The present invention provides compounds of formula (I), which are antagonists of the 5-HT6 receptor.

1. Branchek, T. A., et al. (2000). Annu Rev Pharmacol Toxicol 40: 319-34.    2. Monsma, F. J., Jr., et al. (1993). Mol Pharmacol 43(3): 320-7.    3. Ruat, M., et al. (1993). Biochem Biophys Res Commun 193(1): 268-76.    4. Kohen, R., et al. (1996). J Neurochem 66(1): 47-56.    5. Ward, R. P., et al. (1996). J Comp Neurol 370(3): 405-14.    6. Ward, R. P., et al. (1995). Neuroscience 64(4): 1105-11.    7. Gerard, C., et al. (1997). Brain Res 746(1-2): 207-19.    8. Gerard, C., et al. (1996). Synapse 23(3): 164-73.    9. Glennon, R. A., et al. (2000). J Med Chem 43(5): 1011-8.    10. Roth, B. L., et al. (1994). J Pharmacol Exp Ther 268(3): 1403-10.    11. Sleight, A. J., et al. (1998). Br J Pharmacol 124(3): 556-62.    12. Routledge, C., et al. (2000). Br. J. Pharmacol. 130(7): 1606.    13. Hirst, W. D., et al. (1999). Br. J. Pharmacol. Suppl. ((in press)).    14. Hirst, W. D., et al. (2000). Br. J. Pharmacol. 130: 1597.    15. Bourson, A., et al. (1995). J Pharmacol Exp Ther 274(1): 173-80.    16. Bentley, J. C., et al. (1999). Br J Pharmacol 126(7): 1537-42.    17. Bourson, A., et al. (1998). Br J Pharmacol 125(7): 1562-6.    18. Routledge, C., et al (1999). Br. 3. Pharmacol. 127(Suppl.): 21P.    19. Goldberg, T. E., et al. (1993). Br J Psychiatry 162: 43-8.    20. Hagger, C., et al. (1993). Biol Psychiatry 34(10): 702-12.    21. Lee, M. A., et al. (1994). J Clin Psychiatry 55 Suppl B: 82-7.    22. Purdon, S. E., et al. (2000). Arch Gen Psychiatry 57(3): 249-58.    23. Parada, M. A., et al. (1997). 3 Pharmacol Exp Ther 281(1): 582-8.    24. Rogers, D. C., et al. (1999). Br J Pharamcol 127(suppl.): 22P.    25. Dawson, L. A., et al. (2000). Br J Pharmacol 130(1): 23-6.    26. Dudkin, K. N., et al. (1996). Neurosci Behav Physiol 26(6): 545-51.    27. Koechlin, B., et al. (1999). Nature 399(6732): 148-51.            The present invention provides compounds of formula I:
wherein    X is selected from the group consisting of —O—, —NH—, —S—, —SO2—, —CH2—, —CH(F)—, —CH(OH)—, and —C(O)—;    R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused;    R2 is selected from the group consisting of hydrogen and C1-C3 alkyl;    R3 is selected from the group consisting of hydrogen, fluoro, and methyl;    R4 is selected from the group consisting of hydrogen, allyl, C2-C4 alkyl, fluorinated C2-C4 alkyl, optionally substituted phenyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that R4 is not optionally substituted phenylsulfonyl when X is —SO2—, CH2—, —CH(F)—, —CH(OH)—, or —C(O)—; andpharmaceutically acceptable salts thereof.The present invention also provides compounds of formula II:
wherein    Y is selected from the group consisting of O, NH, and NR9, wherein R9 is selected from the group consisting of C1-C4 alkyl, and optionally substituted phenyl;    R5 and R6 are hydrogen or taken together with the atoms to which they are attached form a benzo ring, provided that R5 and R6 are hydrogen when Y is NR9;    R7 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused;    R8 is selected from the group consisting of hydrogen and C1C3 alkyl; and pharmaceutically acceptable salts thereof.
The present invention also provides for novel pharmaceutical compositions, comprising: a compound of the formula I or II and a pharmaceutically acceptable diluent.
Because the compounds of formula I and II are antagonists of 5-HT6 receptor, the compounds of formula I and II are useful for the treatment of a variety of disorders. Thus, in another embodiment the present invention provides methods of treating disorders associated with 5-HT6, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or II. That is, the present invention provides for the use of a compound of formula I or II and pharmaceutical compositions thereof for the treatment disorders associated with 5-HT6. More specifically, the present invention provides a method of treating disorders selected from the group consisting of cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's Chorea, cognitive deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic lateral sclerosis, and multiple sclerosis, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or an effective amount of a compound of formula II.
In addition, the present invention also provides processes for preparing the compounds of formula I and II and intermediate thereof.
As used herein, the following terms have the meanings indicated:
The term "C1-C3 alkyl" refers to a straight or branched alkyl chain having from one to three carbon atoms, and includes methyl, ethyl, propyl, and iso-propyl.
The term "optionally substituted phenyl" refers to a radical of the formula

wherein Ra is from 1 to 3 groups independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, halogen, benzyloxy, carboxy, C1-C4 alkoxycarbonyl, amido, N—C1-C4 alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
The term "optionally substituted naphthyl" refers to a radical of the formula

wherein Rc is from 1 to 2 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, and nitro.
The term "optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused" refers to radicals of the formula
wherein Q1 is selected from the group consisting of —O—, —S—, and —NRg— wherein Rg is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q2 is —N═, Rd, each Re, and Rf are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl, or Rd and Re (or one of Re) are taken together with the atoms to which they are attached to form an benzo ring which benzo ring is optionally substituted with 1 to 4 substituents independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen, carboxy, C1-C4 alkoxycarbonyl, amido, N—(C1-C4 alkyl)amido, amino, (C1-C4 alkyl)amino, acylamino wherein the acyl group is selected from the group consisting of C1-C4 alkyl and phenyl; cyano, nitro, sulfonylamido, phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; phenoxy, benzyloxy, —NHS(O)2Rh, wherein Rh is selected from the group consisting of C1-C4 alkyl and phenyl; and —S(O)pRi, wherein p is 0, 1, or 2 and Ri is selected from the group consisting of C1-C4 alkyl and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; and Rf is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, and halogen. The term specifically includes furyl, thienyl, pyrrolyl, pyridyl, benzofuryl, benzothienyl, indolyl and quinolinyl; each optionally substituted as described above.
The term "fluorinated C2-C4 alkyl" refers to a straight or branched alkyl chain having from two to four carbon atoms substituted with one or more fluorine atoms. The term includes 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluorobutyl, and the like.
The term "optionally substituted phenylsulfonyl" refers to a radical of the formula

wherein Rj is from 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, nitro, and phenyl.
The term "optionally substituted benzyl" refers to a radical of the formula

wherein Rk is form 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro, trifluoromethyl, and halogen.
The term "optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur" refers to radicals of the formula
wherein Q3 is selected from the group consisting of —O—, —S—, and —NRg— wherein Rg′ is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q4 and Q5 are —CRm, wherein each Rm is independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and trifluoromethyl or one or both of Q4 and Q5 is —N═; and wherein one or two of Q6 are —N═, while the others are CRn; wherein each Rn is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, and trifluoromethyl. The term specifically includes furyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, thioisoxazolyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazidinyl; each optionally substituted as described above.
The term "C1-C4 alkyl" refers to a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.
The term "C2-C4 alkyl" refers to a straight or branched alkyl chain having from two to four carbon atoms, and includes ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.
The term "C1-C4 alkoxy" refers to a straight or branched alkyl chain having from one to four carbon atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, and t-butoxy.
The term "halogen" refers to a chloro, fluoro, bromo or iodo atom.
The term "pharmaceutically-acceptable addition salt" refers to an acid addition salt.
The compound of formula I or II and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. A pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, and the like.
As with any group of pharmaceutically active compounds, some groups are preferred in their end use application. Preferred embodiments of the present invention are given for the compounds of formula I below:
Compounds in which wherein X is selected from the group consisting of —O—, —NH—, and —S— are preferred, with compounds in which X is —O— being more preferred.
Compounds in which R1 is optionally substituted phenyl or optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused are preferred.
When R1 is optionally substituted phenyl preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, benzyloxy, carboxy, C1-C4 alkoxycarbonyl, amido, N—(C1-C4 alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
When R1 is optionally substituted phenyl more preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, cyano, and trifluoromethyl.
Compounds in which R3 is hydrogen or fluorine are preferred.
Compound in which R1 is optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused, the compounds which are benzo fused are preferred, with indolyl being preferred, and indol-3-yl being even more preferred.
When R1 is indol-3-yl, preferred groups are depicted as the radical below:
    a) Ro is selected from the group consisting of hydrogen and C1-C4 alkyl, with hydrogen being more preferred;    b) Rp is selected from the group consisting of hydrogen and C1-C4 alkyl, with hydrogen being more preferred;    c) Rq is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and halogen, with hydrogen being more preferred;    d) Rq′ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl halogen, and —S(O)pRi wherein p is 2 and R1 is phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, with halogen being more preferred;    e) Rq″ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, cyano, trifluoromethyl, and —S(O)pRi, wherein p 2 and R1 is phenyl optionally substituted with C1-C4 alkyl, with halogen being more preferred; and    f) Rq″ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, cyano, and nitro, with hydrogen and halogen being preferred.
Compounds in which R4 is selected from the group consisting of C2-C4 alkyl, fluorinated C2-C4 alkyl and optionally substituted phenyl are preferred.
When R4 is C2-C4 alkyl, particularly preferred groups include propyl, isopropyl, and butyl.
When R4 is fluorinated C2-C4 alkyl, preferred groups include 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,3,3-tetrafluoropropyl.
When R4 is optionally substituted phenyl preferred groups include 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
Preferred embodiments of the present invention are given for the compounds of formula II below:
Compounds in which R7 is optionally substituted phenyl or optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused are preferred.
When R7 is optionally substituted phenyl preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethoxy, and trifluoromethyl.
Compounds in which R7 is optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused, the compounds which are benzo fused are preferred, with indolyl being preferred, and indol-3-yl being even more preferred, with the indol-3-yl depicted above for formula I being more preferred.
Preferred compounds of formula II having the points of attachment depicted below:

While only compounds of formula I are depicted, the compounds of formula I and II are prepared as described in Schemes A and B below. In the Schemes below all substituents, unless otherwise indicated, are as previously defined, and all starting materials and reagents are well known and appreciated in the art and readily available or prepared by methods described herein. In the Schemes below, it is understood that protecting groups can be used, where appropriate to allow for elaboration of a portion of the compounds Of formula I or II. The selection, use, and removal of suitable protecting groups is well known and appreciated in the art (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).

Scheme A depicts alternative methods for the preparation of compounds of formula I by reductive amination.
In one alternative of Scheme A, step a, an appropriate compound of formula (1) is contacted with an appropriate compound of formula (2) in a reductive amination reaction to give a compound of formula I. An appropriate compound of formula (1) is one in which R1 and R2 are as desired in the final product of formula I or give rise to groups desired in the final product of formula I. An appropriate compound of formula (2) is one in which X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
In another alternative of Scheme A, step a, an appropriate compound of formula (3) is contacted with an appropriate compound of formula (4) in a reductive amination reaction to give a compound of formula I. An appropriate compound of formula (3) is one in which R1 and R2 are as desired in the final product of formula I or give rise to groups desired in the final product of formula I. An appropriate compound of formula (4) is one in which X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
The reductive amination depicted in Scheme A, step a, can be carried out under a variety of conditions, such as by hydrogenation using a suitable catalyst or using a suitable reducing agent.
For example, an appropriate amine of formula (1) is contacted with an appropriate aldehyde of formula (2) (or alternately an appropriate amine of formula (4) and an appropriate aldehyde of formula (3)) and a suitable reducing agent to give a compound of formula I. The reaction is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran, dichloromethane, and 1,2-dichloroethane. The reaction may be carried out in the presence of a drying agent, such as sodium sulfate, cupric sulfate, or molecular sieves. The reaction is carried out in the presence of from about 1 to 20 molar equivalents of a suitable reducing agent, such as, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. It may be advantageous to allow Schiff base formation to proceed before addition of the suitable reducing agent. When sodium cyanoborohydride is used it may be advantageous to monitor and adjust the pH during the course of the reaction as is known in the art. The reaction is generally carried out at temperatures of from 0° C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme A, optional step b, not shown, an acid addition salt of a compound of formula I is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art.

Scheme B depicts alternative methods for the preparation of compounds of formula I by formation and reduction of an amide.
In one alternative, Scheme B, step a, depicts contacting an appropriate compound of formula (1) with an appropriate compound of formula (5) in a amide forming reaction to give a compound of formula (6). An appropriate compound of formula (1) is as described in Scheme A. An appropriate compound of formula (5) is one in which A is an activating group, talking the form of an acid halide, activated ester, activated amide, or anhydride, and X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
In another alternative, Scheme B, step a, depicts contacting an appropriate compound of formula (7) with an appropriate compound of formula (4) in a amide forming reaction to give a compound of formula (8). An appropriate compound of formula (7) is one in which A is an activating group as described above and R1 is as desired in the final product of formula I. An appropriate compound of formula (4) is as described in Scheme A. Appropriate compounds of formula (4) and (7) are generally available from commercial sources and can also be prepared by methods described herein and by methods described in the art.
The amide formation reaction depicted in Scheme B, step a, is readily accomplished by a number of methods readily available to the skilled person, including those which are conventionally conducted for peptide synthesis. Such methods can be carried out on the acid, acid halide, activated esters, activated amides, and anhydrides.
For example, well known coupling reagents such as a carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate amide formation. Such coupling reactions are typically use about 1 to 1.5 molar ratios of acid, amine, and coupling reagent and are conventionally conducted in an inert aprotic solvent such as pyridine, dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran and the like. It may be advantageous to use a suitable base, such as triethylamine or N,N-diisopropylethylamine, in such coupling reactions. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 48 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an acid halide can be employed in the reaction. It may be advantageous to use a suitable base to scavenge the acid generated during the reaction, suitable bases include, by way of example, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and the like. Typically, about 1 to 1.5 molar ratios of the acid halide and amine are used. The reaction can be carried out in a variety of inert aprotic solvents such as pyridine, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, and the like. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 12 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an acid halide can be employed in the reaction under Schotten-Baumann conditions. Typically, under such conditions 1 to 10 molar equivalents of amine are used. Such couplings generally use a suitable base to scavenge the acid generated during the reaction, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like. The reaction can be carried out in a variety of mixed solvent systems such as dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and the like; and water. The reaction is preferably conducted at from about 0° C. to about 80° C. until reaction completion which typically occurs within 1 to about 6 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an anhydride (either symmetrical or mixed) can be employed in the reaction. Such anhydrides are formed by numerous methods known in art. Typically, about 1 to 1.5 molar equivalents of the anhydride and amine are used. It may be advantageous to use a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, and the like. The reaction can be carried out in a variety of solvents. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 12 hours. Upon completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme B, steps b, depicts reduction of a compound of formula (6) or (8) to give a compound of formula I.
For example, a compound of formula (6) or (8) is contacted with a suitable reducing agent to give a compound of formula I. Suitable reducing agents are those which are capable of reducing an amide to an amine and include, borane reagents, such as borane dimethyl sulfide complex, hydride transfer reagents, such as aluminum hydride and lithium aluminum hydride, and the like. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 10 equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme B, as an optional step, not shown, an acid addition salt of a compound of formula I is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art.
In Schemes A and B, as an optional step, not shown, as will be appreciated by the skilled person, a compound of formula I in which R2 is hydrogen can be alkylated to give a compound in which R2 is not hydrogen. Methods for alkylating such secondary amines are will known in the art and discussed in Scheme C, step c, below.
In Schemes A and B, as will be appreciated by the skilled person, compounds of formula II are also prepared by the methods described in Schemes A and B using compounds of the formula (9) and (10), below:

An appropriate compound of formula (9) is one in which Y, R5 and R6 are as desired in the final product of formula II and an appropriate compound of formula (10) is one in which A is an activating group, as described above, and Y, R5 and R6 are as desired in the final product of formula II.
Starting material for Schemes A and B are prepared in the Schemes below. In the Schemes below all substituents, unless otherwise indicated, are as previously defined, and all starting material and reagents are well known and appreciated in the art.
Scheme C describes methods for preparing compounds of formula (1).

Scheme C, step a, depicts the reaction of an appropriate aldehyde of formula (24) and nitromethane to give the compound of formula (25). An appropriate aldehyde of formula (24) is one in which R1 is as desired in the final product of formula I. The reaction of the anion of nitromethane with aldehydes to give nitro olefins is well known and appreciated in the art. Modern Synthetic Reactions, H. O. House (2nd ed. The Benjamin/Cummings Publishing Company 1972).
For example, an appropriate aldehyde of formula (24) is condensed with nitromethane to give the compound of formula (25). Typically the reaction is carried out in the presence of an excess of nitromethane. The reaction is performed in a suitable solvent, such as tetrahydrofuran, nitromethane, and dimethyl sulfoxide. The reaction is performed using from about 1.1 to about 3 molar equivalents of a suitable base, such as sodium bis(trimethylsilyl)amide, potassium t-butoxide, sodium hydride, sodium acetate, triethylamine, N,N-diisopropylethylamine, ammonium salts, such as ammonium acetate. The reaction is carried out at temperatures of from about −20° C. to the reflux temperature of the selected solvent and generally require from 6 hours to 48 hours. The product of the coupling reaction can be isolated and purified using techniques well known in the art, including extraction, evaporation, chromatography and recrystallization.
Scheme C, step b, depicts the reduction of a compound of formula (25) to give a compound of formula (1) in which R2 is hydrogen.
For example, an appropriate compound of formula (25) is hydrogenated over a suitable catalyst, such as Raney® nickel or a palladium catalyst. When Raney nickel is used, the reaction is carried out in a suitable solvent, such as ethanol, methanol, water, and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example, using hydrochloric or sulfuric acid. When a palladium catalyst is used palladium-on-carbon is preferred and the reaction is carried out in a suitable solvent, such as ethanol, methanol, tetrahydrofuran, water, and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example, using hydrochloric, trifluoroacetic acid, or sulfuric acid. The reaction is generally carried out at temperatures of from ambient temperature to 70° C. The reaction is carried out with hydrogen at pressures of from 15 psi to 120 psi in an apparatus designed for carrying out reactions under pressure, such as a Parr® hydrogenation apparatus. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, an appropriate compound of formula (25) is contacted with a suitable reducing agent. Suitable reducing agents include hydride transfer reagents, such as aluminum hydride and lithium aluminum hydride, and the like. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 10 equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Additionally, an appropriate compound of formula (25) can be reduced in two steps to a compound of formula (1). For example, the vinyl group of a compound of formula (25) can be reduced using reagents such as sodium borohydride. The reaction is typically carried out using an excess of borohydride in a solvent, such as methanol, ethanol, isopropanol, water, and the like. The intermediate 2-nitroethyl compound can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization. The intermediate 2-nitroethyl compound can then be reduced using a variety of methods, such as the hydrogenation and hydride transfer reagents as discussed above. Also, the intermediate 2-nitroethyl compound can be reduced using metals such as zinc to give the desired amine of formula (1) in which R2 is hydrogen.
Scheme C, step c, depicts the optional alkylation of a compound of formula (1) in which R2 is hydrogen to give a compound of formula (1) in which R2 is not hydrogen.
For example, a compound of formula (1) in which R2 is hydrogen is contacted with a suitable alkylating agent. A suitable alkylating agent is one which transfers a group R2 as is desired in the final product of formula I. Suitable alkylating agents include C1-C3 alkyl halides. The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixtures, or acetonitrile. The reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, or N,N-diisopropylethylamine. The reaction is generally carried out at temperatures of from −78° C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, a compound of formula (1) in which R2 is hydrogen undergoes a reductive amination with an aldehyde or ketone which gives a compound of formula (1) in which R2 is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde, and acetone. The reaction is carried out as described in Scheme A, step a.
In another alternate, for example, a compound of formula (1) in which R2 is hydrogen undergoes amide or carbamate formation followed by reduction to give a compound of formula (1) in which R2 is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde, and acetone. The reaction is carried out as described in Scheme A, step a.
Scheme C, steps d and e, depict an alternative approach to preparing the compounds of formula (1) via formation of an amide using an appropriate compound of formula (7) and an appropriate amine of formula (26) to give an amide of formula (27), followed by reduction to give a compound of formula (1). An appropriate compound of formula (7) is as described in Scheme B. An appropriate amine of formula (26) is one which gives R2 as desired in final compound of formula I. The skilled person will recognize that many of the amides of formula (27) are commercially available and available in the art.
The amide formation and reduction in Scheme C are carried out as described in the Scheme B.
Scheme D describes methods for preparing compounds of formula (1) in which R1 is optionally substituted indol-3-yl.

Scheme D, step a, depicts the two-step reaction of an appropriate indole of formula (28) with oxalyl chloride followed by an appropriate amine of formula (26), R2NH2 to give a compound of formula (29). An appropriate indole of formula (28) is one in which Z′ represents optional substituents on the indole 2- and 4- to 7-positions as desired in the final product of formula I. An appropriate amine of formula (26) is as described in Scheme C, above.
For example, an appropriate indole of formula (28) is contacted with about 1 to 2 molar equivalents of oxalyl chloride to give an intermediate keto-acid chloride. The reaction is carried out in a suitable solvent, such a diethyl ether or tetrahydrofuran. The reaction is generally carried out at temperatures of from 0° C. to 40° C. and generally require from 6 hours to 48 hours. The intermediate keto-acid chloride product can be isolated and purified using techniques well known in the art, including extraction, evaporation, chromatography and recrystallization. Generally, the intermediate keto-acid chloride product is used directly after isolation. The intermediate keto-acid chloride product is contacted with an appropriate amine, R2NH2, as defined above and using the procedures described above.
Scheme D, step b, depicts the reduction of a compound of formula (29) to give a compound of formula (1) in which R1 is optionally substituted indol-3-yl.
For example, a compound of formula (29) is reduced using a suitable reducing reagent such as, lithium aluminum hydride to give a compound of formula (1) which R1 is optionally substituted indol-3-yl. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 12 molar equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 12 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme D, step c, an appropriate indole of formula (28) is formylated to give a compound of formula (30). An appropriate indole of formula (28) is as described in step a, above.
For example, an appropriate indole of formula (28) is reacted with a suitable formyl transfer reagent, such as the Vilsmeier reagent formed from dimethylformamide. Generally, about 1 molar equivalent of formyl transfer reagent is used. The reaction is performed in a suitable solvent, such as benzene, dimethylformamide, tetrahydrofuran, or diethyl ether. The reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 6 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
In Scheme D, step d, an appropriate indole of formula (28) is contacted with (CH3)2N—CH═CH—NO2 to give a compound of formula (30). An appropriate indole of formula (28) is as described in step a, above.
For example, an appropriate indole of formula (28) is reacted with 1-dimethylamino-2-nitroethylene. Generally, about 1 equimolar amounts of reagents. The reaction is performed in a suitable solvent, such as trifluoroacetic acid or dichloromethane containing about 2 to 15 equivalents of trifluoroacetic acid. The reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 24 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme D, steps e and f, depict an the reaction of an aldehyde of formula (30) to give a nitro olefin of formula (31) and the reduction of the nitro olefin to give a compound of formula (1) in which R1 is optionally substituted indol-3-yl. These steps can be carried out using the methods described in Scheme C.
As will be appreciated by the skilled person, in steps not shown, the indole nitrogen of a compound of formula (1) can be substituted, as desired, using suitable amine protecting groups to give compounds in which R1 is 1-substituted indol-3-yl. Also as will be appreciated by the skilled person, in steps described in Scheme C, R2 groups which are not hydrogen can be introduced by various methods.
Scheme E describes methods for preparing compounds of formula (2) in which X is —O— or —S—.

Scheme E, step a, depicts the formation of an acetal of an appropriate compound of formula (11) to give a compound of formula (12). An appropriate compound of formula (11) is one in which X and R3 are as desired in the final compound of formula I. Such acetal formation reactions are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
For example, a compound formula (11) is contacted under acid catalysis with an appropriate alcohol, HOR. An appropriate alcohol is one which gives an acetal with is stable to the reaction in step b and can be removed in step c to give a compound of formula (2). Appropriate alcohols include methanol, ethanol, propanol, 1,3-propane diol, ethylene glycol, and the like.
In Scheme E, step b, an appropriate compound of formula (11), (12), or (14) is reacted with an R4 group transfer reagent, as desired, to give a compound of formula (2), (13), or (15); respectively. Appropriate compounds of formula (11), (12), and (14) are ones in which X and R3 are as desired in the final product of formula I. A variety of reagents that transfers an R4 as desired in the final product are available and suitable for the reaction depicted in Scheme E. Such reagents include halopyridines, halopryidine N-oxides, allyl halides, C2-C4 alkanols, C2-C4 alkyl halides and sulfonates, fluorinated C2-C4 alkanols, fluorinated C2-C4 alkyl halides and sulfonates, optionally substituted phenyl having at least one fluoro or chloro atom, optionally substituted phenylsulfonyl halides or anhydrides, and optionally substituted benzyl halides.
For example, where the appropriate R4 group transfer reagent is a halide, sulfonate, or anhydride, an appropriate compound of formula (11), (12), or (14) is coupled under basic conditions to give a compound of formula (2), (13), or (15); respectively. The reaction is performed in a suitable solvent, such as acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran, pyridine, and dimethyl sulfoxide. The reaction is carried out in the presence of from about 1 to about 3 molar equivalents of a suitable base, such as potassium hydride, sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, and the like. The reaction is carried out at temperature of from about −30° C. to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Of course, when a halopyridine N-oxide is used the N-oxide is remove by reduction to give the R4 as desired in the final product of formula I. Such reductions are readily accomplished by the skilled person, and include catalytic reduction over palladium catalysts using hydrogen or ammonium formate in a suitable solvent such as methanol, ethanol, water, and mixtures thereof.
Alternately, for example, where the appropriate R4 group transfer reagent is an alkanol, the coupling can be carried out under Mitsunobu conditions which are well known in the art. The reaction is carried out in a suitable solvent, such as tetrahydrofuran and diethyl ether using a phosphine, such as triphenylphosphine or a resin bound phosphine and a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-t-butyl azodicarboxylate. The reaction is generally carried out at temperatures of from ambient temperatures to 60° C. The reaction generally requires from 1 hour to 12 hours. The product can be isolated by techniques well known in the art, such as extraction and evaporation. The product can then be purified by techniques well known in the art, such as distillation, chromatography, or recrystallization.
Scheme E, step c, depicts the deprotection of an acetal of formula (13) to give a compound of formula (2). Such deprotections are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
For example, a compound formula (13) is contacted under acid under aqueous conditions to give a compound of formula (2).
In Scheme E, step d, a bromo compound of formula (15) is formylated to give a compound of formula (2).
For example, a compound of formula (15) is metalated by treatment with a metalation reagent such as butyl lithium. The reaction is performed in a suitable solvent, such as hexane, benzene, toluene, tetrahydrofuran or diethyl ether. The reaction is typically carried out in the presence of from about 1 to about 1.5 molar equivalents of a metalating reagent. The metalation reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 6 hours. The metalated species is then treated with a formyl transfer reagent such as dimethylformamide or an alkyl chloroformate to give a compound of formula (2) or a alkoxycarbonyl compound which can be elaborated to an aldehyde as described herein. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme F describes methods for preparing compounds of formula (2) from the versatile intermediate, compound (17), which readily prepared by acetal formation as described above.

Scheme F, step a, depicts an aromatic displacement reaction of an appropriate compound of formula (17) and an appropriate alcohol (R4OH) or an appropriate thiol (R4SH) to give a compound of formula (13) in which X is —O— or —S— are defined above in Scheme E. An appropriate compound of formula (17) is one in which R3 is as desired in the final product of formula I. In an appropriate alcohol (R4OH) or an appropriate thiol (R4SH), R4 is as desired in the final product of formula I, and includes C2-C4 alkyl alcohols and thiols, fluorinated C2C4 alkyl alcohols and thiols, optionally substituted phenols and thiophenols, optionally substituted benzyl alcohols and thiols.
For example, an appropriate compound of formula (17) and an appropriate alcohol (R4OH) or an appropriate thiol (R4SH) are coupled give a compound of formula (13). The reaction is performed in a suitable solvent, such as dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. The reaction is performed using from about 1.1 to about 3 molar equivalents of an appropriate alcohol or thiol. The reaction is carried out in the presence of from about 1 to about 6 molar equivalents of a suitable base, such as potassium hydride, sodium hydroxide, potassium carbonate, sodium carbonate, or sodium hydride. The coupling is performed using a suitable catalyst, such as copper salts. The reaction generally requires from 6 hours to 48 hours. The product of the coupling reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme F, steps b-e, depict a number of reactions of an appropriate compound of formula (17), after metalation as described in Scheme E, step d, to give compounds of formula (18)-(21), respectively. In these steps an appropriate compound of formula (17) is one in which R3 is as desired in the final product of formula I and is not adversely affected by the metalation conditions of the reaction. Generally, these reactions are performed in the solvent used and at the temperature used to form the metalated species. The products of these reactions can be isolated and purified using techniques well known in the art, include quenching, extraction, evaporation, trituration, chromatography, and recrystallization.
For example, in Scheme F, step b, a metalated compound of formula (17) is contacted with an appropriate disulfide (R4S—)2, to give a compound of formula (18). An appropriate disulfide is one that gives R4 as desired in the final product of formula I and gives rise to compounds in which X is —S—. Appropriate disulfides include C1-C4 alkyl disulfides, optionally substituted phenyl disulfides, and optionally substituted benzyl disulfides. The reaction is performed using from about 1 to about 2 molar equivalents of an appropriate disulfide. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction generally require from 12 hours to 48 hours.
For example, in Scheme F, step c, a metalated compound of formula (17) is contacted with an appropriate sulfonyl fluoride (R4SO2F) to give a compound of formula (19). An appropriate sulfonyl fluoride is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —SO2—. Appropriate sulfonyl fluorides include an optionally substituted phenyl sulfonyl fluoride. The reaction is performed using from about 1 to about 3 molar equivalents of an appropriate sulfonyl fluoride. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 0° C. The reaction generally require from 2 hours to 12 hours.
For example, in Scheme F, step d, a metalated compound of formula (17) is contacted with an appropriate acid chloride (R4C(O)Cl) to give a compound of formula (20). An appropriate acid chloride is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —C(O)—. Appropriate acid chlorides include C2-C4 alkyl acid chlorides, fluorinated C2-C4 alkyl acid chlorides, optionally substituted phenyl acid chlorides, optionally substituted benzyl acid chlorides, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle acid chlorides. The reaction is performed using from about 0.8 to about 1.2 molar equivalents of an appropriate acid chloride. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction generally require from 1 hours to 12 hours.
For example, in Scheme F, step e, a metalated compound of formula (17) is contacted with an appropriate aldehyde (R4C(O)H) to give a compound of formula (21). An appropriate aldehyde is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —CH(OH)—. Appropriate aldehydes include C2-C4 alkyl aldehyde, fluorinated C2-C4 alkyl aldehyde, optionally substituted phenyl aldehyde, optionally substituted benzyl aldehyde, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle aldehyde. The reaction is performed using from about 1 to about 3 molar equivalents of an appropriate aldehyde. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −50° C. to about 50° C. The reaction generally requires from 4 hours to 24 hours.
As will be appreciate by the skilled person, compounds of formula (18)-(21) can undergo a number of other transformations which are depicted in Scheme F, steps f-i, to give, ultimately, compounds of formula I having various groups at X. These transformations are trivial and well within the ability of the skilled person. These transformations include oxidation of sulfides (step f) which can be accomplished by peroxide, peracids, and other reagents known in the art; reduction of a benzyl alcohol (step g) which can be accomplished by a variety of reagents, such as triethylsilane/trifluoroacetic acid; halogenation of a benzyl alcohol to give fluoro (step h) using reagents such as DAST and fluorinating reagents; reduction of a ketone (step i) using various hydride transfer reagents or oxidation of a benzylic alcohol (step i) which can be accomplished by manganese dioxide or Swern conditions.
In Scheme F, step j, compounds of the formula (13) and (18)-(23) are deprotected to give an aldehyde of formula (2) as described in Scheme E, step c.
Scheme G describes methods for preparing compounds of formula (5).

Scheme G, step a, a bromo compound of formula (15) is carboxylated to give a compound of formula (5) in which A is —OH.
For example, a compound of formula (15) is metalated as described in Scheme E, step d, and the metalated species is then treated with carbon dioxide to give a compound of formula (5) in which A is —OH. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme G, step b, a bromo compound of formula (15) is alkoxyformylated using an appropriate chloroformate or carbonate to give a compound of formula (32). An appropriate chloroformate or carbonate is one that transfers an RO(O)C— group in which R is methyl, ethyl, or benzyl.
For example, a compound of formula (15) is metalated as described in Scheme E, step d, and the metalated species is then treated with about 1 to 3 molar equivalents of an appropriate chloroformate or carbonate. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction typically requires from 1 to 24 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
In Scheme G, step c, an appropriate compound of formula (33) is reacted with an R4 group transfer reagent, as desired, to give a compound of formula (32). An appropriate compound of formula (33) is one in which X and R3 are as desired in the final product of formula I. Reagents that transfers an R4 are as described in Scheme E.
For example, where the appropriate R4 group transfer reagent is a halide or anhydride, an appropriate compound of formula (34) is coupled under basic conditions with to give a compound of formula (33). The reaction is performed in a suitable solvent, such as dimethylformamide, tetrahydrofuran, or pyridine. The reaction is typically carried out in the presence of from about 1 to about 3 molar equivalents of a suitable base, such as sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, and the like. The reaction is carried out at temperature of from about −30° C. to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Alternately, for example, where the appropriate R4 group transfer reagent is an alkanol, the coupling can be carried out under Mitsunobu conditions which are well known in the art and described in Scheme E.
Scheme G, step d, an ester of formula (32) is deprotected to give a compound of formula (5) in which A is —OH. Such deprotections are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
Scheme G, step e, a compound of formula (5) in which A is —OH is converted to a compound of formula (5) in which A is an activating group, such as acid halide, activated ester, activated amide, or anhydride. The formation of such activated intermediates is well known and appreciated in the art.
For example, an acid halide can be prepared by a variety of reagent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, phosphorous oxychloride, phosphorous trichloride, and phosphorous pentachloride; a mixed anhydride of substituted phosphoric acid, such as dialkylphosphoric acid, diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid; an activated ester, such as phenol ester, p-nitrophenol ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester; or activated amide, such as imidazole, dimethylpyrazole, triazole; are prepared by method which are well known and appreciated in the art. Such activated intermediates may be prepared and used directly or are prepared and isolated before use in the schemes above.
Scheme H describes methods for preparing compounds of formula (4).

Scheme H, step a, a bromo compound of formula (15) is converted to a nitrile of formula (35).
For example, a compound of formula (15) is treated with copper (I) cyanide to give a compound of formula (35). The reaction is performed in a suitable solvent, such as dimethylformamide. The reaction is typically carried out in the presence of from about 1 to about 3 molar equivalents of copper (1) cyanide. The reaction is carried out at temperature of from about ambient temperature to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme H, step b, a nitrile compound of formula (35) reduced to give a compound formula (4) in which R2 is hydrogen.
For example, a nitrile compound of formula (35) is contacted with sodium borohydride in the presence of cobalt chloride. The reaction is carried out in a suitable solvent, such as methanol, or ethanol. The reaction is generally carried out at temperatures of from 0° C. to 50° C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction with aqueous acid, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, a nitrile compound of formula (35) is hydrogenated over a suitable catalyst, such as Raney® nickel. The reaction is carried out in a suitable solvent, when Raney® nickel is used as the catalyst, suitable solvents will generally contain ammonia, such as ethanol/ammonium hydroxide. The reaction is generally carried out at temperatures of from ambient temperature to 50° C. The reaction is carried out at pressures of from 15 psi (103 kPa) to 120 psi (827 kPa) in an apparatus designed for carrying out reactions under pressure, such as a Parr hydrogenation apparatus. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme H, step c, a nitrile compound of formula (35) is converted to a amide of formula (36).
For example, a compound of formula (35) is treated with acid or base under hydrolysis conditions to give a compound of formula (36). The reaction is performed in a suitable solvent, such as ethanol, isopropanol, dimethylsulfoxide, each containing water. The hydrolysis of an aromatic nitrile to an amide is well known and appreciated in the art. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme H, step d, depicts formation of an amide of formula (37) by reacting a compound of formula (5) and an appropriate amine of formula H2NR2 in a amide forming reaction. An appropriate amine of formula H2NR2 is one which gives R2 as desired in the final product of formula I. Suitable methods of forming amides are well known in the art and are described in Scheme B, above.
Scheme H, step e, a amide compound of formula (36) or (37) is reduced to a compound of formula (4). Such reductions of amides are readily carried out as described in Scheme B, above, and as known in the art.
Scheme H, step f, a compound of formula (2) and an appropriate amine of formula H2NR2 undergo reductive amination to give a compound of formula (4). Such reductive aminations are readily carried out as described in Scheme B, above, and by other methods known in the art.
As will be appreciated by the skilled person, the compounds of formula II are readily prepared by methods analogous to those described above.
The present invention is further illustrated by the following examples and preparations. These examples and preparations are illustrative only and are not intended to limit the invention in any way.
The terms used in the examples and preparations have their normal meanings unless otherwise designated. For example, "° C." refers to degrees Celsius; "N" refers to normal or normality; "M" refers to molar or molarity; "mmol" refers to millimole or millimoles; "g" refers to gram or grams; "mL" refers milliliter or milliliters; "mp" refers to melting point; "brine" refers to a saturated aqueous sodium chloride solution; etc. In the 1H NMR, all chemical shifts are given in δ, unless otherwise indicated.

N-(2-arylethyl)benzylamines as antagonists of the 5-HT6 receptor


A repeater includes an up-link circuit and a down-link circuit. The down-link circuit includes a receiver, a radio frequency circuit and a transmitter. The transmitter transmits the repeated second signals to the user equipment and includes an antenna array, a plurality of power amplifiers, a plurality of first phase shifters, a first memory unit, and a first control logic circuit. The antenna array includes a plurality of antenna elements arranged along a first direction, and the number of the plurality of antenna elements is at least four. The first memory unit is configured to store predetermined parameters associated with a predetermined radiation pattern. The first control logic circuit selects a first number of the power amplifiers and the first number of the first phase shifters, and sets normalized gains for the selected plurality of power amplifiers range from 0.7 to 1 unit.

In upcoming era of 5th generation mobile networks, both sub-6 GHz and millimeter-wave (mmWave) frequency bands will be used. In order to achieve ubiquitous coverage range of 5G signal for both outdoor and indoor environments, mmWave repeater is a promising candidate that can be massively deployed in downtowns/suburban areas.
While the beam-alignment between gNodeB (gNB) and repeater is relatively easy because of their fixed positions, such a task will become very difficult between repeater and user equipment (UE) due to the lack of synchronization.
In detail, since there is no synchronization between the UE and the repeater, beam-alignment between the UE and the repeater would be very difficult and lack of economic benefit for off-the-shelf products.
The simplest way is to activate only one antenna element in an antenna array as shown in FIG. 1, which is a schematic diagram showing an omni-directional radiation pattern implemented by activating only one antenna element in the antenna array of an existing repeater. As can be seen from FIG. 1, an effective isotropic radiated power (EIRP) of such implementation would be quite low since only one power amplifier (PA) is activated, which leads to low signal quality and short communication distance between the repeater and the UEs, such as user equipment UE1, UE2 and UE3 in FIG. 1.

Repeater and radiation pattern forming method for the same


A method for fabricating a resistively switching memory cell is provided. The method includes the following steps: depositing a first electrode, applying a layer of a chalcogenide compound to the first electrode, applying a layer of silver or copper, and operating a noble gas plasma in a back-sputtering mode in order to effect silver or copper diffusion into the layer of the chalcogenide compound. Optionally, and if appropriate, further layers for the second electrode are then deposited.

Nonvolatile, resistively switching memory cells include a first electrode, a second electrode and a solid electrolyte that is contact-connected by the two electrodes in a sandwich-type geometry. The solid electrolyte includes an amorphous matrix of a chalcogenide compound and a metal which is distributed in the amorphous matrix and the cations of which migrate in the amorphous matrix to the cathode under the influence of an electric voltage. The memory cells, on account of the migration of these cations, are switchable by a first electric voltage into a state with a low electrical resistance and by a second electric voltage of opposite polarity into a state with a high electrical resistance.
These two physical states (i.e., the state with the high electrical resistance and the state with the low electrical resistance) are used for the storage of information. Usually, the higher electrical resistance is assigned to logic 0 and the lower electrical resistance is assigned to logic 1.
After the brief supply of current has been switched off, specifically both after programming (transition to the state with the low electrical resistance) and after erasing (transition to the state with the high electrical resistance) or reading of the information, the resistance value which was induced last is retained in stable form for a prolonged period of time. Accordingly, the storage of information in resistively switching memory cells is nonvolatile.
The strong increase in the conductivity of the resistively switching memory cell when a voltage is applied is based on electrochemical processes in the solid electrolyte of the memory cell, which leads to the formation of a metallic bridge that extends all the way from the cathode to the anode. Applying a voltage of opposite polarity at least partially removes this bridge again, and the metallically conductive path between the electrodes is interrupted: the memory cell returns to the state with the high resistance. On account of this storage mechanism, nonvolatile, resistively switching memory cells are also known as nonvolatile CBRAM (conductive bridging random access memory) memory cells. This form of memory cells is distinguished by a low switching voltage with short switching times. Furthermore, with this type of memory cells, a high number of switching cycles is achieved with a good thermal stability.
The memory cell designs which have been used hitherto (such as for example floating gate memories, such as flash or DRAM), on account of their mechanism being based on the storage of charges, will reach the limits of scalability within the foreseeable future. The problem with DRAM and flash memory cells is that with ongoing miniaturization of the memory cells, the charge quantity which can be held in a cell is also becoming ever smaller. However, as the charge quantity decreases, so too does the reliability of information storage. Memory cells which are based on capacitive charging no longer operate satisfactorily, on account of the lower voltages and current intensities caused by miniaturization in this "low-energy" range.
Furthermore, as in the case of the flash memory, the high switching voltages and the limited number of read and write cycles, and in the case of the DRAM the very limited duration of storage of the charge state, constitute additional problems which it has not hitherto been possible to solve in an optimum way. The problem of leakage currents within the storage capacitor which exists with the DRAM design, leading to the loss of charge, is currently resolved to only an unsatisfactory extent by constant refreshing of the stored charge.
These and other problems have led to new storage technologies, which are based on concepts other than capacitive charging, having been developed in recent years. In this context, the nonvolatile CBRAM memory cells mentioned above are very promising. These memory cells have been described, for example, in International Patent Application Publication Nos. WO 97/48032 and WO 03/032392, U.S. Pat. No. 6,418,049, and U.S. Patent Application Publication Nos. 2003/020997 and 2003/0209728.
The storage concept of CBRAM memory cells is not based on the storage of charges, but rather on the difference in resistance between two stable states, which is caused by a high mobility of metal ions in a matrix of chalcogenide compound(s) when an electric field is applied.
As noted above, CBRAM memory cells typically include two electrodes and a thin film of a solid electrolyte that is contact-connected by the two electrodes in a sandwich-type geometry. Solid electrolytes may be crystalline or amorphous solids. The solid electrolytes used in CBRAM cells typically include amorphous solids, which can also be referred to as amorphous matrix or glasses. The solid electrolytes are preferably chalcogenide compounds.
Chalcogenides are compounds in which one or more elements of main group VI of the Periodic System (oxygen, sulfur, selenium, tellurium) form the more electronegative compound, which are referred to as oxides, sulfides, selenides and tellurides. Sulfides and selenides have a pronounced tendency to form amorphous solids. They are therefore preferably used for the fabrication of CBRAM cells. Oxides can likewise be formed as amorphous layers, but their structure (microstructure) is generally so dense that the ionic mobility of the metallic component is too low. Sulfides and in particular selenides have a more open microstructure and are therefore preferred from the perspective of switching speed in CBRAM cells.
Germanium from main group IV of the Periodic System can be used as the more electropositive chemical element in the chalcogenide compounds. These IV-VI compounds, as they are known, are suitable as amorphous matrices for CBRAM memory cells; germanium sulfide and germanium selenide represent preferred IV-VI compounds for use as amorphous matrices in the CBRAM memory cells. Alternatively, however, silicon selenide or silicon sulfide are also suitable as amorphous matrices for CBRAM memory cells.
The selenium or sulfur content in germanium selenide GexSe1-x and germanium sulfide GexS1-x may vary over a wide range. Particularly suitable glasses with ideal properties are formed if x is in the range from 0.2 to 0.5 and is, for example, 0.33. Generally, x must have a value which is such that the corresponding selenide or sulfide can easily be formed into a stable glass that is suitable for solid ion conduction. In the description which follows below, all selenide and sulfide glasses are hereinafter referred to as Ge—S and Ge—Se chalcogenide compounds, irrespective of the particular value of x.
In the amorphous matrix which forms the active material of the CRAM memory cell, the metal which is contained, under the influence of an electric field, forms cations which migrate through the amorphous matrix to the cathode under the influence of this field. Particularly suitable metals are silver (Ag) and copper (Cu), with silver being preferred, since it is easy to ionize and in the ionized state (as Ag+) has the required mobility in the amorphous matrix of the chalcogenide glass. The quantity of silver which can be taken up by Ge—Se and Ge—S compounds depends on the Ge/S or Ge/Se quantitative ratio. This saturation concentration is typically a few 10 s of atomic percent, for example Ge0.3Se0.7 is 47.3 atomic percent of silver.
The cathode is typically composed of an inert material, such as molybdenum or tungsten. The cathode may also be composed of tantalum, titanium, such as conductive oxides, nitrides, or highly n-doped or highly p-doped silicon or alloys of the abovementioned materials. As used herein, the term "inert material" means a conductive material which, under the influence of an electric field, conducts the current but does not form cations, or its cations, when an electric field is applied and has no mobility or only an insignificant mobility within the amorphous matrix.
A metal or a chemical compound whose cations are suitable for ion migration through the solid electrolyte is used as the anode. The anode is preferably composed of the metal which is also contained in the solid electrolyte. As result, the quantity of metal which is electrochemically deposited at the cathode can be topped up by the oxidation of the anode. It is therefore preferable to use an anode made from copper, silver or silver compounds, such as for example Ag2S, Ag2Se.
In the processes used hitherto for fabricating CBRAM memory cells, solid electrolytes, such as the preferred Ge—Se—Ag glasses and Ge—S—Ag glasses, have been formed by photolytic dissolution (photodiffusion) of silver in a thin film of the solid electrolyte. One drawback of these fabrication methods is that the photolytic dissolution of silver is carried out in a separate process step, generally by UV exposure, such as by mercury vapor lamps, so that in this step it is necessary for the wafers to be discharged from the vacuum chamber and then reintroduced into the vacuum chamber for further processing following the photodiffusion. As a result of this process step, there is a very high risk of contamination of the wafer and/or of the wafer being covered with foreign particles.

Method for fabricating a resistive memory


The Toy System is a toy for use with a computer having a display. The system includes a plurality of interconnecting hardware toy pieces and a toy design system software for operating the computer. An inventory database stores an inventory of the toy pieces. An inventory database manager module updates the inventory database in response to player input. A design layout module creates and modifies a toy layout in response to player input using software representations corresponding to the inventory of the toy pieces and conforming to a plurality of design rules, and generates a screen indicating the toy layout. A layout database stores the toy layout created by the player using the toy design system. Other features includes inventory management and control allowing a layout based on a fixed inventory, a layout completion module, a layout library module, a design assistance module, a simulation module and an education module. The hardware pieces may be a moveable element, such as a ball, and tracks, support pieces and stunt pieces, for guiding the ball.

This invention relates to a combination hardware and software toy system, and, in particular, toy design system software for designing toy layouts that can be built using interconnecting hardware toy pieces.
Various toys with hardware pieces exist that allow the construction of structures, buildings, vehicles or tracks, including erector sets, race car tracks, and railroad tracks. There are drawing software programs that allow the player to draw a picture the player desires, including structures, buildings, vehicles and tracks. However, the two domains of toys with hardware pieces and software drawing programs have not been combined to provide a useful toy that will easily allow the player to design a toy layout that can be built using the hardware toy pieces. In the prior art, a player could use a drawing program that does not consider the inventory of hardware toy pieces. Alternatively, a player could commence building a toy layout with the hardware toy pieces without knowing the outcome. In either case, the player had no assurance that the toy layout could be completed using the limited quantity of hardware toy pieces available to the player. Furthermore, the player has no assurance that the toy layout will function properly until it is built using the hardware toy pieces.

Toy system including hardware toy pieces and toy design software for designing and building various toy layouts using the hardware toy pieces


In one embodiment the raingear is housed in a pocket located on the top of the backpack so as to allow the wearer to reach over his shoulders to grab hold of a portion of the raingear and lift it out of the pocket and allow it to drape over the entire body of the wearer and backpack. The raingear includes an attachment to the backpack so that it stays attached to the backpack to assure that the raingear will be returned to the pocket. The other embodiment houses the raingear in its own self-contained package that is attachable to the backpack or jacket of a fishing or hunting jacket and the like. The donning and the attachment of the raingear is substantially identical to the first embodiment.

There are sundry back packs and raingear available in the prior art and as one skilled in this art appreciates there is a considerable amount of prior art where the raingear is stored in a back pack or tote bag or the like. Exemplary of such articles are disclosed is the following patents:                French Patent No. 2,553,981 granted to Aime Samuel Achour on Oct. 28, 1983. The raingear in the backpack disclosed in this patent is stored in a pocket adjacent to the back of the wearer and is the backpack is removed from the wearer to get at the raingear.        U.S. Pat. No. 36,685 granted to Brecht et al on Oct. 14, 1862 a combination a backpack that is converted into tent, mattress and raingear and it also must be removed from the user to accommodate these various uses.        U.S. Pat. No. 261,109 granted to Watkinson on Jul. 11, 1882 discloses a tote bag that stores raingear.        U.S. Pat. No. 1,340,351 granted to Whall on May 18, 1920 discloses a foldable raingear.        U.S. Pat. No. 2,967,306 granted to Fabanich on Jan. 10, 1961 is a combined raingear, seat and foldable for ease of carrying adapted particularly for hunters.        U.S. Pat. No. 5,165,111 to Lieberman discloses a backpack with integral garment. In Lieberman, the integral garment is stored in an internal compartment formed continuously along a central panel on the inside of the backpack. The garment may be deployed without removing the backpack from the user's back. However, the Lieberman invention is difficult to deploy by the user since the package that stores the garment is zippered and near the user's back. Moreover, the pack must be constructed of waterproof material since the garment does not cover the pack.        U.S. Pat. No. 5,407,112 granted to Christodoulou et al on Apr. 18, 1995 discloses a combined backpack that stores a raincoat in a pocket located at the top of the backpack and is covered by a detachable tote back that overlies the pocket that stores the raincoat.        U.S. Pat. No. 5,526,969 to Greenberger discloses a backpack that is convertible between a backpack mode and a backpack and protective outer gear mode. The protective outerwear is stored inside of a first pocket. The Greenberger invention suffers from the same problems associated with Christodoulou invention, in that it cannot be quickly deployed without the assistance of another.        U.S. Pat. No. 5,743,448 granted to Tsai on Apr. 28, 1998 which teaches a combined raincoat and backpack where the raincoat conceals the backpack. The raincoat is stored in an interior surface on the front surface of the backpack, i.e. between the backpack and the back of the wearer.        U.S. Pat. No. 6,393,613 granted to Sheu on May 28, 2002 discloses a packet that is held by Velcro® to any of the various facets of the back pack and is removable. The packet stores raingear so that the packet is removed from the backpack when it is desired to dawn the raingear.
This invention solves at least two problems that are not considered nor suggested in the prior art. Namely, the raingear is stored in and attached to the backpack in such a way that it is accessible when the backpack is being worn by the user to the extent that a simple movement of the guide strap allows the user to pull the raingear out of the backpack and don the raingear in a single motion to cover both himself and the backpack. In addition, since the raingear is tied to the pocket of the backpack in such a manner that when deployed the tie does not affect the operation of the donning of the raingear and assures that the raingear will be stored back in the backpack. What this obviates is the preclusion of leaving the raincoat outside of the backpack and forgetting or being too lazy to put it back therein. This will attempt to solve the problem that school children have that lose the raincoat because they have the propensity of forgetting to put or just not putting the raincoat back into the pocket of the heretofore known types of backpacks or tote bags.
In another embodiment of this invention, the raingear is stored in its own flexible container or pouch which is capable of being attached to, mounted in a pocket of or mounted on the top of the backpack. This embodiment operates in the same way as that described in the above paragraphs. Obviously, since the raingear is already packaged, it can be also utilized in combination with other types of articles, such as fishing vests, hunting vest and other types of outdoor clothing. The clothing just mentioned, would require a fastener that complements the fastener on the package containing the raingear so as to be able to be attached thereto and detachable therefrom or alternatively the pouch could be formed integrally on the back of the clothing and accessible to the wearer while on the wearer.

Backpack, pouch or clothing with integral raingear


A system and method are provided for augmenting information on business directory databases. Using the business name contained in a business directory database and Web data mining technology, the website of a business is found and validated, prior to enriching the database entries.

Business directory database Websites, such as the YellowPages.com (YPC) Website, have brought the basic concept of traditional bound business directories into the Internet/WWW age while improving ease of use and functionality. The YPC can trace its history to 1996, when an independent publisher and two telecommunications companies (SBC and BellSouth) each launched their own online directories. They continued to operate separately until November 2004, when SBC and BellSouth entered into a partnership to create the Internet Yellow Pages joint venture, acquiring the online directory publisher then known as WWW.Yellowpages.com, Inc. The three separate sites were combined into one site called YellowPages.com. YPC offers searchable directory listings, and has capabilities to provide information on products/services provided, specialty, brands, payment options, languages spoken, certification & affiliation, coupons & deals, and user reviews. Also, when a user registers with YPC, addresses of interest, recent searches and recently viewed listings can be saved for future reference. Additionally, search information, maps and driving directions can be saved, emailed or sent by text message to a device capable of receiving this type of message.
Customers who search business listings directly are typically looking for a particular type of good or service, and are ready to purchase. The traditional bound business directories are by their nature published periodically (typically annually) and therefore not able to be changed once issued. It is very frustrating for consumers to call or worse travel to a listed business location only to find out they are no longer there or have changed their hours, and then have to start their search all over again. This is not a limitation of the YPC, as it is a live business directory database which is updated continuously as business or other conditions change.
Web and Internet based business directory databases (BDBs), such as The YellowPages.com (or similar), contain a large number of business names, addresses and phone numbers. Only a small fraction of listings contain other frequently requested information such as the URL or domain name or business Internet address, email contact address or hours of operation. Not having a means whereby desired information is readily available or retrievable can leave consumers frustrated and possibly drive them to support those businesses that provide this information in anticipation of the request.
The terms "URL" and "domain name" are frequently used interchangeably. While related, the terms have slightly different meanings. For example, the domain name WWW.example.net corresponds to a domain that includes the URL http://www.example.net/index.html. For future reference herein, the terms URL, domain name and business internet address will all be used interchangeably.
In general terms as used in the present application, a database stores records containing data or elements with defined relationships between the data elements. For example, the following items are all individual data elements within a record in a database: Ace Food Mart, 123 Main Street, Schenectady, N.Y., USA, 12345, 555-555-5555, WWW.Acemart.com. In this case, the defined relationship between data elements is that they collectively represent one business with the following correlation: Business name, street address, city, state, country, zip code, phone number, domain name. Frequently, individual data elements or data fields within a database are augmented. For future reference herein, the terms augment, enrich, modify, change, add and delete may all be used interchangeably, indicating that something, individual data elements or an entire group of elements representing an individual business, has been changed (i.e. address change), added (i.e. new business opens) or deleted (i.e. business closed).
The Internet Corporation for Assignment Names and Numbers (ICANN) manages the assignment of domain names and IP addresses. This is facilitated through accredited domain registrars, including GoDaddy.com who register directly and Google.com who register indirectly through subcontractors. The registrant on the application for the domain name, a person or entity, is the licensee (effectively the owner) of the domain name. The administrative contact is the person designated to receive communications from the registrar related to administration of the domain name. The billing contact is the person designated to receive notices from the registrar concerning renewing the domain name by paying the registration fee. The technical contact is the person designated to receive communications related to technical matters associated with the domain name. Any person or entity named as a contact (administrative, billing or technical) has the power to adversely affect the domain name. For future reference herein, a URL or domain name is "sponsored" by an entity when the registrant and designated contacts of the URL or domain name are responsible for and engaged (either directly or indirectly) in the ongoing activities of the entity (business, non-profit, interest group, government, research institute, and the like).
Businesses that market through the YPC listing could benefit from providing users access to a validated and enriched business directory database (BDB) by:                (1) reduced traffic to their Website, where the same information is repeatedly searched for and retrieved;        (2) reduced call traffic to a switchboard or a call center to field the information requests;        (3) improved perception of the business in the mind of the customer as the business has anticipated frequently requested information and furnished it prior to asking; and        (4) increased revenue as more customers potentially do business with a firm which has anticipated frequently requested information and provided it from a trusted source.Additionally, the provider of the Web and Internet-based business directory databases, such as The YellowPages.com (or similar) may be able to command a premium listing fee from the businesses listing in their database for all the above mentioned reasons.
It would therefore be desirable to augment the information contained in a record of a Business Directory Database and provide it to customers as they are viewing an Internet or Web-based BDB. For example, it would be desirable to provide a URL (business Internet address), hours of operation, product offerings and other information in the record. It would furthermore be advantageous to present that information as part of a listing in a validated and enriched database.

Finding the website of a business using the business name


A method of forming interconnects for three dimensional integrated circuits comprises attaching a metal layer on a first carrier, attaching a first side of a packaging component on the metal layer, wherein the packaging component comprises a plurality of through vias. The method further comprises filling the plurality of through vias with a metal material using an electrochemical plating process, wherein the metal layer functions as an electrode for the electrochemical plating process, attaching a second carrier on a second side of the packaging component, detaching the first carrier from the packaging component, forming a photoresist layer on the metal layer, patterning the photoresist layer and detaching exposed portions of the metal layer.

The semiconductor industry has experienced rapid growth due to continuous improvements in the integration density of a variety of electronic components (e.g., transistors, diodes, resistors, capacitors, etc.). For the most part, this improvement in integration density has come from repeated reductions in minimum feature size, which allows more components to be integrated into a given area. As the demand for even smaller electronic devices has grown recently, there has grown a need for smaller and more creative packaging techniques of semiconductor dies.
As semiconductor technologies evolve, three dimensional integrated circuits have emerged as an effective alternative to further reduce the physical size of a semiconductor chip. In a three dimensional integrated circuit, active circuits such as logic, memory, processor circuits and the like are fabricated on different wafers and each wafer die is stacked on top of a packaging component using pick-and-place techniques. Much higher density can be achieved by employing three dimensional integrated circuits. In sum, three dimensional integrated circuits can achieve smaller form factors, cost-effectiveness, increased performance and lower power consumption.
A three dimensional integrated circuit may comprise an integrated circuit die, an interposer and a package substrate. More particularly, the integrated circuit die is attached to a first side of the interposer through a plurality of solder bumps. Solder bumps are used to provide electrical connection between the integrated circuit die and the interposer. A second side of the interposer is attached to the package substrate by a plurality of interconnect bumps. Interconnect bumps such as solder balls may provide electrical connection between the interposer and the package substrate, which in turn makes electrical connection to a printed circuit board through a plurality of package leads.
In order to reduce the potential solder failure between the integrated circuit die and the package substrate caused by thermal stresses, the interposer is employed to provide a matching coefficient of thermal expansion to the integrated circuit die. The interposer also provides adaptation between smaller contact pads with reduced pitch on an integrated circuit die and larger contact pads with increased pitch on a package substrate. In addition, the interposer may further comprise a variety of circuit elements. These circuit elements may be active, passive, or a combination of active and passive elements.
Three dimensional integrated circuits have some advantages. One advantageous feature of packaging multiple semiconductor dies vertically is that three dimensional package techniques may reduce fabrication costs. Another advantageous feature of three dimensional semiconductor devices is that parasitic losses are reduced by employing various interconnect bumps.
Corresponding numerals and symbols in the different figures generally refer to corresponding parts unless otherwise indicated. The figures are drawn to clearly illustrate the relevant aspects of the various embodiments and are not necessarily drawn to scale.

Method of forming interconnects for three dimensional integrated circuit

Taiwan Semiconductor Manufacturing Company, Ltd.


An apparatus and method for changing a channel according to direct channel change information transmitted from a broadcasting station. The apparatus includes a broadcast receiver, a tuner and a controller for checking parsed DCC information. The broadcast receiver receives a broadcast signal. The tuner tunes channels and stores the tuned channels in memory. The controller parses DCC information received in the broadcast signal and checks for a target channel included in the DCC information. The controller then changes a channel by selecting one among plural virtual channels according to a predetermined priority when several virtual channels correspond to the target channel.

1. Field of the Invention
The present invention relates to a digital broadcast receiver and a directed channel change method thereof, in which a channel is changed according to directed channel change information transmitted from a broadcasting station.
2. Description of the Related Art
Digital broadcasting has recently begun. In digital broadcasting as compared with analog broadcasting, a video signal and an audio signal are converted into digital signals, and then the digital signal is compressed, packeted and transmitted as a transport stream.
Digital broadcasting standards are selected to be adapted to a variety of countries, respectively. A directed channel change table (DCCT) has been proposed as an extended standard of the program and system information protocol (PSIP) of the advanced television systems committee (ATSC) standard selected in North America. Further, there are similar standards for another digital broadcasting selected in Europe or other countries.
Here, the DCCT is a table, having information about how to automatically change a channel under certain conditions, which is transmitted in the PSIP. According to the DCCT, items taken as channel change conditions are tabulated by codes. For example, the item includes local information, population information, genre information, etc. Further, setting information corresponding to such items is set in a broadcast receiver by a user.
When a digital broadcast receiver receives DCCT information, the received DCCT information is compared with the previously set information related to the DCCT. In the case where the received DCCT information is equal to the previously set information related to the DCCT, the channel is changed according to the DCCT information. Then, when a program of the changed channel is finished, the channel returns to an original channel.
However, a plurality of virtual channels may be allocated to one channel number according to local characteristics. For example, in the case of an area located between Seoul and Daejeon in Korea, two channels corresponding to Seoul and Daejeon broadcasting stations may be allocated to one channel number of 11-1. Currently, the ATSC standard has no proposal to solve a problem of channel duplication.
Therefore, in this case, the digital television or a set-top box should select and change one of a plurality of duplicated channels to perform a directed channel change (DCC) function.

Digital broadcast receiver and directed channel change method thereof