbonitrile (I-112-D) as a pale yellow solid (100% yield). Analysis calculated for B^S: C, 59.98; H, 2.52; N, 17.49, found: C, 59.91; H, 2.57; N, 17.43. NaOH (398 mg, 9.95 mmol) is added portionwise to a solution ofI-112-D (674 mg, 4.2 mmol) in 70% EtOH/H2O (20 mL). The solution is heated to reflux at 100°C for 24 h, and the reaction is concentrated in vacuo. The residue is dissolved in H2O (15 L) and washed with ether (3 x 10 mL). Concentrated HCl is used to adjust the pH to 3.5, creating a precipitate. The slurry is filtered, giving thieno[2,3- b]pyridine-6-carboxylic acid (I-l 13-D) as a white solid (45% yield). MS (El) for C8H5NO2S, m/z: 179(M)+.
Intermediate D15: Thienof2,3-c|pyridine-2-carboxylic acid THF (200 mL) is chilled to -70°C in a dry flask under N2, and N-butyllithium
(24.4 mL, 55.0 mmol) is added drop-wise. The reaction is placed in an ice bath and DIA (7.71 mL, 55.0 mmol) in THF (20 mL) is added drop-wise. The solution is again chilled to -70°C, and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise. The reaction is allowed to stir for 4 h at -70°C and ethyl formate (4.44 mL,- 55.0 mmol) in THF (20 mL) is added. The reaction is stined for an additional 3 h at -70°C and quenched with H2O (500 mL). The layers are allowed to separate, and the aqueous layer is extracted with EtOAc (3 x 250 mL). The combined organic layer is dried (MgSO4), filtered, and concentrated to a dark brown solid. The crude material is chromatographed over 250 g slurry-packed silica, eluting with 50% EtOAc/hexane to give 3-chloroisonicotinaldehyde (I-120-D) as an off-white solid (55% yield). MS (El) for C6H4ClNO, m/z: 141 (M)+.
I-120-D (2.12 g, 14.9 mmol) is dissolved in DMF (75 mL) with a small amount of H2O (7.5 mL). Methyl thioglycolate (1.67 mL, 18.7 mmol) and K2CO3 (2.59 g, 18.7 mmol) are added portionwise, and the mixture is stined at 45°C for 24 h. The reaction is quenched with cold H O (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer is washed with 50% NaCl solution (3 x 150 mL), dried (MgSO4), filtered, and concentrated to an orange solid. The crude material is chromatographed over 40 g slurry-packed silica, eluting with 50% EtOAc/hexane to afford ethyl thieno[2,3-cJpyridine-2-carboxylate (I-l 21-D) as a pale yellow solid (22% yield).
I-121-D (577 mg, 2.99 mmol) is combined with 2M NaOH (1.5 mL, 3.0 mmol) in MeOH (15 mL) and H2O (1.5 mL). The reaction is stined at rt for 24 h. The reaction is concentrated in vacuo and the residue is dissolved in H2O (75 L). Concentrated HCl is used to acidify the solution to pH 3. The slurry is filtered, washed with H O and ether, and dried, affording thieno[2,3-cJpyridine-2-carboxylic acid (1-122-D) as an off-white solid (38% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0119 (M+H).
Intermediate D16: Thieno.3,2-b1pyridine-2-carboxyIic acid
3-Chloropyridine (9.5 mL. 99.9 mmol) is dissolved in acetic acid (35 mL) and heated to 98°C. 30% Hydrogen peroxide (28 mL) is added drop-wise, and the reaction stined for 5 h at 98°C. The reaction is cooled and paraformaldehyde is added so that a negative peroxide test is achieved using starch-iodine paper. The solution is concentrated in vacuo and the crude paste is chromatographed over 600 g slurry- packed silica eluting with 4 L of 2% MeOH/CH2Cl2, 2 L of 4% MeOH/CH2Cl2, and finally 1 L of 10% MeOH/CH2Cl2 to afford 3-chloropyridine 1 -oxide (I-125-D) as a pale oil (100% yield). A 2M solution of I-125-D (10 mL, 20 mmol) is combined with an additional
90 mL of CH2C1 . Dimethylcarbamoyl chloride (2.03 mL, 22.0 mmol) is added drop- wise, followed by the addition of trimethyl silylcyanide (2.93 mL, 22.0 mmol) via syringe. The reaction is stirred at rt for 10 days and is quenched with 10% K2CO3 (100 mL). The layers are allowed to separate, and the organic layer is dried (K2CO3), filtered, and concenfrated to an orange solid. The crude material is chromatographed over 160 g slurry-packed silica eluting with 40% EtOAc/hexane to yield 3- chloropyridine-2-carbonitrile (I-126-D) as a white solid (59% yield). MS (El) for C6H3C1N2, m/z: 138 (M)+.
I-126-D (1.01 g, 7.29 mmol) and K2CO3 (1.10 g, 7.96 mmol) are added to DMF (10 mL) and H2O (1 mL). Methyl thioglycolate (0.709 mL, 7.93 mmol) is added drop-wise, and the solution is heated to 40°C and stirred for 3 h. The reaction is quenched with cold H2O (70 mL) and placed on ice to enhance precipitation. The slurry is filtered and the cake is dissolved in CHC13. This organic solution is dried (MgSO4), filtered, and concentrated, affording methyl 3-aminothieno[3,2-b]pyridme- 2-carboxylate (I-127-D) as a yellow solid (84% yield). HRMS (FAB) calculated for C9H8N2O2S+H: 209.0385, found 209.0383 (M+H).
I-127-D (0.919 g, 4.42 mmol) is dissolved in 50% hypophosphorous acid (35 mL) and chilled in an ice bath. Sodium nitrite (0.61 g, 8.84 mmol) is dissolved in a minimal amount of H O and added drop-wise to the previous solution, and the reaction is stined for 3 h in an ice bath. 3M NaOH is used to adjust the pH to 7.9, and the solution is extracted with EtOAc (3 x 100 mL). The combined organic layer is dried (MgSO4), filtered, and concentrated to afford methyl thieno[3,2-bJpyridine-2- carboxylate (I-128-D) as a yellow solid (44% yield). MS (El) for C9H7NO2S, m/z: 193 (M)+.
2M NaOH (0.8 mL, 1.6 mmol) and I-128-D (300 mg, 1.55 mmol) are added to MeOH (8 mL) and H O (1 mL) and is stined for 24 h. The reaction is concentrated in vacuo, and the residue is dissolved with H2O (5 mL). 5% HCl is used to adjust the pH to 3.5, creating a precipitate. The slurry is filtered and washed with ether, affording thieno[3,2-bJpyridine-2-carboxylic acid (I-129-D) as a brown solid (67% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0121 (M+H).
Intermediate D17: Thieno[3,2-b1pyridine-6-carboxyIic acid Methyl 3-aminothiophene-2-carboxylate (1.52 g, 9.68 mmol) is dissolved in
2M NaOH (10 mL, 20 mmol) and heated to reflux in a 115°C oil bath for 30 min. The mixture is cooled to rt, placed in an ice bath, and carefully acidified with concentrated HCl. The slurry is filtered and rinsed with H2O (25 mL). The cake is then dissolved in acetone (50 mL), dried (MgSO4), filtered, and concentrated to a thick paste. The crude material is dissolved in 1-propanol (25 mL), and oxalic acid (0.90 g, 10.0 mmol) is added portionwise. The mixture is heated at 38°C for 45 min, cooled to rt, and diluted with ether. The precipitate is isolated via filtration, and washed with ether, affording 3-amino-thiophene oxalate (I-135-D as a fluffy white solid (70% yield). HRMS (FAB) calculated for C4H5NS+H: 100.0221, found 100.0229 (M+H). 3,3-Dimethyl-2-formyl propionitrile sodium (5.38 g, 32.6 mmol) is dissolved in MeOH (60 mL) with concentrated HCl (6 mL). I-135-D (6.16 g, 32.6 mmol) is suspended in MeOH (200 L) and added drop-wise to the acidic solution. The mixture is heated to reflux at 80°C for 5 h when an additional 20 mL concentrated HCl and 20 mL H2O are added; the mixture continues refluxing for another 12 h. The mixture is concentrated in vacuo, and the residue is dissolved with cold H2O (100 mL). The resulting precipitate is filtered off and dried, giving thieno[3,2-b]pyridine- 6-carbonitrile (I-136-D) as a brown solid (44% yield). HRMS (FAB) calculated for C8H4N2S+H: 161.0173, found 161.0170 (M+H). I-136-D (1.99 g, 12.5 mmol) is dissolved in 70% EtOH/H2O (20 mL), and NaOH (0.52 g, 13.0 mmol) is added portionwise. The mixture is heated at 100°C for 15 h and then allowed to cool to rt. The mixture is concentrated in vacuo. The residue is dissolved in cold H O (30 mL), and the solution is rinsed with ether (3 x 10 mL). The pH is adjusted to 3.5 with concentrated HCl to precipitate the desired product that is removed by filtration to give thieno[3,2-b]pyridine-6-carboxylic acid (1-131 -O) as a tan solid (77% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0118 (M+H).
Intermediate D18: Thieno[3,2-c1pyridine-2-carboxylic acid
4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stining in lOOOmL 1:1 saturated NaHCO3/ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2 x 175 mL), and the combined organic layer is dried (MgSO ), filtered, and concentrated to an oil. THF (300 mL) is chilled to -70°C in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6mL. 168.4 mmol) in THF (50 mL) is added drop-wise, the yellow solution is stined for 30 min, and the reaction is cooled to -70°C. The free-based 4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) and added drop-wise to the chilled yellow solution, that turned dark red after the addition. The reaction is stined at -70°C for 2 h. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise to the dark solution at - 70°C. After 2 hours, the reaction is warmed to -10°C and quenched with water (450 mL). The layers are allowed to separate, and the aqueous layer is extracted with ether (3 x 200 mL). The combined organic layer is dried (MgSO4), filtered, and concentrated in vacuo to an oil. The crude material is chromatographed over 320 g slurry-packed silica eluting with 30% EtOAc/hexane to afford 4-chloropyridine-3- carboxaldehyde (I-140-D) an orange oil which solidified under vacuum to an orange solid (21% yield).
I-140-D (2.53 g, 17.9 mmol) is dissolved in DMF (20 mL) and H2O (2 mL). K2CO3 (2.97 g, 21.5 mmol) and methyl thioglycolate (1.92 mL, 21.5 mmol) are added portionwise. The reaction is stined at 45°C for 24 h, then quenched with cold H2O (100 mL), and the flask is placed on ice to enhance precipitation. The precipitate is isolated by filtration and dried, affording methyl thieno[3,2-cJpyridine-2-carboxylate (I-141-D) as a white solid (92% yield). MS (El) for C9H7NO2S, m/z: 193 (M)+.
I-141-D (2.65 g, 13.7 mmol) is dissolved in MeOH (70 mL) and H2O (5 mL). 2N NaOH (6.86 mL, 13.7 mmol) is added drop-wise, and the reaction is stined at rt for 24 h. The reaction is concentrated in vacuo, and H2O (150 mL) is added to dissolve the residue. The resulting salt solution is acidified to pH 3.5 using concentrated HCl, and the precipitate is isolated by filtration and dried, affording thieno[3,2-c]pyridine-2-carboxylic acid (I- 142-D) as a white powder (57% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0124 (M+H).
Intermediate D19: Thienor2,3-clpyridine-5-carboxylic acid
Glyoxylic acid monohydrate (20.3 g, 221 mmol) and benzyl carbamate (30.6 g, 202 mmol) are added to ether (200 mL). The solution is allowed to stir for 24 h at rt. The resulting thick precipitate is filtered, and the residue is washed with ether, affording ([(benzyloxy)carbonylJamino)(hydroxy)acetic acid (I-150-D) as a white solid (47% yield). MS (CI) for Cι0HnNO5+H m/z: 226 (M+H).
I-150-D (11.6 g, 51.5 mmol) is dissolved in absolute MeOH (120 mL) and chilled in an ice bath. Concentrated sulfuric acid (2.0 mL) is carefully added drop- wise. The ice bath is allowed to expire as the solution stined for 2 days. The reaction is quenched by pouring onto a mixture of 500 g ice with saturated NaHCO solution (400 mL). The solution is extracted with EtOAc (3 x 300 mL), and the combined organic layer is dried (MgSO ), filtered, and concentrated to a pale oil that crystallized upon standing, giving methyl([(benzyloxy)carbonylJamino)(methoxy)-acetate (1-151- D) as a white solid (94% yield). Analysis calculated for C12H15 NO5: C, 56.91; H, 5.97; N, 5.53, found: C, 56.99; H, 6.02; N, 5.60.
I-151-D (11.76 g, 46.4 mmol) is dissolved in toluene (50 mL) under N2 and heated to 70°C. Phosphorous trichloride (23.2 mL, 46.4 mmol) is added drop-wise via syringe, and the solution is stined for 18 h at 70°C. Trimethyl phosphite (5.47 mL, 46.4 mmol) is then added drop-wise, and stirring continued for an additional 2 h at 70°C. The mixture is concentrated in vacuo to an oil, and the crude material is dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 (3 x 50 mL). The organic layer is dried (Na2SO ), filtered, and concentrated to a volume of 30 mL. This remaining solution is stirred vigorously while hexane is added until a precipitate formed. The precipitated solid is removed by filtration, affording methyl ([(benzyloxy)carbonylJamino) (dimethoxyphosphoryl)acetate (1-152-D) as a white solid (84% yield). MS (El) for Cι3Hι8NO7P, m/z 331 (M)+.
1-152-D (12.65 g, 38.2 mmol) and acetic anhydride (9.02 mL, 95.5 mmol) in MeOH (100 mL) were added to a Pan flask. The solution is hydrogenated with 10% Pd/C catalyst (0.640 g) at 45 PSI for 3h. The catalyst is filtered off, and the filtrate is concentrated in vacuo to an oil. The oil is placed under reduced pressure and solidified as the reduced pressure is applied. The white residue is dissolved in a small amount of EtOAc and stined vigorously while pentane is added until a precipitate began to form. The precipitate is removed by filtration to give methyl
(acetylamino)(dimethoxyphosphoryl)acetate (1-153-D) as a white powder (87% yield). MS (CI) for C7Hι4NO6P, m/z: 240 (M+H).
2,3-Thiophene dicarboxaldehyde (1.40 g, 9.99 mmol) is dissolved in CH2C12 (100 mL) and the flask is placed in an ice bath. 1-152-D (2.63 g, 11.0 mmol) is dissolved in CH2C12 (50 mL), l,8-diazabicyclo[5.4.0Jundec-7-ene (1.65 mL, 11.0 mmol) is added, and this solution is added drop-wise to the chilled thiophene solution. The reaction mixture is stined for 1 h while the flask is in an ice bath and then over night at rt. The reaction is concentrated in vacuo, and the crude material is chromatographed over 300 g slurry-packed silica eluting with 50% EtOAc/hexane. The fractions were collected in two different groups to obtain the desired compounds. Each group of fractions is combined and concentrated separately. The first group of fractions affords methyl thieno[2,3-cJpyridine-5-carboxylate (I-154-D) as a white solid (41%) yield), and the second group of fractions affords methyl thieno[3,2- cJpyridine-6-carboxylate (I-155-D) as a yellow solid (38% yield). MS (El) for 1-154- D for C9H7NO2S, m/z: 193 (M)+. MS (El) for I-155-D for C9H7NO2S, m/z: 193 (M)+. I-154-D (736 mg, 3.8 mmol) is dissolved in MeOH (16 mL) with water (2 mL). 2M NaOH (2.0 mL, 4.0 mmol) is added drop-wise and the solution stirred at rt. After 2 days (complete disappearance of ester by TLC), the reaction is concentrated in vacuo. The residue is dissolved in H2O (12 mL), and the pH is adjusted to 3.5 with 10% HCl. The precipitated solid is removed by filtration, and the solid is rinsed with ether, affording thieno[2,3-cJρyridine-5-carboxylic acid (I-156-D) as a white solid (58% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0123 (M+H). Intermediate D20: Thienor3,2-c1pyridine-6-carboxylic acid
Methyl thieno[3,2-cJpyridine-6-carboxylate (I-155-D) (678 mg, 3.5 mmol) is dissolved in MeOH (16 mL) and H2O (2 mL). 2M NaOH (1.8 mL, 3.6 mmol) is added drop-wise, and the solution stirred at rt. After 2 days (complete disappearance of ester by TLC), the solution is concentrated in vacuo. The residue is dissolved in H2O (12 mL), and the pH is adjusted to 3.5 with 10% HCl. The precipitated solid is removed by filtration, and the solid is rinsed with ether, affording thieno[3,2- cJpyridine-6-carboxylic acid (I-160-D) as a white solid (43% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0123 (M+H).
Intermediate D21: lH-Pyrrolor2,3-clpyridine-5-carboxylic acid
2,4-Lutidine (51.4 mL, 0.445 mole) is added drop-wise to 250 mL fuming sulfuric acid in a flask under N2 in an ice bath. The solution is treated portionwise with potassium nitrate (89.9 g, 0.889 mole) over a 15 min period. The reaction is stined lh in an ice bath, 2 h at rt, is gradually warmed in a 100°C oil bath for 5 h, and then in a 130°C oil bath for 4 h. The mixture is cooled, is poured into 1000 mL ice, and the mixture is neutralized with NaHCO3 (1,100 g, 13.1 mole). The precipitated Na2SO is removed by filtration, the solid is washed with 500 mL H O and the filtrate is extracted with 4 x 500 mL ether. The combined organic layer is dried (MgSO ) and is concentrated in vacuo to a yellow oil (50 g). The crude oil is distilled under vacuum to provide three fractions: 16 g recovered 2,4-lutidine (85°C), 16 g 2,4- dimethyl-3-nitro-pyridine (I-169-D) contaminated with 25% 2,4-dimethyl-5-nitro- pyridine (135-145°C), and 16 g 2,4-dimethyl-5-nitro-pyridine (I-170-D) contaminated with 2,4-dimethyl-3-nitropyridine (145-153°C). 1H NMR of C169 (CDC13) δ 2.33, 2.54, 7.10, 8.43 ppm. 1H NMR of C170 (CDC13) δ 2.61, 2.62, 7.16, 9.05 ppm.
I-170-D/I-169-D (75:25) (5.64 g, 37 mmol) is combined with benzeneselenic anhydride (8.2 g, 22.8 mmol) in 300 mL dioxane in a flask under N2. The reaction is warmed to reflux for 10 h, is cooled, and is concentrated to a dark yellow oil. The oil is chromatographed over 250 g silica gel (230-400 mesh) eluting with 15%
EtOAc/hexane to afford 2-formyl-4-methyl-5-nitropyridine (I-l 71-D) (66% yield). HRMS (El) calculated for C7H6N2O3: 166.0378, found 166.0383 (_v ). I-171-D (1.15 g, 6.9 mmol), p-toluene sulfonic acid (41 mg, 0.22 mmol), and ethylene glycol (1.41 mL, 25 mmol) are added to 25 mL toluene in a flask equipped with a Dean-Starke trap. The reaction is warmed to reflux for 2 h, is cooled to rt, and is concentrated in vacuo to an oily residue. The crude oil is chromatographed over 40 g silica gel (Biotage), eluting with 20% EtOAc/hexane to afford 2-(l,3-dioxolan-2-yl)- 4-methyl-5-nitropyridine (1-172-D) (90% yield). MS (El) for C9Hι0N2O4, m/z: 210 (M)+.
1-172-D (1.3 g, 6.2 mmol) and DMF dimethyl acetal (1.12 mL, 8.4 mmol) are added to 15 mL DMF under N2. The reaction is warmed to 90°C for 3 h, is cooled, and the reaction is concentrated in vacuo. The residue is combined with 1.25 g 5% Pd/BaSO in 20 mL EtOH in a 250 mL Pan shaker bottle and the mixture is hydrogenated at ambient pressure until uptake ceased. The catalyst is removed by filtration, and the filtrate is combined with 500 mg 10% Pd/C catalyst in a 250 mL Parr shaker bottle. The mixture is hydrogenated at ambient pressure for 1 h. No additional hydrogen uptake is observed. The catalyst is removed by filtration, and the filtrate is concentrated in vacuo to a tan solid. The crude material is chromatographed over 50 g silica gel (230-400 mesh), eluting with 7% MeOH/CH2Cl2. The appropriate fractions are combined and concentrated to afford 5-(l,3-dioxolan-2-yl)-lH- pyrrolo[2,3-cJpyridine (I-l 73-D) (69%yield). MS for Cι0Hι0N2O2, (El) m/z: 190 (M)+.
I-1730-D (800 mg, 4.21 mmol) is dissolved in 44 mL 10% aqueous acetonitrile. p-Toluene sulfonic acid (630 mg, 3.3 mmol) is added, and the mixture is heated to reflux for 5 h. The mixture is cooled to rt, is concentrated in vacuo, and the resultant residue is diluted with 15 mL saturated NaHCO3. A pale yellow solid is collected, washed with water, and is dried to afford lH-pyrrolo[2,3-cJpyridine-5- carbaldehyde (I-174-D) (81% yield). HRMS (FAB) calculated for C8H6N2O+H: 147.0558, found 147.0564 (M+H).
I-174-D (500 mg, 3.42 mmol) is dissolved in 1.5 mL fonnic acid. The solution is cooled in an ice bath, 30% aqueous hydrogen peroxide (722 μL, 6.8 mmol) is added drop-wise, and the reaction is stined 1 h in an ice bath, and allowed to stand overnight at 5°C. The mixture is diluted with H2O, the solid is collected, washed with H2O and is dried to give 522 mg of an off-white solid. The formate salt is added to 7 mL H2O, 3 mL 2N NaOH is added, and the pH is adjusted to 3 with 5% aqueous HCl. The precipitate is collected and is dried to afford lH-pynolo[2,3-cJpyridine-5- carboxylic acid (I-176-D) (67% yield). ΗRMS (FAB) calculated for C8Η6N2O2+Η: 163.0508, found 163.0507 (M+H).
Intermediate D22: l-Methyl-pyrrolor2,3-clpyridine-5-carboxylic acid
5-(l,3-Dioxolan-2-yl)-lH-pyrrolo[2,3-cJpyridine (1-173-01 (1.05 g, 5.52 mmol) is dissolved in 20 mL THF in a dried flask under N2. 60% Sodium hydride (243 mg, 6.07 mmol) is added, the reaction is stined 30 min, methyl iodide (360 μL, 5.8 mmol) is added, and the reaction is stined overnight at rt. The reaction is concentrated in vacuo and the residue is partitioned between 10 mL saturated NaCl and CH2C12 (4 x 10 mL). The combined organic layer is dried (K2CO3) and is concentrated in vacuo to a tan paste. The crude material is chromatographed over 50 g silica gel (230-400 mesh) eluting with 5% MeOH/CH2Cl2. The appropriate fractions are combined and concentrated to afford 5-( 1,3 -dioxolan-2-yl)-l -methyl- 1H- pyrrolo[2.3-c]pvridine (I-175-D) (86% yield). HRMS (FAB) calculated for CnHι2N2O2+H: 205.0977, found 205.0983.
I-175-D (920 mg, 4.5 mmol) is dissolved in 25 mL 10% aqueous acetonitrile in a flask. p-Toluene sulfonic acid (630 mg, 3.3 mmol) is added, and the mixture is heated to 90°C for 8 h. The mixture is cooled to rt, concentrated in vacuo, and the residue is partitioned between 15 mL saturated NaHCO3 and CH2C12 (4 x 10 mL).
The combined organic layer is dried (K2CO3) and is concentrated in vacuo to afford 1- methyl-pyrrolo[2,3-c]pyridine-5-carbaldehyde (I-177-D) (99% yield). HRMS (FAB) calculated for C9H8N2O+H: 161.0715, found 161.0711.
I-177-D (690 mg, 4.3 mmol) is dissolved in 2 mL formic acid. The solution is cooled in an ice bath, 30% aqueous hydrogen peroxide (970 μL, 8.6 mmol) is added drop-wise, and the reaction is stined 1 h in an ice bath, and allowed to stand overnight at 5°C. The mixture is concentrated to dryness, is suspended in H2O, and the pH is adjusted to 7 with 2N NaOH. The mixture is concentrated to dryness, is dissolved in MeOH, and is passed over 15 mL 50W-X2 ion exchange resin (hydrogen form) eluting with 200 mL MeOH followed by 200 mL 5% Et3N/MeOH. The basic wash is concentrated to dryness to afford l-methyl-pynolo[2,3-cJpyridine-5-carboxylic acid (I-178-D) (78% yield). HRMS (FAB) calculated for C9H8N2O2+H: 177.0664, found 177.0672 (M+H). Intermediate D23: 3-Bromofuro[2,3-clpyridine-5-carboxyiic acid
Furo[2,3-c]pyridin-5-ylmethyl acetate (5.17 g, 27.05 mmol) is dissolved in CH2C12 (130 mL), layered with saturated NaHCO3 (220 mL), treated with Br2 (8.36 mL, 162.3 mmol) and stined very slowly for 4.5 h at rt. The mixture is stined vigorously for 30 min, is diluted with CH2Cl2 (100 mL) and the layers separated. The aqueous layer is exfracted with CH2C12 (2 x 100 mL) and the combined organics are concenfrated to a small volume under a stream of nitrogen. The solution is diluted with EtOH (200 mL), treated with K2CO3 (22.13 g, 160.1 mmol) and stirred for 2.5 days at rt. The mixture is concentrated to dryness, partitioned between 50% saturated NaCl (200 mL) and CH2C12 (5 x 200 mL), dried (Na2SO ) and concentrated in vacuo to a yellow solid (6.07 g). The crude material is adsorbed onto silica gel (12 g) and chromatographed over 250 g slurry-packed silica gel, eluting with a gradient of 50% EtOAc / hexane to 100% EtOAc. The appropriate fractions are combined and concenfrated in vacuo to afford 5.02 g (81%) of (3-bromofuro[2,3-c]pyridin-5- yl)methanol as a white solid. MS (El) m/z 227 (M+).
Oxalyl chloride (1.77 mL, 20.1 mmol) is combined with CH2C12 (60 L) in a dried flask under nitrogen, cooled to -78°C, treated dropwise with DMSO (2.86 mL, 40.25 mmol) and stined for 20 min. The cooled solution is treated drop-wise with a solution of (3-bromofuro[2,3-c]pyridin-5-yl)methanol (4.0 mg, 17.5 mmol) in THF (50 mL), stined for 1 h, then treated drop-wise with Et3N (12.2 mL, 87.5 mmol). The mixture is stirred for 30 min at -78°C, then 30 min at 0°C. The mixture is washed with saturated NaHCO3 (120 mL) and the organics dried (K2CO ) and concentrated in vacuo to a dark yellow solid (3.91 g). The crude material is chromatographed over 150 g slurry-packed silica gel, eluting with 30% EtOAc / hexane. The appropriate fractions are combined and concentrated in vacuo to afford 3.93 g (99%) of 3- bromofuro[2,3-cJpyridine-5-carbaldehyde as a white solid. MS (El) m/z 225 (M+).
3-Bromofuro[2,3-cJpyridine-5-carbaldehyde (3.26 g, 14.42 mmol) is dissolved in THF (100 mL)/t-BuOH (50 mL)/H2O (50 mL), treated with a single portion of NaOCl2 (4.89 g, 43.3 mmol) and KH2PO4 (3.92 g, 28.8 mmol) and stined at rt for 18 h. The white solid is collected via filtration and the filtrate is concentrated in vacuo to dryness. The residue is suspended in water (25 mL), acidified to pH 2 with concentrated HCl and the resulting solid collected via filtration. The collected solids are dried in a vacuum oven at 50°C for 18 h and combined to afford 3.52g (99%) of 3- bromofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (El) m/z: 241 (M+).
Intermediate D24: 3-Chlorofuror2,3-c|pyridine-5-carboxylic acid Furo[2,3-cJpyridin-5-ylmethanol (7.70 g, 51.63 mmol) is dissolved in pyridine
(45 mL), treated with acetic anhydride (14.36 mL, 154.9 mmol) and stined for 18 h at rt. The pyridine is removed in vacuo and the resulting residue dissolved in EtOAc (200 mL), washed with 50% saturated sodium bicarbonate (4 x 90 mL), dried (MgSO ) and concentrated in vacuo to afford 9.32 g (94%) of furo[2,3-c]pyridin-5- ylmethyl acetate as ayellow oil. MS (El) m/z: 191 (M+), 277, 148, 119, 118, 86, 84, 77, 63, 51, 50. .
Furo[2,3-c]pyridin-5-ylmethyl acetate (956 mg, 5 mmol) is dissolved in CH2C12 (40 mL) and cooled to 0°C. Chlorine gas is bubbled through the solution for 15 min, the cooling bath is immediately removed and the mixture stined for 2 h. The mixture is re-cooled to 0°C, saturated with chlorine gas, the cooling bath removed and the solution warmed to rt. The solution is layered with saturated NaHCO3 (20 mL), stined gently for 2 h then stined vigorously for 15 min. The mixture is diluted with saturated NaHCO3 (50 mL), exfracted with CH2C12 (1 x 40 mL then 1 x 20 mL), dried (K2CO3) and concentrated to a volume of 20 mL under a stream of nitrogen. The solution is diluted with EtOH (35 mL), treated with K2CO3 (4.09 g, 29.6 mmol) and stined for 18 h at rt. Water (7 mL) is added and the mixture stined for 2 days. The mixture is concentrated to dryness, partitioned between 50% saturated NaCl (50 mL) and CH2C12 (4 x 50 mL), dried (K CO3) and concentrated in vacuo to a brown solid (833 mg). The crude material is chromatographed over a standard 40 g Biotage column, eluting with 50% EtOAc / hexane. The appropriate fractions are combined and concentrated to afford 624 mg (68%) of (3-chlorofuro[2,3-cJpyridin-5- yl)methanol as a yellow oil. 1H NMR (DMSO-^): δ 4.69, 5.56, 7.69, 8.55, 8.93 ppm. Oxalyl chloride (231 μL, 2.6 mmol) is combined with CH2C12 (10 mL), cooled to -78°C, treated dropwise with DMSO (373 μL, 5.3 mmol) and stined for 20 min. The cooled solution is treated dropwise with a solution of (3-chlorofuro[2,3-cJpyridin- 5-yl)methanol (420 mg, 2.3 mmol) in THF (5 mL) / CH2C12 (5 mL), stined for 1 h, then treated dropwise with Et3N (1.59 mL, 11.45 mmol). The mixture is stined for 30 min at -78°C, then 30 min at 0°C. The mixture is washed with saturated NaHCO3 (20 mL) and the organics dried (K2CO ) and concentrated in vacuo to a yellow solid (410 mg). The crude material is chromatographed over 20 g slurry-packed silica gel, eluting with 15% EtOAc / hexane. The appropriate fractions are combined and concenfrated in vacuo to afford 322 mg (77%) of 3-chlorofuro[2,3-c]pyridine-5- carbaldehyde as a white solid. 1H NMR (CDC13): δ 7.89, 8.33, 9.02, 10.18 ppm.
3-CMorofuro[2,3-cJpyridine-5-carbaldehyde (317 mg, 1.74 mmol) is dissolved in THF (10 mL)/t-BuOH (5 mL)/H2O (5 mL), treated with a single portion of sodium chlorite (592 mg, 5.24 mmol) and KH2PO4 (473 mg, 3.48 mmol) and stined at rt for 18 h. The reaction mixture is concentrated in vacuo to dryness, suspended in water (10 mL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h. The resulting solid is filtered, washed with water and dried in a.vacuum oven at 40°C for 18 h to afford 364 mg of 3-cMorofuro[2,3-cJpyridine-5-carboxylic acid as a white solid. MS (El) m/z: 197 (M+).
Intermediate D25: Benzothienof3,2-c1pyridine-3-carboxyIic acid
N-butyl lithium (150.6 ml, 241 mmol) is added dropwise to ether (100 ml) at -20°C under N2. 3-Bromothianaphthene (10.5 ml, 80.3 mmol) is dissolved in ether (50 ml) and also added dropwise to the chilled solution, stirring cold for 0.5 h. DMF (16.3 ml, 210 mmol) is dissolved in ether (75 ml) and added dropwise, and the solution stined an additional 15 h at -20°C. The reaction is quenched onto ice (300 g) in 10% H2SO4 (200 ml) and stined until both layers turn yellow in color. The resulting slurry is filtered, and the cake is allowed to dry in the air stream, affording 1- benzothiophene-2,3-dicarbaldehyde (I-180-D) as a yellow solid (60% yield). HRMS (FAB) calculated for C10H6O2S+H: 191.0167, found 191.0172 (M+H). l-Benzothiophene-2,3-dicarbaldehyde (I-180-D (1.91 g, 10.0 mmol) is dissolved in CH C1 (100 ml) and chilled in an ice bath. Methyl (acetylamino)(dimethoxyphosphoryl) acetate (1-152-D) (2.63 g, 11.0 mmol) is dissolved in CH2C12 (50 ml) and added to l,8-diazabicyclo[5.4.0Jundec-7-ene (1.65 ml, 11.0 mmol), stirring for 5 minutes. This solution is added dropwise to the chilled thiophene solution. The reaction mixture is stined in the ice bath for 1 h and then over night at rt. The reaction is concentrated in vacuo and the crude material is chromatographed over 500 g slurry-packed silica eluting with 50% ethyl acetate/hexane to afford methyl benzothieno[3,2-cJpyridine-3-carboxylate (I-l 81-D) as a white solid (73% yield). MS for Cι3H9NO2S, (El) m/z: 243 (M)+.
I-181-D (1.43 g, 5.87 mmol) is dissolved in MeOH (25 ml) with H2O (3 ml). 2M NaOH (3.0 ml, 6.0 mmol) is added dropwise and the solution stirred at rt. After 4 days (complete disappearance of ester by TLC), the reaction is concentrated in vacuo. The residue is dissolved in H2O (5 ml) and the pH is adjusted to 3 with 10% HCl. The solution is stined over night before precipitation is complete. The slurry is filtered and the cake is rinsed with ether, giving a 100% yield of benzothieno[3,2- c]pyridine-3 -carboxylic acid (I-182-D)as a white solid. HRMS (FAB) calculated for Cι2H7NO2S+H 230.0276, found 230.0275 (M+H).
Intermediate D26: ThienoF3,4-c1pyridine-6-carboxylic acid
3,4-Dibromothiophene (12.5 ml, 113 mmol) is combined with CuCN (30.4 g, 339 mmol) in DMF (40 ml) in a dry flask under nitrogen utilizing an over-head stiner. The reaction is allowed to reflux at 180°C for 5 h. The dark mixture is then poured into a solution of FeCl3 (113.6 g, 700 mmol) in 1.7M HCl (200 ml) and heated at 65°C for 0.5 h, again using the over-head stiner. The reaction is cooled to rt and extracted with CH2C12 (7 x 300 ml). Each extract is washed individually with 200 ml each 6M HCl (2X), water, saturated NaHCO3, and water. The organics are then combined, dried (MgSO ), filtered, and concentrated, affording 10.49 g (69%) of 3,4- dicyanothiophene as a fluffy tan sδlϊcl. HRMS (El) calcd for C6H2N2S: 133.9939, found 133.9929 (M+).
3,4-Dicyanothiophene (5.0 g, 37.2 mmol) is suspended in benzene (150 ml) in a dry flask under nitrogen utilizing an over-head stiner. Diisobutyl aluminum hydride (1.0M in toluene) (82.0 ml, 82.0 mmol) is added dropwise, and the reaction stined at rt for 2 h. The reaction is then carefully quenched with MeOH (5 ml) and poured onto 30% H2SO4 (60 ml) with ice (200 g). The slurry is stined until all lumps are dissolved, and the layers are allowed to separate. The aqueous layer is extracted with Et2O (4 x 200 ml), and the combined organics are dried (MgSO4), filtered, and adsorbed onto silica. The crude material is chromatographed over 225 g slurry-packed silica, eluting with 40% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.88 g (36%) of 3,4-thiophene dicarboxaldehyde as a pale yellow solid. MS (El) m/z: 140 (M+). 3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH2C12 (40 ml) and chilled to 0°C. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (1.88 g, 7.85 mmol) is dissolved in CH2C12 (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). This solution is added dropwise to the chilled thiophene solution after stirring for 5 min. The reaction mixture is stirred at 0°C for 1 h and then overnight at rt. The volatiles are removed in vacuo and the crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane. The appropriate fractions are combined and concentrated to yield 2.09 g of the carbinol intermediate as a white foam. The intermediate is dissolved in CHC1 (50 ml) and treated with DBU (1.32 ml, 8.8 mmol) and trifluoracetic anhydride (1.24 ml, 8.8 mmol) in a drop-wise fashion. The reaction is stined overnight at rt and is then quenched with saturated NaHCO3 solution (50ml). The layers are separated, and the aqueous layer is extracted with CHC13 (2 x 50 ml). The combined organics are dried (MgSO ), filtered, and concentrated to a yellow oil. This oil is chromatographed over 50 g slurry-packed silica, eluting with 90% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.2 g (88%) of methyl thieno[3,4-cJpyridine-6-carboxylate as a yellow solid. MS (El) m/z: 193 (M+).
Methyl thieno[3,4-c]pyridine-6-carboxylate (250 mg, 1.3 mmol) is dissolved in MeOH (7 ml) and water (1 ml). 2M NaOH (0.72 ml, 1.43 mmol) is added drop- wise. The reaction is stirred overnight at rt and is monitored by TLC. The volatiles are removed in vacuo and the residue is dissolved in water (2 ml). 10% HCl is used to adjust the pH to 3, and the reaction again stined overnight at rt. The aqueous solution is extracted repeatedly with EtOAc (20 x 10 ml). The combined organics are dried (MgSO4), filtered, and concentrated to a yellow solid. The amount of isolated product via extraction is minimal (67 mg), so the aqueous layer is concentrated and found to contain the majority of product. Extraction of the solid aqueous residue with EtOAc provided 225 mg (97%) of thieno[3,4-cJpyridine-6-carboxylic acid as a yellow solid. MS (ET) m/z: 179 (M+).
Intermediate D27: Benzofuran-5-carboxylic acid l-(2,3-Dihydrobenzofuran-5-yl)ethanone is made using a procedure, making non-critical changes, as described in Dunn, J.P.; Ackerman, N.A.; Tomolois, AJ. J. Med. Chem. 1986, 29, 2326. Similar yield (82%) and similar purity (95%) are obtained. 1H NMR (400 MHz, CDC13) δ 7.89, 7.83, 6.84, 4.70, 3.29 , 2.58.
A mixture of l-(2,3-dihydrobenzofuran-5-yl)ethanone (4.0 g, 25 mmol) and sodium hypochlorite [160 L of a 6.0% aqueous solution, (Clorox brand of bleach) J at 55°C is stined for 1 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persists. Hydrochloric acid (80 mL of a 1.0 N aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO ), filtered, and concenfrated in vacuo to afford 3.93 g (97%) of 2,3-dihydrobenzofuran-5-carboxylic acid as a white solid. 1H NMR (400 MHz, CDC13) δ 11.0-10.3, 8.00, 6.87, 4.72, 3.31.
To a stirred solution of 2,3-dihydrobenzofuran-5-carboxylic acid (3.96 g, 24.1 mmol) in MeOH (200 mL) is added concentrated sulfuric acid (0.5 mL). The mixture is heated to reflux for 24 h. The mixture is cooled to rt, followed by the addition of solid sodium bicarbonate. The reaction mixture is concenfrated in vacuo, and the remaining residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to afford 4.22 g (98%) of methyl 2,3-dihydrobenzofuran-5- carboxylate as a white solid. 1H NMR (400 MHz, CDC13) δ 7.93-7.89, 6.82, 4.69, 3.86, 3.28. To a stined solution of methyl 2,3-dihydrobenzofuran-5-carboxylate (4.2 g, 24 mmol) in anhydrous j? -dioxane (150 mL) under argon atmosphere is added 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (6.42 g, 28 mmol). The mixture is heated to reflux for 24 h, followed by cooling to rt. The reaction mixture is partitioned between ether and Vz saturated aqueous sodium carbonate solution. The organic layer is extracted several times with Vi saturated aqueous sodium carbonate solution. The organic layer is washed with water, dried (MgSO ), filtered, and concentrated in vacuo to give a mixture (92%) of recovered starting material methyl 2,3-dihydrobenzofuran- 5-carboxylate and methyl benzofuran-5-carboxylate in a ratio of 1 :3. The crude product is purified by preparative HPLC using a Chiralcel O J column. Elution with heptane-wo-propyl alcohol, (80:20, flow rate = 70 mL/min) gives 0.75 g (18%) of methyl 2,3-dihydrobenzofuran-5-carboxylate as a white solid and 2.5 g (61%) of methyl benzofuran-5-carboxylate as a white solid. 1H NMR for methyl benzofuran-5- carboxylate (400 MHz, CDC13) δ 8.40, 8.07, 7.73, 7.57, 6.89, 3.99. A stined mixture of methyl benzofuran-5-carboxylate (1.3 g, 7.38 mmol) in MeOH (51 mL) and sodium hydroxide (41 mL of a 5 % aqueous solution) is heated to 65°C for 4 h. The mixture is cooled to rt, and MeOH was removed in vacuo. The remaining aqueous layer is exfracted with CH2C12. The CH2C12 layer is discarded, and the aqueous layer is acidified to pH=l with concentrated hydrochloric acid. The aqueous layer is extracted with CHC13. The organic layer is washed with water, dried (MgSO4), filtered and concentrated in vacuo to afford 1.2 g (98%) of benzofuran-5- carboxylic acid as a white solid. 1H NMR (400 MHz, OMSO-d6) δ 12.9, 8.30, 8.11, 7.92, 7.69, 7.09.
Compounds of Formula I where W is (E) are made using the coupling procedures discussed herein and in cited references, making non-critical changes to obtain the desired compounds. The following intermediates to provide W of formula I are for exemplification only and are not intended to limit the scope of the present invention. Other intermediates within the scope of the present invention can be obtained using known procedures or by making slight modifications to known procedures.
It will be apparent to those skilled in the art that the requisite carboxylic acids can be obtained through synthesis via literature procedures or through the slight modification thereof. For example, compounds of Formula I where E° is N and E1 and E2 are O, can be obtained as follows:
Figure imgf000101_0001
Acid A can be prepared from ethyl 4,5-dihydroxypyridine-2-carboxylate (see Z.
Naturfirsch, 34b, 1729-1736, 1979). Alkylation with 1,2-dibromoethane gives B. Saponification of B with aqueous NaOH would provide the requisite carboxylic acid
A. The resulting acid is coupled with an Azabicyclo using conditions described herein.
Substituents can be introduced for RE-I or RE-2 where E° is CH and E1 and E2 are each Oais described in Taniguchi, Eiji, et al., Biosci. Biotech. Biochem., 56 (4), 630-635, 1992. See also Henning, R.; Lattrell, R.; Gerhards, H. J.; Leven, M.;
J.Med.Chem.; 30; 5; 1987; 814-819. This is also applicable to make the final compounds where E° is N, starting with ethyl 4,5-dihydroxvpyridine-2-carboxylate to obtain the ester intermediate which could be saponified:
Figure imgf000102_0001
Furthermore, where E° is N, the compounds where one RE-I is a bond to CRE-I-I or where one RE-2 is a bond to CRE-2- , the compounds can be obtained using methods described herein for E is CH, making non-critical changes. Moreover, where at least one RE-I and/or at least one RE-2 is other than H and is not a bond, the compounds can be obtained using methods described herein for where E° is CH.
Compounds where E° is N, only one of E1 or E2 is O, RE-O is other than H, and one of RE-I or RE-2 is a bond, can be obtained as discussed herein using procedures for where E° is CH. For example, 2-chloro-6-(hydroxymethyl)-4-vinylpyridin-3-ol could be converted into (8-chloro-2-methyl-2H-pyrano[2,3-c]pyridin-6-yl)methanol using the procedures discussed herein. The alcohol could be oxidized to the conesponding carboxylic acid:
Figure imgf000102_0002
Similarly, (8-chloro-2H-pyrano[2,3-c]pyridin-6-yl)methanol can be oxidized to give 8-chloro-2H-pyrano[2,3-c]pyridin-6-carboxylic acid:
Figure imgf000102_0003
Some specific examples are provided for exemplification and are not intended to limit the scope of the present invention:
Intermediate El: 2,3-Dihydro-l,4-benzodioxme-6-carboxyIic acid
A suspension of calcium ethoxide (816mg, 6.3mmol), butene oxide (5.2mL, 93mmol) and 2,4-diiodophenol (2.17g, 6.3nιmol) is heated in a sealed flask at 80°C for 18 h. The reaction mixture is allowed to cool, poured into IN ΗC1 and extracted three times with CΗ2C12. The combined organic extracts are dried (Na2SO ), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (two columns, step gradient of 30-40-50% CH2CI2 in hexanes) to give l-(2,4-diiodophenoxy)butan-2-ol as a clear oil (1.73g, 67%).1HNMR (400 MHz, CDC13) δ 8.04, 7.56, 6.57, 4.03, 3.9, 3.84, 2.42, 1.65, 1.04.
A solution of l-(2,4-diiodophenoxy)butan-2-ol (1.27g, 3.0) in pyridine (12mL) is degassed by repeatedly evacuating the flask then filling with N2. Sodium hydride (60% suspension, 153mg, 3.8mmol) is added and the resulting mixture is stined for 15 min. Copper (I) chloride (15mg, 0.15mmol) is added, and the resulting mixture is heated at 80°C for 2 h. The reaction is allowed to cool, poured into IM HCl and exfracted three times with CH2θ . The combined organic extracts are dried (Na SO ), filtered and concenfrated in vacuo. The resulting material is purified by column chromatography (10% CH2C12 in hexanes) to give 2-ethyl-7-iodo-2,3-dihydro- 1,4-benzodioxine as a clear oil (493mg, 57%). 1H NMR (400 MHz, CDC13) δ 7.20, 7.10, 6.61, 4.22, 4.01, 3.85, 1.7, 1.6, 1.06 .
A solution of 2-ethyl-7-iodo-2,3-dihydro-l,4-benzodioxine (486mg, 1.68mmol) in DMF (3mL) is degassed by repeatedly evacuating the flask and filling with N2. Zn(CN)2 (117mg, 1.Ommol), and Pd(PPh3)4 (97mg, 0.084mmol) are added, and the resulting solution is degassed, and is then heated to 80°C for 1.5 h. The reaction is allowed to cool, poured into water and extracted two times with ether. The combined organic extracts are dried (Na2SO ), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (step gradient, 25-50% CH2C12 in hexanes) to give 3-ethyl-2,3-dihydro-l,4-benzodioxine-6-carbonitrile as a clear oil (296mg, 92%). 1H NMR (400 MHz, CDC13) δ 7.16, 7.13, 6.91, 4.31, 4.05, 3.93, 1.7, 1.6, 1.08.
KOH (218mg, 3.9mmol) is added to a mixture of 3-ethyl-2,3-dihydro-l,4- benzodioxine-6-carbonitrile (247mg, 1.3mmol), ethanol (3mL) and water (lmL). The resulting mixture is heated to 80°C for 24 hours. The reaction is allowed to cool, diluted with water (2mL) and acidified to pH<2 with concentrated HCl. The resulting solid is filtered, washed with water and dried at 60°C under vacuum to give 3-ethyl- 2,3-dihydro-l,4-benzodioxine-6-carboxylic acid as a white solid (249mg, 92%). 1H NMR (400 MHz, DMSO-- ) δ 12.66, 7.43, 7.37, 6.95, 4.38, 4.10, 3.95, 1.64, 1.01.
Intermediate E2: 2-(Phenoxymethyl)-2,3-dihvdro-l,4-benzodioxine-6-carboxyIic acid 6-Bromo-2,3-dihydiO-l,4-benzodioxin-2-yl)methanol is prepared according to literature reports for 6-fluoro-2,3-dihydro-benzo-l,4-dioxin-2-yl)-methanol. See Henning, R.; Lattrell, R.; Gerhards, H. J.; Leven, M.; J.Med.Chem.; 30; 5; 1987; 814- 819. The intermediate is obtained in 70% yield as a solid: 1H NMR (400 MHz, CDC13) δ 7.08, 7.00, 6.81, 4.25-4.40, 4.10-4.20, 3.85-4.00, 1.95; MS (El) m/z 244 (M+).
A mixture of (6-bromo-2,3-dihydro-l,4-benzodioxin-2-yl)methanol (3.94 g, 16.1 mmol) and DMF (35 mL) at rt is treated with a 60% dispersion of NaH in mineral oil (0.706 g, 17.7 mmol). After 15 min, the mixture is treated with benzyl bromide (2.10 mL, 17.7 mmol). After 2 h, the mixture is poured into H2O and extracted with EtOAc (2 x 125 mL). The combined organics are washed with H2O (3 x 100 mL), brine, dried (MgSO ), filtered, and concenfrated. The resulting oil is adsorbed onto SiO2 and chromatographed (Biotage 40M + SIM, 5% EtOAc/Hexane). The product fractions are pooled and concentrated to give an oil which solidified (upon standing) to give 3.91 g (73%) of 2-[(benzyloxy)methylJ-6-bromo-2,3-dihydro- 1,4-benzodioxine: 1H NMR (400 MHz, CDC13) δ 7.30-7.45, 7.06, 6.99, 6.81, 4.60- 4.70, 4.30-4.40, 4.05-4.15, 3.65-3.85; MS (El) m/z 244 (M+).
A mixture of 2-[(benzyloxy)methyl]-6-bromo-2,3-dihydro-l,4-benzodioxine (3.63 g, 10.8 mmol) in THF (60, mL) is cooled in a CO2/acetone bath under N2. A solution of t-butyl lithium in pentane (1.3 M, 17.5 mL, 22.8 mmol) is added. After 5 min, CO2 (g) is bubbled through the mixture and the mixture is warmed to rt. A solution of HCl in methanol is added and the mixture concentrated. The residue is extracted between NaOH (1 N) and EtOAc. The organic layer is discarded. The pH of the aqueous layer is adjusted to - 4 and is extracted with EtOAc (2 x 100 mL). The combined organics are washed with H2O (3 x 100 mL), brine, dried (MgSO4), filtered, and concentrated. The resulting oil is chromatographed (Biotage 40M, 2% MeOH/CH2Cl2). The product fractions are pooled and concentrated to an give oil 1.66 g (51%) of 2-(phenoxymethyl)-2,3-dihydro-l,4-benzodioxine-6-carboxylic acid.
Intermediate E3: 3-f(Benzyloxy)methyn-2,3-dihydro-l,4-benzodioxine-6- carboxylic acid
(R) and (S)-(7-Bromo-2,3-dihydro-benzo-l,4-dioxin-2-yl)-methanol are prepared according to the literature example. The racemic mixture is obtained starting with racemic epichlorohydrin. See Aiba, Y.; Hasegawa, et al., Bioorg.Med.Chem.Lett.; 11; 20; 2001; 2783-2786.
A mixture of 7-bromo-2,3-dihydro-l,4-benzodioxin-2-yl)methanol (2.73 g, 11.1 mmol) and DMF (25 mL) at 0°C is treated with a 60% dispersion of NaH in mineral oil (0.49 g, 12.3 mmol). After 15 min, the mixture is treated with benzyl bromide (1.46 mL, 12.37 mmol). After 2 h, the mixture is poured into H2O and extracted with EtOAc (2 x 125 mL). The combined organic layers are washed with H O (3 x 100 mL), brine, dried (MgSO ), filtered, and concentrated. The resulting oil is adsorbed onto SiO and chromatographed (Biotage 40M + SIM, 5% EtOAc/Hexane). The product fractions are pooled and concentrated to provide an oil, which solidified (upon standing) to give 3.48 g (93%) of 2-[(benzyloxy)methyl]-7- bromo-2,3-dihydro-l,4-benzodioxine.
A mixture of 2-[(benzyloxy)methylJ-7-bromo-2,3-dihydro-l,4-benzodioxine (3.35 g, 10.0 mmol) in THF (60, mL) is cooled in a CO2/acetone bath under N2. A solution of t-butyl lithium in pentane (1.7 M, 6.0 mL, 10.2 mmol) is added. After 5 min, CO2 (g) is bubbled through the mixture and the mixture is warmed to rt. A solution of HCl in methanol is added and the mixture concenfrated. The residue is chromatographed (Biotage 40M, 3% MeOH/CH2Cl2). The product fractions are pooled and concentrated to give 1.19 g (40%) of 3-[(benzyloxy)methylJ-2,3-dihydro- 1 ,4-benzodioxine-6-carboxylic acid as an oil.
Intermediate E4: (3S)-3-r(BenzyIoxy)methyl1-2,3-dihydro-1.4-benzodioxine-6- carboxyl acid
Intennediate E4 is obtained following the procedures discussed for Intermediate E3, making non-critical changes, and starting with [(2S)-7-bromo-2,3- dihydro- 1 ,4-benzodioxin-2-ylJmethanol
Intermediate E5: (3R) 3-[(Benzyloxy)methvπ-2.3-dihydro-l,4-benzodioxme-6- carboxylic acid Intermediate E5 is obtained following the procedures discussed for
Intermediate E3, making non-critical changes, and starting with (3R)-3- [(benzyloxy)methylJ-2,3-dihydro-l,4-benzodioxine-6-carboxylic acid. Intermediate E6: (3SV3-(PhenoxymethyI)-2,3-dihydro-l,4-benzodioxine-6- carboxylic acid
A mixture of [(2S)-7-bromo-2,3-dihydro-l,4-benzodioxin-2-yl]methanol (2.26 g, 9.20 mmol), phenol (0.87 g, 9.2 mmol), triphenylphosphine (2.42 g, 9.20 mmol) and THF (80 mL) is cooled in a 0°C bath under N2. Diethylazodicarboxylate (1.50 ml, 9.5 mmol) is added, and the mixture is allowed to warm to rt overnight. The mixture is adsorbed onto SiO2 and chromatographed (Biotage 40S+SIM, (1:19) EtOAc :hexane). The product fractions are pooled and concentrated to afford 1.45 g (49%) of (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-l,4-benzodioxine as a clear oil.
Intermediate E7: (3R)-3-(Phenoxymethyl)-2,3-dihydro-l,4-benzodioxine-6- carboxylic acid
A mixture of [(2R)-7-bromo-2,3-dihydro-l,4-benzodioxin-2-ylJmethanol (0.648 g, 2.64 mmol), phenol (0.248 g, 2.64 mmol), triphenylphosphine (0.692 g, 2.64 mmol) and THF (26 mL) is cooled in a 0°C bath under N2. Diethylazodicarboxylate (0.42 ml, 2.7 mmol) is added and the mixture allowed to warm to rt overnight. The mixture is concentrated, partitioned between EtOAc and H2O, the organic layer dried (MgSO4), adsorbed onto SiO2, and chromatographed (Biotage 40S+SIM, (1:19) EtOAc :hexane). The product fractions are pooled and concenfrated to afford 0.315 g (37%) of (2R)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-l,4-benzodioxine as an oil. A solution of this oil (0.280 g, 0.87 mmol) and THF (30 ml) is cooled in a CO2 (s)/acetone bath under N2. To this is added a solution of tert-butyl lithium in pentane (1.7 M, 1.10 ml, 1.9 mmol). After stirring for 5 min, CO2 (g) is bubbled through the solution for an additional 10 min. The mixture is treated with MeOH/HCl and allowed to warm to rt. The mixture is concentrated, and the residue is chromatographed (Biotage 40S, (1 :499) MeOH:CH2Cl2). The product fractions are pooled and concentrated to afford 0.103 g (41%) of (3R)-3-(phenoxymethyl)-2,3- dihydro-l,4-benzodioxine-6-carboxylic acid as a solid.
Intermediate E8: 2<3-Dihydro-l,4-dioxino[2,3-c1pyridine-7-carboxylic acid
To a stined solution of 4,5-hydroxypyridine-2-carboxylic acid [see:Kenichi Mochida, et al. J. Antibiot. 1987, 182] (800 mg, 4.18 mmol) in MeOH (30 mL) is added concentrated sulfuric acid (1 L). The mixtxire is heated to reflux for 2 days. The mixture is cooled to rt, followed by addition of solid sodium bicarbonate. The mixture is diluted with water and the precipitate is filtered and dried to give 527 mg (75%) of methyl 4,5-dihydroxypyridine-2-carboxylate: 1H NMR (400 MHz, MeOH- d4) δ 7.68, 7.24, 3.97.
To a stined solution of methyl 4,5-dihydroxypyridine-2-carboxylate (348 mg, 2.06 mmol) in DMF (20 mL) is added solid K2CO3 (3.1 g, 22 mmol) and 1,2- dibromoethane (386 μL, 4.5 mmol). The mixture is heated at 115°C for 2 h. DMF is removed in vacuo, the residue is partitioned between water and EtOAc. The aqueous layer is again exfracted with EtOAc. The combined organic layers are dried (MgSO ) and concentrated in vacuo to give a yellow solid for methyl 2,3-dihydro-l,4- dioxino[2,3-c]pyridine-7-carboxylate (348 mg, 86%): 1H NMR (400 MHz, CDC13) δ 8.29, 7.71, 4.39, 3.99.
To a stined solution of methyl 2,3-dihydro-l,4-dioxino[2,3-c]pyridine-7- carboxylate (300 mg, 1.54 mmol) in MeOH (10 mL) is added NaOH (10 mL of a 5% aqueous solution). The mixture is heated to reflux for 3 h, followed by cooling to rt. The methanol is removed in vacuo and the remaining aqueous layer is acidified to pH=5 with IN HCl, extracted with CH2C12 continuously for 2 days. The organic layer is concentrated to a white solid (245 mg, 88%) for 2,3-dihydro-l,4-dioxino[2,3- c]pyridine-7-carboxylic acid: 1H NMR (400 MHz, DMSO-cQ δ 13-12, 8.21, 7.52, 4.39.
Intermediate E9: Chromane-6-carboxylic acid
A mixture of chromene (see: Chatterjea, J. Indian Chem. Soc. 1959, 35, 78.) (5.00 g, 37.8 mmol) and 10% palladium on activated carbon (250 mg) in glacial acetic acid (100 mL) is placed in a Pan bottle. The mixture is shaken under an atmosphere of hydrogen (45 psi) for 3 h at rt. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to afford 5.00 g (98%) of chromane as light yellow oil: 1H NMR (400 MHz, CDC13) δ 7.15-7.05, 6.89, 6.80, 4.23, 2.84, 2.08-2.02. To a stined solution of acetyl chloride (4.78 mL, 67.1 mmol) in dry CH2C12
(20 mL) in a -10°C bath is added aluminum trichloride (4.76 g, 35.7 mmol) in small portions. The mixture is stined for 15 min until the solution became homogeneous. The solution is added via canula to a separate solution of chromane (4,79 g, 35.7 mmol) in CH2C12 (30 mL) all at -10 °C. After complete addition, the solution is stined at -10°C for 30 min. The solution is poured over a mixture of crushed ice and concenfrated HCl. The mixture is extracted with CH2C12. The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue is purified via crystallization from hexanes to give 4.0 g (64%) of l-(3,4-dihydro-2H-cbromen-6-yl)ethanone as a white solid. 1H NMR (400 MHz, CDC13) hi.16-1.13, 6.75, 4.27, 2.86, 2.57, 2.09-2.03.
A mixture of l-(3,4-dihydro-2H-chromen-6-yl)ethanone (3.80 g, 22.0 mmol) and sodium hypochlorite [150 mL of a 6.0% aqueous solution, (Clorox brand of bleach)J in a 55°C oil bath is stirred for 2 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persisted. HCl (ca 15 mL of a 6.0 M aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO ), filtered, and concentrated in vacuo to afford 3.10 g (82%) of chromane-6-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 12.55, 7.67, 7.6, 6.79, 4.20, 2.77, 1.96-1.90.
Intermediate E10: Chromane-7-carboxylic acid
To a stined solution of methyl 4-formyl-3-hydroxybenzoate [see: Harayama, Chem. Pharm. Bull. 1994, 2170J (0.8 g, 4.1 mmol) and anhydrous K2CO3 (1.1 g, 8.0 mmol) in acetone (12 mL) is added allyl bromide (0.70 mL, 8.1 mmol). The mixture is heated in a 48°C oil bath for 2 h. The reaction mixture is cooled to rt and filtered. The mother liquor is concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (85:15) gives 0.85 g (49%) of methyl 3-(allyloxy)-4-formylbenzoate as a clear solid: 1H NMR (400 MHz, CDC13) δ 10.6, 7.9, 7.7, 6.1, 5.5, 5.4, 4.8, 4.0.
Sodium hydride [220 mg (60% oil dispersion), 5.4 mmol], is washed with pentane (3x) and is suspended in THF (12 mL) in a 0°C ice bath. Methyl triphenylphosphonium bromide (1.7 g, 4.7 mmol) is added. The suspension is allowed to warm to rt and stir for 30 min. A solution of methyl 3-(allyloxy)-4- formylbenzoate (0.85 g, 3.8 mmol) in THF (5 mL) is added via canula. The mixture is stined at rt for 2 h. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried with MgSO4, filtered and concentrated in vacuo to a yellow residue. The crude product is triturated with hexanes, filtered and dried in vacuo to a clear oil for methyl 3-(allyloxy)-4-vinylbenzoate (680 mg, 81%): 1H NMR (400 MHz, CDC13) δ 7.65-7.54, 7.13, 6.13, 5.88, 5.49-5.29, 4.65, 3.93.
To a stined solution of methyl 3-(allyloxy)-4-vinylbenzoate (0.67 g, 3.1 mmol) in CH2C12 (20 mL) at rt is added benzylidene-bis(tricyclohexylphosphine)- dichlororuthenium (63 mg, 0.076 mmol). The mixture is stined at rt for 2 h. The reaction mixture is concentrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO . Elution with hexanes-EtOAc (95:5) gives 372 mg (64%) of methyl 2H-chromene-7-carboxylate as a clear oil: 1H NMR (400 MHz, CDC13) δ 7.56, 7.46, 7.01, 6.46, 5.91, 4.89, 3.91. A mixture of methyl 2H-chromene-7-carboxylate (372 mg, 1.96 mmol) and
10% Pd/C (25 mg) in methanol (15 mL) is stined under 1 atm of hydrogen at rt for 3 h. The mixture is filtered through Celite and the filtrate is concentrated to a yellow residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 140 mg (37%) of methyl chromane-7-carboxylate as a clear oil: 1H NMR (400 MHz, CDC13) δ 7.51, 7.47, 7.10, 4.23, 3.91, 2.85, 2.04.
To a stined solution of methyl chromane-7-carboxylate (140 mg, 0.73 mmol) in MeOH (5 mL) is added NaOH (5 mL of a 5% aqueous solution). The mixture is heated in a 85°C oil bath for 3 h, followed by cooling to rt. The methanol is removed in vacuo and the remaining aqueous layer is acidified to pH=l with concentrated HCl, extracted with EtOAc (3X). The combined organic layers are dried (MgSO4) and concentrated to a white solid for chromane-7-carboxylic acid (130 mg, 100%): 1H NMR (400 MHz, DMSO-J5) δ 13-12, 7.37, 7.24, 7.16, 4.16, 2.79, 1.92.
Intermediate Ell: 2H-chromene-6-carboxyIic acid To a stined solution of ethyl 3-formyl-4-hydroxybenzoate [see: Skattebol,
Ada. Chemica. Scandinavica 1999, 53, 258] (1.9 g, 10.0 mmol) and anhydrous K2CO3 (2.7 g, 19.5 mmol) in acetone (30 mL) is added allyl bromide (1.7 mL, 19.8 mmol). The mixture is heated in a 60°C oil bath for 2 h. The mixture is cooled to rt, filtered and concentrated in vacuo to afford 2.1 g (92%) of ethyl 4-(allyloxy)-3- formylbenzoate as a white solid: 1H NMR (400 MHz, CDC13) δ 10.5, 8.5, 8.2, 7.1, 6.1, 5.5, 5.4, 4.8, 4.4, 1.4.
To a stined suspension of sodium hydride [588 mg (60% oil dispersion), 15 mmol), which had been previously washed with pentane (3x), in THF (30 mL) in a 0°C ice bath is added methyl triphenylphosphonium bromide (4.6 g, 13 mmol). The suspension is allowed to warm to rt and stir for 30 min. A solution of ethyl 4- (allyloxy)-3 -formylbenzoate (2.3 g, 9.8 mmol) in THF (10 mL) is added via canula. The mixture is stined at rt 2 h. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried of MgSO , filtered and concentrated in vacuo to a yellow residue. The crude product is purified by flash chromatography on SiO . Elution with hexanes-EtO Ac (95:5) gives 1.8 g (79%) of ethyl 4-(allyloxy)-3- vinylbenzoate as a clear oil: 1H NMR (400 MHz, CDC13) δ 8.2, 7.9, 7.1, 6.9, 6.1, 5.9, 5.5, 5.3, 4.7, 4.4, 1.4. To a stined solution of ethyl 4-(allyloxy)-3-vinylbenzoate (1.8 g, 7.7 mmol) in
CH2C12 (40 mL) at rt is added benzylidene-bis(tricyclohexylphosphine)- dichlororuthenium (127 mg, 0.15 mmol). The mixture is stined at rt for 2.5 h. The reaction mixture is concenfrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 1.3 g (80%) of ethyl 2H-chromene-6-carboxylate as a clear oil: 1H NMR (400 MHz, CDC13) δ 7.8, 7.7, 6.8, 6.4, 5.8, 4.9, 4.4, 1.4.
To a stined solution of ethyl 2H~chromene-6-carboxylate in MeOH (80 mL) is added NaOH (40 mL of a 5% aqueous solution). The mixture is heated in a 60°C oil bath for 30 min, followed by cooling to rt. The methanol is removed in vacuo and the remaining aqueous layer is acidified to pH=l with concenfrated HCl. The solid precipitate is filtered and washed with water to afford 130 mg (13%) of 2H-chromene- 6-carboxylic acid as a white solid: 1H NMR (400 MHz, CDC13) δ 12-11, 7.9, 7.7, 6.8, 6.5, 5.8, 5.0.
Intermediate E12: 2-Methyl-2J-f-chromene-6-carboxyIic acid
To a stined solution of lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (8 mL) in a 0°C ice bath is added methyl triphenylphonium bromide (1.92 g, 5.38 mmol). The mixture is allowed to warm to rt and stir for 10 min. A solution of methyl 3-formyl-4-hydroxybenzoate (200 mg, 1.11 mmol) in THF (3 mL) is added to the above solution. The mixture is stined at rt for 5 h. The reaction mixture is acidified to pH=5 with IN HCl, and extracted with ether (3X). The combined organic layers are washed with brine, dried (MgSO ), filtered and concentrated to a yellow oil. The crude product is purified by chromatography on SiO2. Elution with hexanes-EtOAc (80:20) gives 130 mg (66%) of methyl 4-hydroxy- 3-vinylbenzoate as a white solid: 1H NMR (400 MHz, CDC13) δ 8.12, 7.86, 6.93, 6.85, 5.84, 5.50, 5.46, 3.92.
To a stined solution of methyl 4-hydroxy-3-vinylbenzoate (410 mg, 2.3 mmol), triphenylphosphine (787 mg, 3.0 mmol), 3-buten-2-ol (260 μL, 3.0 mmol) in THF (15 mL) at 0°C is added a solution of diethyl azadicarboxylate (472 μL, 3.0 mmol) in THF (5 mL). The mixture is allowed to warm to rt and stir overnight. The mixture is concenfrated in vacuo and the residue is purified by chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 371 mg (69%) of methyl 3-fonnyl-4- [(l-methylprop-2-enyl)oxy]benzoate as a clear oil: 1H NMR (400 MHz, CDC13) δ 8.18, 7.89, 7.08, 6.90, 5.94, 5.86, 5.36-5.30, 4.93, 3.91, 1.51.
To a stined solution of methyl 3-formyl-4-[(l-methylprop-2-enyl)oxyJ- benzoate (370 mg, 1.59 mmol) in CH2C12 (8 mL) at rt is added benzylidene- bis(tricyclohexylphosphine)dichlororuthenium (56 mg, 0.068 mmol). The mixture is stined at rt overnight. The reaction mixture is concentrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 225 mg (69%) of methyl 2-methyl-2H-chromene-6- carboxylate as a clear oil: 1H NMR (400 MHz, CDC13) δ 7.82, 7.68, 6.79, 6.41, 5.71, 5.11, 3.89, 1.48. To a stirred solution of methyl 2-methyl-2H-chromene-6-carboxylate (225 mg,
1.10 mmol) in MeOH (5 mL) is added NaOH (5 mL of a 5% aqueous solution). The mixture is heated in a 60°C oil bath for 40 min, followed by cooling to rt. The methanol is removed in vacuo and the remaining aqueous layer is acidified to pH=5 with IN HCl. The solution is extracted with EtOAc (2X), washed with brine, dried (MgSO4) and concentrated in vacuo to afford 209 mg (100%) of 2-methyl-2H- chromene-6-carboxylic acid as a yellow oil: 1H NMR (400 MHz, DMSO-J6) δ 13-12, 7.68, 7.65, 6.80, 6.53, 5.85, 5.10, 1.37.
Intermediate E13: 3,4-Dihydro-2H-pyrano[2,3-cJpyridine-6-carboxylic acid 2-Chloro-3-pyridinol (20.0 g, 0.154 mole andNaHCO3 (19.5g, 0.232 mole, 1.5 equ) are dissolved in 150 ml of water. The reaction mixture is placed in an oil bath at 90°C and after 5 min is treated with 37% aqueous formaldehyde (40.5 ml, 0.541 mole, 3.5 equ) which is added in six unequal doses; 12 ml initially, 3 x 8 ml followed by 1 x 2.2 ml all at 90 min intervals with the final 2.3 ml added after maintaining at 90°C overnight (15 h). After stirring in the 90°C bath for an additional 4 h, the flask is placed in ice bath, and the contents are treated with 100 ml of crushed ice, acidified with 39 ml of 6 N HCl to pH 1 , and the precipitated material is stined for 1.5 h in an ice bath. The undesired solid is removed by filtration, and the filtrate is exfracted seven times with EtOAc. The combined organic extracts are concentrated at reduced pressure, treated with toluene, reconcentrated on rotary evaporator to azeotrope most of the water, suspended in CH2C12 and reconcentrated again at reduced pressure to obtain 19.9 g (81%>) of 2-chloro-6-(hydroxymethyl)-3-pyridinol as apale yellow solid sufficiently pure for subsequent reaction. MS for C6H6ClNO2: m/z: 159 (M)+.
2-Cl loro-6-(hydroxymethyl)-3-ρyridinol (11.6 g, 72.7 mmol) andNaHCO3 (18.3 g, 218 mmol) are dissolved in 200 ml water in a flask. The mixture is stirred until homogeneous, is cooled in an ice bath, is treated with iodine (19.4 g, 76.3 mmol), and is stirred over 60 h at rt as the cooling bath expired. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4 x 50 ml EtOAc. The combined organic layer is dried (MgSO ) and is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 12.9 g (62%) of 2- chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol as an off-white solid. The filtrate is concentrated to a small volume and is chromatographed over 250 g SiO2 (230-400 mesh) eluting with EtOAc/CH2Cl2/hexane/acetic acid 2.5 :4.5 :4:0.1. The appropriate fractions are combined and concentrated to afford an additional 2.4 g (12%) of pure 2- chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol. MS for C6H5ClINO2, m/z: 285 (M)+.
2-Chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (5.7 g, 20 mmol) is combined with bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) in 50 ml DMF under nitrogen. The mixture is treated with tetravinyl tin, is warmed to 60°C for 6 h followed by 50°C for 18 h, and at rt for 72 h. The mixture is diluted with 250 ml EtOAc and is extracted with 4 x 100 ml 2:1 :1 water/saturated NaCl/saturated NaHCO3. The organic layer is dried (MgSO ) and is concentrated in vacuo to a yellow oil. The crude material is chromatographed over 200 g SiO2 (230-400 mesh) eluting with 37% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.45 g (39%) of 2-chloro-6-(hydroxymethyl)-4-vinylpyridin-3- ol as a pale yellow solid. MS for C8H8ClNO2 (El) m/z: 185 (M)+.
I l l - 2-Chloro-6-(hydroxymethyl)-4-vinylpyridin-3-ol (1.35 g, 7.8 mmol) is dissolved in 12 ml DMF in a dry flask under nitrogen. The yellow solution is treated with 60% sodium hydride (312 mg, 7.8 mmol), is stined 30 min, and is treated with allyl bromide (744 μL, 8.6 mmol). The reaction is stirred 6 h at RT, is diluted with 50 ml EtOAc, and is washed with 4 x 25 ml 2 : 1 : 1 water/sat' d NaCl/sat' d NaHCO3. The organic layer is dried (MgSO ) and is concenfrated in vacuo to a yellow oil. The crude material is chromatographed over 50 g SiO2 (230-400 mesh) eluting with 30% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 1.43 g (81%) of [5-(allyloxy)-6-chloro-4-vinylpyridin-2-yl]methanol as a white solid. MS for Ci !H12ClNO2 (El) m/z: 225 (M)+.
[5-(AUyloxy)-6-chloro-4-vinylpyridin-2-ylJmethanol (225 mg, 1.0 mmol) is combined with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (16.5 mg, 0.02 mmol) in 5 ml CH2CI2 and the reaction is stirred 4 h at RT. The volatiles are removed in vacuo and the residue is chromatographed over 15 g Siθ2 (230-400 mesh) eluting with 40% EtOAc/hexane. The appropriate fractions are combined and concenfrated to give 175 mg (89%) of (8-chloro-2H-pyrano[2,3- c]pyridin-6-yl)methanol as a tan solid. MS for C9H8ClNO2 (El) m/z: 197 (M)+. (8-Chloro-2H-pyrano[2,3-cJpyridin-6-yl)methanol (988 mg, 5.0 mmol) is combined with 100 mg 10% Pd/C in 25 ml EtOH containing 3 ml (6 mmol) of 2N aqueous NaOH in a 250 ml PARR shaker bottle. The reaction is hydrogenated at 50 PSI for 48 h, the catalyst is removed by filtration, and the filtrate is concentrated to dryness. The mixture is partitioned between 1 x 10 ml 1:1 saturated NaCl/ cone. NH4OH and 4 x 10 ml CH2CI2 and the combined organic layer is dried (K2CO3). The mixture is concentrated in vacuo to give 730 mg (89%) of 3,4-dihydro-2H-pyrano[2,3- c]pyridin-6-ylmethanol as an off-white solid. HRMS (FAB) calcd for C9HnNO2 +H: 166.0868, found 166.0868 (M+H)+.
Oxalyl chloride (452μL, 5.1 mmol) is dissolved in 15 ml CH2C12 under nitrogen at -78°C. The solution is treated drop-wise with DMSO (729μL, 10.3 mmol) in 5 ml CH2C12 and the mixture is stined 30 min at -78°C. 3,4-Dihydro-2H- pyrano[2,3-c]pyridin-6-ylmethanol (731 mg, 4.4 mmol) is added drop-wise to the reaction mixture in 5 ml CH C12 and the reaction is stined 30 min at -78°C. The mixture is treated with TEA (3.08 ml, 22.1 mmol), is stirred 30 min at -78°C and 2 h at 0°C. The mixture is washed with 1 x 10 ml saturated NaHCO3, is dried (K2CO3), and is concentrated in vacuo. The crude intermediate is chromatographed over 25 g SiO2 (230-400 mesh) eluting with 35% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 685 mg (95%) of the aldehyde as an off-white solid. The aldehyde (685 mg, 4.2 mmol) is combined with NaClO2 (80%, 1.42 g,
12.6 mmol) and KH2PO4 in 15 ml THF/7 ml t-BuOH/ 7 ml water and the reaction is stined overnight under a stream of nitrogen. The reaction is concentrated to dryness in vacuo and the residue is dissolved in 10 ml water. The pH of the mixture is adjusted to 5 with 12 N HCl, the white solid is collected, washed with water, and is dried in vacuo at 50°C to afford 565 mg (82%) of 3,4-dihydro-2H-pyrano[2,3- cJpyridine-6-carboxylic acid as a white solid. ΗRMS (FAB) calcd for C9Η9NO3 +H: 180.0661, found 180.0652 (M+H)+.
Compounds of Formula I where W is (F) are made using the coupling procedures discussed herein and in cited references, making non-critical changes to obtain the desired compounds. The following intermediates to provide W of formula I are for exemplification only and are not intended to limit the scope of the present invention. Other intermediates within the scope of the present invention can be obtained using known procedures or by making slight modifications to known procedures.
Intermediate FI: 1.3-BenzoxazoIe-6-carboxylic acid
A mixture of 4-amino-3-hydroxybenzoic acid (250 mg, 1.63 mmol) and trimethyl orthoformate (500 μL, 4.57 mmol) is heated in an oil bath at 100°C for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give Intermediate FI as a brown solid (237 mg, 89%): 1H NMR (DMSO-J6) δ 13.2, 8.9, 8.3, 8.0, 7.9.
Intermediate F2: 2-Methyl-l -3-benzoxazole-6-carboxyIic acid A mixture of 4-amino-3-hydroxybenzoic acid (500 mg, 3.7 mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an oil bath to 100°C for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give Intermediate F2 as an off-white solid (266 mg, 46%): 1H NMR DMSO-d6) δ 13.1, 8.2, 8.0, 7.7, 2.7.
Intermediate F3: l,3-BenzoxazoIe-5-carboxylic acid A mixture of 4-amino-3-hydroxybenzoic acid (1.0 g, 6.5 mmol) and trimethyl orthoformate (2.0 mL, 18.3 mmol) is heated in an oil bath at 100°C for 30 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concenfrated in vacuo to give Intermediate F3 as a brown solid (290 mg, 27%): 1H NMR (DMSO-^) δ 13.0, 8.9, 8.3, 8.1, 7.9.
Intermediate F4: 2-MethyI-l,3-benzoxazole-5-carboxylic acid
A mixture of 4-amino-3-hydroxybenzoic acid (480 mg, 3.1 mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an oil bath to 107°C for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of silica gel and the filtrate is concentrated in vacuo to give
Intermediate F4 as an orange solid (490 mg, 88%): 1H NMR (DMSO-J6) δ 13.0, 8.2, 8.0, 7.8, 2.7.
Intermediate F5: 5-Indancarboxylic acid To a stined 6% aqueous sodium hypochlorite solution in an oil bath to 55°C is added l-indane-5-yl-ethanone (1.0 g, 6.2 mmol). The solution is stined at 55°C for 2 h, followed by cooling to rt. Solid sodium bisulfite is added until the solution became clear. The mixture is diluted with water, followed by aqueous hydrochloric acid (6.0 M). The solid that forms is filtered and washed several times with water. The solid is dried under high vacuum at 60°C for 5 h to afford Intermediate F5 as a white solid (0.96 g, 95%): 1H NMR (CDC13) δ 8.0, 7.9, 7.3, 3.0, 2.1.
Intermediate F6: fl,31Oxazolo[5,4-c1pyridine-6-carboxylic acid
2-Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO3 (19.5g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a flask. The flask is placed in an oil bath at 90°C, and after 5 minutes, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equ) is added in six unequal doses in the following order: 12 mL, 3 8 mL, then 2.2 mL all at 90-minute intervals and then the final 2.3 mL after the reaction had stined for 15 h at 90°C. The reaction is stined at 90°C for another 4 h and then is cooled by placing the flask in an ice bath. The pH of the reaction is then adjusted to 1 using 6N HCl. The reaction is stined for 1.5 h in an ice bath allowing an undesired solid to form. The undesired solid is removed by filtration, and the filtrate is extracted seven times with EtOAc. The combined organic extracts are concenfrated in vacuo, toluene is added to the flask and removed in vacuo to azeofrope water, and then CH C12 is added and removed in vacuo to obtain 2-chloro-6-(hydroxymethyl)-3-pyridinol (I-10-F) as a pale yellow solid (81% yield) sufficiently pure for subsequent reaction. MS (El) for C6H6ClNO2, m/z: 159(M)+. I-10-F (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL water. The mixture is stined until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4 x 50 mL EtOAc. The combined organic layer is dried (MgSO4), is filtered^ and the filtrate is concenfrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (1-12- F) as an off-white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2/hexane/acetic acid. The desire fractions are combined and concenfrated to afford an additional pure I-12-F (12% yield). MS (El) for C6H5ClINO2, m/z: 285(M)+.
4-(Benzylamino)-2-chloro-6-(hydroxvmethyl)-3-pyridinol (I-13-F) maybe produced by amination of 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (I-12-F) with benzylamine under palladium catalysis. Amination of aryl iodides with primary amines such as benzylamine under palladium catalysis is generally described in a review by B.H. Yang and S.L. Buchwald inJ. Organomet. Chem., 576, 125-146, 1999 and in greater detail in the references therein.
I-13-F maybe oxidized to 4-(benzylamino)-2-chloro-3-hydroxypyridine-6- carboxaldehyde (I-14-F) under a wide variety of conditions (e.g., TPAP andNMO in CH2C1 ). I-14-F may be oxidized to produce the conesponding carboxylic acid I-l 5-F using an oxidizing reagent such as NaClO2 and KH2PO4 in DMSO/H O or Ag2O, or hydrogen peroxide or ruthenium tetroxide. Removal of the benzyl group and the chloro group of Acid I-l 5-F may be accomplished by utilizing hydrogen or a hydrogen source (e.g., cyclohexene, cyclohexadiene, ammonium formate, hydrazine, etc.) in the presence of Pd C or other catalyst, under a variety of conditions and in various solvents, to produce 4-amino-5- hydroxypyridine-2-carboxylic acid (Acid I-16-F).
Cyclocondensation of Acid I-16-F with trimethyl orthoformate in the presence of catalytic j?αrα-toluenesulfonic acid may be conducted to produce [l,3]oxazolo[5,4- cJpyridine-6-carboxylic acid.
Intermediate F7: 2-Benzoisothiophene-5-carboxylic acid
Intermediate F7 can be made by the saponification of the methyl ester I-20-E, which can be made pursuant to Wynberg, Hans, et al., Reel. Trav. Chim. Pays-Bas (1968), 87(10), 1006-1010.
Intermediate F8: 1.3-Benzothiazole-5-carboxylic acid
A solution of sodium sulfide anohydrate (1.15 g, 4.9 mmol) in methanol- water (ca. 10 mL, 1 : 1) is warmed on a hot plate. To this solution is added elemental sulfur (150 mg, 4.6 mmol). Heating is continued for 15 min before the solution is poured into a separate solution of 1.0 g (4.6 mmol) of methyl 4-chloro-3- nifrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48, 837.) in MeOH (5.0 mL).
The mixture is stined for 30 min, followed by cooling in a refrigerator overnight. The solid precipitate is filtered, washed with water and methanol, and dried in vacuo at 50 °C to afford 650 mg (65%) of dimethyl 4,4'-dithio-bis-(3-nitrobenzoate) as a yellow solid: 1H NMR (400 MHz, CDC13) δ 9.0, 8.2, 7.9, 4.0. To a stirred solution of dimethyl 4,4'-dithio-bis-(3-nitrobenzoate) (900mg,
2.12 mmol) in ethanol is added tin powder (1.91 g, 17.0 mmol). The mixture is heated in a 70°C oil bath for 30 minutes before 2.8 mL of concenfrated hydrochloric acid is added drop-wise. After complete addition, the mixture is stined for an additional 10 min, followed by cooling to RT. The reaction mixture is filtered and the fitrate is concentrated in vαcuo to a solid. The solid is washed with l.OM aqueous hydrochloric acid and dried in vαcuo to afford a yellow solid. The solid (750 mg, 3.42 mmol) is suspended in formic acid (4 mL) in a 100°C oil bath. Zinc dust (15 mg) is added to the reaction. The mixture is stined for 10 min, followed by cooling to RT. The mixture is diluted with water and exfracted with EtOAc. The organic layer is dried (MgSO4), filtered and concentrated in vacuo to afford 640 mg (97%) of methyl l,3-benzothiazole-5-carboxylate as a yellow solid: 1H NMR (400 MHz, CDC13) δ 9.1, 8.9, 8.2, 8.1, 4.0. To a stined solution of methyl l,3-benzothiazole-5-carboxylate (290 mg, 1.5 mmol) in MeOH (20 mL) is added sodium hydroxide (10 mL of a 5% aqueous solution). The mixture is heated in a 65°C oil bath for 30 min, followed by cooling to RT. The mixture is diluted with water and extracted with hexanes-ether (1:1). The organic layer is discarded and the aqueous layer is acidified with concenfrated hydrochloric acid to pH=l. The aqueous layer is exfracted with ether. The ethereal layer is dried (MgSO4), filtered and concenfrated in vacuo to a yellow powder for 1,3- benzothiazole-5-carboxylic acid (260 mg, 98%): 1H NMR (400 MHz, DMSO-d6) δ 13-12.5, 9.5, 8.6, 8.3, 8.0.
Intermediate F9: 3-Methyl-l,2-benzisoxazole-6-carboxylic acid
3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stiner and is treated slowly dropwise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stined for 1 h at rt and then treated rapidly dropwise with concenfrated HCl (180 mL). The white solid is collected via filfration, rinsed with water and dried overnight [by pulling air through the solidj in vacuo to afford 13.05 g (54%) of 3- hydroxy-4-iodobenzoic acid as a tan solid. 1H NMR (DMSO- ό): δ 7.13, 7.43, 7.80, 10.71, 12.98 ppm.
3-Hydroxy-4-iodobenzoic acid (12.55 g, 47.5 mmol) is dissolved in MeOH (200 mL), treated slowly dropwise with thionyl chloride (32.3 mL, 442.9 mmol) at rt, then heated to reflux for 20 h. The mixture is concentrated to dryness and partitioned between CH2C12 (100 mL) and saturated NaHCO3 (50 mL). Not all of the residue is solubilized, so the mixture is filtered and the solid is washed with a small amount of CH2C12 and MeOH. The original filtrate and the organic washes are combined, concentrated to dryness, dissolved in 10% MeOH / CH2C12 (200 mL), diluted with water (50 mL) and the layers separated. The organics are washed with saturated NaHCO3 (2 x 50 mL), then water (50 mL), dried (Na2SO ) and concentrated to a tan solid. This solid is triturated with CH2CI2 (50 mL) and filtered. The two solids are combined to afford 9.4 g (70%) of methyl 3-hydroxy-4-iodobenzoate as a beige solid. HRMS (FAB) calcd for C8H7IO3 +Hι: 278.9520, found 278.9521.
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) / CHC13 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL< 58.4 mmol) is added and the mixture is heated to 50°C for 4 h. The mixture is diluted with CHC1 (60 mL), washed with 5% HCl (2 x 40 mL), dried (MgSO ) and concentrated to a brown paste (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc / hexane (1 L) followed by 15 % EtOAc / hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynylJbenzoate as a yellow solid. HRMS (FAB) calcd for d3Hι6O3SI +Hι: 249.0947, found 249.0947.
Methyl 3-hydroxy-4-[(frimethylsilyl)ethynylJbenzoate (540 mg, 2.17 mmole) is combined with 4 ml formic acid under nifrogen. The reaction is warmed to 80°C for 12 h, is cooled to rt, and the volatiles are removed in vacuo. The black residue is chromatographed over 25 g silica gel (230-400 mesh) eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concenfrated to provide 350 mg (83%) of methyl 4-acetyl-3-hydroxybenzoate as a pale yellow solid. 1H NMR (CDCI3) δ 2.70, 3.95, 7.54, 7.64, 7.82, 12.10 ppm.
Methyl 4-acetyl-3-hydroxybenzoate (350 mg, 1.8 mmole) is combined with 5 ml absolute EtOH. The solution is treated with hydroxylamine hydrochloride (125 mg, 1.8 mmole) dissolved in 0.9 ml 2N aqueous NaOH, and the reaction is stined overnight at rt. The volatiles are removed in vacuo and the residue is washed with H2O, collected, and dried to give 294 mg (78%) of methyl 3-hydroxy-4-[N- hydroxyethanimidoyljbenzoate as a tan solid. MS (El) m/z : 209 (M+).
Methyl 3-hydroxy-4-[N-hydroxyethanimidoylJbenzoate (250 mg, 1.19 mmole) is combined with triphenylphosphine (446 mg, 1.7 mmole) in 14 ml dry THF in a dry flask under nifrogen. The solution is treated slowly dropwise with N,N'- diethylazidodicarboxylate (268 μL, 1.7 mmole) in 10 ml dry THF. The reaction is stined 4 h at rt. The volatiles are removed in vacuo and the residue is chromatographed over 30 g silica gel (230-400 mesh) eluting with 10% EtOAc/hexane. The appropriate fractions are combined and concentrated to provide 125 mg (55%) of methyl 3 -methyl- l,2-benzisoxazole-6-carboxylate slightly contaminated (< 10%) with methyl 4-acetyl-3-hydroxybenzoate. !H NMR (CDC13) δ 2.64, 4.00, 7.70, 8.01, 8.25 ppm.
Methyl 3-methyl-l,2-benzisoxazole-6-carboxylate (170 mg, 0.89 mmole) is dissolved in 6 ml MeOH under nitrogen. The solution is treated with 2N aqueous NaOH (1 ml, 2 mmole) and the mixture is stined 4 h at rt. The volatiles are removed in vacuo and the residue is dissolved in 4 ml water. The pH of the solution is adjusted to 3 with 10% aqueous HCl, the white precipitate is collected, is washed with water, and is dried to give 144 mg (92%) of 3-methyl-l,2-benzisoxazole-6-carboxylic acid as a white solid. MS m/z (ESI): 176.2 (M-H)\
Intermediate F10: 3-Methyl-l,2-benzisoxazole-5-carboxylic acid
Intermediate F13 is obtained according to the methods discussed for preparing Intermediate F12 starting with 4-hydroxybenzoic acid.
Intermediate Fll: lH-indazole-6-carboxylic acid
To a stined solution of 3-amino-4-methylbenzoic acid (5.0 g, 33 mmol) in a mixture of water (50 mL) and concenfrated hydrochloric acid (15 mL) in an acetone- crushed ice bath is added a solution of sodium nitrite in water (12 mL) dropwise. The solution is stined for 10 min, followed by the addition of tert-butyl mercaptan (1.8 mL, 16 mmol). The mixture is stined for 1 h. The solid precipitate is filtered, washed with water and dried in vacuo to obtain 3.85 g (95%) of 3-[(E)-(tert- butylthio)diazenylJ-4-methylbenzoic acid as a tan solid: 1H NMR (400 MHz, DMSO- J6) δ 13.2, 7.8, 7.5, 7.3, 2.1, 1.6. To a stined solution of potassium tert-butoxide (8.1 g, 73 mmol) in DMSO
(30 mL) was added a solution of 3-[(E)-(te/'t-butylthio)diazenyl]-4-methylbenzoic acid (1.9 g, 7.3 mmol) at RT. The mixture was stined overnight, followed by the adition of ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was dicarded. The pH of the aqueous layer was adjusted to 4-5 with aqueous IN HCl. The aqueous layer was exfracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ), filtered and concentrated in vacuo to afford 800 mg (97%) of lH-indazole-6-carboxylic acid as a tan solid: !Η NMR (400 MHz, DMSO-^) δ 13.4, 13.0, 8.2, 8.1, 7.9, 7.7. Compounds of Formula I where W is (G) are made using the coupling procedures discussed herein and in US 20020049225A1 and US 20020042428A1, making non-critical changes to obtain compounds where Azabicyclo is other than I. The following intermediates to provide W of fonnula I are for exemplification only and are not intended to limit the scope of the present invention. Other intermediates within the scope of the present invention can be obtained using known procedures or by making slight modifications to known procedures.
It will be apparent to those skilled in the art that the requisite carboxylic acids can be synthesized by known procedures, or modification thereof, some of which are described herein. For example, 3-(pyrrolo[l,2-c]pyrimidine)carboxylic acid can be synthesized from the conesponding pyrrole-2-carboxaldehyde by reaction with an isocyanoacetate in the presence of base as described inJ. Org. Chem. 1999, 64, 7788 andJ Org. Chem. 1976, 41, 1482 or by methods described in Liebigs Ann. Chem. 1987, 491. Scheme 1G depicts this transformation.
Scheme 1G
Figure imgf000121_0001
The pynolo[l,2-a]pyrazine acid fragment can be prepared using the methods shown in Scheme 2G. The ester intermediate can be prepared using methods described in Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993, 49, 8139-46, whereby the requisite pyrrole-2-carboxaldehyde is reacted with aminoester diethylacetal to form the imine. The imine can then be cyclized under acidic conditions to afford the desired bicyclic core. The resulting ester can be hydrolyzed under typical hydrolysis procedures well known in the art to afford the requisite pynolo [ 1 ,2-a]pyrazine acids .
Scheme 2G
Figure imgf000121_0002
The pynole-2-carboxaldehydes can be obtained from commercial sources or can be synthesized by known procedures. For example, pynole-2-carboxaldehyde can be converted into 4-halo, 5-halo and 4,5-dihalopyrrole-2-carboxaldehydes as described in Bull. Soc. Chim. Fr. 1973, 351. See Examples 12-22. Alternatively, substituted pyrroles can be converted into pyrrole carboxaldehydes by Nilsmeier formylation using procedures well known in the art (see J. Het. Chem. 1991, 28, 2053, Synth. Commun. 1994, 24, 1389 ox Synthesis, 1995, 1480. Scheme 3G depicts these transfonnations.
Scheme 3G
ΗW- hhaallooggeennaattiioonn u , lκ|l ..- VViillssmmeeiieerr
:^ — ►- τ Η ^ 3 "
OΗCT OΗC-
R, G-1 - — ™ R, G-1
Νon-limiting examples of W when W is (G): Ethyl pyrrolo[ 1 ,2-cJpyrimidine-3-carboxylate:
Figure imgf000122_0001
A solution of pyrrole-2-carboxaldehyde (3.6g, 38. lmmol) in 40mL dry TΗF is added to ethyl isocyanoacetate (4.3g, 38. lmmol) and DBU (5.8g, 38.2mmol) in 60mL dry TΗF. After stirring at RT overnight, the reaction is neutralized with 10% AcOΗ.
The solvent is removed in vacuo. The residue is taken up in EtOAc/Η2O, the aqueous layer is extracted with EtOAc, dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography on silica gel eluting with 30-70% EtOAc/hexanes. The carboxylate is obtained (4.45g, 61%) as an off-white solid. ]H NMR (400MHz,
CDC13) δ 8.86, 8.24, 7.54, 7.01, 6.78, 4.45, 1.44.
The following compounds are made from the conesponding pynole-2- carboxaldehydes, making non-critical variations:
Ethyl 7-chloropyrrolo[l,2-c]pyrimidine-3-carboxylate. Yield 25% starting from 5- chloropynole-2-carboxaldehyde. 1H NMR (400MHz, CDC13) δ 8.86, 8.21, 6.91-6.89,
6.80-6.77, 4.50-4.43, 1.47-1.42.
Ethyl 6-chloropynOlo[l,2-cJpyrimidine-3-carboxylate. Yield 49% starting from 4- chloropyrrole-2-carboxaldehyde. 1H NMR (400MHz, CDC13) δ 8.76, 8.14, 7.51, 6.72,
4.49-4.42, 1.46-1.41. Ethyl 6-bromopyrrolo[l,2-c]pyrimidine-3 -carboxylate. Yield 9% starting from 4- bromopyrrole-2-carboxaldehyde. 1H NMR (400MHz, CDC13) δ 8.77, 8.15, 7.55, 6.79, 4.49-4.42, 1.46-1.41.
Pyrrolofl .2-c1pyrimidine-3-carboxylic acid hydrochloride:
Figure imgf000123_0001
Ethyl pynolo[l,2-c]pyrimidine-3-carboxylate (4.1g, 21.2mmol) is dissolved/suspended in lOOmL concentrated HCl. The mixture is heated under reflux.
After 4h, the reaction is cooled and the solvent is removed in vacuo. Absolute EtOH is added and the solvent is removed (twice) to afford a yellow-green solid. The solid is triturated with Et2O and dried to give 4.28g (100%) of pynolo[l,2-c]pyrimidine-3- carboxylic acid as the hydrochloride salt. The solid can be recrystallized from EtOH.
1H NMR (400MHz, DMSO) δ 9.24, 8.21, 7.90, 7.06, 6.85.
The following compounds are made from the conesponding ethyl pyrrolo[l,2- cJpyrimidine-3 -carboxylates, making non-critical variations :
7-Chloropyrrolo[l,2-c]pyrimidine-3-carboxylic acid hydrochloride. Yield 77%. 1H
NMR (400MHz, d6-DMSO) δ 9.3, 9.04, 8.25, 7.16-7.14, 6.96-6.94.
6-Chloropyrrolo[l,2-c]pyrimidine-3-carboxylic acid hydrochloride. Yield 95%. 1H
NMR (400MHz, d6-DMSO) δ 11.15, 9.14, 8.15, 8.04, 6.91. 6-Bromopyrrolo[l,2-c]pyrimidine-3-carboxylic acid hydrochloride. Yield 97%. 1H
NMR (400MHz, d6-DMSO) δ 10.2, 9.12, 8.15, 8.04, 6.96.
Imidazo[1.5-a1pyridine-7-carboxylic acid:
Methyl nicotinate 1 -oxide (Coperet, C; Adolfsson, H.; Khuong, T-A. V.; Yudin, A. K.; Sharpless, K. B. J. Org. Chem. 1998, 63, 1740-41.) (5.0 g, 32.2 mmol) and dimethylsulfate (3.2 ml, 33.2 mmol) are placed in a 100 ml flask and heated to 65- 70°C for 2 h. Upon cooling a salt precipitates. The resulting precipitate is dissolved in water (12 ml). An oxygen free solution of KCN (2.5 g, 38.7 mmol) in water (9.5 ml) is added dropwise to the mixture with vigorous stining at 0°C. After stining for 1 h at 0°C, the mixture is warmed to rt and stined overnight. The solution is extracted with CH2C12 (3 x 25 ml) and the combined organic layers are dried (NaSO4), filtered, and the solvent removed under vacuum. The resulting solid is purified by silica gel chromatography (EtOAc) to give a yellow solid (4.2 g, 25.9 mmol, 80%) for methyl 2- cyanoisonicotinate. MS (ESI+) for C8H6N2O2 m/z 163.0 (M+H)+.
To a solution of methyl 2-cyanoisonicotinate (4.22 g, 25.9 mmol) and 10 % palladium on charcoal (2.8 g, 2.6 mmol) in MeOH (400 ml) was added cone. HCl (7.5 ml). The mixture is hydrogenated at rt and balloon pressure, until no more hydrogen is consumed (about 2 h). The reaction mixture is filtered through a pad of celite and the solvent is removed in vacuum to give a yellow solid (4.5 g, 18.8 mmol, 73%) for methyl 2-(aminomethyl) isonicotinate. This compound is used without further purification. MS (ESI+) for C8Hι0N2O2 m/z 167.2 (M+H)+; HRMS (FAB) calcd for C8Hi0N2O2+H 167.0820, found 167.0821.
Procedure A:
A mixture of methyl 2-(aminomethyl) isonicotinate (4.3 g, 18.0 mmol) and acetic formic anhydride (which is prepared by heating to 50°C acetic anliydride (75.0 ml) and formic acid (65.0 ml) for 2 h) is stined at rt for 1 h. The reaction mixture is heated to 35°C with an oil bath for 1 h. The reaction mixture is cooled to 0°C in an ice-bath and neutralized with ammonium hydroxide at such a rate that the temperature did not rise above 5°C. The mixture is extracted with CH2C12 (3 x 200 ml) and the combined organic layers are dried (NaSO ), filtered, and the solvent removed under vacuum. The resulting solid is purified with DOWEX 50WX2-400 ion-exchange resin to give a yellow solid (3.2 g, 18.0 mmol, 100%) for methyl imidazo [1,2- a]pyridin-6-carboxylate. MS (ESI+) for C9H8N2O2 m/z 177.03 (M+H)+.
Procedure B:
Methyl imidazo [l,2-aJpyridin-6-carboxylate (3.2 g, 18.0 mmol) is dissolved in 3N HCl (200 ml) and heated under reflux for 3 h. The solvent is removed under vacuum and the resulting brown solid is recrystallized from H2O/EtOH/Et2O to afford a light brown solid (4.3 g, 21.6 mmol, 119%) for imidazo[l,5-aJpyridine-7-carboxylic acid. HRMS (FAB) calcd for C8H6N2O2+H 163.0508, found 163.0489.
Pyrrolofl -2-a1pyrazine-3-carboxylic acid hydrochloride: Procedure E: Pyrrole-2-carboxaldehyde (recrystallized from EtOAc/hexanes prior to use) (3.67 g, 38.6 mmol) is added to a solution of ethyl 3-ethoxy-O-ethylserinate (7.95 g, 38.6 mmol) in freshly distilled THF or CH2C12 (100 mL) in an oven dried 250 mL flask. 3 A activated molecular sieves (approximately 1/3 the volume of the reaction vessel) are added, and the resulting mixture is allowed to stir under nitrogen until the starting pynole-2-carboxaldehyde is consumed as determined by 1H NMR. The reaction mixture is filtered tlirough a pad of celite, and the solvent removed in vacuo to give an orange oil (9.59 g) for ethyl 3-ethoxy-O-ethyl-N-(lH-pynol-2- ylmethylene)serinate that is used without purification: MS (ESI+) for Cι4Η22N2O4 m/z 282.96 (M+H)+.
Procedure F:
To a hot (65°C) solution of TFA (44 mL, 510 mmol) and phosphorus oxychloride (39.0 g, 140 mmol) is added drop-wise a solution of ethyl 3-ethoxy-O- ethyl-N-(lH-pyrrol-2-ylmethylene)serinate (Dekhane, M; Potier, P; Dodd, R. Η.
Tetrahedron, 49, 1993, 8139-46.) (9.6 g, 28.0 mmol) in anhydrous 1,2-dichloroethane (200 mL). The black mixture is allowed to stir at 65°C for 18 h at which point it is cooled to rt and neutralized with sat. NaΗCO3 and solid NaHCO3 to pH ~ 9. The phases are separated and the basic phase extracted with EtOAc (4 x 100 mL). The organic phases are combined, washed with brine, dried (NaSO ), filtered, and concentrated to give a black oil that is purified with silica gel chromatography (35% EtO Ac/heptanes to 50% over several liters) to give a light brown solid for ethyl pyrrolo[l,2-a]pyrazine-3-carboxylate. Yield 24%. HRMS (FAB) calcd for Ci0HioN2O2+H 191.0820, found 191.0823. Pyrrolo[l,2-aJpyrazine-3-carboxylic acid hydrochloride is prepared from ethyl pyrrolo[l,2-a]pyrazine-3-carboxylate, using Procedure B to give a pale brown solid. Yield 90%. HRMS (FAB) calcd for C8H6O2N2+H 163.0508, found 163.0513,
Pyrazinofl,2-a1indole-3-carboxylic acid hydrocholoride: To a suspension of lithium aluminum hydride (10.6g, 264 mmol) in THF (200 mL) is added dropwise a solution of ethyl indole-2-carboxylate (50.0 g, 256 mmol) in THF (250 mL) over 25 minutes. After 3 h, water (10.6 mL) is carefully added, followed by 15% NaOH (10.6 mL), followed by additional portion of water (31.8 mL). The resulting suspension is dried (Na2SO ) and filtered through celite. After concentration under reduced pressure, the white solid (34.0 g) is crystallized from EtOAc/hexanes to give white needles for lH-indol-2-ylmethanol. Yield 83%. ΗRMS (FAB) calcd for C9Η9NO+Η 148.0762, found 148.0771. lH-hιdole-2-carbaldehyde is prepared according to Berccalli, E. M., et al, J.
Org. Chem. 2000, 65, 8924-32, and crystallized from EtOAc/hexanes to give a yellow/brown plates. Yield 81%. MS (ESI+) for C9Η7NO m/z 146.1 (M+H)+.
Ethyl 3-ethoxy-O-ethyl-N-(lH-indol-2-ylmethylene)serinate is prepared using Procedure E to give an orange oil. Yield 94%. MS (ESI+) for Ci8H24N2O4 m/z 333.8 (M+H)+.
Procedure G:
Ethyl 9H-beta-carboline-3-carboxylate and ethyl pyrazino[l,2-a]indole-3- carboxylate are prepared according to Dekhane, M., et al, Tetrahedron, 49, 1993, 8139-46, to give a dark colored solid that is purified with silica gel chromatography (20% to 75% EtOAc/hexanes as the eluent) to give the ethyl 9H-beta-carboline-3- carboxylate as a brown solid (yield 16%) and the ethyl pyrazino[l,2-a]indole-3- carboxylate as a brown soild (yield 35%). Ethyl 9H-beta-carboline-3-carboxylate; MS (ESI+) for Cι4Ηι2N2O2 m/z 241.10 (M+H)+; MS (ESI-) for Cι4Hι2N2O2 m/z 239.15 (M~H)\
Procedure H:
To a solution of ethyl pyrazino[l,2-aJindole-3-carboxylate (0.49 g, 2.0 mmol) in EtOH (30 mL) is added crushed potassium hydroxide (1.1 g, 20.0 mmol) followed by water (30 mL). The resulting dark colored solution is stined at rt for 40 min and then neutralized with cone. HCl to pH ~2. The acidic mixture is concentrated to dryness to afford pyrazino[l,2-a]indole-3-carboxylic acid hydrochloride. HRMS (FAB) calcd for Cι2H8N2O2+H 213.0664, found 213.0658.
Compounds of Fonnula I where W is (H) are made using the coupling procedures discussed herein, making non-critical changes. The following intermediates to provide formula I where W is (H) are for exemplification only and are not intended to limit the scope of the present invention. Other intermediates within the scope of the present invention can be obtained using known procedures or by making slight modifications thereof.
It will be apparent to those skilled in the art that the requisite carboxylic acids or carboxylic acid equivalents for when W is (H) can be obtained through synthesis via literature procedures or tlirough the slight modification thereof. For example, methods to prepare carboxylic acids or carboxylic acid equivalents starting from pyrroles or pyrazoles are known to one of ordinary skill in the art (see J. Org. Chem. 1987, 52, 2319, Tetrahedron Lett. 1999, 40, 2733 and Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic Synthesis", 3rd Edition, p. 549, New York:Wiley, (1999)). Several pyrroles and pyrazoles of the Formula W-H are commercially available or can be obtained by methods described in Synthesis 1997, 563, J. Heterocyclic Chem. 1993, 30, 865 , Heterocycles 1982, 19, 1223 andJ. Org. Chem. 1984, 49, 3239.
Example 1(H): N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-bromo-lH-ρyrazole-l- carboxamide hydrochloride:
Figure imgf000127_0001
HCl
A solution of 4-bromopyrazole (0.52g, 3.5mmol) in 30mL EtOAc is added to excess phosgene (lOmL, 20% solution in toluene) in EtOAc. After complete addition, the solution is refluxed for 1 h, cooled and concentrated in vacuo. EtOAc is added, and the mixture is concentrated again. The residue is treated with 20mL THF, (R)- (+)-3-aminoquinuclidine dihydrochloride (0.7 lg, 3.5mmol) and excess TEA (5. OmL, 68. lmmol). After 60h, IN NaOH solution is added. The mixture is extracted with CHC1 , dried (MgSO4), filtered and concenfrated. The residue is purified by flash chromatography (Biotage 40S, 90:9: 1 CHCl3/MeOH/NH4OH). Example 1 (H) is prepared and recrystallized from MeOH/EtOAc to afford 289 mg (25%) of a white solid. HRMS (FAB) calcd for CπHι5BrN4O+H 299.0508, found 299.0516.
Example 2(H): N-[(3R)-l-azabicyclo[2.2.2Joct-3-ylJ-4-iodo-lH-pyrazole-l- carboxamide hydrochloride:
Figure imgf000128_0001
Phenyl chloroformate (0.75mL, 6. Ommol) is added dropwise to a solution of 4- iodopyrazole (1.05g, 5.4mmol) and TEA (0.9mL, 6.5mmol) in 15mL CH2C12. The reaction is stined at RT. After 60h, water is added. The mixture is extracted with CH2C12, dried (MgSO4), filtered and concenfrated. Hexane is added and the solvent is removed in vacuo. A white solid forms on standing to provide 1.6g (95%) of phenyl 4-iodo-lH-pyrazole-l -carboxylate. MS (El) m/z 315.1 (M+).
Phenyl 4-iodo-lH-pyrazole-l -carboxylate (1.6g, 5.2mmol) and (R)-(+)-3- aminoquinuclidine dihydrochloride (l.Og, 5.2mmol) are suspended in lOmL DMF. DIEA (2.7mL, 15.5mmol) is added dropwise. After 36 h, the solvent is removed and the residue is taken up in IN NaOH and CHC13. The aqueous layer is extracted with CHC13, dried (MgSO ), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH) to provide 1.66g (93%) of the product as a white solid. A portion of the material is converted into the hydrochloride salt and recrystallized from MeOH/EtOAc. HRMS (FAB) calcd for CnHι5IN4O+H 347.0370, found 347.0357.
Example 3(H): N-r(3R)-l-azabicvclor2.2.21oct-3-vll-4-(2-chloror)henvn-lH- pyrazole- 1 -carboxamide hydrochloride:
Figure imgf000128_0002
Hydrazine hydrate (0.55mL, 11.3mmol) is added to a suspension of 2- chlorophenylmalondialdehyde dissolved in 20mL EtOH. The mixture is heated under reflux for 3 min, then allowed to stir at RT overnight. The solvent is removed in vacuo to provide 4-(2-clιlorophenyl)-lH-pyrazole as a yellow solid. MS (El) m/z 177.0 (M").
4-Nitrophenyl chloroformate (2.3g, 11.5mmol) and 4-(2-chlorophenyl)-lH- pyrazole (2.0g, 1 l.Ommol) are dissolved in 30mL CH2C1 and cooled to 0°C. TEA (1.7mL, 12. Ommol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25g) and TEA are added. After lh, water is added. The mixture is extracted with CH2C1 , dried (MgSO ), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-lH-pyrazole-l- carboxylate. A portion of 4-nitrophenyl 4-(2-chlorophenyl)- 1 H-pyrazole- 1 -carboxylate
(0.34g, l.Ommol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (0.22g, 1. lmmol) are suspended in 5mL DMF. TEA (0.4mL, 3. Ommol) is added dropwise. After 18 h, IN NaOH is added, and the solvent is removed under reduced pressure. The residue is taken up in IN NaOH and CHC13. The aqueous layer is extracted with CHC13, dried (MgSO ), filtered and concenfrated. The residue is purified by chromatography (Biotage 40S, 90:9:1
Figure imgf000129_0001
The hydrochloride salt is prepared and recrystallized from MeOH/EtOAc to provide 102 mg (28%) of the product. HRMS (FAB) calcd for Cι7Hι9ClN4O+H 331.1325, found 331.1312.
Example 4(H): N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-4-iodo-lH-pyrazole-l- carboxamide:
Figure imgf000129_0002
A solution of 4-iodopyrazole (1.05 g, 5.4 mmol) in 15 mL CH C1 is treated with TEA (0.90 mL, 6.5 mmol) and phenylchloroformate (0.75 ml, 6.0 mmol). The mixture is stined for 5h and treated with H2O (1 mL). The aqueous layer is discarded and the organic dried (MgSO4). The mixture is filtered, and evaporated to a yellow oil which solidifies upon evaporation from hexane. A portion of this solid (0.628 g, 2.0 mmol) is added to DMF (10 ml) containing (3R,5R)-l-azabicyclo[3.2.1Joctan-3-amine dihydrochloride (0.398 g, 2.0 mmol). Diisopropylethyl amine (1.1 mL, 6.0 mmol) is added and the mixture becomes nearly homogeneous. The mixture is extracted between EtOAc and H2O. The organic layer is washed with H2O (3X), brine, dried (MgSO4), and the mixture is evaporated. The resulting material is taken up in hot EtOAc, filtered through celite, and allowed to stand at RT. The resulting solid is collected and dried to afford Example 4(H) (0.142 g, 20 %) as a white solid: HRMS (ESI) calcd for CnHι5Ν4OI (MH+) 347.0370, found 347.0370. Anal. Calcd for CnHi5IN4O: C, 38.17; H, 4.37; N, 16.18. Found: C, 38.43; H, 4.42; N, 16.11. Materials and Methods for identifying binding constants: Membrane Preparation. Male Sprague-Dawley rats (300-350g) are sacrificed by decapitation and the brains (whole brain minus cerebellum) are dissected quickly, weighed and homogenized in 9 volumes/g wet weight of ice-cold 0.32 M sucrose using a rotating pestle on setting 50 (10 up and down strokes). The homogenate is centrifuged at 1,000 x g for 10 minutes at 4 °C. The supernatant is collected and centrifuged at 20,000 x g for 20 minutes at 4 °C. The resulting pellet is resuspended to a protein concentration of 1 -8 mg/mL. Aliquots of 5 mL homogenate are frozen at -80 °C until needed for the assay. On the day of the assay, aliquots are thawed at room temperature and diluted with Kreb's - 20 mM Hepes buffer pH 7.0 (at room temperature) containing 4.16 mM NaHCO3, 0.44 mM KH2PO4, 127 mM NaCl, 5.36 mM KC1, 1.26 mM CaCl2, and 0.98 mM MgCl2, so that 25 - 150 μg protein are added per test tube. Proteins are determined by the Bradford method (Bradford, M.M., Anal. Biochem., 72, 248-254, 1976) using bovine serum albumin as the standard. Binding Assay. For saturation studies, 0.4 mL homogenate are added to test tubes containing buffer and various concenfrations of radioligand, and are incubated in a final volume of 0.5 mL for 1 hour at 25 °C. Nonspecific binding was determined in tissues incubated in parallel in the presence of 0.05 ml MLA for a final concentration of 1 μM MLA, added before the radioligand. hi competition studies, drugs are added in increasing concentrations to the test tubes before addition of 0.05 ml [3H]-MLA for a final concentration of 3.0 to 4.0 nM [3H]-MLA. The incubations are terminated by rapid vacuum filtration through Whatman GF/B glass filter paper mounted on a 48 well Brandel cell harvester. Filters are pre-soaked in 50 mM Tris HCl pH 7.0 - 0.05 % polyethylenimine. The filters are rapidly washed two times with 5 mL aliquots of cold 0.9% saline and then counted for radioactivity by liquid scintillation spectrometry.
Data Analysis, hi competition binding studies, the inhibition constant (Ki) was calculated from the concentration dependent inhibition of [3HJ-MLA binding obtained from non-linear regression fitting program according to the Cheng-Prusoff equation (Cheng, Y.C. and Prussoff, W.H., Biochem. Pharmacol. , 22, p. 3099-3108, 1973). Hill coefficients were obtained using non-linear regression (GraphPad Prism sigmoidal dose-response with variable slope). It will be apparent to those skilled in the art that the requisite carboxylic acids or carboxylic acid equivalents for when W is (H) can be obtained through synthesis via literature procedures or through the slight modification thereof. For example, methods to prepare carboxylic acids or carboxylic acid equivalents starting from pynoles or pyrazoles are known to one of ordinary skill in the art (see J. Org. Chem. 1987, 52, 2319, Tetrahedron Lett. 1999, 40, 2733 and Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic Synthesis", 3rd Edition, p. 549, New York: Wiley, (1999)). Several pyrroles and pyrazoles of the Fonnula W-H are commercially available or can be obtained by methods described in Synthesis 1997, 563, J. Heterocyclic Chem. 1993, 30, 865, Heterocycles 1982, 19, 1223 andJ Org. Chem. 1984, 49, 3239.
Blood-Brain Barrier Penetration
Pharmacokinetics of the compounds of formula I can be evaluated in mice to determine the ability of each compound to penetrate the blood-brain barrier. Each mouse receives a single intravenous administration at 5 mg/kg. Blood samples are collected by serial sacrifice at 5 min (IN only), 0.5, 1, 2, 4, and 8 h after dosing with two mice per collection time. Blood was placed into tubes containing heparin and centrifuged for plasma. Brain samples were also collected at 0.5 and 1 h increments from the same mouse used for blood collection. Plasma and brain samples were analyzed for drug concentrations using a LC-MS/MMS method. Pharmacokinetics (clearance, volume of distribution, and half-life) were evaluated from the plasma concentration-time data (See Gibaldi and Perrier in Pharmacokinetics, Nol I, 2nd ed, New York: Marcel Dekker, 1982). Compounds having a large volume of distribution will have good distribution into the body tissues. Comparison of the drug concentration in brain and plasma (brain/plasma ratio) provides the direct information of brain penetration. Higher numbers refer to higher brain penetration. Conclusion
Both combinations of two, three and all four types of drugs are described and claimed herein; however a combination of two drugs where one is a full agonist to an al Nicotinic Acetylcholine Receptor (nAChR) otherwise lαiown as an α7 nAChR full agonist, examples provided above, are prefened. Where three drugs are used in combination it is prefened that one be an al nAChR full agonist. The combinations of drugs may be administered either at the same or different times, either in the same or different form, hi one embodiment they may be given a month apart or they may be given in a co-administration where the two or three drugs are given on or about the same time in the same manner. Here the combination refers to administration such that the patients blood contains the two, three or four drugs at the same time at some point during freatment.
Also disclosed are specific administrations where the two or three drugs must be provided to the patient at about the same time, that is within a week and more preferably on the same day.

Claims

Claims:
1. A composition comprising an effective amount of an alpha 7 nAChR full agonist and at least one of an effective amount of a beta secretase inhibitor, effective amount of an acetylcholineesterase inhibitor, and an effective amount of a gamma secretase inhibitor.
2. The composition of claim 1, wherein alpha 7 nAChR full agonist is a compound of Formula I:
Azabicyclo-N(Rι)-C(=X)-W Formula I wherein Azabicyclo is
Figure imgf000133_0001
VII wherein X is O, or S;
Ro is H, lower alkyl, substituted lower alkyl, or lower haloalkyl;
Each Ri is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
Each R2 is independently F, Cl, Br, I, alkyl, substituted alkyl, haloalkyl, cycloalkyl, aryl, or R2 is absent provided that kι_2, kι-6, k , k5, k6, or k7 is 0; kι-2 is 0 or 1 ; kι_6 is 0 or 1, provided that the sum of kι-2 and kι-6 is one; k2 is 0 or 1; k5 is 0, 1, or 2; k6 is 0, 1, or 2; k7 is 0 or 1; R2-3 is H, F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl;
Each R3 is independently H, alkyl, or substituted alkyl;
R4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, Cl, Br, I, -OH, -CN, -NH2, -NH(alkyl), or -N(alkyl)2; R5 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of -O-, =N-, -N(Rιo)-, and -S-, and having 0-1 substituent selected from R9 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R5 is 9-membered fused- ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula
Figure imgf000134_0001
wherein Li is O, S, or NRio,
Figure imgf000134_0002
wherein L is CR12 or N, L2 and L3 are independently selected from CRι2, C(Rι2)2, O, S, N, or NRio, provided that both L2 and L3 are not simultaneously O, simultaneously S, or simultaneously O and S, or
Figure imgf000134_0003
wherein L is CRι2 or N, and L2 and L3 are independently selected from CRι , O, S, N, or NRio, and each 9-membered fused-ring moiety having 0-1 substituent selected from R9 and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, wherein the R5 moiety attaches to other substituents as defined in formula I at any position as valency allows;
R6 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from =N- and having 0-1 substituent selected from R9 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R6 is 10- membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from =N-, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R and 0-3 substituent(s) independently selected from F, Cl, Br, or I, wherein the R6 moiety attaches to other substituents as defined in formula I at any position as valency allows;
R7 is alkyl, substituted alkyl, haloalkyl, -ORn, -CN, -NO2, -N(R8) ; Each R8 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rι3, cycloalkyl substituted with 1 substituent selected from Rι3, heterocycloalkyl substituted with 1 substituent selected from Rι3, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl; R is alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, -ORi4, -SRM, -N(RM)2, -C(O)Rι4, -C(O)N(Rι4)2, -CN, -NRι4C(O)RM, -S(O)2N(Rι4)2, -NR14S(O)2Rι4, -NO2, alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or Rι3, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or Rι , or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or Rι3;
Rio is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R7 and further having 0-3 substituents independently selected from F, Cl, Br, or I; Each Rn is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
Each Rι2 is independently H, F, Cl, Br, I, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -CN, -NO2, -ORι4, -SRJ4, -N(Rι )2, -C(O)Ri4, -C(O)N(Rι4)2, -NRι4C(O)R14, -S(O)2N(RM)2, -NRι4S(O)2RR14, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that where valency allows the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -ORι , -SRι4, -N(Rι4)2, -C(O)Ri4, -NO2, -C(O)N(Rι4)2, -CN, -NRι4C(O)Rι4, -S(O)2N(R14)2, or -NRι4S(O)2Rι4, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I; R13 is -OR14, -SRi4, -N(Rι4)2, -C(O)RM, -C(O)N(Rι4)2, -CN, -CF3, -NRι4C(O)Rι4, -S(O)2N(Rι4)2, -NRMS(O)2Rι4, or -NO2;
Each Rι4 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
wherein W is (A):
Figure imgf000136_0001
(A-1 ) (A-2) wherein RA-ιa is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, -R5, R6, -ORA-3, -ORA--., -SRA-3, F, Cl, Br, I, -N(RA-3)2, -N(RA-5)2, -C(O)RA-3, -C(O)RA-5, -CN, -C(O)N(RA-3)2, -C(O)N(RA-6)2, -NRA-3C(O)RA.3, -S(O)RA-3, -OS(O)2RA-3, -NRA-3S(O)2RA-3, -NO2, and -N(H)C(O)N(H)RA-3; RA-ib is -O-RA-3, -S-R -3, -S(O)-RA.3, -C(O)-RA-7, and alkyl substituted on the ω carbon with RA-7;
Each RA-3 is independently selected from H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl; RA-4 is selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, or substituted heterocycloalkyl;
Each R -5 is independently selected from cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl; Each RA-6 is independently selected from alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R , R6, phenyl, or substituted phenyl;
RA- is selected from aryl, R5, or R6;
wherein W is (B):
Figure imgf000137_0001
wherein B° is -O-, -S-, or -N(RB-o)S
1
B and B are independently selected from =N-, or =C(RB-I)-; B3 is =N-, or =CH-, provided that when both B1 and B2 are =C(RB-ι)- and B3 is =CH-, only one =C(RB-ι)- can be =CH-, and further provided that when B° is -O-, B2 is =C(RB-i)- and B3 is =C(H)-, B1 cannot be =N-,
RB-O is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, limited substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, or aryl, and provided that when B is (B-2) and B is =N- and B is N(RB-O), RB-O cannot be phenyl or substituted phenyl;
RB-I is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limited substituted alkyl, limited substituted alkenyl, limited substituted alkynyl, aryl, -ORB-2, -ORB-3, -SRB-2, -SRB-3, F, Cl, Br, I, -N(RB- )2, -N(RB-3)2, -C(O)RB-2, -C(O)RB-3, -C(O)N(RB-2)2, -C(O)N(RB-3)2, -CN, -NRB-2C(O)RB-4, -S(O)2N(RB-2)2, -OS(O)2RB-4, -S(O)2RB-2, -S(O)2RB-3, -NRB-2S(O)2RB-2, -N(H)C(O)N(H)RB-2, -NO2, R5, and R6;
Each RB-2 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl;
Each RB-3 is independently H, alkyl, haloalkyl, limited substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl; RB-4 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
wherein W is (C):
(C) is a six-membered heterocyclic ring system having 1-2 nifrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nifrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six- six-fused-ring system, and further having 1-2 substitutents independently selected
Each Rc-i is independently H, F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, substituted phenyl, -NO2, -CN, -ORc_2, -SRC-2, -SORc. , -SO2Rc-2, -NRc-2C(O)Rc-3, -NRc-2C(O)Rc-2, -NRC-2C(O)Rc- , -N(RC-2)2, -C(O)RC-2. -C(O)2RC-2, -C(O)N(Rc-2)2, -SCN, -NRc-2C(O)Rc-2, -S(O)N(RC-2)2, -S(O)2N(RC-2)2, -NRC- S(O)2Rc-2, R5, or R6;
Each Rc-2 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rc-5, cycloalkyl substituted with 1 substituent selected from Rc-5, heterocycloalkyl substituted with 1 substituent selected from Rc-5, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
Each Rc-3 is independently H, alkyl, or substituted alkyl;
Rc-4 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, Cl, Br, I, -OH, -CN, -NH2, -NH(alkyl), or -N(alkyl)2;
Rc-5 is -CN, -CF3, -NO2, -ORC-6, -SRC-6, -N(Rc-6)2, -C(O)Rc.6, -SORc-6, -SO2RRc-6, -C(O)N(Rc-6)2, -NRc-6C(O)Rc-6, -S(O)2N(Rc-6)2, or -NRc-6S(O)2Rc-6;
Each Rc-6 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
wherein W is (D):
Figure imgf000138_0001
provided that the bond between the -C(=X)- group and the W group may be attached at any available carbon atom within the D group as provided in RD_ι, RD-3, and RD-4; D°, D1, D2, and D3 are N or C(RD-ι) provided that up to one of D°, D1, D2, or D3 is N and the others are C(RD-I), further provided that when the core molecule is attached at D2 and D° or D1 is N, D3 is C(H), and further provided that there is only one attachment to the core molecule;
D4— D5— D6 is selected from N(RD-2)-C(RD.3)=C(RD-3), N=C(RD-3)-C(RD-4)2, C(RD.3)=€(RD-3)-N(RD-2), C(RD-3)2-N(RD-2)-C(RD-3)2, C(RD-4)2-C(RD-3)=N, N(RD.2)-C(RD-3)2-C(RD-3)2, C(RD.3)2-C(RD-3)2-N(RD-2), O-C(RD-3)=C(RD-3),
O-C(RD.3)2-C(RD-3)2, C(RD-3)2-O-C(RD-3)2, C(RD-3)=C(RD-3)-O, C(RD-3)2-C(RD.3)2-O, S-C(RD-3)=C(RD.3), S-C(RD-3)2-C(RD-3)2, C(RD.3)2-S-C(RD-3)2, C(RD-3)=C(RD-3)-S, or C(RD-3)2-C(RD_3)2-S; provided that when C(X) is attached to W at D2 and D6 is O, N(Rp- ), or S, D4— D5 is not CH=CH; and further provided that when C(X) is attached to W at D2 and D4 is O, N(RD-2), or S, D5— D6 is not CH=CH;
Each RD-ι is independently H, F, Br, I, Cl, -CN, -CF3, -ORD.5, -SRD-5, -N(RD-5)2, or a bond to -C(X)- provided that only one of RD-I, RD-3, and RD-4 is said bond;
Each RD-2 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, or R6;
Each RD-3 is independently H, F, Br, Cl, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORD-ιo, -C(O)N(RD-n)2, -NRD-ι0CORD-12, -N(RD-ι0)2, -SRD-ι0, -S(O)2RD-ιo, -C(O)RD-I2> -CO2RD-IO, aryl, R5, R6, a bond to -C(X)- provided that only one of RD-ι, RD-3, and RD-4 is said bond; Each RD-4 is independently H, F, Br, Cl, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORD-ιo, -C(O)N(RD-ii)2, -NRD-ιoCORD-ι2, -N(RD-n)2, -SRD-ι0, -CO2RD-ι0, aryl, R5, R6, a bond to -C(X)- provided that only one of RD-ι, RD-3, and Ro- is said bond; Each Ro-5 is independently H, C1-3 alkyl, or C2.4 alkenyl;
D7 is O, S, or N(RD-2);
D8 and D9 are C(Ro-ι), provided that when the molecule is attached to the phenyl moiety at D9, D8 is CH; Each RD-ιo is H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
Each RD-ιι is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rι3, cycloalkyl substituted with 1 substituent selected from Rι3, heterocycloalkyl substituted with 1 substituent selected from R13, haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
RD-i2 is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
wherein W is (E):
Figure imgf000140_0001
E° is CH or N;
RE-O is H, F, Cl, Br, I, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, R5, R6, -ORE-3, -ORE- , -SRE-3, -SRE-5, -N(RE-3)2, -NRE-3RE-6, -N(RE.6)2, -C(O)RE-3, -CN, -C(O)N(RE.3)2, -NRE-3C(O)RE-3, -S(O)RE-3, -S(O)RE-5, -OS(O)2RE-3, -NRE-3S(O)2RE-3, -NO2, or -N(H)C(O)N(H)RE-3; E1 is O, CRE-ι-ι, or C(RE-ι-ι)2, provided that when E1 is CRE-I-I, one RE-ι is a bond to CRB-I-1, and further provided that at least one of E1 or E2 is O;
Each RE-I-I is independently H, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -ORE, or -N(RE)2, provided that at least one RE-ι-ι is H when E1 is C(RE_ι-ι)2; Each RE_ι is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E1 provided that E1 is CRE-ι-ι;
E2 is O, CRE- -2, or C(RE-2-2)2, provided that when E2 is CRE-2-2, one RE-2 is a bond to CRE-2-2, and further provided that at least one of E1 or E2 is O; Each RE-2-2 is independently H, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -ORE, or -N(RE)2, provided that at least one RE-2-2 is H when E2 is C(RE.2-2)2;
Each RE-2 is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E2 provided that E2 is CRE. -2;
Each RE is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
Each RE-3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, Cl, Br, or I or substituted phenyl;
RE- is H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or substituted phenyl;
Each RE-5 is independently H, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, or R6;
Each RE-6 is independently alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R5, R6, phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, Cl, Br, or i;
wherein W is (F):
Figure imgf000141_0001
(F-1) (F-2)
F° is C(H) wherein F1— F2— F3 is selected from O-C(RF.2)=N,
O-C(RF-3)(RF-2)-N(RF-4), O-C(RF.3)(RF.2)-S, O-N=C(RF-3), O-C(RF-2)(RF.3)-O,
S-C(RF.2)=N, S-C(RF-3)(RF.2)-N(RF-4), S-N=C(RF-3), N=C(RF-2)-O, N=C(RF-2)-S, N=C(RF-2)-N(RF-4), N(RF-4)-N=C(RF-3), N(RF-4)-C(RF-3)(RF-2)-O, N(RF-4)-C(RF-3)(RF-2)-S, N(RF-4)-C(RF,3)(RF-2)-N(RF-4), C(RF-3)2-O-N(RF-4), C(RF-3)2-N(RF-4)-O, C(RF.3)2-N(RF.4)-S, C(RF-3)=N-O, C(RF-3)=N-S, C(RF.3)=N-N(RF-4), or C(RF-3)2-C(RF-2)(RF-3)-C(RF-3)2;
F° is N wherein F1 — F2 — F3 is selected from O-C(RF-2)=N, O-C(RF-3)(RF-2)-N(RF-4), O-C(RF-3)(RF-2)-S, O-N=C(RF-3) O-C(RF-2)(RF-3)-O, S-C(RF-2)=N, S-C(RF-3)(RF-2)-N(RF-4), S-N=C(RF.3), N=C(RF-2)-O, N= (RF-2)-S, N=C(RF-2)-N(RF-4), N(RF-4)-N=C(RF-3), N(RF-4)-C(RF.3)(RF.2)-O, N(RF-4)-C(RF.3)(RF-2)-S, N(RF.4)-C(RF-3)(RF.2)-N(RF-4), C(RF-3)2-O-N(RF-4), C(RF-3)2-N(RF-4)-O, C(RF.3)2-N(RF-4)-S, C(RF-3)=N-O, C(RF-3)=N-S, C(RF-3)=N-N(RF-4), C(RF-3)=C(RF-2)-C(RF-3)2, or C(RF-3)2-C(RF-2)(RF-3)-C(RF-3)2;
F4 is N(RF-7), O, or S;
RF-ι is H, F, Cl, Br, I, -CN, -CF3, -ORF-8, -SRF-8, or -N(RF.8)2;
RF-2 is H, F, alkyl, haloalkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R5, R6, -N(RF- )-aryl, -N(RF- )-substituted phenyl, -N(RF_4)-substituted naphthyl, -O-substituted phenyl, -O-substituted naphthyl, -S-substituted phenyl, -S-substituted naphthyl, or alkyl substituted on the ω carbon with RF-9;
RF-3 is H, F, Br, Cl, I, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, -CN, -NO2, -ORF-8,
-C(O)N(RF-8)2, -NHRF-8, -NRF-8CORF-8, -N(RF-8)2, -SRF-8, -C(O)RF-8, -CO2RF-8, aryl, R5, or R6;
RF-4 is H, or alkyl;
RF-7 is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, Cl, Br, or I;
RF-8 is H, alkyl, substituted alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;
RF-9 is aryl, R5, or R6;
wherein W is (G):
Figure imgf000143_0001
G1 is N or CH;
Each G2 is N or C(RG-I), provided that no more than one G2 N; Each RG-I is independently H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, haloalkenyl, alkynyl, substituted alkynyl, haloalkynyl, -CN, -NO2, F, Br, Cl, I, -C(O)N(RG-3)2, -N(RG-3)2, -SRG-6, -S(O)2RG-6, -ORG-6, -C(O)RG-6, -CO2RG-6, aryl, R5, R6, or two RG_ι on adjacent carbon atoms may combine for W to be a 6-5-6 fused-tricyclic-heteroaromatic-ring system optionally substituted on the newly formed ring where valency allows with 1-2 substitutents independently selected from F, Cl, Br, I, and RG-2;
RG_2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORG-8, -SRG-8, -S(O)2RG.8, -S(O)RG-8, -OS(O)2RG-8, -N(RG-8)2, -C(O)RG-8, -C(S)RG-8, -C(O)ORG-8, -CN, -C(O)N(RG.8)2, -NRG-8C(O)RG.8, -S(O)2N(RG-8)2, -NRG-8S(O)2RG.8, -NO2, -N(RG-8)C(O)N(RG.8)2, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, phenyl having 0-4 substituents independently selected from F, Cl, Br, I and RG-7, naphthyl, or naphthyl having 0-4 substituents independently selected from F, Cl, Br, I, or RG-7; provided that whenG adjacent to the bridge N is C(RG-ι) and the other G are
CH, that RG-! is other than H, F, Cl, I, alkyl, substituted alkyl or alkynyl;
Each RG-3 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from RG-4, cycloalkyl substituted with 1 substituent selected from RG- , heterocycloalkyl substituted with 1 substituent selected from RG- , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
RG-4 is -ORG-5, -SRG-5, -N(RG-5)2, -C(O)RG.5, -SORG-5, -SO2RG-5, -C(O)N(RG-5)2, -CN, -CF3, -NRG.5C(O)RG-5, -S(O)2N(RG-5)2, -NRG-5S(O)2RG-5, or -NO2; Each RG-5 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl; RG-6 is H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 0-4 substituents independently selected from F, Cl, Br, I, and RG- ;
RG.7 is alkyl, substituted alkyl, haloalkyl, -ORG-5, -CN, -NO2, -N(RG-3)2; Each RG.8 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or RG-7;
whereinW is (H)
Figure imgf000144_0001
H' is N or CH;
Each RH-ι is independently F, Cl, Br, I, -CN, -NO2, alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam heterocyclcoalkyl, aryl, R5, R6, -OR8, -SR8, -SOR8, -SO2R8, -SCN, -S(O)N(R8)2, -S(O)2N(R8)2, -C(O)R8, -C(O)2R8, -C(O)N(R8)2, C(R8)=N-OR8, -NC(O)R5, -NC(O)RH-3, -NC(O)R6, -N(R8)2, -NR8C(O)R8, -NR8S(O)2R8, or two RH-ι on adjacent carbon atoms may fuse to form a 6-membered ring to give a 5-6 fused, bicyclic moiety where the 6-membered ring is optionally substituted with 1-3 substitutents selected from RH-2;
Figure imgf000144_0002
RH-2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORH-3, -SRH-3,
-S(O)2RH-3, -S(O)RH- , -OS(O)2RH-3, -N(RH-3)2, -C(O)RH-3, -C(S)RH.3, -C(O)ORH.3, -CN, -C(O)N(RH-3)2, -NRH-3C(O)RH_3, -S(O)2N(RH-3)2, -NRH-3S(O)2RH.3, -NO2, -N(RH-3)C(O)N(RH-3)2, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, phenyl having 0-4 substituents independently selected from F, Cl, Br, I and R7, naphthyl, naphthyl having 0-4 substituents independently selected from F, Cl, Br, I, or R7, or two RH-2 on adjacent carbon atoms may combine to form a tlτree-ring-fused-5- 6-6 system optionally substituted with up to 3 substituents independently selected from Br, Cl, F, I, -CN, -NO2, -CF3, -N(RH-3)2, -N(RH-3)C(O)RH-3, alkyl, alkenyl, and alkynyl; Each RH-3 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4 independently selected from F, Cl, Br, I, or R7; or phannaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof.
3. The composition of claim 2, wherein the agonist is
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide;
N- [(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] dibenzo [b, d] thiophene-2-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]isoquinoline-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzodioxole-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methylfiiro[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]isoquinoline-3-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-methylfuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzoxazole-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methyl-l,3-benzoxazole-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]thieno[2,3-c]pyridine-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]thieno[3,2-c]pyridine-6-carboxamide;
N-[(l S,2R,4R)-7-azabicyclo[2.2.1 ]hept-2-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethylfuro[2,3-c]pyridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-isopropylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]thieno[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6-carboxamide; 5 - { [(2R)-7-azoniabicyclo [2.2.1 ]hept-2-ylamino] carbonyl } -3 -ethylfuro [2,3 -cjpyridin-
6-ium dichloride;
5- { [(2R)-7-azoniabicyclo [2.2.1 ]hept-2-ylamino] carbonyl } -3 -isopropylfuro [2,3 - c]pyιidin-6-ium dichloride; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-l-azabicyclo[2.2.2]oct-3-yl[l]benzothieno[3,2-c]pyridine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzothiazole-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-cMorofuro[2,3-c]pyridine-5-carboxamide;
N-l-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pvridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,4-c]pyridine-6-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-3-methylfuro[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-3-methylfuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,3-dihydro-l-benzofuran-5-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]thieno[2,3-c]pyridine-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-6-carboxamide;
N-[(3R,4S)- 1 -azabicyclo[2.2.1 ]hept-3-yl]thieno[3,2-c]pyridine-6-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-ethylfuro[2,3-c]pyridine-5-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-isopropylfuro[2,3-c]pyridine-5- carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-chlorofuro[2,3-c]pyridine-5- carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]3-chlorofuro[2,3-c]pyridine-5-carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-4-chlorobenzamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]thieno[3,4-c]pyridine-6-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]dibenzo[b,d]thiophene-2-carboxamide;
N-[(3R,4S)- 1 -azabicyclo [2.2.1 ]hept-3-yl]- 1 -benzofuran-5 -carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l]benzothieno[2,3-c]pyridine-3-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl][l]benzothieno[2,3-c]pyridine-3- carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-l-benzofuran-5-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]dibenzo[b,d]furan-2-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-l-benzofuran-5-carboxamide; N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-3-bromofuro[2,3-c]pyridine-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-bromofuro[2,3-c]pyridine-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-2-naphthamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]pvnolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]thieno[2,3-c]pyridine-5-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]tbieno[3,2-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-lH-indole-6-carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]thieno[2,3-c]pyridine-5- carboxamide;
3-methyl-N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide;
N-[(2S,3R)-2-methyl- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzofuran-5-carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6- carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]pynolo[l,2-c]pyrimidine-3- carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzothiazole-6-carboxamide; N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]pynolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l-benzothiophene-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]pyrrolo[l,2-c]pyrimidine-3-carboxamide;
N-[(3R,4S)- 1 -azabicyclo[2.2.1 ]hept-3-yl]pynolo[ 1 ,2-c]pyrimidine-3-carboxamide;
N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-3-bromofuro[2,3-c]pyridine-5-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-l,3-benzodioxole-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-bromo-l-benzofuran-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-bromo-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-bromothieno[2,3-c]pyridine-5-carboxamide; N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-bromothieno[2,3-c]pyridine-5- carboxamide;
N-[(3R,4S)- 1 -azabicyclo[2.2.1 ]hept-3-yl]-l -benzothiophene-5-carboxamide;
N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-methyl-l-benzofuran-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-methyl-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methyl-l-benzofuran-6-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-l-benzofuran-6-carboxamide;
N- [(2S , 3R)-2-methyl- 1 -azabicyclo [2.2.2] oct-3 -yl] - 1 -benzofuran-6-carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-l-benzothiophene-5-carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]- 1 -benzothiophene-6-carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]pyrrolo[ 1 ,2-a]pyrazine-3-carboxamide;
N-[(3R,4S)-1 -azabicyclo[2.2.1 ]hept-3-yl]-l -benzothiophene-6-carboxamide;
N- [(3R)- 1 -azabicyclo[2.2.2] oct-3-yl] - 1 -methyl- 1 H-indole-6-carboxamide; N-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-l-benzofuran-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-l-benzofuran-5-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-isopropyl-l-benzofuran-5- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethvnylfuro[2,3-c]pyridine-5-carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-lH-indazole-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-methyl-l-benzofuran-5-carboxamide;
N- [( 1 S ,2R,4R)-7-azabicyclo [2.2.1 ]hept-2-yl] -2-methyl- 1 -benzofuran-5 -carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]pyrazino[l,2-a]indole-3-carboxamide;
3-bromo-N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]pynolo[l,2-a]pyrazine-3-carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-7-methoxy-2-naphthamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]pynolo[l,2-a]pyrazine-3-carboxamide;
N-[(3R,5R)-l-azabicyclo[3.2.1]oct-3-yl]-l,3-benzothiazole-6-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl]-3-bromo-l-benzofuran-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l]benzofuro[2,3-c]pyridine-3-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl][l]benzofuro[2,3-c]pyridine-3- carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethvnyl-l-benzofuran-5-carboxamide;
N- [( 1 S ,2R,4R)-7-azabicyclo [2.2.1 ]hept-2-yl] -3 -ethynyl- 1 -benzofuran-5 -carboxamide;
N- [(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] -2H-chromene-6-carboxamide;
N- [(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] -3 -prop- 1 - ynyl- 1 -benzofuran-5 -carboxamide; N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-phenyl-l,3-benzodioxole-5-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-6-bromopynOlo[l,2-a]pyrazine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-prop-l-ynylfuro[2,3-c]pyridine-5- carboxamide;
N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]pynolo[l,2-a]pyrazine-3- carboxamide;
N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]indolizine-6-carboxamide;
2-amino-N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l,3-benzothiazole-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-6-ethynylpyrrolo[l,2-a]pyrazine-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-8-methoxy-2-naphthamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]indolizine-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl][l,3]dioxolo[4,5-c]pyridine-6-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl][l,3]dioxolo[4,5-c]pyridine-6- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-cyano-l-benzofuran-5-carboxamide; N-[(3R,4S)-l-azabicyclo[2.2.1]hept-3-yl][l,3]dioxolo[4,5-c]pyridine-6-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro-l,4-benzodioxine-6- carboxamide;
N- [(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] -7-hydroxy-2-naphthamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-ethynylfuro[2,3-c]pyridine-5- carboxamide;
N-[(l S,2R,4R)-7-azabicyclo[2.2.1 ]hept-2-yl]-6-chloroisoquinoline-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro-l,4-benzodioxine-6- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-2,3-dihydro-l,4-benzodioxine-6- carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-6-methylisoquinoline-3-carboxamide;
N-[(lS,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-6-methylisoquinoline-3-carboxamide;
N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-cyanofuro[2,3-c]pyridine-5-carboxamide; N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-2-naphthamide; and
N- [(3R)- 1 -azabicyclo [2.2.2] oct-3 -yl] dibenzo [b,d] fixran-2-carboxamide, provided that the agonist is a free base or a pharmaceutically acceptable salt thereof.
4. Use of an effective amount of an al nAChR full agonist for the preparation of a medicament to treat disease or disorder involving cholinergic hypofunction in a mammal in need thereof, provided that the medicament is administered over an effective therapeutic interval with at least one inhibitor wherein the inhibitor is a beta secretase inhibitor, an acetylcholinesterase inhibitor, and a gamma secretase inhibitor.
5. The use of claim 4, wherein the disease or condition is cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), senile dementia, amyotrophic lateral sclerosis, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, Parkinson's disease, age-related macular degeneration.
6. The use of claim 4 or 5, wherein the mammal is a human.
7. The use of claim 4, 5, or 6, wherein the medicament contains the agonist and at least one of the beta secretase inhibitor, the acetylcholineesterase inhibitor, and the gamma secretase inhibitor.
8. The use of any one of claims 4-7, wherein the agonist is a compound of Formula I according to claim 2.
9. The use of any one of claims 4-7, wherein the full agonist is a compound of Formula I according to claim 3.
10. The use of any one of claims 3-9, wherein the Acetylcholinesterase inhibitor is physostigmine, aricept, rivastigamine, galantamine, monoamine acridines and derivatives, piperidinyl-alkanoyl heterocyclic compounds, N-benzyl-piperidine derivatives, 4-(l-benzylpiperidyl)-substituted fused quinoline derivatives, and cyclic amide derivatives.
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