EP1940833A1 - Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof - Google Patents

Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof

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Publication number
EP1940833A1
EP1940833A1 EP06815264A EP06815264A EP1940833A1 EP 1940833 A1 EP1940833 A1 EP 1940833A1 EP 06815264 A EP06815264 A EP 06815264A EP 06815264 A EP06815264 A EP 06815264A EP 1940833 A1 EP1940833 A1 EP 1940833A1
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EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
azabicyclo
oct
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06815264A
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German (de)
English (en)
French (fr)
Inventor
Richard Schumacher
Mihaela Diana Danca
Jianguo Ma
Brian Herbert
Truc Minh Nguyen
Wenge Xie
Ashok Tehim
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Memory Pharmaceuticals Corp
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Memory Pharmaceuticals Corp
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Publication date
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Publication of EP1940833A1 publication Critical patent/EP1940833A1/en
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine 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
    • A—HUMAN NECESSITIES
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    • A61P25/22—Anxiolytics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds, which act as ligands for the ⁇ 7 nAChft subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
  • nAChR nicotinic acetylcholine receptors
  • muscarinic receptors There are two types of receptors for the neurotransmitter, acetylcholine: muscarinic receptors and nicotinic receptors, based on the selectivity of action of muscarine and nicotine, respectively.
  • Muscarinic receptors are G-protein coupled receptors.
  • Nicotinic receptors are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channels increases.
  • Nicotinic alpha-7 receptor protein forms a homo-pentameric channel in vitro that is highly permeable to a variety of cations (e.g., Ca +4 ).
  • Each nicotinic alpha-7 receptor has four transmembrane domains, named Ml , M2, M3, and M4.
  • the M2 domain has been suggested to form the wall lining the channel. Sequence alignment shows that nicotinic alpha-7 is highly conserved during evolution.
  • the M2 domain that lines the channel is identical in protein sequence from chicken to human.
  • the alpha-7 receptor see, e.g., Revah et al. (1991), Nature, 353, 846-849; Galzi et al.
  • the nicotinic alpha-7 receptor channel is expressed in various brain regions and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic alpha-7 receptors are localized on both presynaptic and postsynaptic terminals and have been suggested to be involved in modulating synaptic transmission. It is therefore of interest to develop novel compounds, which act as ligands for the oc7nACh receptor subtype, for the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors.
  • This invention relates to novel compounds, which act as ligands for the ⁇ 7 nACh receptor subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
  • the present invention includes compounds of Formulas I, II, III, or IV:
  • X is O or S
  • X I to X 4 are each, independently, N, CH, CR 1 , or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 , X 3 and X 4 are each CH or CR 1 , and group A is attached at the 3 -position to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 and X 3 are each CH or CR 1 , X 4 is N
  • group A is attached at the 3 -position to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 and X 4 are each CH or CR 1 , X 3 is N, and group A is attached
  • X 9 to X 12 are each, independently, N, CH, CR 4 , or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I),
  • X 9 , X 10 , X 11 and X 12 are each CH or CR 4 , and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV), X 9 , X 10 and X 1 ' are each CH or CR 4 , X 12 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV), or X 9 , X 10 and X 12 are each CH or CR 4 , X 1 !
  • X 9 , X 1 ' and X 12 are each CH or CR 4 , X 10 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV));
  • X 13 to X 16 are each, independently, N, CH, CR, or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV) (for example, X 13 , X 14 , X 15 and X 16 are each CH or CR, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (TVQ, X 13 , X 14 and X 15 are each CH or CR, X 16 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV), or X 13 , X 14 and X 16 are each CH or CR, X !5 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV), or X 13 , X 15 and X 16 are each CH or
  • R' is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;
  • R is H, F, Cl, Br, I, OH, CN, COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , " NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(C w -alkyl-O)i. 2 -C w - alkyl, NR 2 -C,.
  • 6 -alkyl-NR 6 R 7 NR 2 -Ci -6 -alkyl-CONR 6 R 7 , NR 2 -CO-C 1-6 -alkyl-Ar, NR 2 -Ci. 6 -alkyl-CO-O-R 2 , NR 2 -Ci -6 -alkyl-NR 2 (CO-O-R 2 ), -C ⁇ -alkyl-NR 2 , -0-C,.
  • 6-alkyl-NR 6 R 7 alkyl having 1 to 4 carbon atoms, fluorinated alkyl having l ! to 4 carbon atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene CgHs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, Ci -6 -alkoxy, NR 6 R 7 , CO-NR 6 R 7 , C 2-6 -alkoxycarbonyl, or
  • R is not NH 2 ; or R is of one of the following formulas
  • n 2 to 4;
  • n 3 to 5;
  • two R can together form a 5-membered fused ring structure containing at least one N atom
  • R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(C 1-6 -alkyl-O), -2 -C, -6 - alkyl, NR 2 -C,. 6 -alkyl-NR 6 R 7 , NR 2 -Ci. 6 -alkyl-CONR 6 R 7 , NR 2 -CO-d -6 -alkyl-Ar,
  • NR 2 -Ci -6 -alkyl-CO-O-R 2 NR 2 -Ci. 6 -alkyl-NR 2 (CO-O-R 2 ), -C ]-6 -alkyl-NR 2 , -0-C 1- 6 -alkyl-NR 6 R 7 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by
  • cycloalkyl having 3 to 7 carbon atoms cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, Ci -6 -alkoxy, NR 6 R 7 , CO-NR 6 R 7 , C 2 - 6 -alkoxycarbonyl, or - CO-R 10 , cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g., SCH 3 ), fluorinated al
  • R 1 is of one of the following formulas
  • two R 1 can together form a 5-membered fused ring structure containing at least one N atom;
  • R 2 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated Ci -4 -alkyl-CO-, C 3-7 -cycloalkyl-CO-, Ci 4 -alkyl-NH- CO-, C 3-7 -CyClOaIkYl-NH-CO-, Het, Ar-C M -alkyl-, Ar-C M -alkyl-CO-, Ar-C M - alkyl-SO 2 -, Ci -4 -alkyl-O-Ci.
  • R 3 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(Ci.
  • alkyl having 1 to 4 carbon atoms alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, Ci -6 -alkoxy, NR 6 R 7 , CO-NR 6 R 7 , C 2-6 -alkoxycarbonyl, or -
  • R 3 is of one of the following formulas
  • two R 3 can together form a 5-membered fused ring structure containing at least one N atom;
  • R 4 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 5 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 ,
  • alkyl having 1 to 4 carbon atoms alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to
  • alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, Ci -6 -alkoxy, NR 6 R 7 , CO-NR 6 R 7 , C 2-6 -alkoxycarbonyl, or - CO-R 10 , cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylme
  • hydroxyalkoxy having 2 to 4 carbon atoms e.g., 2,2,2-trifluoro-l-hydroxyl-l-(trifluoromethyl)ethyl
  • fluorinated hydroxyalkoxy having 2 to 4 carbon atoms monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-Ci -6 -alkyl-O-, Het-Ci -6 -alkyl-O-,
  • Het-CO-Het- Het-Ci -6 -alkyl-NR 2 -, or Ar-d. 6 -alkyl-Het-O-; or
  • R is of one of the following formulas
  • two R 4 can together form a 5-membered fused ring structure containing at least one N atom;
  • R 5 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or
  • R 6 and R 7 are each, independently, H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms, or R 6 and R 7 together are an alkylene group containing 4-6 carbon atoms which forms a ring with the N atom (e.g., piperidinyl, pyrrolidinyl);
  • R 8 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to
  • 6 carbon atoms e.g., propynyl, pentenyl
  • the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar, or Het; R 9 is alkyl having 1 to 4 carbon atoms, Ar, Ar-alky
  • R !0 is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms,
  • Ar is an aryl group having 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen (F, Cl, Br, or I, preferably F or Cl), dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino
  • Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., indanyl, tetrahydronaphthenyl, etc.); and
  • the compound is selected from Formulas I, II, III, or IV:
  • X is O or S
  • X 1 to X 4 are each, independently, N, CH, CR 1 , or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 , X 3 and X 4 are each CH or CR 1
  • group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 and X 3 are each CH or CR 1 , X 4 is N
  • group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV)
  • X 1 , X 2 and X 4 are each CH or CR 1 , X 3 is N
  • group A is attached at the 3-position to
  • X 1 , X 3 and X 4 are each.CH or CR 1 , X 2 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), QI), (III) or (IV));
  • X 5 to X 8 are each, independently, N, CH, CR 3 , or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I),
  • X 9 to X 12 are each, independently, N, CH, CR 4 , or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV) (for example, X 9 , X 10 , X 1 1 and X 12 are each CH or CR 4 , and group A is attached at the 3-position to the remainder of the structure of formulas
  • X 13 to X 16 are each, independently, N, CH, CR, or C-, wherein C- represents the point of attachment of group A to the remainder of the structure of formulas (I),
  • X 13 , X 14 , X 15 and X 16 are each CH or CR 3 and group A is attached at the 3 -position to the remainder of the structure of formulas (I), (II), (III) or (IV), X 13 , X 14 and X 15 are each CH or CR, X 16 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV), or X 13 , X 14 and X 16 are each CH or CR, X ls is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II),
  • X 13 , X IS and X 16 are each CH or CR, X 14 is N, and group A is attached at the 3-position to the remainder of the structure of formulas (I), (II), (III) or (IV));
  • R' is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;
  • R is H, F, Cl, Br, I, OH, CN, COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(Ci. 6 -alkyl-O)i -2 -C 1-6 - alkyl, NR 2 -Ci -6 -alkyl-NR 6 R 7 , NR 2 -Ci.
  • 6 -alkyl-CONR 6 R 7 NR 2 -CO-C 1-6 -alkyl-Ar, NR 2 -C,. 6 -alkyl-CO-O-R 2 , NR 2 -C,.
  • alkyl having 1 to 4 carbon atoms fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, C
  • each alkyl group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-Ci -6 -alkyl-O-, Het-Ci -6 -alkyl-O-, Het-CO-Het-, Het-Ci -6 -alkyl-NR 2 -, or Ar-Ci_ 6 -alkyl-Het-O-,
  • R is of one of the following formulas
  • n 2 to 4;
  • n 3 to 5;
  • two R can together form a 5-membered fused ring structure containing at least one N atom
  • R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 5 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(Ci -6 -alkyl-O)i -2 -Ci -6 - alkyl, NR 2 -C, -6 -alkyl-NR 6 R 7 , NR 2 -Ci -6 -alkyl-CONR 6 R 7 , NR 2 -CO-Ci -6 -alkyl-Ar, NR 2 -Ci -6 -alkyl-CO-O-
  • 6 -alkyl-NR 2 (CO-O-R 2 ), -Ci. 6 -alkyl-NR 2 , -0-C 1 . 6-alkyl-NR 6 R 7 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-,
  • R 1 is of one of the following formulas
  • two R ! can together form a 5-membered fused ring structure containing at least one N atom
  • R 2 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated Ci- 4 -alkyl-CO-, C 3-7 -cycloalkyl-CO-, Ci ⁇ -alkyl-NH- CO-, Cs-y-cycloalkyl-NH-CO-, Het, Ar-d- 4 -alkyl-, Ar-Ci -4 -alkyl-CO-, Ar-Ci -4 - alkyl-SO 2 -, Ci -4 -alkyl-O-Ci -4 -alkyl- (e.g., CH 2 CH 2 -O-CH 3 ), Ar-Cwalkyl-NH- CO-, or Het-NH-CO- (e.g., (l-azabicyclo[2.2.2]oct-3-yl
  • R 3 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 6 R 7 ,
  • alkyl having 1 to 4 carbon atoms fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO
  • hydroxyalkoxy having 2 to 4 carbon atoms
  • fluorinated hydroxyalkoxy having 2 to 4 carbon atoms
  • monoalkylamino having 1 to 4 carbon atoms
  • dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-Ci -6 -alkyl-O-, Het-Ci -6 -alkyl-O-,
  • Het-CO-Het- Het-C, -6 -alkyl-NR 2 -, or Ar-C,. 6 -alkyl-Het-O-; or
  • R is of one of the following formulas
  • R 4 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , -O-(C, -6 -alkyl-O), -2 -C 1-6 - alkyl, NR 2 -d -6 -alkyl-NR 6 R 7 , NR 2 -C,.
  • alkyl having 1 to 4 carbon atoms alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF3), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is unsubstituted or substituted by HCO-, Ci -6 -alkoxy, NR 6 R 7 , CO-NR 6 R 7 , C 2-6 -alkoxycarbonyl, or -
  • R is of one of the following formulas
  • two R 4 can together form a 5-membered fused ring structure containing at least one N atom;
  • R 5 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon " atoms (e.g., CF 3 ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar
  • R 6 and R 7 are each, independently, H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms, or R 6 and R 7 together are an alkylene group containing 4-6 carbon atoms which forms a ring with the N atom (e.g., piperidinyl, pyrrolidinyl);
  • R 8 is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms,
  • R 9 is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl wherein the alkyl portion has 1 to 4 carbon atoms, or Het;
  • R 10 is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted 'or substituted by Ar or Het (e.g., phenylacetylene C ⁇ Hs-C ⁇ C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms
  • Ar is an aryl group having 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen (F, Cl, Br, or I, preferably F or Cl), dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino
  • Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen (F, Cl, Br, or I, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) which is optionally substituted, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl), halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon
  • Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., indanyl, tetrahydronaphthenyl, etc.); and R u is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms (e.g., CF 3 ), alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g., propynyl, pentenyl), wherein the alkyl, halogenated alkyl, alkenyl, or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g., pheny
  • Z is alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., chloromethyl, chloroethyl), cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl), or arylalkylhaving 7 to 16 carbon amtoms (e.g., benzyl), and anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate.
  • anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate.
  • the compound is selected from Formulas I-IV, wherein: R 2 if present, is H, alkyl having 1 to 4 carbon atoms, fluorinated alky] having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated Ci -4 -alkyl-CO-, C 3 .
  • Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having 6 to 10 carbon atoms which is optionally substituted, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 C atoms, di(halogenated alkyl)amino wherein each alkyl group has 1 to 8 C atoms, (halogenated alkyl)amino having 1 to 8 carbon atom
  • the group A for example, an indazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, or isothiazolo[5,4-b]pyridinyl group, can be attached to the remainder of the structure via any suitable attachment point.
  • A when A is of subformula (a), e.g., an indazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (b), e.g., a benzothiazolyl group, it is preferably attached to the remainder of the compound via its 4 or 7 position.
  • A when A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3- ⁇ osition.
  • A when A is of subformula (a), e.g., an indazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (b), e.g., a benzothiazolyl group, it is preferably attached to the remainder of the compound via its 4 or 7 position.
  • A when A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (a), e.g., an indazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (b), e.g., a benzothiazolyl group, it is preferably attached to the remainder of the compound via its 4 or 7 position.
  • A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (a), e.g., an indazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A when A is of subformula (b), e.g., a benzothiazolyl group, it is preferably attached to the remainder of the compound via its 4 or 7 position.
  • A is of subformula (c), e.g., a benzoisothiazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • A is of subformula (d), e.g., a benzisoxazolyl group, it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
  • the following subformulas illustrate some of the preferred attachments between the A groups, e.g., indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl, and isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula I .
  • the R, R 1 , R 3 , and/or R 4 substituent is generally present 1, 2, or 3 times, preferably 1 or 2 times, more preferably once.
  • the following subformulas further illustrate some of the preferred attachments between the A groups, e.g., groups, e.g., indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3- c]pyridinyl, and isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula II.
  • the R, R 1 , R 3 , and/or R 4 substituent is generally present 1 , 2, or 3 times, preferably 1 or 2 times, more preferably once.
  • the following subformulas further illustrate some of the preferred attachments between the A groups, e.g., indazole, benzothiazole, benzoisotbiazole, benzisoxazole, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl, and isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula III.
  • the R, R 1 , R 3 , and/or R 4 substituent is generally present 1, 2, or 3 times, preferably 1 or 2 times, more preferably once.
  • the following subforraulas further illustrate some of the preferred attachments between the A groups, e.g., indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-c]pyridinyl, and isothiazolo[5,4-b]pyridinyl, and the remainder of the structure for Formula IV.
  • the R, R 1 , R 3 , and/or R 4 substituent is generally present 1, 2, or 3 times, preferably 1 or 2 times, more preferably once.
  • X is preferably O.
  • R' is preferably H, cyclopropylmethyl, or CH 3 , particularly H.
  • Alkyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms.
  • Suitable alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert- butyl.
  • Alkenyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 2 to 6 carbon atoms. Suitable alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, and pentenyl.
  • Alkynyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 2 to 6 carbon atoms.
  • Suitable alkynyl groups include but are not limited to ethyne (ethynyl), propyne (propynyl), butyne (butynyl), etc.
  • Alkoxy means alkyl-O- groups in which the alkyl portion has 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Suitable alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.
  • Alkoxyalkyl means alkyl-O-alkyl- groups in which each alkyl portion independently has 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Suitable alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, and methoxyethyl.
  • Alkylthio means alkyl-S- groups in which the alkyl portion preferably has 1 to 4 carbon atoms. Suitable alkylthio groups include but are not limited to methylthio and ethylthio.
  • Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.
  • Suitable cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Other suitable cycloalkyl groups include but are not limited to spiropentyl, bicyclo[2.1.0]pentyl, and bicyclo[3.1.0]hexyl.
  • Cycloalkoxy means cycloalkyl-O- groups in which the cycloalkyl portion preferably is a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.
  • Cycloalkylalkyl groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkyl groups include but are not limited to, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and cyclopentylmethyl.
  • Cycloalkylalkoxy groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkoxy groups include but are not limited to, for example, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, and cyclopentylmethyloxy.
  • Cycloalkyl and cycloalkylalkyl structures can be substituted by, for example, Ci -4 - alkyl, Ci -4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialklyamino in which each alkyl group has 1 to 4 carbon atoms.
  • Aryl as a group or substituent per se or as part of a group or substituent (e.g., Ar, OAr, Ar-Ci- 6 -alkyl-O-, or Ar-Ci- ⁇ -alkyl-Het-O-), refers to an aromatic carbocyclic radical having 6 to 10 carbon atoms, unless indicated otherwise.
  • Suitable aryl groups include but are not limited to phenyl, napthyl and biphenyl.
  • Substituted aryl groups include the above-described aryl groups which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalky], hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and/or acyloxy (e.g., acetoxy).
  • Heterocyclic groups e.g., the Het portions of Het, OHet, Het-Ci, 6 -alkyl-O-, Het-
  • CO-Het-, and Het-Ci ⁇ -alkyl-NR 2 refer to saturated, partially saturated and fully unsaturated heterocyclic groups having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom.
  • the heterocyclic group contains 1 to 3 hetero-ring atoms selected from N, O and S.
  • Suitable saturated and partially saturated heterocyclic groups include, but are not limited to dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like.
  • Suitable heteroaryl groups include but are not limited to furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like.
  • heterocyclic groups are 2-furyl, 3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 3-thienyl, l,3-thiazoly-2-yl, 1,3-oxazol- 2-yl, pyrrolidin-1-yl, 6-pyrrolidin-1-yl, piperidin-1-yl, 6-piperazin-1-yl, morpholin-4-yl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4- pyridyl, 3-quinolinyl, 4-quinolinyl, l,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 5-indolyl, 1
  • Heterocyclic groups also include substituted and unsubstituted azabicyclo and oxaazabicyclo groups, for example, 2,5-diazabicyclo[2.2.1]hept-2-yl, methyl-2,5- diazabicyclo[2.2.1]hept-2-yl, trifluoroethyl-2,5-diazabicyclo[2.2. l]hept-2-yl, 2-oxa-5- azabicyclo[2.2. l]hept-5yl, 5-methyl-2,5-diazabicyclo[2.2.
  • Substituted heterocyclic groups refer to the heterocyclic groups described above, which are substituted in one or more places by, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and/or dialkylamino.
  • Suitable substituted heterocyclic groups include 2-methylpiperazin-l-y, 3-methylpiperazin-1-yl, 4- methylpiperazin-1-yl, 3,4-dimethylpiperazin-1-yl, 4-methyl-l,4-diazepan-1-yl, 3- methoxypyrrolidin-1-yl, l-methylpyrrolidin-3-yl, l-methyl-4,5-dihydro-1H-imidazol-2- yl, 3-(cyclopropylmethoxy)pyrrolidin-1-yl, 6-chloroisothiazolo[5,4-b]pyridinyl, 4- (cyclopropylcarbonyl)piperazin- 1 -yl, and 1 -(cyclopropylcarbonyl)octahydro-6H- pyrrolo[3,4-b]pyridin-6-yl.
  • Substituted radicals are, in each case, substituted one or more times, and preferably have 1 to 3 substituents, especially 1 or 2 substituents of the exemplified substituents. These substituents are in each case independently selected. Thus, the substituents can be the same or different.
  • ⁇ alogenated radicals such as halogenated alkyls are preferably fluorinated and include but are not limited to perhalo radicals such as trifluoromethyl.
  • R is not NH 2 or NHCH 3 . According to a further aspect of the invention, R is not NH2, NHCH3, or N(CH3) 2 . According to a further aspect of the invention, R is not NH 2 , monoalkylamino, or dialkylamino.
  • R 2 is Het-NH- CO-.
  • the Het group is preferably an azabicyclo group, for example, 1- azabicyclo[2.2.2]oct-3-yl.
  • Het is substituted by cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl).
  • the cycloalkyl portion when Het is substituted by cycloalkylalkyl, preferably has 3 to 5 carbon atoms (e.g., cyclopropyl), and the alkyl portion preferably has 1 to 2 carbon atoms.
  • the Het group is preferably an azabicyclo group, for example, 2,5- diazabicyclo[2.2.1]hept-2-yl.
  • Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl), halogenated alkyl other than trifluorornethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl
  • the compound is selected from Formula I-IV wherein at least one R, R 1 , R 3 , R , and R 5 group is Het or OHet in which the Het group is selected from, in each case substituted or unsubstituted, azabicyclooctyl (e.g., l-azabicyclo[2.2.2]oct-3-yl), oxa-azabicycloheptyl (e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl), diazabicycloheptyl (e.g., 2,5- diazabicyclo[2.2.
  • azabicyclooctyl e.g., l-azabicyclo[2.2.2]oct-3-yl
  • oxa-azabicycloheptyl e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl
  • diazabicycloheptyl e.g., 2,
  • At least one of X 1 , X 2 , X 3 , and X 4 is N; least one of X 5 , X 6 , X 7 , and X 8 is N; at least one of X 9 , X !0 , X u , and X 12 is N; and/or at least one of X 13 , X 14 , X 15 , and X 16 is N.
  • at least one of X 1 , X 2 , X 3 , and X 4 is N, and 1 or 2 of the remaining X 1 - X 4 are CR 1 .
  • At least one of X 5 , X 6 , X 7 , and X 8 is N, and 1 or 2 of the remaining X 5 - X 8 are CR 3 .
  • at least one of X 9 , X 10 , X 11 , and X 12 is N, and 1 or 2 of the remaining X 9 - X 12 are CR 4 .
  • at least one ofX 13 , X 14 , X 15 , and X 16 is N, and 1 or 2 of the remaining X 13 - X 16 are CR.
  • X 4 is N and X 1 , X 2 , and X 3 are each CH or CR 1 .
  • X 3 is N and X 1 , X 2 , and X 4 are each CH or CR 1 .
  • X 12 is N and X 9 , X 10 , and X 11 are each CH or CR 4 .
  • Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoromethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH 2 ), alkyl(halogenated alkyl)amino where
  • Het is a heterocyclic group, which is fully saturated and which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 C atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 3 OCH 2 ), alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 C atoms, di(halogenated alkyl)amino wherein each alkyl group has
  • Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, i having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy) halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 3 OCH 2 ), or alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms (e.g., OCHF 2
  • Het is a fully saturated heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH 2 ), or alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms.
  • halogenated alkoxy having 1 to 8 carbon atoms e.g., OCHF 2
  • cycloalkylalkoxy having 4 to 7 carbon atoms e.g.
  • A is of formula (a) having at least one R 1 substituent that is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 3 OCH2)
  • A is of formula (a) having at least one R 1 substituent that is a fully saturated heterocyclic group which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 C atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH 2 ), or alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms.
  • halogenated alkoxy having 1 to 8 C atoms e.g.,
  • A is of formula (c) having at least one R 4 substituent that is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 3 OCH 2
  • A is of formula (c) having at least one R substituent that is a fully saturated heterocyclic group which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH3OCH 2 ), or alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms.
  • halogenated alkoxy having 1 to 8 carbon atoms e.g.,
  • A is of formula (d) having at least one R substituent that is OH, O-(Ci -6 -alkyl-O)i -2 -Ci-6-alkyl, - O-Ci- 6 -alkyl-NR 6 R 7 , alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCFs 1 OCHF 2 ), hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to.4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHe
  • A is of formula (d) having at least one R substituent that is OH, O-(Ci -6 -alkyl-O)i -2 -Ci- 6 -alkyl, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF 3 ⁇ OCHF 2 ), hydroxyalkoxy having 2 to 4 carbon atoms, or fluorinated hydroxyalkoxy.
  • R substituent that is OH, O-(Ci -6 -alkyl-O)i -2 -Ci- 6 -alkyl, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycl
  • A is of formula (d) having at least one R substituent that is OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF 31 OCHF 2 ), hydroxyalkoxy having 2 to 4 carbon atoms, or fluorinated hydroxyalkoxy.
  • R substituent that is OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF 31 OCHF 2 ), hydroxyalkoxy having 2 to 4 carbon atoms, or fluorinated hydroxyalkoxy.
  • A is of formula (a) having at least one R 1 substituent that is dihydroimidazolyl.
  • A is of formula (a) having at least one R 1 substituent that is Het other than thiazolyl, and wherein R 2 is alkyl having 2 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated C M -alkyl-CO-, C 3-7 -cycloalkyl-CO-, Ci- 4 -alkyl-NH-CO-, C 3-7 ⁇ cycloalkyl- NH-CO-, Het, Ar-Cw-alkyl-, Ar-Cw-alkyl-CO-, Ar-C ]-4 -alkyl-SO 2 -, Ci 4 -alkyl-0-C ]-4 - alkyl- (e.g., CH 2 CH 2 -O-CH 3 ), or Ar-C M -
  • A is of formula (c) having at least one R 4 substituent that is imidazolyl (e.g., imidazol-1-yl), pyrrolyl, pyrazolyl, Q-salkyl-pyrazolyl (e.g., 3-methyl-1H-pyrazol-1-yl, 5-methyl-1H- pyrazol-1-yl), oxa-azabicycloheptyl (e.g., 2-oxa-5-azabicyclo[2.2.1]heptyl), diazabicycloheptyl (e.g., 2,5-diazabicyclo[2.2.1]hept-2-yl), Ci.galkyl-diazabicycloheptyl (e.g., 5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl), halogenated Q-salkyl- diazabicycloheptyl (e.g.
  • Z is alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., chloromethyl, chloroethyl), cycloalkylalkyl having 4 to 7 carbon atoms (e.g., cyclopropylmethyl), or arylalkylhaving 7 to 16 carbon amtoms (e.g., benzyl), and anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate.
  • groupA is preferably of formula (a) or (c).
  • X 1 to X 4 are each, preferably, CH or CR 1
  • X 9 to X 12 are each, preferably, CH or CR 4 .
  • the compound is selected from formula Ip according to the following subgenera:
  • X 13 -X 16 are independently CH or CR wherein at least one of X 13 -X 16 is other than CH;
  • X is O
  • R is H, alkyl (e.g., CH 3 or C 2 H 5 , particularly CH 3 ) or cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopropylethyl, particularly cyclopropylmethyl); and
  • At least one R is alkoxy (e.g., OCH 3 ) or Het (e.g., 3-methoxy-pyrrolidin-l- yl [such as (3R)-3-methoxypyrrolidin-1-yl, (3S)-3-methoxypyrrolidin-l- yi.
  • the compound is selected from formula Ia or Ij according to the following subgenera:
  • one of X 1 -X 4 is N or one of X 9 -X 12 is N and the others of X 1 -X 4 or of X 9 - X 12 are CH, CR 1 or CR 4 ;
  • R is H, alkyl (e.g., CH 3 or C 2 Hs, particularly CH 3 ) or cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopropylethyl, particularly cyclopropylmethyl);
  • R 2 is H
  • R 1 and R 4 are independently selected from H, halogen (e.g., Cl or F), Ar
  • Het e.g., 3-dimethylaminopyrrolidin-1-yl.
  • the compound is selected from the following subgenera:
  • X 8 is N
  • a compound according to formula Ia or Ij having at least one R 1 or R 4 which is substituted Het and at least one of the Het substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 2 OCH 3 ), alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8 carbon atoms, di(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms, or (halogenated al
  • a compound according to formula Ia or Ij having at least one R 1 or R 4 which is substituted Het and at least one of the Het substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 2 OCH 3 ), or alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8 carbon atoms;
  • halogenated alkoxy having 1 to 8 carbon atoms e.g., OCHF 2
  • cycloalkylalkoxy having 4 to 7 carbon atoms e
  • a compound according to formula Ia or Ij having at least one R 1 or R 4 which is a substituted fully saturated Het group (e.g., pyrrolidinyl or piperidinyl) and at least one of the Het substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g., OCHF 2 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (e.g., CH 2 OCH 3 ), alkyl(halogenated alkyl)amino, wherein each alkyl group has 1 to 8 carbon atoms, di(halogenated alkyl group
  • alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl
  • alkoxyalkyl having 2 to 8 carbon atoms e.g., CH 2 OCH3
  • alkyl(halogenated alkyl)amino wherein each alkyl group has 1 to 8 carbon atoms
  • a compound according to formula Ip having at least one R substituent that is OH, O-(Ci -6 -alkyl-O), -2 -Ci -6 -alkyl, -O-Q 1-6 -alkyl-NR 6 R 7 , alkoxy having 1 to 4 carbon atoms (e.g., OCH 3 ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g., cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCFs 1 OCHFa), hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having at least one R substituent that is OH, O-(Ci -6 -alkyl-O), -2 -Ci -6 -alkyl, -O-Q 1-6 -alkyl-NR 6 R 7 , alkoxy
  • cycloalkoxy having 3 to 7 carbon atoms e.g., OCH 3
  • cycloalkylalkoxy having 4 to 7 carbon atoms e.g., cyclopropylmethoxy
  • fluorinated alkoxy having 1 to 4 carbon atoms e.g., OCF ⁇ , OCHF 2
  • hydroxyalkoxy having 2 to 4 carbon atoms or fluorinated hydroxyalkoxy
  • imidazolyl e.g., imidazol-1-yl
  • pyrrolyl pyrazolyl
  • Ci-salkyl-pyrazolyl e.g., 3-methyl-1H-pyrazol-1-y
  • Ci -8 alkyl- diazabicycloheptyl e.g. trifluoroethyl-2,5-diazabicyclo[2.2. l]hept-2-yl
  • ((Ci-salkyFhN-), alkoxyalkyl, or alkyl (fluorinated alkyl)amino e.g., 3- (cyclopropylmethoxy)pyrrolidin-1-yl, 3-(hydroxy)pyrrolidin-1-yl (such as 3-(3R)-hydroxypyrrolidin-1-yl, 3-(3S)-hydroxypyrrolidin-1-yl), 3- (difluoromethoxy)pyrrolidin- 1 -yl), 3-(dimethylamino)pyrrolidin- 1 -yl (such as 3-(3 S)-(dimethylamino)pyrrolidin- 1 -yl, 3-(3R)-
  • the compound of formulas I-IV is selected from:
  • a compound listed above in either a free base form or in the form of a pharmaceutically acceptable salt
  • a compound listed above in either a free base form or in the form of a pharmaceutically acceptable salt
  • a compound listed above in a free base form or solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof
  • the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
  • the compound of formulas I-IV is selected from:
  • salts listed above can also be in free base form or in the form of another pharmaceutically acceptable salt, and free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),
  • a compound listed above in a free base form or solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof
  • the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
  • the compound of formulas I-IV is selected from:
  • salts listed above can also be in free base form or in the form of another pharmaceutically acceptable salt, and free base forms listed above can also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above (in either a free base form or in the form of a pharmaceutically acceptable salt) can also be in the form of a solvate (such as a hydrate),
  • a compound listed above in either a free base form or in the form of a pharmaceutically acceptable salt
  • a compound listed above in a free base form or solvate or ⁇ -oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof
  • the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
  • the compound of formulas I-IV is:
  • the compound of formulas I-IV is selected from:
  • salts listed above can also be in free base form or in the form of another pharmaceutically acceptable salt, and free base forms listed above can also be in the form of a pharmaceutically acceptable salt,
  • a compound listed above in either a free base form or in the form of a pharmaceutically acceptable salt
  • a compound listed above in either a free base form or in the form of a pharmaceutically acceptable salt
  • a compound listed above in a free base form or solvate or ⁇ -oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof
  • the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer.
  • compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of stimulating or activating inhibiting alpha-7 nicotinic receptors, e.g., as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating a neurological syndrome, e.g., loss of memory, especially long-term memory, cognitive impairment or decline, memory impairment, etc. method of treating a disease state modulated by nicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., those mentioned herein.
  • a mammal e.g., a human, e.g., those mentioned herein.
  • the compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials by one of ordinary skill.
  • Acids that were used in the preparation of the bicyclobase amides were commercially available or were prepared by known procedures described in the literature or as described below.
  • indazole-3-carboxylic acid was commercially available.
  • a variety of the simple substituted indazole-3-acids, such as the bromoindazole acids, were prepared from the corresponding isatins by basic hydrolysis, diazotization, and reduction (Snyder, H.R. et al., J. Am. Chem. Soc. 1952, 74, 2009).
  • N(I)- and N(2)-protected indazole acids were prepared from the ester through reaction with methoxyethoxymethyl chloride (MEM-Cl) or trimethylsilylethoxymethyl chloride (SEM-Cl) and either sodium hydride or di- isopropylethylamine.
  • MEM-Cl methoxyethoxymethyl chloride
  • SEM-Cl trimethylsilylethoxymethyl chloride
  • N(I)- Alkylated indazole-3-carboxylic acids were prepared from the corresponding indazole esters by standard alkylation or Mitsunobu procedures.
  • N(I)- Arylated indazole-3-carboxylic acids were prepared from the corresponding indazole esters by copper mediated cross couplings with boronic acids.
  • ⁇ on-aromatic heterocyclic derivatives were prepared from the corresponding bromides by metal-halogen exchange, trapping of indazole aryllithiums with ketones, followed by reduction or acid mediated elimination.
  • Aromatic substituted indazole-3-acids were prepared from the corresponding bromides via palladium mediated cross-coupling with boronic acids or aryl zinc reagents (Reeder, M.R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696).
  • Amino indazole acids were prepared using a palladium mediated cross-coupling reaction with secondary amines. Phenol derivatives were prepared from the corresponding methoxy acids using boron tribromide. 6-Amino- and 6-phenyl-7-azaindazole-3-carboxylic acids were prepared from the commercially available 6-fluoro material by reaction with a secondary amine or by nickel mediated cross-coupling with aryl Grignard reagents.
  • 5-difluoromethoxyindazole-3-acid was prepared from 3-bromo-4-nitrophenol by reaction with ethyl difluoroacetate, reaction with diethyl malonate, decarboxylative saponification, esterification, reduction of the nitro group, and diazotization.
  • 6- Difluoromethoxyindazole-3-acid was prepared in a similar manner from 2-bromo-5- difluoromethoxynitrobenzene.
  • the 2-bromo-5-difluoromethoxynitrobenzene was prepared from 4-nitrophenol by ether formation, nitro reduction with concomitant protection as the amide, nitration, amide hydrolysis, and a Sandmeyer reaction with copper (I) bromide.
  • ⁇ -Benzyloxyindazole-3-carboxylic acid and ester were prepared from 4-methoxy nitrobenzene by nitro reduction with concomitant protection as the amide, nitration, amide hydrolysis, Sandmeyer reaction with copper (I) bromide, and demethylation.
  • the phenol was alkylated with benzyl bromide and the arylbromide was subjected to reaction with diethyl malonate, decarboxylative saponification, esterification, reduction of the nitro group, and diazotization.
  • the 5-benzyloxy analog was prepared in a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker, K.A.; Mindt, T.L. Org. Lett. 2002, 4, 4265.)
  • the benzyl group was removed by hydrogenolysis and the resulting phenol was transformed to ether derivatives via either alkylation or Mitsunobu reaction conditions.
  • 4-Methoxyindazole acid was prepared from 4- methoxyaniline by amide formation, nitration, amide hydrolysis, Sandmeyer reaction with copper (I) bromide, nitro reduction, isatin formation and rearrangement to the indazole, followed by hydrogenolytic removal of the bromine.
  • 5-Azaindazole-3-acid was prepared from 4-chloropyridine by metallation and trapping with diethyloxalate, cyclization with hydrazine, and saponification.
  • 6-Azaindazole-3-acid was prepared from 4-chloro-3-nitropyridine by reaction with a malonate anion, decarboxylation, nitro reduction, diazotization, and saponification.
  • the benziosoxazole esters were prepared from simple benzene derivatives using similar techniques. For example, ethyl 6-bromobenzisoxazole-3-carboxylate was prepared from 2-nitro-l,4-dibromobenzene by reaction with dimethylmalonate, a saponification/decarboxylation sequence, esterification, and reaction with isoamyl nitrite under basic conditions.
  • the 6-methoxybenzisoxazole ester compound was prepared, analogously, from 2,4-dinitrochlorobenzene. Reduction of the resultant 6-nitro group followed by diazotization and oxidation provided the 6-hydroxy compound.
  • the ether was obtained by simple alkylation.
  • the benzisothiazole carboxylic acids were also prepared using similar strategies outlined for the indazole acids.
  • 6-methoxybenzisothiazole-3-carboxylic acid was prepared from 3-methoxythiophenol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide, and sodium hydroxide.
  • Amino substituted benzisothiazole acids were prepared from the requisite bromide by a palladium mediated cross-coupling reaction with secondary amines or benzophenone imine. The primary and secondary amines generated this way serve as intermediates for other ligands.
  • 7-Azabenzisothiazole-3-carboxylic acid was prepared from 2-chloronicotinoyl chloride by reaction with the diethylmalonate anion and decarboxylation followed by reaction of the ketone with sulfer, ammonium hydroxide, and ammonia to generate the 7-aza-3-methylbenzisothiazole core.
  • the acid was installed using a benzylic oxidation with N-bromosuccinamide and hydrolysis, followed by basic permanganate oxidation of the alcohol.
  • 7-Aza-6- chlorobenzisothiazole-3-acid was synthesized from the 7-aza-3-methylbenzisothiazole core by oxidation of the pyridine ring nitrogen followed by a rearrangement reaction mediated by triphosgene to install a chlorine atom at the 6-position.
  • the synthesis was completed by a benzylic oxidation in a similar manner to the unsubstituted azabenzisothiazole acid.
  • the bicycloamines, 3-aminoquinuclidine and the R- and S- enantiomers thereof, used in the preparation of the bicyclobase amides were commercially available.
  • the N- alkylated quinuclidines were prepared by acylation of 3-aminoquinuclidine followed by reduction of the amide.
  • the bicyclobase amides were prepared from the acids and the bicycloamines using standard peptide coupling agents, such as O(benzotriazol- 1-y X)-N 1 N 1 N ',N - tetramethyluroniurn hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-
  • standard peptide coupling agents such as O(benzotriazol- 1-y X)-N 1 N 1 N ',N - tetramethyluroniurn hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-
  • HATU NN,N',N'-tetramethyluronium hexafluorophosphate
  • TBTU O-(benzotriazol-1-yl)- NNN'.N'-tetramethyluronium tetrafJuoroborate
  • HOBt hydroxybenztriazole
  • EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
  • CDI carbonyl diimidazole
  • CIP 2-chloro-l,3,-dimethylimidazolinium hexafluorophosphate
  • the nicotinic ligands can, alternatively, be prepared by modification of other nicotinic ligands.
  • the cyclic urea ligand was prepared from the corresponding bromide ligand by a palladium-catalyzed cross-coupling reaction.
  • Amino- substituted ligands were prepared by similar palladium mediated coupling reactions with secondary amines or benzophenone imine. The primary and secondary amines generated this way serve as intermediates for other ligands, as understood by those of ordinary skill in the art.
  • 5-Alkoxybenzisothiazole ligands were prepared by palladium mediated cross coupling with pinacolborane dimer followed by oxidation and alkylation.
  • the indazole quinuclidine carboxamides were derivatized at the indazole nitrogen under Mitsunobu conditions or through the copper mediated coupling with boronic acids.
  • Quaternary quinuclidine salts were prepared by the reaction of the final product with alkylating agents.
  • N-Oxides were prepared by the reaction of the final product with oxidants.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivitization, are also useful.
  • the optically active compounds of Formulas I-IV can likewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization.
  • the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compounds are deuterated.
  • Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the efficacy and increase the duration of action of drugs.
  • Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981 :476229 CAPLUS.
  • the present invention also relates to useful forms of the compounds as disclosed herein, including free base forms and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
  • an appropriate base e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3- phenylpropionates, picrates, pivalates, propionates
  • the pharmaceutically acceptable salt can be a hydrochloride, a hydrobromide, a hydroformate, or a maleate.
  • the salts of the present invention also include quaternary ammonium salts obtained by reacting the main compound, functioning as a nucleophile, with agents bearing nucleofugal groups.
  • agents include, but are not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, methyl tosylate, methyl mesylate, ethyl iodide, ethyl bromide, ethyl chloride, ethyl triflate, ethyl tosylate, ethyl mesylate, propyl iodide, propyl bromide, propyl chloride, cyclopropylmethyl bromide, benzyl bromide, methylene chloride, and dichloroethane.
  • methyl iodide methyl bromide, methyl chloride
  • methyl triflate methyl tosylate, methyl mesylate, ethyl i
  • the quaternary ammonium salt can be formed at the N atom of the azabicyclo structute as shown in the following formula:
  • Z is, for example, methyl, chloromethyl, ethyl, chloroethyl, propyl, cyclopropylmethyl, or benzyl
  • anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate. See, for example, compounds 1, 13, and 165.
  • the salts formed are pharmaceutically acceptable for administration to mammals.
  • pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent.
  • alkyl halide addition salts e.g., salts formed by reaction with methyl iodide
  • the free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
  • polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
  • Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
  • the compounds of the invention can be administered alone or as an active ingredient of a formulation.
  • the present invention also includes pharmaceutical compositions of compounds of Formulas I-IV, containing, for example, one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention can be administered to anyone needing stimulation of alpha-7 receptors.
  • Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.
  • solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
  • liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose.
  • Topical administration may also involve transdermal administration via means such as transdermal patches.
  • Aerosol formulations suitable for administering via inhalation also can be made.
  • the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions.
  • the aerosol formulation can be placed into a pressurized acceptable propellant.
  • the compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or memory loss, e.g., other ⁇ -7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine).
  • each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.
  • the compounds of the invention can be used in conjunction with "positive modulators" which enhance the efficacy of nicotinic receptor agonists. See, e.g., the positive modulators disclosed in WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational therapy can be used in treating conditions/diseases associated with reduced nicotinic transmission.
  • a ⁇ peptides and thereby inhibit the binding of the peptides to ⁇ 7nACh receptor subtypes. See, e.g., WO 99/62505.
  • the present invention further includes methods of treatment that involve activation of ⁇ -7 nicotinic receptors.
  • the present invention includes methods of selectively activating/stimulating ⁇ -7 nicotinic receptors in a patient (e.g., a mammal such as a human) wherein such activation/stimulation has a therapeutic effect, such as where such activation may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory.
  • Such methods comprise administering to a patient (e.g., a mammal such as a human), an effective amount of a compound of Formulas 1-IV, alone or as part of a formulation, as disclosed herein.
  • a method of treating a patient e.g., a mammal such as a human
  • a disease state e.g., memory impairment
  • the disease state involves decreased nicotinic acetylcholine receptor activity.
  • a method for the treatment or prophylaxis of a disease or condition resulting from dysfunction of nicotinic acetylcholine receptor transmission in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for the treatment or prophylaxis of a disease or condition resulting from defective or malfunctioning nicotinic acetylcholine receptors, particularly ⁇ 7nACh receptors, in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for the treatment or prophylaxis of a disease or condition resulting from suppressed nicotinic acetylcholine receptor transmission in a patient comprising administering an amount of a compound according to Formulas I-IV effective to activate ⁇ 7nACh receptors.
  • a method for the treatment or prophylaxis of a psychotic disorder, a cognition impairment (e.g., memory impairment), or neurodegenerative disease in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for the treatment or prophylaxis of a disease or condition resulting from loss of cholinergic synapses in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for the treatment or prophylaxis of a neurodegenerative disorder by activation of cc7nACh receptors in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for protecting neurons in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for the treatment or prophylaxis of a neurodegenerative disorder by inhibiting the binding of A ⁇ peptides to ⁇ 7nACh receptors in a patient (e.g., a mammal such as a human) comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for protecting neurons in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a method for alleviating inhibition of cholinergic function induced by A ⁇ peptides in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
  • a subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment.
  • the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.
  • the compounds of the present invention are nicotinic alpha-7 ligands, preferably agonists, especially partial agonists, for the alpha-7 nicotinic acetylcholine receptor.
  • Assays for determining nicotinic acetylcholine activity are known within the art. See, e.g., Davies, A.R., et al., Characterisation of the binding of
  • Nicotinic acetylcholine receptors are ligand-gastrol ion-channel receptors that are composed of five subunit proteins which form a central ion-conducting pore.
  • Nicotinic acetylcholine receptors are ligand-gastrol ion-channel receptors that are composed of five subunit proteins which form a central ion-conducting pore.
  • neuronal nACh receptor subunits ⁇ 2 - ⁇ 9 and ⁇ 2 - ⁇ 4
  • There are also five further subunits expressed in the peripheral nervous system ( ⁇ l, ⁇ l, ⁇ , ⁇ , ⁇ ).
  • the nACh receptor subtypes can be homopentameric or heteropentameric.
  • the subtype which has received considerable attention is the homopentameric ⁇ 7 receptor subtype formed from five ⁇ 7 subunits.
  • the ⁇ 7nACh receptors exhibit a high affinity for nicotine (agonist) and for ⁇ -bungarotoxin (antagonist).
  • the ⁇ 7nACh receptor agonists can be useful in the treatment of psychotic diseases, neurodegenerative diseases, and cognitive impairments, among other things. While nicotine is a known agonist, there is a need for the development of other ⁇ 7nACh receptor agonists, especially selective agonists, which are less toxic or exhibit fewer side effects than nicotine.
  • the compound anabaseine i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine is a naturally occurring toxin in certain marine worms (nemertine worms) and ants. See, e.g., Kem et al., Toxicon, 9:23, 1971.
  • Anabaseine is a potent activator of mammalian nicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25, 99, 1985.
  • anabaseine analogs such as anabasine and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6- tetrahydro-2',3'-bipyridine) are also known nicotinic receptor agonists. See, e.g., US 5,602,257 and WO 92/15306.
  • abnormal sensory inhibition is a sensory processing deficit in schizophrenics and GTS-21 has been found to increase sensory inhibition through interaction with ⁇ 7nACh receptors. See, e.g., Stevens et al., Psychopharmacology, 136: 320-27 (1998).
  • Tropisetron i.e., IaH, 5 ⁇ H-tropan-3 ⁇ -yl indole-3-carboxylate.
  • Tropisetron CICS 205-930 The 5-HT3-Antagonist Tropisetron CICS 205-930 is a Potent and Selective A7 Nicotinic Receptor Partial Agonist. Bioorg. Med. Chem. Lett. 2001, 319-321).
  • Agents that bind to nicotinic acetylcholine receptors have been indicated as useful in the treatment and/or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder), and other uses such as treatment of nicotine addiction, inducing smoking cessation, treating pain (i.e., analgesic use), providing neuroprotection, and treating jetlag.
  • psychotic diseases including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders],
  • a method of treating a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], and/or cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder) comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
  • psychotic diseases including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases]
  • cognitive disorders such as Alzheimer's disease, Lewy Body Dementia,
  • Neurodegenerative disorders included within the methods of the present invention include, but are not limited to, treatment and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse Lewy Body disease, progressive supranuclear palsy (Steel- Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3, olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedy's disease), primary
  • ⁇ 7nACh receptor agonists such as the compounds of the present invention can be used to treat age-related dementia and other dementias and conditions with memory loss including age-related memory loss, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica and frontal lobe dementia. See, e.g., WO 99/62505.
  • a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions with memory loss comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
  • the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, mild cognitive impairment due to aging, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formulas I-IV.
  • Amyloid precursor protein (APP) and A ⁇ peptides derived therefrom, e.g., A ⁇ i- 4 o , A ⁇ i. 42 , and other fragments, are known to be involved in the pathology of Alzheimer's disease.
  • the A ⁇ i. 42 peptides are not only implicated in neurotoxicity but also are known to inhibit cholinergic transmitter function.
  • a ⁇ peptides bind to ⁇ 7nACh receptors.
  • agents which block the binding of the A ⁇ peptides to ⁇ -7 nAChRs are useful for treating neurodegenerative diseases. See, e.g., WO 99/62505.
  • stimulation ⁇ 7nACh receptors can protect neurons against cytotoxicity associated with A ⁇ peptides. See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.
  • a method of treating and/or preventing dementia in an Alzheimer's patient which comprises administering to the subject a therapeutically effective amount of a compound according to Formulas I-IV to inhibit the binding of an amyloid beta peptide (preferably, A ⁇ i- 42 ) with nACh receptors, preferable ⁇ 7nACh receptors, most preferably, human ⁇ 7nACh receptors (as well as a method for treating and/or preventing other clinical manifestations of Alzheimer's disease that include, but are not limited to, cognitive and language deficits, apraxias, depression, delusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities).
  • the present invention also provides methods for treating other amyloidosis diseases, for example, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle- Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
  • other amyloidosis diseases for example, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle- Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
  • nicotinic receptors have been implicated as playing a role in the body's response to alcohol ingestion.
  • agonists for cc7nACh receptors can be used in the treatment of alcohol withdrawal and in anti-intoxication therapy.
  • a method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to Formulas I- IV.
  • Agonists for the ⁇ 7nACh receptor subtypes can also be used for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity.
  • a method of treating a patient to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity comprising administering to the patient an effective amount of a compound according to Formulas I- IV.
  • agonists for the ⁇ 7nACh receptor subtypes can also be used in the treatment of nicotine addiction, inducing smoking cessation, treating pain, and treating jetlag, obesity, diabetes, and inflammation.
  • a method of treating a patient suffering from nicotine addiction, pain, jetlag, obesity, diabetes, and/or inflammation, or a method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
  • the inflammatory reflex is an autonomic nervous system response to an inflammatory signal.
  • the autonomic nervous system Upon sensing an inflammatory stimulus, the autonomic nervous system responds through the vagus nerve by releasing acetylcholine and activating nicotinic ⁇ 7 receptors on macrophages. These macrophages in turn release cytokines. Dysfunctions in this pathway have been linked to human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. Macrophages express the nicotinic ⁇ 7 receptor and it is likely this receptor that mediates the cholinergic anti-inflammatory response. Therefore, compounds with affinity for the ⁇ 7nACh receptor on macrophages may be useful for human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005, 257(2), 156-66.
  • a method of treating a patient e.g., a mammal, such as a human
  • an inflammatory disease or disorder such as, but not limited to, rheumatoid arthritis, diabetes or sepsis
  • administering comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
  • labeled derivatives of the compounds of Formulas I-IV can be used in neuroimaging of the receptors within, e.g., the brain.
  • labeled agents in vivo imaging of the receptors can be performed using, e.g., PET imaging.
  • the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
  • Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
  • a method of treating a patient suffering from, for example, mild cognitive impairment (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated w/open-heart-surgery, cardiac arrest, and/or general anesthesia memory deficits from early exposure of anesthetic agents, sleep deprivation induced cognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy- related cognitive impairment, Down's syndrome, Alcoholism related dementia, drug/substance induced memory impairments, Dementia Puglistica (Boxer Syndrome), and animal dementia (e.g., dogs, cats, horses, etc.) comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
  • MCI mild cognitive impairment
  • VaD vascular dementia
  • AACD age-associated cognitive decline
  • amnesia associated w/open-heart-surgery cardiac arrest
  • general anesthesia memory deficits from early exposure of anesthetic agents
  • the dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
  • the compounds of the invention can be administered to patients, e.g., mammals, particularly humans, at typical dosage levels customary for ⁇ -7 nicotinic receptor agonists such as the known ⁇ -7 nicotinic receptor agonist compounds mentioned above.
  • the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day.
  • Unit dosage forms can contain, for example, 1-200 mg of active compound.
  • the compounds can be administered in single or multiple dosages.
  • Analytical HPLC was performed on 4.6 mm x 100 mm Xterra RP !8 3.5 ⁇ columns using a gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water (0.1 % formic acid) over 6 min.
  • a gradient of 5/95 to 60/40 acetonitrile (0.1% formic acid)/water (0.1% formic acid) was used.
  • a gradient of 10/90 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) over 8 min was used.
  • Preparative HPLC was performed on 30 mm x 100 mm Xterra Prep RPi g 5 ⁇ columns using (i) an 8 min gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) (compounds 1-50, 54-57, 59, 60, 63-77, 79-131, and 149- 185), (ii) a 30 min gradient of 5/95 to 95/5 acetonitrile (0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid) (compounds 51 -53), (iii) an 8 min gradient of 10/90 to 60/40 acetonitrile (0.1% formic acid)/water (0.1% formic acid) (compounds 58, 61, 62, 78, and 132-137), (iv) an 8 min gradient of 5/95 to 60/40 acetonitrile (0.1% formic acid)/water (0.1% formic acid) (
  • Procedure 1 provides a preparation of substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols.
  • esters were prepared from the acid using ethanol and sulfuric acid:
  • Ethyl 6-bromobenzisothiazole-3-carboxylate Ethyl 6-methoxybenzisothiazole-3-carboxylate. fer/-Butyl 5-bromo- 1 ,2-benzisothiazole-3-carboxylate.
  • Procedure 2 provides a method for the preparation of isatins from anilines and the conversion of the isatins to the corresponding indazole-3-carboxylic acids.
  • the amide was added to sulfuric acid (1.9L) and the reaction mixture was heated at 60 0 C for 6h. The reaction mixture was allowed to cool to room temperature and was cautiously poured onto ice (7 kg). The precipitated solids were collected by filtration, washed with water, and dried to provide the isatin in 61% yield.
  • 6-Bromo- 1 H-indazole-3 -acid 5-Methoxy- lH-indazole-3-acid. 6-Methoxy-1H-indazole-3-acid.
  • Procedure 3 provides a method for the trapping of indazole aryllithiums with ketones and the coupling with 3-aminoquinuclidine to form heterocyclic derivatives.
  • tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a 2-fold excess of di-terf-butyldicarbonate followed by treatment with sodium hydroxide.
  • sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at O 0 C was slowly added a solution of t ⁇ rt-butyl 6- bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL).
  • 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid /ert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3- carboxylic acid (76%). The acids were coupled with quinuclidine amine according to procedure A.
  • 6-(4- ⁇ ydroxytetrahydropyran-4-yl)-1H-indazole-3 -carboxylic acid tert-bu ⁇ y ⁇ ester (1.0 mmol) was taken up in trifluoroacetic acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6- (tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid.
  • Procedure 4 provides a method for the preparation of N-I -alkylated indazole-3- carboxylic acids from the corresponding indazole ester.
  • the aqueous layer was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and concentrated, thus providing the acid in 95% yield.
  • 6-Bromo-l-methyl-1H-indazole-3-carboxylic acid 6-Bromo-l-ethyl-1H-indazole-3-carboxylic acid. 1 -Ethyl-6-methoxy- 1 H-indazole-3 -carboxy lie acid.
  • Procedure 5 provides a method for the preparation of 5-difluoromethoxyindazole- 3-acid from 3-bromo-4-nitrophenol.
  • Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40 mL) at 0 0 C. The reaction mixture was warmed to 60 0 C and maintained for 0.5 h. A solution of the difluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture was heated at 100 0 C for 5 h. The cooled solution was poured onto ice water, and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester in 112% yield as an oil.
  • the diester (167 mmol), sodium hydroxide (500 mmol), and water (335 mL) were combined and heated at 60 0 C for 1 h.
  • the reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL).
  • the pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 0 C for 1 h.
  • Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 0 C. After 0.5 h, the acid (101 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2x200 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 60% yield as a brown oil.
  • the ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL), and was treated with ammonium chloride (243 mmol) and iron powder (301 mmol).
  • the reaction mixture was heated at reflux for 10 minutes and the suspension was filtrated through Celite and the filter cake was washed with ethanol three times.
  • the filtrate was concentrated, the residue was suspended in 2 N hydrochloric acid and was stirred vigorously for 0.5 h.
  • the aqueous layer was washed with ethyl acetate (3x50mL) and the pH adjusted to 9-10 with 5 M sodium hydroxide.
  • the aqueous layer was extracted with chloroform (3xl00mL) and the combined organic layers were dried (magnesium sulfate).
  • Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0 mmol) were added to the organic layer and the suspension was heated at reflux for 16 h.
  • the solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (100 mL).
  • the aqueous layer was further extracted with dichloromethane (2x100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the N-acetylindazole ester in 79% yield as a brown oil.
  • Procedure 6 provides a method for the preparation of 6-difluoromethoxyindazole-
  • the nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol).
  • the reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the p ⁇ adjusted to 9-10 with 5 M sodium hydroxide.
  • the aqueous layer was extracted with ethyl acetate (3x10OmL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil.
  • the oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h.
  • the reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate.
  • the precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
  • Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min. The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3x1 OmL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro- amide in 83% yield.
  • the amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60 0 C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid.
  • the aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 0 C in order to completely dissolve the aniline.
  • the reaction mixture was cooled to 0 0 C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5 0 C and filtered.
  • Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 0 C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10 0 C.
  • the reaction mixture was heated at 60 0 C for 30 min and then at 100 0 C for 10 min to ensure completion.
  • the reaction mixture was allowed to cool to rt and was extracted with dichloromethane (3x40mL).
  • the combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water.
  • the > organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid.
  • the diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 0 C for 1 h.
  • the reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL).
  • the pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 0 C for 1 h.
  • the suspension was cooled to 0 0 C and the solids were collected by filtration and dried to provide the acid in 64% yield.
  • Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 0 C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield as a brown oil.
  • Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64 mmol), and acetic acid (7.0 mL) at 0 0 C.
  • Zinc dust (14.6 mmol) was added in portions over 15 min and the reaction mixture was maintained for 30 min at 0 0 C and then for 1.5 h at rt. Additional zinc powder (6.15 mmol) was added and the reaction maintained for 3 h.
  • the suspension was filtered through Celite and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was further extracted with ethyl acetate (3x2 OmL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the acetamide in 92% yield as a brown oil.
  • Acetic anhydride (13.7 mmol), ' isoamyl nitrite (13.7 mmol), and potassium acetate (2.04 mmol) were added to a solution of the acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated at reflux for 16 h. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 rtiL) and dichloromethane (20 niL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the crude N-acetylindazole ester as a brown oil.
  • the ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was maintained for 24 h at 60 0 C. After cooling to rt, the aqueous layer was washed with dichloromethane (3x3 OmL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and the precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 26% yield.
  • Procedure 7 provides a method for the coupling between brominated benzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylic esters and Grignard reagents to form heteroaromatic-substituted acids.
  • the aqueous layer was extracted with ethyl acetate (3 x 250 mL) and the combined extracts were dried over sodium sulfate and concentrated to dryness.
  • the residue was purified by chromatography using a gradient of 100/0 to 97/3 chloroform/methanol to provide the ester in 80% yield.
  • the ester was suspended in methanol (100 mL) and was treated with 8 M sodium hydroxide (30 mL). The mixture was heated at 60 0 C for 3 h, cooled to rt, filtered, and was acidified to p ⁇ ⁇ 2 by the slow addition of cone, hydrochloric acid.
  • the aqueous layer was concentrated and the residue was triturated with water. The resultant solid was recrystallized from water to give the acid in 81% yield.
  • the Grignard reagent of thiazole is commercially available.
  • the aryllithium and the corresponding arylzinc reagent can be generated according to the procedure outlined by Reeder, M.R.; et. al., Org. Proc. Res. Devel. 2003, 7, 696.
  • the zinc reagent of oxazole was prepared according to this procedure.
  • 6-(l,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid 6-(l,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.
  • 6-(l,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid 6-(l,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.
  • l-Ethyl-6-(l,3-oxazol-2-yl)-1H-indazole-3-carboxylic acid 6-(l,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.
  • Procedure 8 provides a method for the preparation of N-methoxyethoxymethyl and N-trimethylsilylethoxymethyl protected indazole acids and esters from the corresponding indazole esters using alkylation conditions.
  • the reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (95/5 to 85/15 hexanes/ethyl acetate to provide the protected indazole in 89% yield.
  • esters and acids were prepared using this method:
  • Procedure 9 provides a method for the preparation of alkoxy indazole acids from the corresponding benzyloxy indazole esters using Mitsunobu conditions.
  • Diisopropyl azodicarboxylate (0.841 mmol) was added dropwise to a solution of ethyl 6-hydroxy-l-[(2-methoxyethoxy)methyl]-1H-indazole-3-carboxylate (0.765 mmol), l-methyl-3-pyrrolidinol (0.917 mmol), and triphenylphosphine (1.15 mmol) in tetrahydrofuran (4.6 mL). The reaction was maintained for 16 h and was concentrated.
  • Procedure 10 provides a method for the preparation of 4-methoxyindazole acid from 4-methoxyaniline.
  • a solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0- 5 0 C) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90 0 C for 2 h).
  • the reaction mixture was maintained for 40 min and was filtered.
  • the filtrate was added dropwise to a cold (0-5 0 C) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min.
  • the reaction mixture was warmed to 60 0 C and was maintained for 30 min.
  • the reaction mixture was warmed to reflux and was maintained for 1 h.
  • the reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3 x 1 L). The combined organic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50% yield as a yellow solid.
  • the aqueous layer was decanted and the residual red oil, which solidifies upon standing, was purified by chromatography (6/6/1 petroleum ether/dichloromethane/ethyl acetate) to provide the ⁇ -oxime amide in 29% yield as a light yellow solid.
  • the ⁇ -oxime amide (58.6 mmol) was added in one portion to warm (40 0 C) 90% sulfuric acid (16 mL) and the reaction mixture was heated at 60 0 C for 30 min. The reaction mixture was allowed to cool to rt and was poured into ice water. The precipitated orange solids were collected by filtration and dried. The crude product was purified by chromatography (15/1 petroleum ether/ethyl acetate) to provide the isatin in 57% yield as a yellow solid.
  • the isatin (20.7 mmol) was mixed with 1 M sodium hydroxide (23 mL) and the reaction mixture was heated to 30-40 0 C for 30 min.
  • the reaction mixture was cooled to 0 0 C and treated with a solution of sodium nitrite (20.7 mmol) in water (5.1 mL) and was maintained for 20 min. That solution was added dropwise to a cold (0-5 0 C) solution of concentrated sulfuric acid (2.24 mL) in water (43.3 mL) and the reaction mixture was maintained for 0.5 h.
  • a solution of tin (II) chloride (50.5 mmol) in concentrated hydrochloric acid (19.6 mL) was added dropwise and the reaction mixture was maintained at 0-5 0 C for 1 h.
  • the precipitated solids were isolated by filtration and dried to provide the indazole acid as a yellow solid (100% by mass).
  • Acetylchloride (18 mL) was added to methanol (180 mL) at 0 0 C and the reaction mixture maintained for 1 h.
  • the indazole acid (21.8 mmol) was added and the reaction mixture was heated at reflux for 3 h.
  • the solution was concentrated to dryness and the residue was suspended in water and the pH adjusted to 7 with saturated sodium hydrogen carbonate.
  • the mixture was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated.
  • the crude product was purified by chromatography (2/1 petroleum ether/ethyl acetate) to provide the indazole ester in 5% yield (two steps) as a yellow solid.
  • Procedure 11 provides a method for the preparation of benzyloxy-substituted indazole-3-carboxylic acids and esters from the corresponding bromo nitrobenzenes.
  • Acetic anhydride (34 mL) and zinc dust (4.59 mmol) were added to a solution of 4-methoxynitrobe ⁇ zene (230 mmol) in glacial acetic acid (34 mL) and the reaction mixture was heated at reflux for 0.5 h..
  • the reaction mixture was poured into water (340 mL) and the pH of the solution was adjusted to 8 with 10% sodium hydroxide.
  • the precipitated solids were isolated by filtration, washed with water (100 mL), and dried to provide the acetamide in 88% yield.
  • nitroacetamide 180 mmol was added to 4 M sodium hydroxide (180 mL) and the reaction mixture was maintained for 2 h at 60 0 C.
  • the precipitated solids were isolated by filtration, washed with water, and dried to provide the nitroaniline in 70% yield as a red solid.
  • the reaction mixture was partitioned between water (2.0 L) and dichloromethane (600 mL) and the aqueous layer was further extracted with dichloromethane (300 mL).
  • the combined organic layers were washed with 10% sodium hydroxide (200 mL), water (600 mL), 10% hydrochloric acid (300 mL), and water (600 mL), dried (magnesium sulfate) and concentrated to provide the nitrobromide in 83% yield as a yellow oil.
  • Benzyl bromide (131 mmol) and potassium carbonate (130 mmol) were added to a solution of the nitrophenol (87.0 mmol) in 2/1 acetonitrile/acetone (840 mL).
  • the reaction mixture was heated at reflux for 17 h and was concentrated to dryness.
  • the residue was suspended in ethyl acetate (756 mL), filtered, and the organic layer was washed with water (567 mL), 1 M hydrochloric acid (2 x 567 mL), and brine (567 mL).
  • the organic layer was dried (magnesium sulfate) and concentrated to the benzyl ether in 78% yield.
  • Diethyl malonate (890 mmol) was added drop wise over 1 h to a suspension of sodium hydride (520 mmol) in dimethylsulfoxide (100 mL) at 0 0 C.
  • the benzyl ether (44.0 mmol) was added and the reaction mixture was heated at 100 0 C for 5 h.
  • the reaction mixture was poured into ice water and was extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the diethylmalonate addition product.
  • the diethylmalonate addition product was diluted with a 4 M solution of sodium hydroxide (100 mL) and the reaction mixture was heated at 60 0 C for 6 h.
  • the solution was extracted with dichloromethane (3 x 50 mL) and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid.
  • the reaction mixture was heated at 60 0 C for 1 h, allowed to cool to rt, and was extracted with ethyl acetate (3 x 50 mL).
  • the combined organic layers were dried (magnesium sulfate) and concentrated to provide the phenylacetic acid in 78% yield as a solid.
  • the phenylacetic acid (350 mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [acetyl chloride (5 mL) was added to ethanol (100 mL)] and the reaction mixture was heated at reflux for 20 h. The reaction mixture was concentrated to dryness and the residue was partitioned between saturated sodium bicarbonate (200 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to provide the ester in 77% yield.
  • the nitro ester (27.0 mmol) was dissolved in acetic acid (60 mL) and acetic anhydride (44 mL) and was cooled to 0 0 C.
  • Zinc dust 153 mmol was added and the reaction mixture was allowed to warm to rt and was maintained for 2 h. Additional quantities of zinc dust (2 x 45.9 mmol) were added during a 3 h course of time.
  • the reaction mixture was filtered and the filter cake was washed with ethanol (100 mL).
  • the combined filtrates were concentrated and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate (50 mL).
  • the solution was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to provide the acetamide in 82% yield.
  • the acetylated indazole ester (15.0 mmol) was suspended in 2 M sodium hydroxide (35 mL) and the reaction mixture was heated at 60 0 C for 24 h. The pH of the solution was adjusted to 1-2 with concentrated hydrochloric acid and the solids were collected by filtration and dried to provide 6-benzyloxy-1H-indazole-3-carboxylic acid in 28% yield as a yellow solid.
  • 6-Benzyloxy-1H-indazole-3-carboxylic acid (1.85 mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [prepared from ethanol (20 mL) and acetyl chloride (5 mL)] and the reaction mixture was heated at reflux for 25 h and was concentrated. The residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated.
  • ethanolic hydrochloric acid prepared from ethanol (20 mL) and acetyl chloride (5 mL)
  • the ester can be obtained from the acetylated indazole ester by maintaining the acetylated material in 2 M ammonia in methanol for 30 min.
  • Procedure 12 provides a method for the preparation of N(I)- difluoromethylindazole acids from the corresponding indazole-3-carboxylic acids.
  • Acetyl chloride (141 mmol) was added dropwise to a solution of 6-methoxy-3- indazole-carboxylic acid (26.0 mmol) in ethanol (200 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to rt and was concentrated. The residue was dissolved in ethyl acetate (300 mL) and was washed with aqueous sodium bicarbonate (2 x 50 mL). The combined aqueous layers were back- extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (50 mL), dried (sodium sulfate), concentrated, and dried under vacuum to afford 4.91 g (86%) of the ester as a solid.
  • the solid was dissolved in ethanol (20.0 mL) and a 5.0 M solution of sodium hydroxide (3.6 mL) was added.
  • the reaction mixture was maintained at rt for 2 h, diluted with water (50 mL) and acidified with 6.0 N hydrochloric acid.
  • the precipitate was collected and dried to provide the acid in 65% yield.
  • Procedure 13 provides a preparation of 5-azaindazole-3-carboxlic acid from 4- chloropyridine.
  • the reaction mixture was cooled to -78 0 C and the hexanes solution of 4-chloropyridine was added dropwise and the mixture was maintained for 1 h. Diethyl oxalate (56.7 mmol) was added to the orange homogeneous solution and the mixture was allowed to warm to rt. Analysis by LC/MS revealed that the main product was not the ethyl oxalate, but the N,N-diisopropylamide. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic washed with brine (25 mL), dried (magnesium sulfate), and concentrated.
  • Procedure 14 provides a preparation of 6-azaindazole-3-carboxlic acid from 4- chloro-3-nitropyridine.
  • terr-Butyl ethyl propane- 1,3-dioate (26.6 mmol) was added to a suspension of sodium hydride (1.11 g) in tetrahydrofuran (50.0 mL) at 0 0 C. The reaction mixture was allowed to warm to rt and was maintained for 30 min. The reaction mixture was then cooled to 0 0 C and a solution of 4-chloro-3-nitropyridine (12.6 mmol) in tetrahydrofuran/NN-dimethylformamide (9/1, 10 mL) was added dropwise. The mixture was allowed to warm to rt and was maintained for 1 h.
  • the reaction was quenched with water (50 mL) and was neutralized with acetic acid to a p ⁇ of 5 (the color went from dark brown to yellow on neutralization).
  • the mixture was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and concentrated to provide the product in 94% yield.
  • the crude tert-butyl ethyl (3-nitropyridin-4-yl)malonate (12.6 mmol) was dissolved in 4/1 dichloromethane/trifluoroacetic acid (25.0 mL) and the mixture was heated at reflux for 2 h.
  • the reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the ethyl acetate layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated.
  • the residue was purified by chromatography (95/5 dichloromethane/ethyl acetate) to provide the product in 77% yield.
  • Amyl Nitrite (18.9 mmol) was added to a solution of ethyl (3-aminopyridin-4- yl)acetate (9.43 mmol), potassium acetate (11.3 mmol), and acetic anhydride (28.3 mmol) in chloroform (10.0 mL) and the reaction was heated at 60 0 C for 16 h. The cooled reaction mixture was carefully diluted with aqueous sodium bicarbonate and was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and concentrated.
  • the residue was pre- purified by chromatography (50/50 to 0/100 hexanes/ethyl acetate) to yield a complex mixture of products.
  • the mixture was dissolved in ethanol (10.0 mL), diluted with 5.0 M sodium hydroxide (5.00 mL), and the reaction mixture was maintained for 16 h.
  • the reaction mixture was concentrated to ⁇ 5 mL, diluted with water (20 mL), and was neutralized with acetic acid. The yellow solid was collected by filtration to provide the desired product in 18% yield.
  • Procedure 15 provides a preparation of aminobenzisothiazole-3-carboxlic acids from the ester.
  • the reaction mixture was filtered through Celite (ethyl acetate) and the filtrate was concentrated.
  • the residue was purified by chromatography (70/30 to 50/50 hexanes/ethyl acetate) to provide the purified ester.
  • the ester was dissolved in dichloromethane/trifluoroacetic acid (4:1, 2.00 mL) and was maintained for 16 h.
  • the reaction mixture was concentrated to provide the product in 23% yield. The product was used without further purification.
  • 6-(3-Ethoxypyrrolidin- 1 -yl)- 1 ,2-benzisothiazole-3 -carboxylic acid 6-[(l 1 S l ,45)-2-Oxa-5-azabicyclo[2.2. l]hept-5-yl]-1,2-benzisothiazole-3-carboxylic acid.
  • ferZ-Butyl T-bromo-1,2-benzisothiazole-3-carboxylate 6-[(l 1 S l ,45)-2-Oxa-5-azabicyclo[2.2. l]hept-5-yl]-1,2-benzisothiazole-3-carboxylic acid.
  • esters were prepared from the N-Boc intermediates using trifluoroacetic acid:
  • Procedure 16 provides a preparation of 6-amino-7-azaindazole-3-carboxlic acids from tert-butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate.
  • Methanesulfonyl chloride (5.52 mmol) was added dropwise to a cold (0 0 C) solution of tert-butyl 6-(3-hydroxypyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-3- carboxylate (2.63 mmol) and triethylamine (6.57 mmol) in dichloromethane (2.7 mL).
  • the reaction mixture was maintained at rt for 16 h and was diluted with water (25 mL).
  • the dichloromethane layer was separated and was transferred to a silica gel column.
  • the column was eluted using a gradient of 90/10 to 0/100 hexanes/ethyl acetate to provide the bis-mesylate in 60% yield and the monomesylate in 28% yield.
  • tert-Butyl 1 -(methylsulfonyI)-6-3-[(methylsulfonyl)oxy]pyrrolidin-1-yl-1H- pyrazolo[3,4-b]pyridine-3-carboxylate (0.380 mmol) was diluted with a 2.0 M solution of dimethylamine in tetrahydrofuran (5.0 mL) in a microwave vessel. The reaction mixture was subjected to microwave irradiation at 135 0 C for 80 min.
  • the reaction mixture was concentrated and the residue was purified by chromatography ⁇ 100/0 to 90/10 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethylethylamine] ⁇ to provide the purified ester.
  • the ester was dissolved in 4/1 dichloromethane/trifluoroacetic acid (5.00 mL) and the mixture was maintained at rt for 16 h. The volatiles were removed and the residue was dissolved in water. The mixture was neutralized with half saturated sodium bicarbonate and the solid precipitate was collected by filtration to provide the product in 79% yield.
  • Procedure 17 provides a preparation of fluorinated benzisothiazole-3-carboxlic acids from the ester of the corresponding benzisothiazole-3-carboxlic acid.
  • Procedure 18 provides a preparation of 6-phenyl-1H-pyrazolo[3,4-b]pyridine-3- carboxylic acid from tert-b ⁇ tyl 6-phenyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate.
  • the reaction mixture was concentrated and the residue was diluted with water (5 mL).
  • the reaction mixture was neutralized to p ⁇ 5-7, stirred vigorously for 1 h, and the precipitated solids were collected by filtration to provide the acid in 92% yield.
  • the following acid was prepared using this method:
  • Procedure 19 details the preparation of ethyl 6-bromobenzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.
  • the ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%).
  • Procedure 20 details the preparation of ethyl 6-methoxybenzisoxazole-3- carboxylate from l-chloro-2,4-dinitrobenzene.
  • This aqueous solution was added to a cold (0 0 C) solution of copper (II) nitrate (149 mmol) in water (80 mL) and the reaction mixture was allowed to warm to rt. After 5 min., copper (I) oxide (2.78 mmol) was added to the mixture and the reaction mixture was maintained for 1 h at rt. The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate in 99% yield as a brown oil.
  • Procedure 21 provides a preparation of 7-azabenzisothiazole-3-carboxlic acid from 2-chloronicotinic acid.
  • 2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL) and the resulting solution was heated at reflux for 18 h. The volatiles were removed by evaporation to provide 2-chloronicotinoyl chloride in 98% yield as a white solid.
  • N-Bromosuccinamide (10.7 mmol) was added to a solution of 3- methylisothiazolo[5,4-b]pyridine (10.0 mmol) in carbontetrachloride (20 mL). Benzoyl peroxide (0.82 mmol) was added and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered through Celite (ethyl acetate) and the eluent was concentrated to provide crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine as a yellow solid.
  • 2,2,2-Trifluoroethylmethanesulfonate (0.330 mmol) was added to a solution of ethyl 6-[(lS,45)-2,5-diazabicyclo[2.2. l]hept-2-yl]-l ,2-benzisothiazole-3-carboxylate (0.165 mmol) in NN-diisopropylethylamine (0.20 mL) and acetonitrile (15 mL) and the resulting mixture was maintained for 16 h at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (90/10 to 70/30 hexanes/ethyl acetate) to yield the purified ester.
  • the ester was dissolved in ethanol (5.0 mL) and an aqueous solution of sodium hydroxide (5.0 M, 2.0 mL) was added. The reaction was maintained at room temperature for 4 h, then diluted with water (50 mL) and neutralized with acetic acid. The precipitate was collected by filtration to provide 6- [( lS,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2. l]hept-2-yl]- 1 ,2-benzisothiazole-3- carboxylic acid in 29 % yield. The following acid was prepared using a similar procedure:
  • Procedure 23 provides a preparation of amidine substituted indazole-3 -carboxylic acids from the corresponding aldehydes.
  • N-Methyl-1,2-ethanediamine (4.7 mmol) was added to a soluton of fers-butyl 6- formyl-1H-indazole-3-carboxylate (4.2 mmol) in fer/-butanol (40 mL) and the reaction mixture was maintained for 30 min.
  • Potassium carbonate (10 mmol) and iodine (5.3 mmol) were added and the slurry was heated at 70 0 C for 3 h.
  • the reaction mixture was allowed to cool to rt and was quenched with aqueous sodium thiosulfate (40 mL).
  • Procedure 24 provides a preparation of N-alkyl aminobenzisothiazole-3- carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic esters.
  • Procedure 25 provides a preparation of N-alkyl aminobenzisothiazole-3- carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic esters.
  • Cyclopropylmethyl bromide (1.71 mmol) was added to a suspension of ethyl 6- [(lS ⁇ -2,5-diazabicycloP ⁇ . ⁇ hept ⁇ -ylJ-1,2-benzisothiazole-3-carboxylate (0.857 mmol) and sodium bicarbonate (3.43 mmol) in acetonitrile (10.0 mL) and the reaction mixture was heated at 60 0 C for 6 h. The acetonitrile was decanted from the solids and the solids were washed with acetonitrile (2 x 5 mL).
  • the acetonitrile solution was transferred to a silica gel column and the mixture was purified by chromatography ⁇ 9/1 to 7/3 ethyl acetate/ [(50/50/2) ethyl acetate/methanol/dimethylethylamine] ⁇ to yield the purified ester.
  • a 5.0 M solution of sodium hydroxide in water (2.00 mL) was added to a solution of the ester in ethanol (5.0 mL) and the reaction mixture was maintained for 16 h.
  • the reaction was neutralized with acetic acid and the reaction mixture was transferred to a SCX column (1Og).
  • the column was flushed with water (200 mL) and methanol (100 mL) and the product was eluted with 2.0 M ammonia in methanol to provide the product in 50% yield.
  • the acid was used without further purification.
  • Procedure 26 provides a preparation of 6-hydroxybenzisothiazole-3-carboxylic acid and the ester from the corresponding anisole.
  • Procedure 27 provides a preparation of 7-aza-6-chlorobenzisothiazole-3- carboxylic acid from 2-chloronicotinoyl chloride.
  • Procedure 28 provides a preparation of N-acylated aminobenzisothiazole-3- carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic esters.
  • Procedure 29 provides a preparation of nitrile substituted indazole-3-carboxylic acids from the corresponding bromoindazole-3-carboxylic esters.
  • Zinc Cyanide (1.00 mmol) was added to a solution of ethyl 6-bromo-1H-indazole- 3-carboxylate (0.502 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0502 mmol) in NN-dimethylformamide (5.00 mL) and the reaction mixture was heated at 100 0 C for 16 h. The reaction mixture was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x) and the combined organic layers were washed with brine and dried (sodium sulfate).
  • Procedure 30 provides a method for the preparation of N-alkylated 3- aminoquinuclidines from 3-aminoquinuclidine.
  • Acetyl chloride (12 mmol) was added dropwise to a solution of (R)-3- aminoquinuclidine (10 mmol) and N,N-diisopropylethylamine (30 mmol) in dichloromethane (100 mL). The resulting solution was maintained at rt for 4 h and was evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150 mL) and was treated with lithium aluminum hydride (66 mmol) in small portions. The reaction mixture was quenched with sodium sulfate decahydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through Celite.
  • the filtrate was concentrated and the residue was then diluted with freshly prepared methanolic hydrogen chloride (generated by the dropwise addition of 3 mL of acetyl chloride into 30 mL of methanol) and maintained at rt for 15 min.
  • the residue obtained by the removal of the volatiles was recrystallized (2-propanol/methanol) to provide the secondary amine in 41% yield as a colorless solid.
  • Procedure 31 provides a method for the preparation of cyclic ureas from diamines.
  • Procedure 32 provides a method for the preparation of 3-alkoxypyrrolidines from N-Boc-3-hydroxypyrrolidine.
  • l-Boc-3-hydroxypyrrolidine (16.1 mmol) was added in portions to a suspension of sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL) at 0 0 C.
  • the reaction mixture was diluted with tetrahydrofuran (60 mL) and allowed to warm to rt.
  • Methyl iodide (21.0 mmol) was added to the cloudy suspension after 1 h and the reaction mixture was maintained at rt for 6 h.
  • the reaction mixture was concentrated and redissolved in ethyl acetate (100 mL).
  • An alternative procedure used for the removal of the ⁇ -Boc groups entails exposure to trifiuoroacetic acid for 4 h. followed by concentration of the reaction mixture. This procedure may be useful for the production of the amine as a free base.
  • Procedure 33 provides a preparation of SEM protected hydroxypyrrolidines from hydroxypyrrolidine.
  • the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated.
  • the residue was purified by chromatography 95/5 to 80/20 hexanes/ethyl acetate to provide the Boc-protected product.
  • the residue was heated neat at 350 °C for 3 h.
  • the resulting brown oil was purified by chromatography [100/0 to 80/20 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethylethylamine)] to give a brown oil after concentration.
  • the oil was dissolved in ethanol and the solution was treated with activated carbon, filtered, and concentrated to provide the product in 52% yield.
  • Procedure 34 provides a preparation of 3-trifluoromethoxypyrrolidine from hydroxypyrrolidine.
  • the residue was purified by chromatography 95/5 to 80/20 hexanes/ethyl acetate to provide the Boc-protected product.
  • the purified product (ca. 2g) was dissolved in a 4/1 mixture of dichloromethane/trifluoroacetic acid (20.0 mL) and was maintained for 4 h. The solvent was removed and the residue was purified by chromatography [100/0 to 90/10 ethyl acetate/(50/50/2 ethyl acetate/methanol/dimethylethylamine)].
  • the product was unexpectedly volatile and much of it was lost on concentration.
  • the final yield for the product was 2%.
  • Procedure 35 provides a preparation of 3-cyclopropylmethoxypyrrolidine from hydroxypyrrolidine.
  • a solution of 3 -hydroxy-pyrrolidine-hydrochloride (162 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (210 mmol) and a solution of benzyl chloroformate (210 mmol) in tetrahydrofuran (50 mL).
  • the resulting solution was maintained for 16 h at rt.
  • the reaction mixture was concentrated and the residue was dissolved in ethyl acetate (200 mL).
  • the solution was washed with brine (3 x 100 mL), dried (magnesium sulfate), and concentrated to provide the protected amine in 90% yield as a yellow liquid.
  • the reaction mixture was concentrated and the residue was diluted with ethyl acetate (200 mL) and water (200 mL) and the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic layers were washed with brine (2 x 200 mL) and dried (magnesium sulfate).
  • the residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide the product in 81% yield.
  • Procedure A provides a method for the coupling between 3-aminoquinuclidine and benzisoxazole carboxylic esters to form carboxamide derivatives.
  • the aqueous layer was back-extracted with dichloromethane (30 mL) and the combined organic layers were washed with brine and dried (sodium sulfate).
  • the organic layer was loaded on a 10 g SCX column.
  • the column was washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia wash was concentrated.
  • the residue was purified by chromatography [40/60 to 0/100 ethyl acetate/(70/30/l ethyl acetate/methanol/ammonium hydroxide)] to provide the product in 63% yield as a colorless oil.
  • Procedure B provides a method for the coupling between 3-aminoquinuclidine and benzisothiazole carboxylic acids to form carboxamide derivatives.
  • the aqueous layer was extracted with 95/5 dichloromethane/methanol (2X), and the combined organic layers were washed with brine and dried over sodium sulfate.
  • the reaction mixture was loaded on a 1O g SCX column and the column was washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia wash was concentrated.
  • the crude product was purified by chromatography 100/0 to 30/70 ethyl acetate/[(50/50/2) ethyl acetate/methanol/dimethylethylamine] or by preparative HPLC, thus providing the amide in 75% yield as a colorless solid.
  • Procedure C provides a method for the coupling between 3-aminoquinuclidine and carboxylic acids to form carboxamide derivatives.
  • the aqueous layer was further extracted with 9/1 dichloromethane/methanol (5 x 100 mL) and the combined organic layers were concentrated.
  • the residue was purified by chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/l ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus providing the product in 30%-70% yield.
  • Procedure D provides a method for the coupling between 3-aminoquinuclidine and carboxylic acids to form carboxamide derivatives.
  • Procedure E provides a method for the coupling between 3-aminoquinuclidine and carboxylic acids, amines, and indazoles to form amide and urea derivatives.

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