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[ "1. ", "Field of the Invention\nThis invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer\"\"s disease.", "\nThe following publications, patents and patent applications are cited in this application as superscript numbers:\n1 Glenner, et al., ", "Biochem. ", "Biophys. ", "Res. ", "Commun. (", "1984) 120:885-890.", "\n2 U.S. Pat. ", "No. ", "4,666,829, issued May 19, 1987, to G. G. Glenner et al., ", "entitled xe2x80x9cPolypeptide Marker for Alzheimer\"\"s Disease and Its Use for Diagnosis.xe2x80x9d\n3 Selkoe, Neuron. (", "1991) 6:487-498.", "\n4 Goate, et al., ", "Nature (1990) 349:704-706.", "\n5 Chartier Harlan, et al., ", "Nature (1989) 353:844-846.", "\n6 Murrell, et al., ", "Science (1991) 254:97-99.", "\n7 Mullan, et al., ", "Nature Genet. (", "1992) 1:345-347.", "\n8 Schenk, et al., ", "International Patent Application Publication No. ", "WO 94/10569, xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, published May 11, 1994.", "\n9 Selkoe, Scientific American, xe2x80x9cAmyoid Protein and Alzheimer\"\"s Diseasexe2x80x9d, pp. ", "2-8, November, 1991.", "\n10 Yates et al., ", "U.S. Pat. ", "No. ", "3,598,859.", "\n11 Tetrahedron Letters 1993, 34(48), 7685.", "\n12 R. F. C. Brown et al., ", "Tetrahedron Letters 1971, 8, 667-670.", "\n13 A. O. King et al., ", "J. Org. ", "Chem. ", "1993, 58, 3384-3386.", "\n14 U.S. Provisional Application Serial No. ", "60/019,790, filed Jun. 14, 1996.", "\n15 R. D. Clark et al., ", "Tetrahedron 1993, 49(7), 1351-1356.", "\n16 Citron, et al., ", "Nature (1992) 360:672-674.", "\n17 P. Seubert, Nature (1992) 359:325-327.", "\n18 Hansen, et al., ", "J. Immun. ", "Meth.(1989) 119:203-210.", "\n19 Games et al., ", "Nature (1995) 373:523-527.", "\n20 Johnson-Wood et al., ", "PNAS USA (1997) 94:1550-1555.", "\nAll of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.", "\n2. ", "State of the Art\nAlzheimer\"\"s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. ", "AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. ", "AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. ", "The disease is currently estimated to affect about two to three million individuals in the United States alone. ", "AD is at present incurable. ", "No treatment that effectively prevents AD or reverses its symptoms and course is currently known.", "\nThe brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. ", "Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. ", "Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. ", "Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down\"\"s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). ", "At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.", "\nThe principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (xcex2AP) or sometimes Axcex2, Axcex2P or xcex2/A4. ", "xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. ", "No. ", "4,666,82922.", "\nMolecular biological and protein chemical analyzes have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. ", "Knowledge of the structure of the gene encoding APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). ", "The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.", "\nSeveral lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. ", "See, for example, Selkoe3. ", "The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. ", "A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). ", "Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. ", "In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. ", "The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.", "\nDespite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). ", "Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis in vivo.", "\nCompounds which inhibit xcex2-amyloid peptide release and/or its synthesis in vivo are disclosed in U.S. patent application Ser. ", "No. ", "08/996,422, filed Dec. 22, 1997 (Attorney Docket No. ", "002010-062) and entitled xe2x80x9cCycloalkyl, Lactam, Lactone and Related Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting xcex2-Amyloid Peptide Release, and/or its Synthesis by Use of Such Compounds,xe2x80x9d the disclosure of which is incorporated herein by reference in its entirety. ", "The present invention is directed to deoxy derivatives of such compounds.", "\nThis invention is directed to the discovery of a class of compounds which inhibit xcex2-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition.", "\nAccordingly, in one of its composition aspects, the present invention provides compounds of formula I: \nwherein\nW is a cyclic group selected from the group consisting of: \nxe2x80x83wherein\nring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;\nring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;\nring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;\nY is represented by the formula: \nxe2x80x83provided that at least one Y is xe2x80x94(CHR2)axe2x80x94NHxe2x80x94;\nR1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;\nR2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;\neach R2xe2x80x2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;\nR3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;\neach R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;\nR5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;\nQ is oxygen, sulfur, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;\nZ is represented by the formula xe2x80x94Txe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94, wherein T is selected from the group consisting of a bond covalently linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, oxygen, sulfur and xe2x80x94NR6, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl group;\nXxe2x80x2 is hydrogen, hydroxy or fluoro,\nXxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;\na is an integer from 2 to about 6;\nf is an integer from 0 to 2;\nm is an integer equal to 0 or 1;\nn is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof.", "\nA subgenus of compounds within formula I wherein m=1 and n=1 can be represented by formula I: \nwherein Zxe2x80x2 is xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, xe2x80x94Txe2x80x94CH2xe2x80x94 or xe2x80x94Txe2x80x94C(O)xe2x80x94 wherein T is selected from the group consisting of oxygen, sulfur and xe2x80x94NR6, wherein R6 is hydrogen, acyl, alkyl, aryl, or heteroaryl; Xxe2x80x2 is hydrogen, hydroxy or fluoro, and Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group; and\nR1, R2xe2x80x2, W and a are as defined hereinabove with respect to formula I;\nand pharmaceutically acceptable salts thereof.", "\nThis invention also provides for novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the formula I above.", "\nAdditionally, in one of its method aspects, this invention is directed to a method for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of xcex2-amyloid peptide.", "\nBecause the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8.9, the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. ", "Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.", "\nIn yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.", "\nIn formula I above, rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. ", "More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. ", "Still more preferably, rings A and B are independently aryl.", "\nParticularly preferred A and B rings include, by way of example, phenyl, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like.", "\nPreferred C rings include, by way of example, pyrrolidinyl, piperidinyl, morpholino and the like.", "\nWhen m is zero (i.e., there is a covalent bond from R1 to NH), R1 is preferably aryl (including substituted aryl) or heteroaryl (including substituted heteroaryl). ", "In this embodiment, further preferred R1 groups include\n(a) phenyl,\n(b) a substituted phenyl group of the formula: \nwherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rband Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;\nRb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rbxe2x80x2 are either both hydrogen or both substituents other than hydrogen,\n(c) 2-naphthyl,\n(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,\n(e) heteroaryl,\n(f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the xe2x80x94NH group, and\n(g) alkyl.", "\nWhen m is zero, particularly preferred substituted phenyl R1 groups include mono-, di- and tri-substituted phenyl groups including 3,5-disubstituted phenyls such as 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, etc.; ", "3,4-disubstituted phenyls such as 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, 3,4-methylenedioxyphenyl, etc.; ", "4-substituted phenyls such as 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-ethoxy)ethylphenyl, etc., ", "3,4,5-trisubsituted phenyls such as 3,4,5-trifluorophenyl, 3,4,5-trichlorophenyl, etc.", "\nSpecific R1 groups for when m is zero include 3,4-dichlorophenyl, 4-phenylfurazan-3-yl, and the like.", "\nWhen m is zero, other preferred R1 substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, phenyl, and the like.", "\nWhen m is one, preferred R1 groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.; ", "substituted aryl groups such as monosubstituted phenyls (preferably substituents at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and trisubstituted phenyls (preferably substituents at the 3,4,5 positions). ", "Preferably, the substituted phenyl groups do not include more than 3 substituents. ", "Examples of substituted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.", "\nWhen m is one, other preferred R1 groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl, (CH3)2CHxe2x95x90CHCH2CH2CH(CH3)xe2x88x92, xcfx86C(O)CH2xe2x80x94, thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH3OC(O)CH2xe2x80x94, benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl), methoxymethyl, CH3CHxe2x95x90CHxe2x80x94, CH3CH2CHxe2x95x90CHxe2x80x94, (4-chlorophenyl)C(O)CH2xe2x80x94, (4-fluorophenyl)C(O)CH2xe2x80x94, (4-methoxyphenyl)C(O)CH2xe2x80x94, 4-(fluorophenyl)-NHC(O)CH2xe2x80x94, 1-phenyl-n-butyl, (xcfx86)2CHNHC(O)CH2CH2xe2x80x94, (CH3)2NC(O)CH2xe2x80x94, (xcfx86)2CHNHC(O)CH2CH2xe2x80x94, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH2xe2x80x94, 4-methoxyphenyl-C(O)CH2xe2x80x94, phenyl-C(O)CH2xe2x80x94, CH3C(O)N(xcfx86)xe2x80x94, ethenyl, methylthiomethyl, (CH3)3CNHC(O)CH2xe2x80x94, 4-fluorophenyl-C(O)CH2xe2x80x94, diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH2xe2x80x94, benzo[b]thiophen-3-yl, (CH3)3COC(O)NHCH2xe2x80x94, trans-styryl, H2NC(O)CH2CH2xe2x80x94, 2-trifluoromethylphenyl-C(O)CH2, xcfx86C(O)NHCH(xcfx86)CH2xe2x80x94, mesityl, CH3CH(xe2x95x90NHOH)CH2xe2x80x94, 4-CH3xe2x80x94xcfx86xe2x80x94NHC(O)CH2CH2xe2x80x94, xcfx86C(O)CH(xcfx86)CH2xe2x80x94, (CH3)2CHC(O)NHCH(xcfx86)xe2x80x94, CH3CH2OCH2xe2x80x94, CH3OC(O)CH(CH3)(CH2)3xe2x80x94, 2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH3-benzofuran-3-yl, 2-(2,4-dichlorophenoxy)ethyl, xcfx86SO2CH2xe2x80x94, 3-cyclohexyl-n-propyl, CF3CH2CH2CH2xe2x80x94 and N-pyrrolidinyl.", "\nWhen present, R2 is preferably selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.", "\nEach R2 is preferably (and independently) selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.", "\nParticularly preferred R2 and R2xe2x80x2 substituents (when R2xe2x80x2 is other than hydrogen) include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2xe2x80x94 cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2xe2x80x94(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like. ", "Preferably, R2xe2x80x2 is methyl.", "\nPreferably, R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. ", "In another preferred embodiment, R3 is alkyl, substituted alkyl or aryl. ", "More preferably, R3 is alkyl.", "\nParticularly preferred R3 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.", "\nWhen present, R4 is preferably alkyl or substituted alkyl.", "\nR5 is preferably alkyl; substituted alkyl; phenyl; substituted phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl and the like; cycloalkyl, such as cyclohexyl and the like; or heteroaryl or heterocyclic, such as 1-piperdinyl, 2-pyridyl, 2-thiazyl, 2-thienyl and the like.", "\nPreferably, f is 0 or 1. ", "More preferably, f is 0.", "\nWhen Y is the group xe2x80x94(CHR2xe2x80x2)axe2x80x94NHxe2x80x94, the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and still more preferably a is equal to 2. ", "In a preferred embodiment, Y has the formula xe2x80x94CHR2xe2x80x2xe2x80x94CH2xe2x80x94NHxe2x80x94, where R2xe2x80x2 is as defined herein, including the described preferred embodiments.", "\nIn one preferred embodiment of this invention, W is a cyclic group of the formula: \nwherein\neach R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alky, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl;\neach R7 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl;\nR8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;\np is an integer from 0 to 4; q is an integer from 0 to 4.", "\nPreferably, R6 and R7 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy. ", "More preferably, when present, R6 and R7 are fluoro.", "\nR8 is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. ", "More preferably, R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.", "\nParticularly preferred R8 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.", "\nIn another preferred embodiment of this invention, W is a cyclic group of the formula: \nwherein R6, R7, and p are as defined herein and r is an integer from 0 to 3.", "\nIn still another preferred embodiment of this invention, W is a cyclic group of the formula: \nwherein R6 and p are as defined herein.", "\nIn yet another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6 and p are as defined herein.", "\nIn still another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8 and p are as defined herein; and\neach R9 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; and g is an integer from 0 to 2.", "\nWhen present, R9 is preferably alkyl or substituted alkyl.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8, R9, g and p are as defined herein.", "\nIn yet another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8, R9, g and p are as defined herein.", "\nIn still another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, each R8 and p are as defined herein.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, each R8, R9, g and p are as defined herein.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8 and p are as defined herein; and\nR10 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R10 and p are as defined herein; and\nDxe2x80x94E is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and xe2x80x94Nxe2x95x90CHxe2x80x94.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8, R9, g and p are as defined herein; and\nQ is oxygen, sulfur, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nwherein R6, R8 and p are as defined herein.", "\nIn another preferred embodiment of this invention, W is a cyclic ring of the formula: \nIn the above formulae, preferably each R6 is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R7 is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy and halo; each R8 is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; each R9 is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q and r are 0 or 1. ", "More preferably, g, p, q and r are 0.", "\nCompounds of this invention include, by way of example, the following: \ni.e., 5S-[Nxe2x80x2-(2S-hydroxy-3-methylbutyryl)-2S-aminoprop-1-yl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.", "\nThe products of this invention include mixtures of R,S enantiomers at any stereochemical center. ", "Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. ", "In the formulas set forth herein, a mixture of R,S enantiomers at the stereochemical center is sometimes indicated by a squiggly line as per convention. ", "Othertimes, no stereochemical designation is made at the stereochemical center and this also infers that a mixture of enantiomers is present.", "\nAlso included within the scope of this invention are prodrugs of the compounds of formula I above including acylated forms of alcohols and thiols, aminals of one or more amines, and the like.", "\nAs above, this invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer\"\"s disease. ", "However, prior to describing this invention in further detail, the following terms will first be defined.", "\nThe term xe2x80x9cxcex2-amyloid peptidexe2x80x9d refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal xcex2-amyloid peptide. ", "In whatever form, the xcex2-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the xcex2-amyloid precursor protein (APP). ", "Its 43-amino acid sequence is:\n1\nAsp Ala Glu Phe Arg His Asp Ser Gly Tyr\n11\nGlu Val His His Gln Lys Leu Val Phe Phe\n21\nAla Glu Asp Val Gly Ser Asn Lys Gly Ala\n31\nIle Ile Gly Leu Met Val Gly Gly Val Val\n41\nIle Ala Thr (SEQ ID NO: 1)\nor a sequence which is substantially homologous thereto.", "\nxe2x80x9cAlkylxe2x80x9d refers to monovalent alkyl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. ", "This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.", "\nxe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.", "\nxe2x80x9cAlkylenexe2x80x9d refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. ", "This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.", "\nxe2x80x9cSubstituted alkylenexe2x80x9d refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl. ", "Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. ", "Preferably such fused cycloalkyl groups contain from 1 to 3 fused ring structures.", "\nxe2x80x9cAlkenylenexe2x80x9d refers to divalent alkenylene groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms. ", "This term is exemplified by groups such as ethenylene (xe2x80x94CHxe2x95x90CHxe2x80x94), the propenylene isomers (e.g., xe2x80x94CH2CHxe2x95x90CHxe2x80x94 and xe2x80x94C(CH3)xe2x95x90CHxe2x80x94) and the like.", "\nxe2x80x9cSubstituted alkenylenexe2x80x9d refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, -SO2-aryl, and xe2x80x94SO2-heteroaryl. ", "Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.", "\nxe2x80x9cAlkarylxe2x80x9d refers to -alkylene-aryl groups preferably having from 1 to 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. ", "Such alkaryl groups are exemplified by benzyl, phenethyl and the like.", "\nxe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-Oxe2x80x94xe2x80x9d. ", "P referred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.", "\nxe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-Oxe2x80x94xe2x80x9d where substituted alkyl is as defined above.", "\nxe2x80x9cAlkylalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-o-alkylxe2x80x9d which includes by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3) and the like.", "\nxe2x80x9cAlkylthioalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-S-alkylxe2x80x9d which includes by way of example, methylenethiomethoxy (xe2x80x94CH2SCH3), ethylenethiomethoxy (xe2x80x94CH2CH2SCH3), n-propylene-thio-iso-propoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylenethio-t-butoxy (xe2x80x94CH2SC(CH3)3) and the like.", "\nxe2x80x9cAlkenylxe2x80x9d refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. ", "Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), and the like.", "\nxe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.", "\nxe2x80x9cAlkynylxe2x80x9d refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. ", "Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.", "\nxe2x80x9cSubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.", "\nxe2x80x9cAcylxe2x80x9d refers to the groups alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94 and heterocyclic-C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.", "\nxe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.", "\nxe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94NH2.", "\nxe2x80x9cSubstituted aminoxe2x80x9d refers to the group xe2x80x94N(R)2 where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group. ", "When both R groups are hydrogen, xe2x80x94N(R)2 is an amino group. ", "Examples of substituted amino groups include, by way of illustration, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.", "\nThe term xe2x80x9camino-blocking groupxe2x80x9d or xe2x80x9camino-protecting groupxe2x80x9d refers to any group which, when bound to an amino group, prevents undesired reactions from occurring at the amino group and which may be removed by conventional chemical and/or enzymatic procedures to reestablish the amino group. ", "Any known amino-blocking group may be used in this invention. ", "Typically, the amino-blocking group is selected so as to render the resulting blocked-amino group unreactive to the particular reagents and reaction conditions employed in a subsequent pre-determined chemical reaction or series of reactions. ", "After completion of the reaction(s), the amino-blocking group is selectively removed to regenerate the amino group. ", "Examples of suitable amino-blocking groups include, by way of illustration, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, 1-(1xe2x80x2-adamantyl)-1-methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloc), benzyloxymethyl (Bom), 2-p-biphenylisopropyloxycarbonyl (Bpoc), tert-butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl-methyloxycarbonyl (Fmoc), 4-methylbenzyl, 4-methoxybenzyl, 2-nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob), trityl (Trt), and the like. ", "If desired, amino-blocking groups covalently attached to a solid support may also be employed.", "\nxe2x80x9cAminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.", "\nxe2x80x9cAminoacyloxyxe2x80x9d refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.", "\nxe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, and heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.", "\nxe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). ", "Preferred aryls include phenyl, naphthyl and the like.", "\nUnless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. ", "Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.", "\nxe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.", "\nxe2x80x9cCarboxyalkylxe2x80x9d refers to the groups xe2x80x9cxe2x80x94C(O)Oalkylxe2x80x9d and xe2x80x9cxe2x80x94C(O)O-substituted alkylxe2x80x9d where alkyl is as defined above.", "\nxe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. ", "Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.", "\nxe2x80x9cSubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.", "\nxe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. ", "Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.", "\nxe2x80x9cSubstituted cycloalkenylxe2x80x9d refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.", "\nxe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.", "\nxe2x80x9cHeteroarylxe2x80x9d refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).", "\nUnless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, \"\"SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. ", "Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). ", "Preferred heteroaryls include pyridyl, pyrrolyl and furyl.", "\nxe2x80x9cHeteroaryloxyxe2x80x9d refers to the group xe2x80x9c-O-heteroarylxe2x80x9d.", "\nxe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.", "\nUnless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl. ", "Such heterocyclic groups can have a single ring or multiple condensed rings. ", "Preferred heterocyclics include morpholino, piperidinyl, and the like.", "\nExamples of heterocycles and heteroaryls include, but are not limited to, pyrrole, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.", "\nxe2x80x9cHeterocyclooxyxe2x80x9d refers to the group xe2x80x9c-O-heterocyclexe2x80x9d.", "\nxe2x80x9cKetoxe2x80x9d or xe2x80x9coxoxe2x80x9d refers to the group xe2x80x9cxe2x95x90Oxe2x80x9d.", "\nxe2x80x9cOxyacylaminoxe2x80x9d refers to the group xe2x80x94OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.", "\nxe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.", "\nxe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94S-alkyl.", "\nxe2x80x9cSubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.", "\nxe2x80x9cThioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.", "\nxe2x80x9cThioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.", "\nxe2x80x9cThioketoxe2x80x9d refers to the group xe2x80x9cxcex1Sxe2x80x9d.", "\nThe term xe2x80x9c5,7-dihydro-6H-dibenz[b,d]azepin-6-onexe2x80x9drefers to a polycyclic xcex5-caprolactam ring system having the formula: \nwherein, for nomenclature purposes, the atoms and bonds are numbered and lettered, respectively, as shown.", "\nThe term xe2x80x9c5,6-dihydro-4H-quino[8,1-ab][3]benzazepin-8(9H)-onexe2x80x9d refers to a polycyclic xcex5-caprolactam ring system having the formula: \nwherein, for nomenclature purposes, the atoms and bonds are numbered and lettered, respectively, as shown.", "\nThe term xe2x80x9c1,3,4,7,12,12a-hexahydropyrido[2, 1-b][3]benzazepin-6(2H)-onexe2x80x9d refers to a polycyclic xcex5-caprolactam ring system having the formula: \nwherein, for nomenclature purposes, the atoms and bonds are numbered and lettered, respectively, as shown.", "\nThe term xe2x80x9c4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2(1H)-onexe2x80x9d refers to a polycyclic E-caprolactam ring system having the formula: \nwherein, for nomenclature purposes, the atoms and bonds are numbered and lettered, respectively, as shown.", "\nAs to any of the above groups which contain 1 or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.", "\nxe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.", "\nThe term xe2x80x9cprotecting groupxe2x80x9d or xe2x80x9cblocking groupxe2x80x9d refers to any group which when bound to one or more hydroxyl, thiol, carboxyl groups or other protectable functional group of the compounds which prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the unprotected functional group. ", "The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.", "\nPreferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. ", "which can be removed by mild hydrolysis conditions compatible with the nature of the product.", "\nCompound Preparation\nWhen m and n are one, the compounds of formula I are readily prepared by conventional reductive amination, followed by acylation as illustrated in Scheme 1. ", "\nAs shown in Scheme 1, a protected aldehyde or ketone 1 (where B1 is a protecting group and R2xe2x80x2 and a are as defined herein) can be coupled with an amine compound, such as 2 (where R6, R7, R8, p and q are as defined herein), by conventional reductive amination to provide, after deprotection, intermediate 3. ", "In Scheme 1, amine 2 is merely representative and those skilled in the art will recognize that amino derivatives of any of the other ring systems described herein may be employed in this reaction. ", "Typically, this reaction is conducted by contacting amine 2 with an excess of 1, preferably with 1.1 to 2 equivalents of 1, and an excess, preferably 1.1 to 1.5 equivalents, of a reducing agent, such as sodium cyanoborohydride. ", "Generally, this reaction is conducted in an essentially inert diluent, such as methanol, at a temperature ranging from about 0xc2x0 C. to about 50xe2x80x2 C., preferably at ambient temperature, for about 0.5 to 3 hours. ", "Removal of the amine protecting group using conventional procedures and reagents then affords intermediate 3.", "\nIntermediate 3 can then be acylated or coupled with a carboxylic acid, e.g., 4 (where R1, T, Xxe2x80x2 and Xxe2x80x3 are as defined herein), to provide compound 5. ", "This reaction is typically conducted using conventional coupling reagents and procedures and at least a stoichiometric amount of intermediate 3 and carboxylic acid 4. ", "For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. ", "can be used to facilitate coupling. ", "The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. ", "Alternatively, the acid halide of compound 4 can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. ", "Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.", "\nAlternatively, compound 5 can be prepared by reductive amination of a compound of formula 6: \nwhere R1, R2xe2x80x2, T, Xxe2x80x2, Xxe2x80x3 and a are as defined herein, with amine 2, using conventional reagents and procedures.", "\nCompounds of formula 1, where n is 1 and m is 0, can similarly be prepared by reductive amination of an intermediate of formula 7: \nwhere B2 is a suitable amine protecting group and R1, R2xe2x80x2 and a are as defined herein, with amine 2, followed by deprotection using conventional procedures.", "\nWhen n is two and both of Y are represented by the formula xe2x80x94(CHR2xe2x80x2)axe2x80x94NHxe2x80x94, the compounds of formula I can be prepared by further reductive alkylation of intermediate 3 with, for example, compound 6 or 7, using conventional reagents and procedures. ", "Alternatively, intermediate 3 can be reductively alkylated with protected aldehyde or ketone 1 and the resulting intermediate deprotected and acylated using procedures similar to those described above.", "\nCompounds in which n is two and one of Y is represented by the formula xe2x80x94(CHR2xe2x80x2)axe2x80x94NHxe2x80x94 and the other Y is represented by the formula xe2x80x94CHR2xe2x80x94C(O)NHxe2x80x94 can be prepared by coupling intermediate 3 with a protected carboxylic acid of formula 8: \nwhere R1, R2, Z and m are as defined herein, using conventional coupling reagents and procedures such as those described above, to afford compounds of formula I.\nAlternatively, compounds of formula I can be prepared by first coupling an amine, such as 2, with a protected carboxylic acid 9, and then, after deprotection, reductively alkylating the resulting intermediate 10 as illustrated in Scheme 2. ", "\nWhen n is 2, the aldehyde, ketone or carboxylic acid units may also be coupled together prior to reaction with an amine using the reductive amination or acylation procedures described above, as appropriate. ", "The resulting intermediate is then coupled to the amine, such as 2, to afford compounds of formula I.\nSynthesis of Aldehyde. ", "Ketone and Carboxylic Acid Starting Materials\nThe aldehyde, ketone and carboxylic acids employed in the above reactions can be readily prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether m is zero or one, whether n is one or two, etc.", "\nThe aldehyde and ketone compounds, e.g. 1, 6 and 7, employed in this invention can be readily prepared by oxidizing the corresponding alcohol using conventional oxidizing agents. ", "For example, Swern oxidation of N-protected amino primary alcohols affords the corresponding aldehyde. ", "Typically, this reaction is conducted by contacting the alcohol with a mixture of oxalyl chloride and dimethyl sulfoxide in the presence of a tertiary amine, such as triethylamine. ", "Generally, this reaction is conducted in an inert diluent, such as dichloromethane, at an intial temperature of about xe2x88x9278xc2x0 C. and then at ambient temperature for about 0.25 to 2 hours to afford the aldehyde. ", "The alcohols employed in this reaction are either commercially available or can be prepared using conventional reagents and procedures. ", "For example, suitable alcohols can be prepared by reduction of the corresponding amino acids or amino acid esters using conventional reducing agents such as lithium aluminum hydride and the like.", "\nThe carboxylic acids of formula 8, where m is 0, can be prepared by various conventional procedures. ", "For example, reaction of a halo acetic acid 11 (where Zxe2x80x2 is a halo group such as chloro or bromo and R2 is as defined herein) with a primary amine 12 (where R1 is as defined herein) provides an amino acid 13 as illustrated in Scheme 3. ", "Alternatively, leaving groups other than halo may be employed such as triflate and the like. ", "Additionally, suitable esters of 11 may be employed in this reaction. ", "\nAs shown in Scheme 3, a suitable haloacetic acid derivative 11 is reacted with a primary amine 12 under conditions which provide for amino acid 13. ", "This reaction is described by, for example, Yates, et al.10 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 11 with primary amine 12 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like. ", "The reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. ", "to scavenge the acid generated by the reaction. ", "The reaction is preferably conducted at from about 25xc2x0 C. to about 100xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. ", "This reaction is further described in U.S. Pat. ", "No. ", "3,598,859, which is incorporated herein by reference in its entirety. ", "Upon reaction completion, N-substituted amino acid 13 is recovered by conventional methods including precipitation, chromatography, filtration and the like.", "\nEach of the reagents employed in this reaction (e.g., haloacetic acid 11, and primary amine 12) are well known in the art with a plurality of each being commercially available.", "\nIn an alternative embodiment, the R1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation. ", "For example, a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a halo-R1 compound, Zxe2x80x2xe2x80x94R1 where Zxe2x80x2 is a halo group such as chloro or bromo and R1 is as defined above. ", "The reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction. ", "The reaction typically proceeds at from 15xc2x0 C. to about 250xc2x0 C. and is complete in about 1 to 24 hours. ", "Upon reaction completion, N-substituted amino acid ester is recovered by conventional methods including chromatography, filtration and the like. ", "This ester is then hydrolyzed by conventional methods to provide for carboxylic acid 8, where m is 0.", "\nIn still another alternative embodiment, esterified amino acids of formula 8, where m is 0, can be prepared by reductive amination of a suitable pyruvate ester 14 (where R is typically an alkyl group and R2 is as defined above) with a primary amine 12 (where R1 is as defined herein) in the manner illustrated in Scheme 4. ", "\nThe reaction shown in Scheme 4 is typically conducted by combining approximately stoichiometric equivalents of pyruvate ester 14 and amine 12 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown). ", "The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2/palladium on carbon and the like to form the N-substituted amino acid ester 15. ", "In a particularly preferred embodiment, the reducing agent is H2/palladium on carbon which is incorporated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N-substituted amino acid ester 15.", "\nThe reaction is preferably conducted at from about 20xc2x0 C. to about 80xc2x0 C. at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours. ", "Upon reaction completion, N-substituted amino acid ester 15 is recovered by conventional methods including chromatography, filtration and the like. ", "Subsequent hydrolysis of the ester 15 leads to the corresponding carboxylic acid derivative 8, where m is 0.", "\nThe carboxylic acids of formula 8, where m is 1, can be prepared by conventional coupling of an acetic acid derivative 4 (where R1, T, Xxe2x80x2 and Xxe2x80x3 are as defined herein) with a primary amine of an esterified amino acid (where R is typically an alkyl group and R2 is as defined herein) as illustrated in Scheme 5. ", "\nAs shown in Scheme 5, this reaction merely involves coupling of a suitable acetic acid derivative 4 with the primary amine of amino acid ester 16 under conditions which provide for the N-acetyl derivative 17. ", "This reaction is conventionally conducted as described for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters 17 of this invention. ", "For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. ", "can be used to facilitate coupling. ", "The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. ", "Alternatively, the acid halide of compound 4 can be employed and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. ", "Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.", "\nThe coupling reaction of 4 and 16 is preferably conducted at from about 0xc2x0 C. to about 60xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. ", "Upon reaction completion, N-acetyl amino acid ester 17 is recovered by conventional methods including precipitation, chromatography, filtration and the like or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.).", "\nEach of the reagents (e.g., acetic acid derivative 4 and amino acid ester 16) are well known in the art with a plurality of each being commercially available.", "\nCarboxylic acids, such as 4, can also be coupled to amines prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. ", "A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))11. ", "Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds.", "\nPolymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. ", "A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. ", "Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. ", "Preferably, the reactive moiety is a chloromethyl group. ", "Additionally, the polymer\"\"s backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.", "\nCertain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. ", "Examples of these hydroxylated resins include the 4-hydroxymethylphenyl-acetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994 catalog, page 115). ", "The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.", "\nPreferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. ", "As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. ", "These resins are commercially known as Merrifield\"\"s resins and are available from Aldrich Chemical Company of Milwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899). ", "Methods for the preparation of PEPC and its polymer supported forms are outlined in Scheme 6. ", "\nSuch methods are described more fully in U.S. patent application Ser. ", "No. ", "60/019,79014 filed Jun. 14, 1996 which application is incorporated herein by reference in its entirety. ", "Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. ", "The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. ", "The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.", "\nThe carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45xc2x0 C., for from about 3 to 120 hours. ", "Typically, the product may be isolated by washing the reaction with CHCl3 and concentrating the remaining organics under reduced pressure. ", "As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.", "\nPreparation of Cyclic Compounds (e.g. Benzaepinones. ", "Dibenzazepinones. ", "Benzodiazepines and Related Compounds)\nThe cyclic compounds and amino-substituted derivatives thereof, such as 2, employed in the reactions described above are either known in the art or can be prepared by art-recognized procedures using commercially available starting materials and reagents.", "\nFor example, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one may be prepared by cyclizing a chloromethyl amide intermediate using the procedures set forth in R. F. C. Brown et al., ", "Tetrahedron Letters 1971, 8, 667-67012 and references cited therein.", "\nAdditionally, the synthesis of a representative cyclic compuond, i.e., a 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, is illustrated in Scheme 7. ", "As will be readily apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 1 and the reaction conditions described below can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other cyclic amines suitable for use in this invention. ", "\nAs shown in Scheme 7, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivatives, 23, wherein R6, R7, p and q are as defined above, can be readily prepared in several steps from a 2-bromotoluene derivative 18 and a 2-bromoaniline derivative 20. ", "In this synthetic procedure, the 2-bromotoluene derivative, 18, is first converted into the corresponding 2-methylphenylboronate ester, 19. ", "This reaction is typically conducted by treating 18 with about 1.0 to about 2.1 equivalents of an alkyl lithium reagent, preferably sec-butyl lithium or tert-butyl lithium, in an inert diluent, such as THF, at a temperature ranging from about xe2x88x9280xc2x0 C. to about xe2x88x9260xc2x0 C. for about 0.25 to about 1 hour. ", "The resulting lithium anion is then treated in situ with an excess, preferably 1.5 equivalents, of a trialkylborate, such as trimethylborate. ", "This reaction is initially conducted at xe2x88x9280xc2x0 C. to about xe2x88x9260xc2x0 C. and then allowed to warm to about 0xc2x0 C. to about 30xc2x0 C. for about 0.5 to about 3 hours. ", "The resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction mixture with an excess, preferably about 2.0 equivalents, of pinacol. ", "This reaction is typically conducted at ambient temperature for about 12 to about 24 hours to afford the 2-methylphenylboronate ester, 19, in which both Ra groups are preferably joined together to form xe2x80x94C(CH3)2C(CH3)2xe2x80x94.", "\nIn a separate reaction, the amino group of a 2-bromoaniline derivative, 20, is converted into the N-Boc derivative 21 by treating 20 with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate. ", "Typically, this reaction is conducted at a temperature ranging from 25xc2x0 C. to about 100xc2x0 C. for about 12 to 48 hours to afford the N-Boc-2-bromoaniline derivative 21.", "\nAs further illustrated in Scheme 7, the 2-methylphenylboronate ester, 19, and the N-Boc-2-bromoaniline derivative 21 can then be coupled to form the biphenyl derivative 22. ", "This reaction is typically conducted by contacting 21 with about 1.0 to about 1.2 equivalents of 19 and about 1.0 to about 1.2 equivalents of potassium carbonate in the presence of a pallidium catalyst, preferably tetrakis(triphenylphosphine)pallidium(0). ", "Generally, this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperature ranging from about 50xc2x0 C. to about 100xc2x0 C. for about 6 to 24 hours.", "\nBiphenyl derivative 22 is then readily converted into the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one 23 by carboxylation of the 2-methyl group, followed by cyclization to form the xcex5-caprlactam. ", "The carboxylation reaction is typically conducted by contacting 22 with about 2.0 to about 2.5 equivalents of a suitable base, such as sec-butyllithium, tert-butyllithium and the like, in an inert diluent, such as THF, at a temperature ranging from about xe2x88x92100xc2x0 C. to about xe2x88x9220xc2x0 C. for about 0.5 to 6 hours. ", "The resulting dianion is then treated with excess anhydrous carbon dioxide to form the carboxylate. ", "Treatment of the carboxylate with excess hydrogen chloride in a suitable diluent, such as methanol, at a temperature ranging from about 25xc2x0 C. to about 100xc2x0 C. then affords the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one 23. ", "Various other cyclic compounds can be prepared by routine modifications of the above described procedures.", "\nPreferred synthetic procedures for aminating a representative compound are illustrated in Scheme 8. ", "It will be readily apparent to those of ordinary skill in the art that the synthetic procedure illustrated in Scheme 8 and the following reaction conditions can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other amino compounds suitable for use in this invention. ", "\nAs shown in Scheme 8, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 23, is optionally N-alkylated using conventional reagents and conditions to provide a 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24. ", "Typically, this reaction is conducted by first contacting 23 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis(trimethysilyl)amide and the like, in an inert diluent, such as DMF, THF and the like, at a temperature ranging from about xe2x88x9278xc2x0 C. to about 50xe2x80x2 C. for about 0.25 to about 6 hours. ", "The resulting anion is then treated in situ with an excess, preferably about 1.1 to about 2.0 equivalents, of an alkyl, substituted alkyl, cycloalkyl halide, etc., ", "typically a chloride, bromide or iodide. ", "This reaction is typically conducted at a temperature ranging from about 0xc2x0 C. to about 60xc2x0 C. for about 1.0 to about 48 hours to afford the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24.", "\nThe 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 24 is then oximated by contacting 24 with an excess, preferably with about 1.0 to 1.5 equivalents of a 15 suitable base, such as sodium bis(trimethysilyl)amide and the like, in the presence of about 1.0 to about 2.0 equivalents of an alkyl nitrite. ", "Suitable alkyl nitrites for use in this reaction include, by way of example, butyl nitrite, isoamyl nitrite and the like. ", "This reaction is typically conducted in an inert diluent, such as THF and the like, at a temperature ranging from about xe2x88x9210xc2x0 C. to about 20xc2x0 C. for about 0.5 to about 6 hours to afford the 7-alkyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative 25.", "\nReduction of 25 using conventional reagents and conditions then affords the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26. ", "Preferably, this reduction reaction is conducted by hydrogenating the oxime 25 in the presence of a catalyst, such as Raney nickel. ", "This reaction is typically conducted under about 200 psi to about 600 psi of hydrogen at a temperature of about 70xc2x0 C. to about 120xc2x0 C. for about 8 to 48 hours in a diluent, preferably a mixture of ethanol and ammonia (about 20:1). ", "Alternatively, in another preferred procedure, the oxime may be reduced using 10% Pd/C and between about 30 to about 60 psi of hydrogen at a temperature ranging from about 20xc2x0 C. to about 50xc2x0 C. for about 4 hours. ", "The resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.", "\nAlternatively, 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones, 26, can be prepared by first forming the 5-iodo derivative 27 of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 23. ", "This reaction is typically conducted as described in A. O. King et al.13 by treating 23 with an excess, preferably about 1.2 to about 2.5 equivalents, of trimethylsilyl iodide in the presence of an excess of a trialkyamine, such as triethylamine, diisopropylethylamine, TMEDA and the like, at a temperature ranging from about xe2x88x9220xc2x0 C. to about 0xc2x0 C. for about 3 to 30 minutes and then adding about 1.1 to about 2.0 equivalents of iodine (I2). ", "Typically, after addition of the iodide, the reaction is stirred at a temperature ranging from about 0xc2x0 C. to about 20xc2x0 C. for about 2 to about 4 hours to afford 5-iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 27.", "\nDisplacement of iodide from 27 using an alkali metal azide then affords 5-azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 28. ", "Typically, this reaction is conducted by contacting 27 with about 1.1 to about 1.5 equivalents of sodium azide in an inert diluent, such as DMF, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 12 to about 48 hours.", "\nThe azido derivative 28 is then reduced to the corresponding amino derivative 29 using conventional procedures and reagents. ", "For example, the azido group is preferably reduced by contacting 28 with an excess, preferably with about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixture of THF and water. ", "This reduction reaction is typically conducted at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 12 to 48 hours to afford 5-amino-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 29.", "\nThe amino group of 29 is then protected or blocked using a conventional amino blocking group. ", "Preferably, compound 29 is treated with about 1.0 to about 1.1 equivalents of di-tert-butyl dicarbonate in the presence of an excess, preferably about 2 to about 3 equivalents, of a trialkylamine, such as triethylamine. ", "This reaction is typically conducted in an inert diluent, such as THF, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for 3 to about 24 hours to provide 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 30.", "\nCompound 30 is then optionally N-alkylated to afford, after de-blocking of the amino group, a 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 26. ", "The N-alkylation reaction is typically conducted by treating 30 with about 1.0 to 1.5 equivalents of an alkyl halide, a substituted alkyl halide or a cycloalkyl halide in the presence of about 1.0 to about 1.5 equivalents of a suitable base, such as cesium carbonate and the like. ", "This reaction is generally conducted in an inert diluent, such as DMF and the like, at a temperature ranging from about 25xc2x0 C. to about 100xc2x0 C. for about 12 to about 48 hours.", "\nRepresentative alkyl, substituted alkyl and cycloalkyl halides suitable for use in this N-alkylation reaction include, by way of illustration, 1-iodo-2-methylpropane, methyl bromoacetate, 1-chloro-3,3-dimethyl-2-butanone, 1-chloro-4-phenylbutane, bromomethylcyclopropane, 1-bromo-2,2,2-trifluoroethane, bromocyclohexane, 1-bromohexane and the like.", "\nThe N-Boc protecting group is then removed using conventional procedures and reagents to afford the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 26. ", "This deblocking reaction is typically conducted by treating the N-Boc compound 30 with anhydrous hydrogen chloride in an inert diluent, such as 1,4-dioxane, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 2 to about 8 hours. ", "The resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.", "\nThe 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones, 26, can also be prepared via an azide transfer reaction as illustrated in Scheme 9. ", "\nAs shown in Scheme 9, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 23, is first N-alkylated as described above using conventional reagents and conditions to provide a 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24.", "\nThe 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 24 is then reacted with an azide transfer reagent to afford 5-azido-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 31. ", "Typically, this reaction is conducted by first contacting 24 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as lithium diisopropylamine and the like, in an inert diluent such as THF, at a temperature ranging from about xe2x88x9290xc2x0 C. to about xe2x88x9260xc2x0 C. for about 0.25 to about 2.0 hours. ", "The resulting anion is then treated with an excess, preferably with about 1.1 to about 1.2 equivalents, of an azide transfer reagent, such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide). ", "This reaction is typically conducted at a temperature ranging from about xe2x88x9290xc2x0 C. to about xe2x88x9260xc2x0 C. for about 0.25 to about 2.0 hours. ", "The reaction mixture is then typically treated with an excess of glacial acetic acid and the mixture is allowed to warm to ambient temperature and then heated at about 35xc2x0 C. to about 50xc2x0 C. for about 2 to 4 hours to afford the 5-azido-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative 31. ", "Reduction of 31 as described above using conventional reagents and conditions then affords the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26.", "\nIf desired, the aryl rings of 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones, 26, and similar or related compounds may be partially or fully saturated by treatment with hydrogen in the presence of a hydrogention catalyst. ", "Typically, this reaction is conducted by treating 26 with hydrogen at a pressure of about 10 to about 100 psi in the presence of a catalyst, such as rhodium on carbon. ", "This reaction is typically conducted at a temperature ranging from about 20xc2x0 C. to about 100xc2x0 C. for about 12 to 96 hours in a suitable diluent, such as ethyl acetate/acetic acid (1:1) and the like.", "\nOther methods for preparing intermediates useful in this invention are described in U.S. patent application Ser. ", "No. ", "09/102,726, filed on Jun. 22, 1998 and in U.S. patent application Ser. ", "No. ", "09/337,408, filed on even date herewith (Attorney Docket No. ", "002010-345), both entitled xe2x80x9cPolycyclic xcex1-Amino-xcex5-caprolactams and Related Compoundsxe2x80x9d, the disclosures of which are incorporated herein by reference in their entirety.", "\nAdditionally, the synthesis of various benzapinones and related compounds are described in Busacca et al., ", "Tetrahedron Lett., ", "33, 165-168 (1992); Crosisier et al., ", "U.S. Pat. ", "No. ", "4,080,449; J. A. Robl et al. ", "Tetrahedron Lett., ", "36(10), 1593-1596 (1995); Flynn et al. ", "J. Med. ", "Chem. ", "36, 2420-2423 (1993); Orito et al. ", "Tetrahedron, 36, 1017-1021 (1980); Kawase et al., ", "J. Org. ", "Chem., ", "54, 3394-3403 (1989); Lowe et al., ", "J. Med. ", "Chem. ", "37, 3789-3811 (1994); Robl et al., ", "Bioorg. ", "Med. ", "Chem. ", "Lett., ", "4, 1789-1794 (1994); Skiles et al., ", "Bioorg. ", "Med. ", "Chem. ", "Lett., ", "3, 773-778 (1993); Grunewald et al., ", "J. Med. ", "Chem., ", "39(18), 3539-(1996); Warshawsky et al., ", "Bioorg. ", "Med. ", "Chem. ", "Lett., ", "6, 957-962 (1996); Ben-Ishai, et al., ", "Tetrahedron, 43, 439-450 (1987); van Neil et al, Bioorg. ", "Med. ", "Chem. ", "5, 1421-1426 (1995); and reference cited therein. ", "These publications and patents are incorporated herein by reference in their entirety.", "\nSimilarly, various benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents. ", "For example, a 2-aminobenzophenone can be readily coupled to xcex1-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2-aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[xcex1-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone. ", "Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents, of mercury (II) chloride then affords the 2-[N-(xcex1-amino)-Nxe2x80x2-(benzyloxycarbonyl)-glycinyl]aminobenzophenone. ", "This intermediate can then be readily cyclized by treatment with glacial acetic acid and ammonium acetate to provide the 3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one 1. ", "Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.", "\nAlternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. ", "The conditions for these and related reactions are described in the examples set forth below. ", "Additionally, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are readily alkylated at the 1-position using conventional procedures and reagents. ", "For example, this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF. ", "This reaction is typically conducted at a temperature ranging from about xe2x88x9278xc2x0 C. to about 80xc2x0 C. for about 0.5 to about 6 hours. ", "The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. ", "Generally, this reaction is conducted at a temperature of about 0xc2x0 C. to about 100xc2x0 C. for about 1 to about 48 hours.", "\nAdditionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. ", "Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. ", "Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. ", "Such procedures are described in further detail in the example set forth below.", "\nIn the synthesis of compounds of formula I using the synthetic methods described herein, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. ", "Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. ", "Such reaction protocols can involve inversion of the chiral center during synthesis.", "\nAccordingly, unless otherwise indicated, the products of this invention are a mixture of R,S enantiomers. ", "Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. ", "Alternatively, chiral products can be obtained via purification techniques which separates enantiomers from a R,S mixture to provide for one or the other stereoisomer. ", "Such techniques are well known in the art.", "\nPharmaceutical Formulations\nWhen employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. ", "These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. ", "These compounds are effective as both injectable and oral compositions. ", "Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.", "\nThis invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. ", "In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. ", "When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. ", "Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.", "\nIn preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. ", "If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. ", "If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.", "\nSome examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. ", "The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. ", "The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.", "\nThe compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. ", "The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. ", "Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).", "\nThe active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. ", "It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient\"\"s symptoms, and the like.", "\nFor preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. ", "When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. ", "This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.", "\nThe tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. ", "For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. ", "The two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. ", "A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.", "\nThe liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.", "\nCompositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. ", "The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. ", "Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. ", "Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. ", "Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. ", "Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "\nMeteor in Flip Flops – Meteor.js camp – 5 places left - Maciej001\nhttps://meteorinflipflops.com\n======\nMaciej001\nA 7-days intensive Meteor.js hands-on camp in Las Palmas, Gran Canaria -21-28\nFebruary 2016. ", "The course will be run by world class tutors: Rahul Choudhury\nand Lukas van Driel of Q42. ", "Grab your place today (only 5 places left) and\nlearn advanced meteor.js technics with other project builders.", "\n\n------\nfaceyspacey\nabsolutely fantastic idea and location!! ..", "let me know if you ever need any\nadditional tutors in the future.", "\n\n~~~\nMaciej001\nThanks! ", "It's like a dream comes true :) We will definitely have lots of fun\nthere.", "\n\n" ]

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[ "Q:\n\nHow to highlight focused custom buttonfield (ImageButtonField) on Blackberry?", "\n\nI made a custom ButtonField class where I have an image as a button. ", "However, I would like to be able to select this image and to know it is selected, either by partially highlighting it or putting a square around it, whatever. ", "I have a BitmapField in my UI that highlights itself in blue when I select it, but my other images that use ImageButtonField, do not have the blue highlight. ", "I do not want the bitmap to disappear completely when selected.", "\nhere is the code :\npackage mypackage;\n\nimport net.rim.device.api.system.", "Bitmap;\nimport net.rim.device.api.system.", "Characters;\nimport net.rim.device.api.ui.component.", "BitmapField;\n\n public class ImageButtonField extends BitmapField{\n\n public ImageButtonField(Bitmap image) {\n super(image);\n }\n\n public boolean isFocusable() {\n return true;\n }\n\n protected boolean navigationClick(int status, int time) {\n fieldChangeNotify(0);\n return true;\n }\n\n protected boolean trackwheelClick(int status, int time) {\n fieldChangeNotify(0);\n return true;\n }\n\n protected boolean keyChar(char character, int status, int time) {\n if(Characters.", "ENTER == character || Characters.", "SPACE == character) {\n fieldChangeNotify(0);\n return true;\n }\n return super.keyChar(character, status, time);\n }\n}\n\nAny help modifying this class so it works would help immensely. ", "I have had no success trying to make this work!", "\n\nA:\n\nTo remove default styling attributes you can add following methods:\nprotected void applyTheme(Graphics arg0, boolean arg1) {\n}\n\nprotected void drawFocus(Graphics graphics, boolean on) {\n}\n\nYou can override paint method and do paint whatever you want by checking focus status, e.g. following code will paint a red transparent layer over the bitmap image.", "\nprotected void paint(Graphics graphics) {\n super.paint(graphics);\n if (isFocus()) {\n graphics.setGlobalAlpha(128);\n graphics.setColor(0xFF0000);\n graphics.fillRect(0, 0, getWidth(), getHeight());\n }\n}\n\nActually I didn't understand your question well :).", "\n\n" ]

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[ "Italian politician Matteo Salvini is the head of the country's far-right League party, which formed a populist coalition alongside the anti-establishment Five Star Movement in June. ", "In addition to his post as interior minister, Salvini serves as deputy prime minister to Giuseppe Conte, a newcomer to politics chosen by both parties as their head of government.", "\n\nDW: After 100 days as part of a new government, do you feel like you have addressed Italy's most pressing issues, such as poverty and unemployment?", "\n\nMatteo Salvini: I am very happy with the 100 days. ", "Under my remit, which is security, immigration, and public security, we have achieved extraordinary results. ", "Regarding employment, taxes and pensions, in the autumn the new government will make its mark, with a new path, change, growth, so I'm not worried about data for this period. ", "We are already working on growth, which should finally rebound.", "\n\nRead more: Italy's popular populists\n\nInternational markets seem skeptical though. ", "The famous \"spread,\" that is the risk premium for Italian bonds, has doubled since you came to power. ", "How do you explain that?", "\n\nThere are people who are speculating. ", "There are also people who are against us. ", "Our government is free and independent from the multinationals, from big finance, from banking powers — both international and European. ", "We have no fears. ", "The Italian economy is sound. ", "Italian business is sound. ", "So the economic reforms will provide all the answers that the so-called markets and the lords of the \"spread\" are waiting for.", "\n\nIt seems like Italy's new prime minister, Giuseppe Conte, is not very present. ", "You are more present than he is. ", "Do you feel like you are the real head of the government?", "\n\nNo, we have two different personalities. ", "He is a man of mediation and listening. ", "He visited Donald Trump. ", "He will go to China. ", "He attends the European summits. ", "I am deputy prime minister, along with Luigi di Maio [of the 5-Star party] . ", "We are party leaders. ", "So it's clear that due to our characters and our roles we tend to be more present, but we are a good team.", "\n\nLet's turn to the European Union and the topic of migration. ", "You seem at odds with the EU on some points. ", "Do you feel like the goal going forward is to find a compromise with the EU or are you on confrontation course?", "\n\nEven though I am often described as a hooligan, I am always trying to reason, to discuss, to ask questions. ", "Take the revision of the Treaty of Dublin and Operation Sophia for instance. ", "We are making proposals, we are waiting, we are suggesting. ", "It is clear that I had to stop the migrant landings. ", "Last year in the period up to August, 100,000 migrants arrived and the European Union did little or nothing. ", "This year we had fewer than 20,000 landings, and the European Union is still doing little or nothing. ", "So I am still willing to debate, but more recently, we've also been talking with some non-European Union countries, such as Albania, Serbia and Montenegro.", "\n\nSalvini with Hungarian Prime Minister Victor Orban during a meeting at the end of August in Milan\n\nOn the issue of migration, you recently agreed to form an alliance with Hungarian Prime Minister Victor Orban. ", "And yet you've stated that you want to see redistribution of migrants across the EU. ", "Orban doesn't want that — but German Chancellor Angela Merkel does. ", "So aren't you closer to Merkel than Orban on this?", "\n\nI'm trying to get something good out of everybody. ", "Victor Orban talks about defending Europe's borders, about protection in the countries of origin and investment in Africa, and I agree with him. ", "Angela Merkel is proposing a redistribution inside Europe, and I can agree even with this position in the very near future. ", "What we have to do is help these people so that they don't flee their countries. ", "We should be rapidly investing €500 million ($580 million)\n\nin Africa. ", "I believe that both Germany and Hungary are right regarding certain issues.", "\n\nYou've seen what's been happening in Chemnitz, Germany at the moment, with the extreme right, and with the Alternative for Germany (AfD) party. ", "Some are blaming Angela Merkel, saying that this is the result of the migration crisis. ", "Do you agree?", "\n\nI would say that Angela Merkel certainly underestimated the risk of a social clash when she claimed that there was space for hundreds of thousands of people in Germany. ", "I still remember what happened during the New Year's Eve celebrations in Cologne in 2015, and also elsewhere. ", "However, violence is never a solution! ", "Violence calls for violence, but the German government has been underestimating the problem for years, and the rise of the AfD is clearly a reaction.", "\n\nYour government has been in office for 100 days now. ", "Do you think it will hold another year?", "\n\nYes, I think that this government will have a long life if it respects its obligations to the Italian people.", "\n\nIs it harder than you thought it would be?", "\n\n(Laughing) I'm happy that I can finally participate in what is happening.", "\n\nIs it harder than you thought it would be, yes or no?", "\n\nWell, it is not easy. ", "Italy is a big country. ", "We have important challenges to face, but I was tired of being in the opposition." ]

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[ "The influence of resin flexural modulus on the magnitude of ceramic strengthening.", "\nThe aim was to determine the magnitude of ceramic resin-strengthening with resin-based materials with varying flexural moduli using a regression technique to assess the theoretical strengthening at a 'zero' resin-coating thickness. ", "The hypothesis tested was that experimentally, increasing resin flexural modulus results in increased resin-strengthening observed at a theoretical 'zero' resin-coating thickness. ", "Vitadur Alpha dentin porcelain disk (n=250) were condensed, fired, alumina particle air abraded and randomly assigned into ten groups. ", "Groups were resin-coated at 50, 100 and 150μm with Venus Flow, Rely-X Veneer and Clearfil AP-X before biaxial flexure testing at 24h and the stress at failure calculated using a multilayer analysis. ", "An analytical methodological approach was undertaken to predict the biaxial flexure stresses under boundary conditions that reflected the experimental test and a finite element model was used to verify the analytical prediction. ", "The magnitude of resin-reinforcement was significantly influenced by resin-coating type (P<0.001) and resin-coating thickness (P=0.013), however, a significant interaction was observed between resin-coating type and thickness (P=0.048). ", "Linear regression identified a 17, 38 and 47% biaxial flexure strength contribution when Venus Flow, Rely-X Veneer and Clearfil AP-X were used, respectively. ", "The finite element model determined the maximum principal stress was within 3.3% of the predicted analytical solution. ", "Experimentally, the flexural modulus and thickness of resin-based material used to cement DBC or PLV restorations have a significant impact on the magnitude of resin-strengthening observed. ", "However, for resin-based materials with different flexural moduli the variability in the relationships between thickness and observed increases in biaxial flexure strength of the ceramic requires careful characterization to optimize clinical performance." ]

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[ "Click on the\narrows to look to the left or rightINFO:This little city is completely made of paper: The\nbuildings and cars are papercraft/kirigami\nand the smaller models like the animals and tress are 100% origami" ]

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[ "OAKLAND, Calif. -- Forced to go small, the Golden State Warriors keep coming up big.", "\n\nEast or West, they are the best team in the NBA right now -- and they want everyone to know it.", "\n\nStephen Curry had 32 points and 12 assists, Draymond Green got his first career triple-double, and the Warriors rolled past the Toronto Raptors 126-105 on Friday night in a matchup of conference leaders.", "\n\n\"One thing we always say when we're playing against a team like this is, 'This is a team we could possibly play later on in the year,'\" Green said. \"", "Try to make a statement.\"", "\n\nDid they ever.", "\n\nGreen finished with 16 points, 13 assists and 11 rebounds, and three others scored in double digits to help the NBA-best Warriors (26-5) wear down the Raptors (24-9) in the second half. ", "Golden State started the third quarter on a 23-5 run and thwarted the Raptors' brief rally with contributions from all over.", "\n\n\"I went in the locker room and just told them, 'I don't have much to say other than wow,'\" Warriors coach Steve Kerr said.", "\n\nToronto's loss allowed Atlanta to move into first in the East.", "\n\nGreivis Vasquez scored 25 points, and Kyle Lowry had 22 points and eight assists for the Raptors, who lost consecutive road games for the first time this season. ", "Toronto fell to 2-3 on its six-game trip, which ends at Phoenix on Sunday.", "\n\nGolden State kept up its blistering pace without a true center as Andrew Bogut (right knee) and backup Festus Ezeli (left ankle) continue to recover from nagging injuries.", "\n\nKerr mixed and matched smaller lineups -- using Green and Marreese Speights down low and sometimes nothing but forwards on the floor -- to push the pace and maximize his team's versatility.", "\n\nThe Big 3-0 -- And 10 Stephen Curry ended up with 32 points and 12 assists Friday, his 13th 30-10 game the past two seasons. ", "That's nearly twice as many 30-10 games as anybody else in the NBA in that span. ", "Most 30-Point, 10-Assist Games\n\nPast Two Seasons Player 30-10 Gms. ", "Stephen Curry 13 << James Harden 7 Kevin Durant 4 Chris Paul 4 >> Including Friday -- ESPN Stats & Information\n\nThe Warriors outshot Toronto 53.3 percent to 46.5 percent. ", "They also tied a season-low with nine turnovers, while the Raptors had 17.", "\n\n\"That's a well-oiled machine. ", "Their small lineup is one of the best in the league,\" Raptors coach Dwane Casey said.", "\n\nThe Warriors went 5-for-6 from 3-point range in the first quarter to take a 40-31 lead. ", "It was the most points Golden State has scored and the most the Raptors have allowed in the first quarter this season.", "\n\nEven with the Warriors putting on an offensive spectacle, Toronto didn't go away easily.", "\n\nLowry overcame early foul trouble and Vasquez hit four 3s in the first half to help the Raptors regroup from a 14-point deficit. ", "Golden State led just 66-61 at intermission.", "\n\n\"When we feel threatened,\" Speights said, \"we always play better.\"", "\n\nJust as they have so often during the best start in franchise history, the Warriors leaned on their defense and their leading man to pull away behind one big burst.", "\n\nCurry capped the spurt by throwing down a hard dunk as Lowry tried to block him from behind. ", "Curry screamed as Lowry tried to inbound the ball and the announced sellout crowd of 19,596 roared to its feet -- along with several teammates.", "\n\n\"I couldn't stop screaming when he did that either,\" Green said.", "\n\nThe Raptors, playing without All-Star guard DeMar DeRozan (torn muscle in left groin) for the 16th straight game, closed to 110-101 before Curry finished with a flurry -- scoring 10 points in a three-minute span.", "\n\nThe Warriors also got key contributions from Speights (26 points and eight rebounds), Klay Thompson (20 points), David Lee (12 points and seven rebounds) and Justin Holiday (nine points).", "\n\n\"Their small ball really got to us,\" Lowry said. \"", "I think they kind of just went up and down a little bit too fast at a pace we didn't really want.\"", "\n\nTIP-INS\n\nRaptors: Toronto has lost 10 in a row at Golden State, a skid that dates to February 2004. ... ", "The Raptors are 11-6 since DeRozan's injury. ... ", "Landry Fields started at small forward after missing the last five games recovering from a concussion. ", "He had two points and three rebounds.", "\n\nWarriors: Golden State has won 11 straight home games and is 13-1 at Oracle Arena this season. ... ", "The Warriors are 10-0 against the Eastern Conference.", "\n\nSHARING THE ROCK\n\nThe Warriors had 35 assists, the league-most 11th time they've had at least 30. ", "It also was the first time the Warriors had at least 35 assists in consecutive games since April 1994.", "\n\nUP NEXT\n\nRaptors: At Phoenix on Sunday.", "\n\nWarriors: Host Oklahoma City on Monday." ]

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[ "---\nabstract: 'The world’s largest cosmic-ray detector is nearing completion in the remote Pampas of Argentina. ", "This instrument measures extensive air-showers with energies from ${10^{18}-10^{20}}$ eV and beyond. ", "A surface detector array of area 3000 ${km^2}$ records the lateral distribution of charged particles at ground level. ", "A fluorescence detector overlooking the surface detector records the longitudinal light profiles of showers in the atmosphere to make a calorimetric energy measurement. ", "A “test beam” for the fluorescence detector is generated by a calibrated laser near the array center. ", "This talk will focus on detector characterizations essential to the first science results that have been reported from the observatory. ", "Plans to construct a larger instrument in the northern hemisphere will also be outlined.'", "\naddress: |\n Department of Physics, University of Utah, Salt Lake City, UT 84112, USA\\\n email: wiencke@cosmic.utah.edu\nauthor:\n- 'L. Wiencke for the Pierre Auger Collaboration'\ntitle: Extracting first science measurements from the southern detector of the Pierre Auger observatory\n---\n\n[**1. ", "Introduction**]{}\\\nThe origin of cosmic rays with energies beyond $10^{18}$ eV is a long standing puzzle. ", "For each decade of energy increase the differential flux falls by three orders of magnitude to approach, at $10^{20}$ eV, a scant one event per $km^{2}$ per century. ", "This alone hints at the formidable instrumental challenges. ", "Fore-runner experiments have operated different types of detectors in different locations. ", "This complicates the understanding of these data in combination because the differing systematics that necessarily underlay astrophysical interpretations can not be compared directly.", "\n\nThe Pierre Auger Observatory combines the surface and air-fluorescence techniques with two co-located detectors. ", "Deployment of the baseline configuration in the south (Fig. ", "\\[map\\]) is about 75% complete (1100+ of 1600 tanks, 3 of 4 fluorescence “eyes”, 3 of 4 LIDARs, 1 of 2 central lasers) and is expected to finish in 2007.", "\n\n![", "Configuration of the Pierre Auger Observatory southern detector.(see text.)[]{data-label=\"map\"}](array-base.eps){width=\"80.00000%\"}\n\n![", "Rp resolution of CLF vertical tracks as reconstructed using mono (1 FD eye only) and hybrid (1 FD eye + SD timing) data.[]{data-label=\"clf-rp\"}](clf-photo.eps){width=\"100.00000%\"}\n\n![", "Rp resolution of CLF vertical tracks as reconstructed using mono (1 FD eye only) and hybrid (1 FD eye + SD timing) data.[]{data-label=\"clf-rp\"}](resolRp.eps){width=\"100.00000%\"}\n\n[**2. ", "Pierre Auger Detectors and their Characterization**]{}\\\nThe surface detector (SD) [@XB2005] of 1600 water cherenkov tanks samples the charged particle lateral distribution of extensive air-showers (EASs) at ground level. ", "With continuous operation and area of 3000 $km^{2}$, the SD provides the statistical engine. ", "After correcting for zenith angle, the density of charged particles 1000 m from the shower core provides an energy estimator. ", "For a $10^{19}$ eV EAS with zenith angle less than 50 degrees, the statistical uncertainty in S1000 is of order 10% [@PER2005]. ", "Angular accuracy is a function of the number of tanks triggered, which depends primarily on shower energy and zenith angle. ", "For EASs measured by at least 5 tanks, this accuracy is better than 1 degree [@CB2005]. ", "Essentially all events above $10^{19}eV$ meet these criteria.", "\n\nA fluorescence detector (FD) of four “eyes” overlooking the SD operates at night to record the longitudinal light profiles of EASs as they develop through the atmosphere. ", "This calorimetric energy measurement does not rely on interaction models; the amount of fluorescence light emitted is proportional to the energy deposited in the atmosphere. ", "At present the systematic energy uncertainty is less than 25% (Table \\[errors\\]). ", "This value is expected to decrease as improvements are expected in the three largest terms: fluorescence yield, detector photometric calibration, and atmospherics. ", "About 10% of the observed EASs are recorded by both detectors (FD and SD) to construct a “Rosetta stone” hybrid data sample now in excess of 30,000 events.", "\n\n![", "Energy as measured by the FD (vertical axis) vs s1000 as measured by the SD (horizontal axis).[]{data-label=\"e38new\"}](resolChi0.eps){width=\"100.00000%\"}\n\ns ![", "Energy as measured by the FD (vertical axis) vs s1000 as measured by the SD (horizontal axis).[]{data-label=\"e38new\"}](energy-s38-new.eps \"fig:\"){width=\"100.00000%\"}\n\nOne important role of the FD, through hybrid data, is to verify the pointing accuracy and to determine the energy scale of the SD [@S2005]. ", "To realize this, the Auger design incorporates various methods and instruments to determine the geometrical reconstruction accuracy[@M2005] and the photometric energy scale of the FD[@PB2005] and to measure the density profile [@K2005] and the distribution of aerosol in the atmosphere through which the FD observes EASs [@R2005].", "\n\nTest beams of $E>10^{17} eV$ particles are unavailable. ", "Pulsed UV lasers, however, provide a practical alternative. ", "The total amount of light scattered from a 5 mJ energy UV beam pulse directed vertically into the atmosphere is roughly equivalent to the amount of fluorescence light emitted by a shower with energy in the region of the predicted GZK suppression. ", "The baseline configuration includes two laser facilities, dubbed the CLF [@A2005] (Fig. ", "\\[clf\\]) and the XLF (under construction), near the middle of the SD. ", "The remotely controlled CLF operates during FD data collection to send light simultaneously via optical fiber into a SD tank and via mirrors into the sky. ", "The hybrid laser data sample is used to measure the relative timing between the FD and the SD[@AL2005], and to realize significant improvements in geometric reconstruction by invoking the constraint of SD timing (Figs. ", "\\[clf-rp\\],\\[clf-ang\\]). ", "Fitting the longitudinal profile of CLF tracks observed by the FD provides an hourly data base of aerosol optical depth measurements. ", "A comparison between the laser pulse energy and the energy as reconstructed from FD measurements tests, under aerosol-free conditions, the photometric calibration of the FD and the modeling of molecular atmosphere over a total light path of 60 km. ", "The current level of agreement is better than 15%.", "\n\nAnalysis of hybrid EAS data led to many of the first science results. ", "Hybrid events have set the energy scale (Fig. ", "\\[e38new\\]) for the first energy spectrum measurement [@S2005], set a limit on the flux of neutral EeV particles pointing back to the galactic center [@AS2005], and set limits on the photon fraction of shower composition [@RI2005].", "\n\n Term Error(%) Term Error(%)\n ---------------------------------- ----------------------------- ------------------------------ ----------\n Light collection 5 Atmosphere (aerosols) 10\n Detector photometric calibration 12 Atmosphere (clouds) 5\n Geometric reconstruction 2 Atmosphere (density profile) 2\n Correction for Missing Energy 3 Fluorescence yield 15\n [**Quadrature Sum = 23**]{} \n\n : Current estimates of systematic error components to the FD energy measurement.[]{data-label=\"errors\"}\n\n\\\n\\\n[**3. ", "The Northern Detector and Enhancements in the South**]{}\\\nThe collaboration has selected southeast Colorado to site the northern detector. ", "Much of this area is accessed by a mile square grid of roads and could support deployment of an array much larger than that in the south. ", "A proposal is in preparation. ", "Enhancement of the southern detector is also anticipated by adding muon counters, in-fill surface detectors and higher elevation angle FD telescopes to reduce the energy threshold towards $10^{17} eV$. R&D in radio detection is also planned.", "\n\n[99]{} Auger Collaboration, Proc. ", "of 29th ICRC, [**7**]{} p1 (2005). ", "Auger Collaboration, Proc of 29th ICRC, [**7**]{} p167 (2005). ", "Auger Collaboration, Proc of 29th ICRC, [**7**]{} p17 (2005). ", "Auger Collaboration, Proc. ", "of 29th ICRC, [**7**]{} p387 (2005). ", "Auger Collaboration, Proc of 29th ICRC, [**7**]{} p369 (2005). ", "P. Bauleo et al., ", "Proc of 29th ICRC, [**8**]{} p5 (2005). ", "J. Blmer et al., ", "Proc of 29th ICRC, [**7**]{} p123 (2005). ", "R. Cester et al., ", "Proc of 29th ICRC, [**8**]{} p347 (2005). ", "A. Arqueros et al., ", "Proc of 29th ICRC, [**8**]{} p335 (2005). ", "P. Allison et al., ", "Proc of 29th ICRC, [**8**]{} p307 (2005). ", "Auger Collaboration, Proc of 29th ICRC, [**7**]{} p67 (2005). ", "Auger Collaboration, Proc. ", "of 29th ICRC, [**7**]{} p147 (2005).", "\n" ]

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[ "No matter how many times we stumble upon barely used, low-mileage examples of decades-old sports cars, it continues to amaze me how some people can hold on to these gems for years on end without driving them.", "\n\nI forget who said/wrote it, but I remember someone playfully saying that doing so, is like being married to a beautiful woman or man and not going to bed with them to save their purity for their next relationship…\n\nDespite being 22 years old, this 1992 Acura (Honda for markets outside North America) NSX we discovered on eBay has only travelled 2,209 miles (3,554 km) or just a mere 100 miles a year since new! ", "The current owner claims that the car is all-original, and the pictures appear to support that.", "\n\nThe car is listed on eBay with a starting bid of $66,000 and a “Buy it Now” price of $77,000.", "\n\neBay Seller’s Description:\n\n“I bought the car hoping to keep it for a long long time. ", "I since have made a job change and am liquidating a few things. ", "I acquired this from a local car collector/can am racer/business friend mine. ", "He bought it new in Madison, WI. ", "He drove it to Janesville, WI. ", "Where he cared for it in a climate controlled environment. ", "It has only been driven on sunny days and intentionally only around 100 miles per year.", "\n\nThis car is 100% original and nearly unused. ", "All you would need to do is put the included original window sticker back in the window and back it on to the showroom. ", "It sure would look nice next to a new 2015!", "\n\nEvery item functions perfectly. ", "The car has never been scratched, scuffed, dented in any way. ", "The wheels on this car are absolutely perfect, never curbed, pitted or stained. ", "The tires are the original tires, which do not show any signs of age at all. ", "The A022 tires are no longer made. ", "Power antenna works perfectly. ", "Original tool kit in trunk has never had a piece removed, let alone used.”", "\n\nBy John Halas\n\nPHOTO GALLERY" ]

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[ "Have equivalences between established between French degrees and degrees in other countries ?", "\n\nFrance recognizes no formal equivalences between its postsecondary degrees and degrees in other countries. ", "Each French institution makes its own admission decisions based on the applicant's background and the demands of the program.", "\n\nTo enter the French university system, international students must show that they are eligible to enroll in a university program in their country of residence.", "\n\nSearch form\n\nSearch\n\nMon CampusFrance\n\nUsername or e-mail *\n\nPassword *\n\nNew user To access all features, you need to create a personal account. ", "Register now. ", "It's free!" ]

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[ "This invention relates to a dry planographic printing plate and dry planographic printing method as well as an apparatus therefore suitable for production of printed matter in small lots--some 100 to 1,000 copies.", "\nHeretofore, the small offset printing method has extensively been used for the office service, whereas the letterpress printing, gravure printing, and offset printing methods have suitably been employed for producing prints in large lots. ", "This small offset printing, however, requires water and ink, so that it lacks in simplicity of operations.", "\nAn object of this invention is to provide a dry planographig printing plate and dry planographic printing method as well as an apparatus therefore capable of securing ease of operations possesed by copying machines and accomplishing with ease the printing of something like 100 to 1,000 copies.", "\nThe above and other objects of this invention will be apparent in the following detailed description of illustrative embodiments thereof which is to be read in connection with the accompanying drawings, wherein FIGS. ", "1 to 5 show the dry planographic printing plate of the invention, and FIGS. ", "6 to 9 are illustrative of the dry planographic printing method in which said planographic printing plate is employed." ]

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