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WO2004039366A1 - Agonistes nicotiniques de l'acetylcholine dans le traitement du glaucome et d'une neuropathie de la retine - Google Patents

Agonistes nicotiniques de l'acetylcholine dans le traitement du glaucome et d'une neuropathie de la retine Download PDF

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Publication number
WO2004039366A1
WO2004039366A1 PCT/IB2003/004707 IB0304707W WO2004039366A1 WO 2004039366 A1 WO2004039366 A1 WO 2004039366A1 IB 0304707 W IB0304707 W IB 0304707W WO 2004039366 A1 WO2004039366 A1 WO 2004039366A1
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substituted
alkyl
cycloalkyl
heterocycloalkyl
haloalkyl
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PCT/IB2003/004707
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English (en)
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David Martin Linn
Erik Ho Fong Wong
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Pharmacia & Upjohn Company Llc
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Priority to AU2003269413A priority Critical patent/AU2003269413A1/en
Publication of WO2004039366A1 publication Critical patent/WO2004039366A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Nicotinic acetylcholine receptors play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety.
  • the present invention relates to molecules that have a greater effect upon the ⁇ 7 nAChRs as compared to other closely related members of this large ligand-gated receptor family.
  • the invention provides compounds that are active drug molecules with fewer side effects as neuroprotective agents in retinal neuropathy.
  • the ⁇ 7 nAChR is one receptor system that has proved to be a difficult target for testing. Native ⁇ 7 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 c I 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,
  • Eisele et al. used the N- terminus of the avian (chick) form of the oc7 nAChR receptor and the C-terminus of the mouse form of the 5-HT 3 gene. However, under physiological conditions the ⁇ 7 nAChR is a calcium channel while the 5-HT 3 R is a sodium and potassium channel. Indeed, Eisele et al.
  • US 6,277,855 discloses a method of treating dry eye disease with nicotinic acetylcholine receptor agonists.
  • ⁇ 7 nAChRs have been found on retinal ganglion cells.
  • the present invention involves the neuroprotection of retinal cells provided by alpha7 AChR full agonists and related uses and methods of treatment.
  • the present invention discloses a method for treating, or a use of the compounds of the present invention to prepare a medicament to treat, glaucoma, diabetic retinopathy, or age- related macular degeneration by the administration of ⁇ 7 nAChR full agonists to a mammal in need thereof.
  • the present invention discloses a method of treating glaucoma, diabetic retinopathy, or age-related macular degeneration by the administration of ⁇ 7 nAChR agonists to a mammal in need thereof.
  • One aspect of the present invention includes ⁇ 7 nAChR full agonists as described herein in formula I.
  • Another aspect of the present invention includes 7 nAChR full agonists as described elsewhere: 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.
  • an ⁇ 7 nAChR full agonist is a ligand that is a full agonist of the nicotinic acetylcholine receptor relative to nicotine.
  • the use of the term ⁇ 7 nAChR full agonist is used interchangeably with ⁇ 7 nAChR agonists when discussing the compounds of the present invention.
  • Embodiments of the invention may include one or more or combination of the following.
  • One embodiment of the present invention provides a method for treating, or use of a compound of the present invention for preparing a medicament to treat, any one or more of the following disease or condition: glaucoma, diabetic retinopathy, or age-related macular degeneration.
  • the invention includes treating a mammal suffering from glaucoma, diabetic retinopathy, or age-related macular degeneration by administering an ⁇ 7 nAChR agonist in conjunction with another agent, as described herein.
  • the compounds of the present invention and the other agent(s) can be administered simultaneously or at separate intervals.
  • the compounds of the present invention and the other agent can be incorporated into a single pharmaceutical composition.
  • two separate compositions i.e., one containing compounds of the present invention and the other containing the other agent, can be administered simultaneously.
  • a further embodiment of the present invention provides a method comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition containing said compound to the mammal, or preparing a medicament using a compound of the present invention to treat glaucoma, diabetic retinopathy, or age-related macular degeneration.
  • 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; l,3-benzodioxole-5-yl; 2,3-dihydro-l,4-benzodioxine- 6-yl; l,3-benzoxazole-5-yl; thieno[2,3-c]pyridine-5-yl; thieno[3,2-c]pyridine-6-yl; [ 1 ]benzothieno[3,2-c]pyridine-3-yl; 1 ,3-benzothiazole-6-yl;
  • 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;
  • the present invention also includes pharmaceutical compositions containing the active compounds, and methods to treat the identified diseases.
  • the present invention also includes a pharmaceutical composition comprising a compound of the present invention, including Formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is administered bucal, intravaginally, rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval.
  • the pharmaceutical composition is administered to deliver a compound of the present invention in an amount of from about 0.001 to about 100 mg/kg of body weight of said mammal per day.
  • the pharmaceutical composition is also admimstered to deliver a compound of the present invention in an amount of from about 0.1 to about 50 mg/kg of body weight of said mammal per day.
  • the pharmaceutical composition is also administered to deliver a compound of the present invention in an amount of from about 0.1 to about 20 mg/kg of body weight of said mammal per day.
  • the daily dose can be administered in 1 -4 doses per day.
  • a pharmaceutical composition comprising a compound of the present invention, including Formula I, or a pharmaceutically acceptable salt thereof, and another agent, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is administered to independently administer said compound and said agent bucal, intravaginally, rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval.
  • the pharmaceutical composition is administered to deliver a compound of the present invention in an amount of from about 0.001 to about 100 mg/kg of body weight of said mammal per day.
  • the pharmaceutical composition is also administered to deliver a compound of the present invention in an amount of from about 0.1 to about 50 mg/kg of body weight of said mammal per day.
  • the pharmaceutical composition is also administered to deliver a compound of the present invention in an amount of from about 0.1 to about 20 mg/kg of body weight of said mammal per day.
  • the daily dose can be administered in 1-4 doses per day.
  • the compounds of Formula I where 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 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), R 2 has any definition or specific value discussed herein.
  • exo and endo axe 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 1R, 2R, 4S isomer.
  • the e o 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 1R, 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 e o-(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.
  • compositions can include one or more compounds, each having an e o 2R configuration, or mixtures of compounds having exo 2R and other configurations.
  • 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 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-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.
  • Some embodiments of compounds of Formula I for when Azabicyclo is II include racemic mixtures where R 2 is absent (k 2 is 0) or is at C2 or C6; or Azabicyclo II has the exo-A(S) stereochemistry and R 2 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,4R,5R), (1S,4S,5R), (1S,4S,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 (Azabicyclo III) includes R2- 3 is H, or is other than H and either occurs at any carbon with sufficient valancy or is bonded at C3
  • the compounds of Formula I (Azabicyclo IV) 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-( ⁇ S,AR,6S), exo-(lR,AS,6R), endo-(lS,AR,6R), and endo-(lR,AS,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 IV) includes R 2 - 3 is H, or is other than H and either occurs at any carbon with sufficient valancy or is bonded at C3.
  • 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, exo-3R, 5R, exo-3S, 5S:
  • Azabicyclo V Another group of compounds of Formula I (Azabicyclo V) includes compounds where Azabicyclo V moiety has the stereochemistry of 3R, 5R, or is a racemic mixture and the moiety is either not substituted with R 2 (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 VI) 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 VI Another group of compounds of Formula I (Azabicyclo VI) includes compounds where Azabicyclo VI moiety is either not substituted with R 2 (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.
  • Stereoselective syntheses and/or subjecting the reaction product to appropriate purification steps produce substantially optically pure materials.
  • Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically 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 substitutuents 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 optically pure materials.
  • Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
  • Alpha 7 nAChR agonists within the scope of the present invention include compounds of Formula I:
  • Ro is H, lower alkyl, substituted lower alkyl, or lower haloalkyl
  • 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 , or k 6 is 0; k ⁇ - 2 is 0 or 1; k ⁇ _ 6 is 0 or 1, provided that the sum of kj- 2 and k ⁇ - 6 is one; k 2 is 0 or 1 ; k 5 is 0, 1, or 2; k 6 is 0, 1, or 2; 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 t 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 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 )
  • 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
  • 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 ,
  • 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) 2 R 8 , phenyl, or phenyl having 1 substituent selected from R and further having 0-3 substituents independently selected from F, CI, Br,
  • Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 10 )-, or -O-;
  • Haloheterocycloalkyl is heterocycloalkyl having 1-4 substituents independently selected from F, or CI;
  • Substituted heterocycloalkyl is heterocycloalkyl 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) 2 R 8 , phenyl, or phenyl having 1 substituent selected from R 9 and further having 0-3 substituents independently selected from F, CI, Br
  • 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 R ⁇ 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 Ri i and 0-2 substituents independently selected from F, CI, Br, or I;
  • Li is O, S, or NRio
  • L is CR 12 or N
  • L 2 and L 3 are independently selected from CR ⁇ 2 , C(R ⁇ 2 ) 2 , O, S, N, or NRio, provided that both L 2 and L 3 are not simultaneously O, simultaneously S, or simultaneously O and S, or wherein L is CR 12 or N, and L 2 and L 3 are independently selected from CR 12 , O, S, N, or NRio, and each 9-membered fused-ring moiety having 0-1 substituent selected from R 9 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 formula I at any position as valency allows;
  • R 7 is alkyl, substituted alkyl, haloalkyl, -ORn, -CN, -NO 2 , -N(R 8 ) 2 ;
  • Each R 8 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R 13 , cycloalkyl substituted with 1 substituent selected from R 13 , 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 H , -SR 14 , -N(R 14 ) 2 , -C(O)R H , -C(O)N(R ]4 ) 2 , -CN, -NR 14 C(O)Ri4, -S(O) 2 N(R ⁇ 4 ) 2 , -NR, 4 S(O) 2 R ⁇ 4 , -NO 2 , alkyl substituted with 1-4 substituent(s) independently selected from F, CI, Br, I, or R 13 , 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 i3 ;
  • Rio 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, CI, Br, or I;
  • Each Ri i is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • Each R 12 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 ⁇ 4 ) 2 ,
  • -C(O)R 14 -C(O)N(R 14 ) 2 , -NR, 4 C(O)R ⁇ 4 , -S(O) 2 N(R 14 ) 2 , -NR 14 S(O) 2 R 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 ⁇ 4 , -SR ⁇ 4 , -N(R 14 ) 2 , -C(O)R 14 , -NO 2 , -C(O)N(R 14 )
  • Each R )4 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • W is (A):
  • R A -i a 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 - 3 , -OR A -4, -SR A -3, F, CI, Br, I, -N(R A -3) 2 , -N(R A .
  • R A -ib is -O-R A -3, -S-R A - 3 , -S(O)-R A - 3 , -C(O)-R A -7, 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-l 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 -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 A- 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 - is selected from aryl, R 5 , or R 6 ;
  • B° is -O-, -S-, or -N(RB-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 .
  • Each R B - 2 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, heterocyclo-alkyl, 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 from R C - ⁇ ;
  • 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, haloheterocyloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenyl, substituted phenyl, -NO 2 , -CN, -OR c - 2 , -SRc- 2) -SOR C - , -SO 2 R c -2, -NR c - 2 C(O)R c -3, -NR c - 2 C(O)Rc-2, -NR C - 2 C(O)Rc- 4 , -N
  • Rc- 6 is independently H, alkyl, cycloalkyl, heterocyclo-alkyl, haloalkyl, halocycloalkyl, or haloheterocycloalkyl;
  • 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 ⁇ is said bond;
  • Each R D - 2 is independently H, alkyl, haloalkyl, substituted alkyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, R 5 , or R 6 ;
  • Each R D - 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-.O, -C(O)N(Rr seemingly) 2 - -NR D - ⁇ 0 COR D - 12 , -N(R D - 10 ) 2 , -SR D - ⁇ o, -S(O) 2 R D -,o, -C(O)R D - 12, -CO R D -I O , aryl, R 5 , R , a bond to -C(X)- provided that only one of R D - ⁇ , R D - 3 , and
  • Each Ro--- t 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(R D -n) 2 , -NR D - 10 COR D -i2, -N(R D -n) 2 , -SR D - ⁇ o, -CO 2 R D .
  • R D - 5 is independently H, C1- 3 alkyl, or C 2 - 4 alkenyl
  • D 7 is O, S, or N(R D . 2 );
  • D 8 and D 9 are C(R D - I ), provided that when the molecule is attached to the phenyl moiety at D 9 , D 8 is CH;
  • Each R D - IO is independently H, alkyl, cycloalkyl, haloalkyl, substituted phenyl, or substituted naphthyl;
  • Each R D - I 1 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R1 3 , cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R 13 , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • R D - I2 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 , -ORE ⁇ , -SR E .
  • E 1 is O, CRE-I-I, or C(RE-I-I) 2 , provided that when E 1 is CR E - I - I , one R E - ⁇ is a bond to E 1 , and further provided that at least one of E 1 or E 2 is O;
  • Each R E - I - I is independently H, F, Br, CI, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -OR E , or -N(R E ) 2 , provided that when E 1 is C(R E - ) 2 and when one R E - ⁇ - ⁇ is F, Br, CI, CN, -OR E , or -N(R E ) 2 , the other R E - ⁇ - ⁇ is H;
  • Each E - I is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E 1 provided that E 1 is R E - ⁇ - ⁇ ;
  • E 2 is O, CRE-2-2, or C(RE-2-2)2, provided that when E 2 is CR E -2-2, one R E - 2 is a bond to E 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 when E 2 is C(R E . 2 . 2 ) 2 and when one R E - 2 - 2 is F, Br, CI, CN, -OR E , or -N(R E ) 2 , the other R E - 2 - 2 is H;
  • Each R E - 2 is independently H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, or a bond to E 2 provided that E 2 is CR E - 2 - 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 - 5 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 and further having 0-3 substituents independently selected from F, CI, Br, or i; wherein W is (F):
  • N(R F -4)-N C(R F - 3 ), N(R F - 4 )-C(R F - 3 )(R F - 2 )-O, N(R F - 4 )-C(R F - 3 )(RF- 2 )-S, N(R F - 4 )-C(R F .
  • R F - ! is H, F, CI, Br, I, -CN, -CF 3 , -OR, 8 , -SR F . 8 , or -N(R F - 8 ) 2 ;
  • R F - 2 is H, F, alkyl, haloalkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R 5 , R 6 , -N(R F - 4 )-aryl, -N(R F .
  • 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 , -OR], -C(O)N(R F - 8 ) 2 , -NHR,, -NR,COR F _ 8 , -N(R 8 ) 2 , -SR,, -C(O)R F . 8 , -CO 2 R,, aryl, R 5 , or R 6 ;
  • R I 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 , -ORi, -C(O)NH 2 , -NHRi, -SRi, -CO 2 R!, aryl, phenoxy, substituted phenoxy, heteroaryl, -N(R F - )-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, -OR t , -C(O)NH 2 , -NHRi, -SRi, -CO 2 R ⁇ , 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, CI, I, -ORi, -C(O)NH 2 , -NHR 1; -SRi, -CO 2 R, aryl
  • R F - 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, CI, Br, or I;
  • R F - 8 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(Ro- ⁇ ), 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, CI, I, -C(O)N(R G . 3 ) 2 , -N(R G - 3 ) 2 , -SR, 9 ,
  • -S(O) 2 R ⁇ , -ORG-6, -C(O)RG- 6 ,-CO 2 R G -6, aryl, R 5 , R 6 , or two R G - I 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, CI, Br, I, and RQ. 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)RG- 8 , -OS(O) 2 RG- 8 , -N(R G - 8 ) 2 , -C(O)R G - 8 , -C(S)R G . 8 , -C(O)OR G .
  • Each R G . 3 is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from cycloalkyl substituted with 1 substituent selected from R GA , heterocycloalkyl substituted with 1 substituent selected from R G - 4 , haloalkyl, halocycloalkyl, haloheterocycloalkyl, phenyl, or substituted phenyl;
  • R G . 4 is -ORG-S, -SR G - 5 , -N(R G . 5 ) 2 , -C(O)R G . 5 , -SOR G ,, -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 ,S(0) 2 R G ,, or -NO 2 ;
  • Each R G . 5 is independently H, alkyl, cycloalkyl, heterocyclo-alkyl, 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, CI, Br, I, and R G - 7 ;
  • R G - 7 is alkyl, substituted alkyl, haloalkyl, -OR G - 5 , -CN, -NO 2 , -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, CI, Br, I, or R G - 7 ;
  • H' is N or CH
  • Each R H - ⁇ is independently F, CI, Br, I, -CN, -NO , alkyl, haloalkyl, substituted alkyl, alkenyl, haloalkenyl, substituted alkenyl, alkynyl, haloalkynyl, substituted alkynyl, cycloalkyl, halocycloalkyl, substituted cycloalkyl, heterocycloalkyl, haloheterocycloalkyl, substituted heterocycloalkyl, lactam heterocyclcoalkyl, aryl, R 5 , R 6 , -OR H - 3 , -SR H -3, -SOR H - 3 , -SO 2 R H - 3 , -SCN, -S(O)N(R H - 3 ) 2 , -S(O) 2 N(RH- 3 ) 2 , -C(O)R H -3, -C(
  • R H - is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, haloheterocycloalkyl, -ORj- 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 .
  • 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.
  • FLIPR 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
  • IP A refers to isopropyl alcohol.
  • THF refers to tetrahydrofuran
  • DMSO dimethylsulfoxide
  • DMF 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 4 refers to sodium sulfate.
  • 2 CO 3 refers to potassium carbonate.
  • MgSO 4 refers to magnesium sulfate.
  • Halogen or halo is F, CI, 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 C,- j indicates a moiety of the integer 'i" to the integer "j" carbon atoms, inclusive.
  • C1- 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
  • 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.
  • 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 A - 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 ⁇ 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 CI, OH, or mixed anhydride.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • 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 may be 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 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.
  • the amount of therapeutically effective compound(s) that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound(s) employed, and thus may vary widely.
  • the compositions contain well know carriers and excipients in addition to a therapeutically effective amount of compounds of Formula I.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.001 to about 100 mg/kg/day for an adult, preferably any amount within the range of about 0.1 to about 50 mg/kg/day for an adult, including ranges within the range of about 0.1 to about 50 mg/kg/day.
  • a total daily dose of about 1 to 1000 mg of active ingredient may be appropriate for an adult.
  • the daily dose can be administered in one to four doses per day.
  • the composition for therapeutic use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients.
  • 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 controlled-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 administration 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 ocular disorders may be treated by administering directly (e.g., topically) to the eye by use of a pharmaceutical formulation that is any one or more of the following: solution, lyophilized solution, cream, ointment, emulsion, suspension and slow release formulations.
  • Administration of these formulations to the eye can be either via the topical route or through one or more of a variety of intraocular routes such as subconjunctival, intracameral, intravitreal, subtenons, intrascleral, transcleral, retrobulbar etc.
  • the formulation would contain from about 0.001 to about 10% (wt/vol) of the active ingredient, or any range therein, e.g., from about 0.1 to about 5% (wt vol) of the active ingredient.
  • Preparation of the composition can be carried out by mixing the active ingredient(s) with an ophthalmologically compatible carrier.
  • ophthalmologically compatible carrier Such carrier compounds are known, and there are a number of systems based on physiologic saline, oil solutions or ointments suggested in the literature for application of medicaments to the eye.
  • the carrier or vehicle may furthermore contain ophthalmologically compatible preservatives including benzalkonium chloride, surfactants including polysorbate 80, liposomes or polymers including methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid. The latter substances may be used for increasing the viscosity of the solution.
  • the composition has an effective residence time in the eye of about 2 to about 24 hours, more preferably about 4 to about 24 hours and most preferably about 6 to about 24 hours.
  • Lacrimation is the production of tear fluid, and can remove matter from the eyes both by external wash-out and by lacrimal drainage into the nasopharyngeal cavity via the nasolacrimal ducts.
  • Effective residence time herein is meant a period of time following application of the composition to the eye during which the concentration of the compound in the target ocular tissue remains above the minimum therapeutic level. The composition therefore provides sustained release an effective residence time over a period of at least about 2 hours.
  • a composition of the invention can illustratively take the form of a liquid wherein the drug is present in solution, in suspension or both.
  • solution/suspension herein refers to a liquid composition wherein a first portion of the drug is present in solution and a second portion of the drug is present in particulate form, in suspension in a liquid matrix.
  • a liquid composition herein includes a gel.
  • the liquid composition is aqueous.
  • the composition can take the form of an ointment.
  • the composition can take the form of a solid article that can be inserted between the eye and eyelid or in the conjunctival sac, where it releases the drug as described. See, e.g., U.S. Patent No. 3,863,633 and U.S. Patent No. 3,868,445. Release is to the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact.
  • Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be biodegradable or non- biodegradable.
  • suitable non-biodegradable polymers are silicone elastomers.
  • the composition is an aqueous solution, suspension or solution/suspension, which can be presented in the form of eye drops.
  • a desired dosage of the drug can be metered by administration of a known number of drops into the eye.
  • administration of 1-6 drops will generally deliver about 25 to about 300 ⁇ l of the composition.
  • Aqueous compositions of the invention preferably contain from about 0.01% to about 50% (wt vol), more preferably about 0.1% to about 20%, still more preferably about 0.2% to about 10%, and most preferably about 0.5% to about 5%, weight/volume of the selective ⁇ 7 agonist.
  • a composition of the invention contains a concentration of the selective ⁇ 7 agonist that is therapeutically or prophylactically effective in a weight/volume concentration of about 0.1% to about 50%, preferably about 0.5% to about 20%, and most preferably about 1% to about 10%.
  • a composition of the invention has relatively high loading of the drug and is suitable for a relatively long residence time in a treated eye.
  • the weight/volume concentration of the drug in the composition is about 1.3%) to about 50%, preferably about 1.5% to about 30%, and most preferably about 2% to about 20%, for example about 2% to about 10%.
  • 1-6 drops are administered.
  • the total amount of drops should contain the desired dose of the drug for administration to an eye. Administration of a larger volume to the eye risks loss of a significant portion of the applied composition by lacrimation.
  • Aqueous compositions of the invention have ophthalmically acceptable pH and osmolality.
  • ophthalmically acceptable with respect to a formulation, composition or ingredient herein means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. It will be recognized that transient effects such as minor irritation or a "stinging" sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the formulation, composition or ingredient in question being "ophthalmically acceptable” as herein defined. However, preferred formulations, compositions and ingredients are those that cause no substantial detrimental effect, even of a transient nature.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • ⁇ 7 nAChR is a ligand-gated Ca ⁇ channel formed by a homopentamer of ⁇ 7 subunits.
  • ⁇ -btx ⁇ - bungarotoxin
  • the invention involves the neuroprotection provided by alpha7 AChR agonists on RGCs and related uses and methods of treatment.
  • ⁇ 7 nAChRs can provide direct therapy (neuroprotection) of RGCs: by activating postsynaptic receptors to stimulate intracellular neuroprotective cascades and/or the release of beneficial factors (e.g., nerve growth factor (NGF)), by activating presynaptic receptors to increase the release of inhibitory amino acids such as GABA which would dampen hyperexcitability, or by a combination of the preceding mechanisms.
  • beneficial factors e.g., nerve growth factor (NGF)
  • Glaucoma is a family of diseases characterized by the loss of RGCs and pathological changes in the optic disk and optic nerve resulting in the loss of visual field. While glaucoma is usually associated with an elevation of intraocular pressure (IOP) (elevated IOP is the main risk factor for glaucoma), this is not always observed. A significant amount of patients (approximately 40%) present with the characteristics of glaucoma have normal IOP, such patients are identified as “normotensive.” Also, there are subjects with elevated IOP but exhibit no signs of glaucoma. This latter group is identified as "ocular hypertensives.” Therefore, there exists a need for a safe and effective method for treating glaucoma derived from not only "pressure dependent” but also "independent” events.
  • IOP intraocular pressure
  • Neuroprotection in glaucoma is a therapeutic paradigm aimed at blocking primary destructive events and/or enhancing survival mechanisms of the RGCs and their axons and optic nerve fibers.
  • An important potential advantage of the neuroprotective treatment is that it allows treatment of a disease for which the specific etiology is either unknown or differs among patients. This is particularly relevant to glaucoma, a heterogeneous group of disorders that share common characteristic morphological features of the optic nerve head and patterns of visual loss.
  • RGC viability depends on a balance of positive (survival) and negative (death) stimuli, and the RGCs fail to survive if this balance is disturbed.
  • RGC death Several pathophysiological mechanisms have been hypothesized to have a role in causing RGC death in glaucoma.
  • One specific trigger of RGC death is excitotoxicity.
  • ⁇ MDA N-methyl-D-aspartate
  • ⁇ MDA receptor antagonists are under development as neuroprotective agents for the treatment of glaucoma.
  • An alternative approach to blocking glutamate excitotixicity is through the development of inhibitors of N-acetylated-alpha-linked acidic dipeptidase ( ⁇ AALADase).
  • Alpha 7 nAChR agonists offer a unique therapy to glaucoma patients without elevated IOP, (i.e., normotensives), by providing neuroprotection to the RGCs.
  • ⁇ 7 agonists can be combined with other IOP lowering drugs for patients with "pressure" dependent glaucoma.
  • the compounds of the present invention can be combined with other IOP lowering drugs that included, but are not limited to, any of the following: Xalatan, Xalcom, Trusopt, or Alphagan.
  • ⁇ 7 compounds can be used with other neuroprotective agents including, but limited to, the following: COX inhibitor (including a COX-2 inhibitor), an i ⁇ OS inhibitor (see, e.g., ⁇ eufeld, et al, Proc. Nat 'I Acad. Sci., Vol 96, pp. 9944- 9948 (1999)), a p38 kinase inhibitor (see, e.g., Kikuchi, et al, J. Neuroscience, 20 (13):5037-5044 (2000)), or a T ⁇ F- ⁇ inhibitor (see, e.g., Tezel, G and Wax, M, J. Neuroscience, 20(23):8693-8700 (2000)).
  • COX inhibitor including a COX-2 inhibitor
  • an i ⁇ OS inhibitor see, e.g., ⁇ eufeld, et al, Proc. Nat 'I Acad. Sci., Vol 96, pp. 9944- 9948 (1999)
  • al agonists provide unique therapy to elevated IOP glaucoma patients, normotensive glaucoma patients and ocular hypertensives.
  • the compounds of the present invention can be used as a neuroprotective agent when the eye experiences effects resulting in increased pressure. Such effects result from environmental incidents including, but not limited to, a bacterial infection, inflammation from an autoimmune response, and trauma-induced pressure (e.g., trauma to the eye socket). It is preferred that the compounds of the present invention be administered with other agents to treat the cause resulting in IOP, e.g., administering the compounds of the present invention in addition to an antibacterial agent to treat the bacterial infection.
  • the compounds of the present invention can also be administered to a mammal who is pre-disposed to acquire glaucoma, regardless of whether the glaucoma results from IOP or other factors.
  • One of ordinary skill in the art can identify said mammals predisposed to acquire glaucoma. In such cases, the compounds of the present invention would provide preventative measures to prolong the onset of glaucoma or possibly avoid the onset of glaucoma.
  • Diabetic retinopathy is the most common complication of diabetes, affecting over 90% of persons with diabetes and progressing to legal blindness in about 5%.
  • the vascular features of long-term diabetic retinopathy are well documented, but the non- vascular pathology has received less attention until a recent observation that both experimental diabetes in rats and diabetes mellitus in humans are accompanied by increased apoptosis of retinal neural cells (Barber et al, 1998; J. Gin. Invest., 102, 783-791).
  • the increase in the frequency of apoptosis occurred after only 1 month of experimental diabetes in rats is similar to that observed in a human retina after 6 years of diabetes.
  • diabetic retinopathy There are two stages of diabetic retinopathy, an early stage known as the preproliferative stage and a late stage known as the proliferative stage.
  • the proliferative stage microvascular abnormalities including neovascularization are common.
  • the preproliferative stage of diabetic retinopathy neuronal apoptosis and neurodegeneration occur by an unknown mechanism (see, e.g. Nakamura et al., J. Biol. Chem., Vol 276(47):43748-43755 (2001)).
  • the only therapy for diabetic retinopathy is targeted against the late phase and consists of laser surgery on new blood vessels to halt growth.
  • An ⁇ 7 nAChR agonist provides therapy for the early, preproliferative stage of diabetic retinopathy by targeting neuronal apoptosis and neurodegeneration. This would fill an unmet medical need and be the first therapy to target this early stage. It is possible that an interaction or cascade exists between the early and late stage, and a therapy targeted at the early stage would provide some benefit by reducing the severity or preventing the late stage (comparable to IOP management in glaucoma).
  • ⁇ 7 nAChRs have been associated with blood vessels and activation of these receptors with an ⁇ 7 nAChR agonist can target the late stage independently by activating anti-angiogenic pathways.
  • a combination therapy utilizing an ⁇ 7 nAChR agonist against the early stage of diabetic retinopathy, and compounds with an indication against the late stage would provide additional benefit over each alone.
  • Existing compounds with utility for combining with an ⁇ 7 nAChR agonist would include, but not be limited to, matrix metalloproteinase inhibitors (MMPi) and vascular endothelial growth factor inhibitors (VEGFi) to prevent the growth of new blood vessels, and COX inhibitors (including COX-2 inhibitors) and glucocorticoid steroids to target inflammation.
  • the ⁇ 7 nAChR agonist and the other agent can be administered simultaneously or at separate intervals.
  • the ⁇ 7 nAChR agonist and the other agent can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition.
  • two separate compositions i.e., one containing ⁇ 7 nAChR agonist and and the other containing the other agent, can be administered simultaneously. Examples of other agents are discussed herein with regard to the different diseases to be treated.
  • a pharmaceutical combination therapy composition can include therapeutically effective amounts of the a 7 nAChR agonist, noted above, and a therapeutically effective amount of the other agent, including but not limited to, Xalatan, Xalcom, Truspot, Alhagan, MMPi, VEGFi, COX-2 inhibitors, or glucocorticoid steroids.
  • 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, parentarally, or topically and maybe formulated as sustained relief dosage forms and the like.
  • compositions containing the ⁇ 7 nAChR agonist and the other agent are administered on a different schedule.
  • One may be administered before the other as long as the time between the two administrations falls within a therapeutically effective interval.
  • a therapeutically effective interval is a period of time beginning when one of either (a) the ⁇ 7 nAChR agonist, or (b) the other agent is administered to a mammal and ending at the limit of the beneficial effect in the treatment of the disease to be treated with a combination of (a) and (b).
  • the methods of administration of the ⁇ 7 nAChR agonist and the other agent may vary. Thus, either agent or both agents may be administered rectally, topically, orally, sublingually, or parenterally.
  • Age-related macular degeneration is a common eye disease of the macula which is a tiny area in the retina that helps produce sharp, central vision required for "straight ahead" activities that include reading and driving. Persons with AMD lose their clear, central vision.
  • AMD takes two forms: wet and dry.
  • the dry form of AMD features changes in the non-neuronal retinal pigment epithelium (RPE) and the photoreceptors of the macula.
  • RPE retinal pigment epithelium
  • the RPE is a layer of vascularized, pigmented cells located directly behind the retina and separates the retina from the choroid.
  • the RPE normally provides metabolic support and is involved in the recycling of components of the photosensitive cascade of photoreceptors.
  • drusen there is the accumulation of a yellow exudate in the RPE called drusen during AMD.
  • the neurodegenerative changes in the RPE and formation of drusen are thought to be manifestations of a dysfunction between the photoreceptors and the RPE in the macula. The reason for this dysfunction is unknown but possibly involves the high metabolic demand of the macula.
  • the abnormal ingrowth of blood vessels from the choroid through the RPE often results in fluid and/or blood (“wet") accumulation under the retina and can ultimately result in severe loss of vision.
  • an ⁇ 7 nAChR agonist can activate a neuroprotective cascade within the RPE cells and prevent any dysfunction with the photoreceptors.
  • the compounds of the present invention are useful to treat AMD.
  • a healthy RPE would be more likely to provide a barrier against choroidal neovascularization and therefore the "wet" stage.
  • Laser surgery can treat some cases of wet AMD. Therefore, there is a need of a pharmaceutical agent to address AMD.
  • Use of an ⁇ 7 nAChR agonist and compounds with an indication against neovascularization provide additional benefit over each alone for AMD.
  • Existing compounds with a utility for combining with an ⁇ 7 nAChR agonist include, but are not limited to, matrix metalloproteinase inhibitors (MMPi) and vascular endothelial growth factor inhibitors (VEGFi) to prevent the growth of new blood vessels, COX inhibitors including COX-2 inhibitors, and glucocorticoid steroids to target inflammation.
  • MMPi matrix metalloproteinase inhibitors
  • VEGFi vascular endothelial growth factor inhibitors
  • 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).
  • 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 Acta 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 corresponding 6-substituted-3- quinuclidinone by methods known 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 corresponding mesylate or tosylate, followed by displacement with sodium azide and reduction as described inJ. 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. Perkin Trans. 7409-420 (1991), J. Org. Chem. 3982-3996 (2000)).
  • Int 6 can be oxidized to the aldehyde and treated with an organometallic reagent to provide Int 20 using procedures described in Tetrahedron (1999), 55, p 13899.
  • Int 20 can be converted into the amine using methods described for the synthesis of ejco-3- amino-l-azabicyclo[2.2.1]heptane as the bis(hydro para-toluenesulfonate) salt. Once the amine is obtained, the desired salt can be made using standard procedures.
  • Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is added to a stirred 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 over Na 2 SO , filtered and concentrated in vacuo.
  • the residue is purified by flash chromatography on silica gel.
  • Step D Preparation of trans-A-amixio- 1 -(phenylmethyl)-3-pyr ⁇ olidineacetic acid ethyl ester (Int 4).
  • Int 4 A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH (100 mL) is placed in a Parr bottle and hydrogenated for 4 h under an atmosphere of hydrogen (46 psi) at rt.
  • Step E Preparation of trans-A-( 1 , 1 -dimethylethoxycarbonylamido)- 1 -
  • 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.
  • LiAlH powder (627 mg, 16.5 mmol) is added in small portions to a stirred solution of Int 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) in a -5°C bath. The mixture is stirred 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 IO 2 CO 3 is added, and the mixture is stirred for 1 h, then filtered. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel.
  • TEA 8.0 g, 78.9 mmol
  • CH 2 C1 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 over Na 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, transferred to a Parr 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.
  • 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 CH 2 C1 2 (3X), and the combined organic layers are washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the crude product is purified by flash chromatography on silica gel. Elution with CHCl 3 -MeOH-NH 4 OH (92:7:1) affords Int 16 as a colorless oil (41% yield): ⁇ NMR (CDC1 3 ) ⁇ 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.
  • the respective amine precursors for Azabicyclo III and Azabicyclo IN can be prepared by reduction of an oxime or an imine of the corresponding N-2-azabicyclo[2.2.1]- 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]heptanones with hydroxylamine hydrochloride in the presence of a base.
  • the imines can be prepared by treatment of the N-2- azabicyclo[2.2.1]-heptanones with a primary amine under dehydrating conditions.
  • the N-2-azabicyclo[2.2.1]heptanones can be prepared by known procedures (see Tet. Zett. 1419-1422 (1999), J. Med. Chem. 2184-2191 (1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).
  • the exo- and en o-l-azabicyclo[3.2.1]octan-3-amines are prepared from 1- azabicyclic[3.2.1]octan-3-one (Thill, B. P., Aaron, H. S., J.
  • (3S)-l-[(S)-l-Phenethyl]-3-(hydroxymethyl)pyrrolidine A suspension (3S)-1- [(S)-l-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid (82.30 g, 352.8 mmol) in Et 2 O (200 mL) was added in small portions to a slurry of LiAlH 4 (17.41 g, 458.6 mmol) in Et 2 O (700 mL). The mixture began to reflux during the addition.
  • the resulting oxime (3.1 mmol) is treated with acetic acid (30 mL) and hydrogenated at 50 psi over PtO 2 (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 over MgSO , filtered, treated with ethereal HCl, and evaporated to give the give e /o-[3.2.1]-Amine.
  • 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 extracted with water. The organic layer is dried over anhydrous MgSO , 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: ⁇ NMR (CDC1 3 ) ⁇ 6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.
  • 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 C H 3 BrO 2 C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
  • (+/-) exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1 ]heptane- 2-carboxylic acid (+/-)Erc-io-7-tert-butyl 2-methyl 7-azabicyclo[2.2.1]heptane-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.
  • (+/-) exo-tert-b tyl 2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -7- azabicyclo[2.2.1 ]heptane-7-carboxylate (+/-)E o-7-(tert-butoxycarbonyl)-7- azabicyclo[2.2.1]heptane-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 over anhydrous MgSO 4 and concentrated in vacuo to an amber oil.
  • 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)carbonyl]amino ⁇ -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) + . [ ⁇ ] 25 D 22, (c 0.42, chloroform).
  • the intermediates providing the W of formula I either are commercially available or prepared using known procedures, making non-critical changes.
  • Compounds of Formula 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.
  • 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 stirred 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 CH 2 C1 2 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.
  • 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 stirred 3 h at rt and is diluted with 200 mL CHC1 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-c]pyridin-5-yl]methanol (I-5-D) as a white solid (46% yield).
  • the later-eluting pool of fractions is combined and concentrated to provide (7- chlorofuro[2,3-c]pyridin-5-yl)methanol (I-4-D) as a white solid (27%o yield).
  • 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 C1 2 is added drop-wise, and the mixture is stirred for 20 min.
  • I-17-D (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO.
  • KH 2 PO 4 (221 mg, 1.6 mmol) in 3 mL H 2 O is added and then NaClO 2 (920 mg, 8.2 mmol) in 7 mL H 2 O is added, and the reaction is stirred 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/CH 2 Cl 2 .
  • 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 3 and stirred 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 stirred at RT for 18 h.
  • the mixture is slowly transferred into a solution of NaHCO 3 (45 g, 541 mmol) in water (600 mL), then strirred for 0.5 h.
  • EtOAc 200 mL
  • the combined organics are dried over Na 2 SO 4 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), stirred for 5 min then added dropwise to a 0°C solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHCI 3 (80 mL). The mixture is stirred 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-c]pyridine-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 2 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 CH2CI2 is added drop-wise, and the mixture is stirred for 20 min.
  • (7-Chlorofuro[2,3-c]pyridin-5-yl)methanol (I-4-D) (5.5 g, 30 mmol) in 10 mL CH 2 C1 2 is added, and the reaction is stirred 30 min at -78°C.
  • TEA (21.3 mL, 153 mmol) is then added.
  • 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 Parr 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.
  • Oxalyl chloride (869 ⁇ L, 9.9 mmol) is dissolved in 50 mL CH 2 CI 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 CH2CI2 is added drop-wise, and the mixture is stirred for 20 min.
  • 1-21-D (1.53 g, 8.5 mmol) in 5 mL CH 2 C1 2 is then added, and the reaction is stirred 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 stirred 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).
  • Oxalyl chloride (784 ⁇ L, 8.9 mmol) is dissolved in 25 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, and DMSO (1.26 mL, 17.8 mmol) in 5 mL CH 2 C1 2 is added.
  • the mixture is stirred for 20 min and I-25-D (1.53 g, 8.5 mmol) in 5 mL CH 2 C1 2 is added.
  • the reaction is stirred 1 h, TEA (5.9 mL, 42.5 mmol) is added, and the reaction is stirred 30 min at -78°C.
  • 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 stirred for 20 min, and I-54-D (1.88 g, 11.5 mmol) is added.
  • the mixture is stirred for 1 h at -78°C, then 30 min at 0-5°C.
  • the material is washed with saturated NaHCO3 (75 mL), dried over 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 C1 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 over Na 2 SO , filtered, and concentrated to a tan solid (1.69 g, greater than 100% isolated yield).
  • the solid is diluted with CHCI 3 and is heated to reflux for 3 h. The flask is removed from heat, allowed to cool slightly, then filtered.
  • 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 stirred 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.
  • I-40-D (207 mg, 1.0 mmol) is added to TEA (139 ⁇ L, 1.0 mmol) in CH 2 C1 2 (5 mL) at rt and 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (393 mg, 1.0 mmol) is added.
  • the solution is stirred 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 over ⁇ a 2 SO 4 , filtered, and concentrated to a yellow oil which solidified upon standing.
  • 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.
  • 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.
  • zinc chloride (66.1 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).
  • 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 H 2 O (100 mL) and neutralized with NaHCO 3 , then extracted repeatedly with CHCI3 (12 x 80 mL, 6 x 50 mL). The combined organic layer is dried over Na 2 SO 4 , filtered, and concentrated to a brown solid.
  • THF (200 mL) is chilled to -70°C in a dry flask under N 2 , 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.
  • DIA 7.71 mL, 55.0 mmol
  • 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.
  • a 2M solution of 1-125 -D (10 mL, 20 mmol) is combined with an additional 90 mL of CH 2 C1 2 .
  • 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% K 2 CO 3 (100 mL). The layers are allowed to separate, and the organic layer is dried over K 2 CO 3 , filtered, and concentrated to an orange solid.
  • 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 H 2 O (25 mL). The cake is then dissolved in acetone (50 mL), dried over MgSO , 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.
  • I-135-D (6.16 g, 32.6 mmol) is suspended in MeOH (200 mL) 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 H O are added; the mixture continues refluxing for another 12 h. The mixture is concentrated in vacuo, and the residue is dissolved with cold H 2 O (100 mL). The resulting precipitate is filtered off and dried, giving thieno[3,2-b]pyridine- 6-carbonitrile (1-136-0 as a brown solid (44% yield). HRMS (FAB) calculated for C 8 H 4 N 2 S+H: 161.0173, found 161.0170 (M+H). I-136-D (1.99 g, 12.5 mmol) is dissolved in 70% EtOH/H 2 O (20 mL), and
  • 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 stirred 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[5.4.0]undec-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 stirred for 1 h while the flask is in an ice bath and then over night at rt.
  • Methyl thieno[3,2-c]pyridine-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 stirred 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 (1,100 g, 13.1 mole).
  • 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/CH 2 Cl 2 . The appropriate fractions are combined and concentrated to afford 5-(l,3-dioxolan-2-yl)-lH- pyrrolo[2,3-c]pyridine (1-173-D) (69%yield).
  • I-174-D (500 mg, 3.42 mmol) is dissolved in 1.5 mL formic 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 stirred 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.
  • 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 stirred very slowly for 4.5 h at rt. The mixture is stirred vigorously for 30 min, is diluted with CH C1 2 (100 mL) and the layers separated. The aqueous layer is extracted with CH 2 CI 2 (2 x 100 mL) and the combined organics are concentrated 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 over Na 2 SO 4 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.
  • 3-Bromofuro[2,3-c]pyridine-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 stirred 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 stirred 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), stirred gently for 2 h then stirred vigorously for 15 min.
  • the mixture is diluted with saturated NaHCO 3 (50 mL), extracted with CH 2 C1 2 (1 x 40 mL then 1 x 20 mL), dried over K 2 CO and concentrated to a volume of 20 mL under a stream of nitrogen.
  • the solution is diluted with EtOH (35 mL), treated with K CO 3 (4.09 g, 29.6 mmol) and stirred for 18 h at rt. Water (7 mL) is added and the mixture stirred for 2 days.
  • the mixture is concentrated to dryness, partitioned between 50% saturated NaCl (50 mL) and CH 2 C1 2 (4 x 50 mL), dried over K 2 CO 3 and concentrated in vacuo to a brown solid (833 mg).
  • 3-Chlorofuro[2,3-c]pyridine-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 stirred 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.
  • 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[5.4.0]undec-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 stirred 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 stirrer. 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 stirrer. 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 stirrer.
  • Diisobutyl aluminum hydride (1.0M in toluene) (82.0 ml, 82.0 mmol) is added dropwise, and the reaction stirred at rt for 2 h. The reaction is then carefully quenched with MeOH (5 ml) and poured onto 30% H 2 SO (60 ml) with ice (200 g). The slurry is stirred until all lumps are dissolved, and the layers are allowed to separate.
  • 3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH C1 2 (40 ml) and chilled to 0°C.
  • 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.
  • 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 stirred overnight at rt. The aqueous solution is extracted repeatedly with EtOAc (20 x 10 ml). The combined organics are dried over MgSO 4 , filtered, and concentrated to a yellow solid.
  • 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.
  • E° is N
  • the compounds where one R E -I is a bond to CR E - I - I or where one R E - 2 is a bond to CR E - 2 - 2
  • the compounds can be obtained using methods described herein for E° is CH, making non-critical changes.
  • 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.
  • 6-Bromo-2,3-dihydro-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.
  • 2-Chloro-3-pyridinol (20.0 g, 0.154 mole and NaHCO 3 (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).
  • 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 stirred for 1.5 h in an ice bath. The undesired solid is removed by filtration, and the filtrate is extracted 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 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. NH OH and 4 x 10 ml CH 2 C1 2 and the combined organic layer is dried (K 2 CO 3 ).
  • 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 C 9 H ⁇ ]NO 2 +H: 166.0868, found 166.0868 (M+H) + .
  • 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 stirred 30 min at -78°C.
  • DMSO 7.3 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 2 C1 and the reaction is stirred 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 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 x 8 mL, then 2.2 mL all at 90-minute intervals and then the final 2.3 mL after the reaction had stirred for 15 h at 90°C.
  • the reaction is stirred 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 stirred for 1.5 h in an ice bath allowing an undesired solid to form.
  • 4-(Benzylamino)-2-chloro-6-(hydroxymethyl)-3-pyridinol may be 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 in J. Organomet. Chem., 576, 125-146, 1999 and in greater detail in the references therein.
  • I-13-F may be oxidized to 4-(benzylamino)-2-chloro-3-hydroxypyridine-6- carboxaldehyde (I-14-F) under a wide variety of conditions (e.g., TPAP and NMO in CH 2 C1 ).
  • I-14-F may be oxidized to produce the corresponding carboxylic acid I-15-F using an oxidizing reagent such as NaClO 2 and KH PO 4 in DMSO/H 2 O or Ag 2 O, or hydrogen peroxide or ruthenium tetroxide.
  • Removal of the benzyl group and the chloro group of Acid I-15-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 acid may be conducted to produce [ 1 ,3]oxazolo[5 ,4- c]pyridine-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 sulfidemanohydrate (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- nitrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48, 837.) in MeOH (5.0 mL). The mixture is stirred for 30 min, followed by cooling in a refrigerator overnight.
  • 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 (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 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540 mg, 2.17 mmole) is combined with 4 ml formic acid under nitrogen. 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 concentrated to provide 350 mg (83%) of methyl 4-acetyl-3-hydroxybenzoate as a pale yellow solid. ⁇ NMR (CDC1 3 ) ⁇ 2.70, 3.95, 7.54, 7.64, 7.82, 12.10 ppm.
  • Methyl 3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate (250 mg, 1.19 mmole) is combined with triphenylphosphine (446 mg, 1.7 mmole) in 14 ml dry THF in a dry flask under nitrogen.
  • the solution is treated slowly dropwise with N,N'- diethylazidodicarboxylate (268 ⁇ L, 1.7 mmole) in 10 ml dry THF.
  • the reaction is stirred 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 pyrrolo[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 pyrrolo[l,2-a]pyrazine acids.
  • the pyrrole-2-carboxaldehydes can be obtained from commercial sources or can be synthesized by known procedures.
  • pyrrole-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 Vilsmeier formylation using procedures well known in the art (see J. Het. Chem. 1991, 28, 2053, Synth. Commun. 1994, 24, 1389 or Synthesis, 1995, 1480.
  • Scheme 3G depicts these transformations.
  • Ethyl pyrrolo[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 Et 2 O and dried to give 4.28g (100%) of pyrrolo[l,2-c]pyrimidine-3- carboxylic acid as the hydrochloride salt. The solid can be recrystallized from EtOH. ⁇ NMR (400MHz, DMSO) ⁇ 9.24, 8.21, 7.90, 7.06, 6.85.
  • 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).
  • 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 anhydride (75.0 ml) and formic acid (65.0 ml) for 2 h) is stirred 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 CH 2 C1 (3 x 200 ml) and the combined organic layers are dried over NaSO 4 , filtered, and the solvent removed under vacuum.
  • acetic formic anhydride which is prepared by heating to 50°C acetic anhydride (75.0 ml) and formic acid (65.0 ml) for 2 h
  • the reaction mixture is heated to 35°C with an oil bath for 1 h
  • Methyl imidazo [l,2-a]pyridin-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 H 2 O/EtOH/Et O to afford a light brown solid (4.3 g, 21.6 mmol, 119%) for imidazo[l,5-a]pyridine-7-carboxylic acid.
  • HRMS (FAB) calcd for C 8 H 6 N 2 O 2 +H 163.0508, found 163.0489.
  • 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. 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 pyrrole-2-carboxaldehyde is consumed as determined by ⁇ NMR.
  • reaction mixture is filtered through 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-pyrrol-2- ylmethylene)serinate that is used without purification: MS (ESI+) for C 14 ⁇ 22 N 2 O 4 m/z 282.96 (M+H) + .
  • Pyrrolo[l,2-a]pyrazine-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 C1 2 .
  • the reaction is stirred at RT. After 60h, water is added.
  • the mixture is extracted with CH 2 C1 2 , dried (MgSO ), filtered and concentrated. 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-l H-pyrazole- 1 -carboxylate.
  • Phenyl 4-iodo-l H-pyrazole- 1 -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 CHCI 3 , dried (MgSO 4 ), filtered and concentrated.
  • Retinal ganglion cells obtained from adult pig retina were dissociated and cultured according to the method described by Barres et al. (1988). After removal of retinas from the eyecups, they were transferred to fresh culture medium, subsequently chopped into small fragments, and enzymatically treated with papain (27 units/mg) for 20 minutes at 37 C. Enzymatic treatment was inactivated by rinsing tissue in fresh culture medium and DNase. Tissue dissociation was achieved by gently triturating the retinal tissue using a sterile Pasteur pipette.
  • the cDNA encoding the N-terminal 201 amino acids from the human ⁇ 7 nAChR that contain the ligand binding domain of the ion channel was fused to the cDNA encoding the pore forming region of the mouse 5HT 3 receptor as described by Eisele JL, et al., Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities, Nature (1993), Dec. 2;366(6454):479-83, and modified by Groppi, et al., WO 00/73431.
  • the chimeric ⁇ 7-5HT 3 ion channel was inserted into pGS175 andpGS179 which contain the resistance genes for G-418 and hygromycin B, respectively. Both plasmids were simultaneously transfected into SH- EP1 cells and cell lines were selected that were resistant to both G-418 and hyrgromycin B. Cell lines expressing the chimeric ion channel were identified by their ability to bind fluorescent ⁇ -bungarotoxin on their cell surface. The cells with the highest amount of fluorescent ⁇ -bungarotoxin binding were isolated using a Fluorescent Activated Cell Sorter (FACS).
  • FACS Fluorescent Activated Cell Sorter
  • Cell lines that stably expressed the chimeric ⁇ 7-5HT 3 were identified by measuring fluorescent ⁇ -bungarotoxin binding after growing the cells in minimal essential medium containing nonessential amino acids supplemented with 10% fetal bovine serum, L-glutamine, 100 units/ml penicillin streptomycin, 250 ng/mg fungizone, 400 ⁇ g/ml hygromycin B, and 400 ⁇ g/ml G-418 at 37° C with 6% CO 2 in a standard mammalian cell incubator for at least 4 weeks in continuous culture.
  • the cells were incubated with the dye for 60 min at 37° C and is washed with a modified version of Earle's balanced salt solution (MMEBSS) as described in WO 00/73431.
  • MMEBSS Earle's balanced salt solution
  • the ion conditions of the MMEBSS was adjusted to maximize the flux of calcium ion through the chimeric ⁇ 7-5HT 3 ion channel as described in WO 00/73431.
  • the activity of compounds on the chimeric ⁇ 7-5HT 3 ion channel was analyzed on FLIPR.
  • the instrument was set up with an excitation wavelength of 488 nanometers using 500 milliwatts of power. Fluorescent emission was measured above 525 nanometers with an appropriate F-stop to maintain a maximal signal to noise ratio.
  • Agonist activity of each compound was measured by directly adding the compound to cells expressing the chimeric ⁇ 7-5HT 3 ion channel and measuring the resulting increase in intracellular calcium that is caused by the agonist-induced activation of the chimeric ion channel.
  • the assay is quantitative such that concentration-dependent increase in intracelluar calcium is measured as concentration-dependent change in Calcium Green fluorescence.
  • the effective concentration needed for a compound to cause a 50% maximal increase in intracellular calcium is termed the EC 5 o.
  • Another way for measuring ⁇ 7 nAChR agonist activity is to determine binding constants of a potential agonist in a competition binding assay.
  • ⁇ 7 nAChR agonists there is good correlation between functional EC 50 values using the chimeric ⁇ 7-5HT 3 ion channel as a drug target and binding affinity of compounds to the endogenous ⁇ 7 nAChR.
  • 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
  • 0.4 mL homogenate are added to test tubes containing buffer and various concentrations 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 mis MLA for a final concentration of 1 ⁇ M, added before the radioligand.
  • drugs are added in increasing concentrations to the test tubes before addition of 0.05 mis [-1HJ-MLA for a final concentration 3.0 to 4.0 nM.
  • 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 counted for radioactivity by liquid scintillation spectrometry. Data Analysis.

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Abstract

L'invention concerne un procédé d'utilisation et une méthode de traitement du glaucome, d'une rétinopathie diabétique ou de la dégénérescence maculaire liée à l'âge, laquelle méthode consiste à administrer des agonistes α7 nAChR à un mammiféres qui le nécessite.
PCT/IB2003/004707 2002-11-01 2003-10-20 Agonistes nicotiniques de l'acetylcholine dans le traitement du glaucome et d'une neuropathie de la retine WO2004039366A1 (fr)

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US7713976B2 (en) 2005-12-16 2010-05-11 Novartis Ag [(1H-indol-5-yl)-heteroaryloxy]-1-aza-bicylco[3.3.1]nonanes as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
US7713977B2 (en) 2005-12-16 2010-05-11 Novartis Ag (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenerative disorders
EP2409703A1 (fr) 2007-08-02 2012-01-25 Targacept, Inc. Traitement avec ligands alpha7 sélectifs
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
US8236803B2 (en) 2002-09-04 2012-08-07 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
US8476296B2 (en) 2009-01-26 2013-07-02 Targacept, Inc. Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide
US8609662B2 (en) 2004-07-14 2013-12-17 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases
WO2014111871A1 (fr) 2013-01-17 2014-07-24 Aurigene Discovery Technologies Limited Dérivés de 4,5-dihydroisoxazole utilisés comme inhibiteurs de nampt
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WO2015089218A1 (fr) 2013-12-10 2015-06-18 David Wustrow Composés monocycliques pyrimidine/pyridine comme inhibiteurs du complexe p97
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US10370370B2 (en) 2015-06-10 2019-08-06 Axovant Sciences Gmbh Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
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US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
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US7713976B2 (en) 2005-12-16 2010-05-11 Novartis Ag [(1H-indol-5-yl)-heteroaryloxy]-1-aza-bicylco[3.3.1]nonanes as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
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US8163729B2 (en) 2007-01-16 2012-04-24 Wyeth Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof
EP2409703A1 (fr) 2007-08-02 2012-01-25 Targacept, Inc. Traitement avec ligands alpha7 sélectifs
EP2484363A1 (fr) 2007-08-02 2012-08-08 Targacept, Inc. (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide
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