Heterocyclic aromatic compounds useful as growth hormone secretagogues

FIELD OF THE INVENTION

[0001] The present invention relates to novel heterocyclic aromatic compounds which stimulate endogenous production and/or release of growth hormone, and to methods for treating obesity, improving bone density (to treat osteoporosis) and stimulating increase in muscle mass and muscle strength employing such compounds.

BACKGROUND OF THE INVENTION

[0002] The pituitary gland secretes growth hormone which stimulates growth in body tissue capable of growing and affects metabolic processes by increasing rate of protein synthesis and decreasing rate of carbohydrate synthesis in cells. Growth hormone also increases mobilization of free fatty acids and use of free fatty acids for energy.

[0003] The prior art is replete with patents/applications which disclose compounds which are useful as growth hormone secretagogues.

[0004] The following patents/applications, disclose benzofused lactams which are disclosed as being useful in promoting release of growth hormone:

[0005] U.S. Pat. Nos. 5,206,235; 5,283,741; 5,284,841; 5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261; 5,438,136; 5,545,735; 5,583,130; 5,606,054; 5,672,596 and 5,726,307; WO 96-05195 and WO 95-16675.

[0006] The following patents/applications, disclose diverse chemotypes as being useful in promoting release of growth hormone:

[0007] U.S. Pat. Nos. 5,536,716; 5,578,593; 5,622,973; 5,652,235; 5,663,171; WO 94-19367; WO 96-22997; WO 97-24369 and WO 98-58948.

SUMMARY OF THE INVENTION

[0008] In accordance with the present invention, novel heterocyclic aromatic compounds are provided which are growth hormone secretagogues and have the structure

[0009] including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof,

[0010] wherein R1 is alkyl, aryl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl (where the above groups are defined below) and these groups may be optionally substituted by 1, 2 or 3-substituents selected from halogen, —OR8, —OC(O)R8, alkyl, phenyl, phenoxy, halophenyl, —CF3, —OCF3, —N(R8a)C(O)(R8), or —N(R8)(R8a);

[0011] R1a is H, alkyl, or cycloalkyl;

[0012] Xa is heteroaryl, which preferably include

[0013] A is oxygen, sulfur, —NH—, —N—R5, or —NC(O)—R2;

[0014] B is —CR5b or —N—;

[0015] Z is a bond or —S—;

[0016] G is oxygen or sulfur;

[0017] U is oxygen, sulfur, —NH—, or —N—R5b;

[0018] R2 is alkyl, aryly, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryl, or heteroarylalkyl (where the above groups are defined below) and these groups may optionally be substituted by 1, 2 or 3-substituents selected from halogen, —OR8b, —OC(O)R8b, alkyl, phenyl, phenoxy, halophenyl, —CF3, —OCF3, —N(R8c)C(O)(R8b), or —N(R8c)(R8b);

[0019] R3 is H, halogen, alkyl, aryl, alkenyl, alkynyl, alkaryl, alkoxy, aryloxy or J1, and where alkyl, aryl, alkenyl, alkynyl, arylalkyl, alkoxy, or aryloxy may be optionally substituted with 1 to 3 J1;

[0020] R4 and R4a are the same or different and are independently H, halogen, —CF3, alkyl, or aryl;

[0021] R5 is H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, —SO2T1, —SO2N(T1a)T1, or heteroarylalkyl, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;

[0022] R5a and R5b are the same or different and are independently H, alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, cycloalkylalkoxyalkyl, heteroarylalkyl, or J1, and where alkyl, aryl, alkenyl, arylalkenyl, alkynyl, arylalkyl, arylalkynyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroaryl, heteroaryloxyalkyl, cycloalkylalkoxyalkyl, or heteroarylalkyl may be independently optionally substituted with 1 to 3 J1;

[0023] where x and y are independently 0 to 3 and z is 1 to 3;

[0024] Xc is a bond, —N—R6a or —O—;

[0025] R7 and R7a are the same or different and are independently H, alkyl, —CF3, phenyl, aryl, arylalkyl, and cycloalkyl; or one or both of R7 and R7a can be independently joined to one or both of R9 and R10 groups (of Xb) to form an alkylene bridge of 1 to 5 carbon atoms; or R7 and R7a are joined together to form aring of from 3-7 carbon atoms;

[0026] R6, R6a, R6b, R6c, R8, R8a, R8b, R8c, R8d, R8e, R8f, R8g, R8h, R8i, R8k, R8l, and R8m are the same or different and are independently H, alkyl, cycloalkyl, alkenyl or aryl;

[0027] R8j is H, alkyl, aryl, hydroxy or —OC(O)R8k;

[0028] Xb is

[0029] R9 and R10 are the same or different and are independently selected from H, alkyl, and substituted alkyl where the substituents may be 1 to 3 hydroxys, 1 to 3 C1-C10-alkanoyloxy; 1 to 3 C1-6 alkoxy, phenyl, phenoxy, C1-C6-alkoxycarbonyl; or R9 and R10 can together form —(CH2)tXd(CH2)u— where Xd is C(R8h)(R8j), —O— or —N(R6b), t and u are independently 1-3;

[0030] R11 is H, C1-C6alkyl, —CF3, arylalkyl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C1-10alkanoyloxy, 1 to 3 C1-6 alkoxy, phenyl, phenoxy or C1-6alkoxycarbonyl;

[0031] R12 and R13 are independently H, C1-C6alkyl, —CF3, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxy, 1 to 3 C1-C10-alkanoyloxy, 1 to 3 C1-6 alkoxy, or C1-C6 alkoxycarbonyl;

[0032] J1 is nitro, —(CH2)vN(T1a)C(O)T1, —(CH2)vCN, —(CH2)vN(T1a)C(O)OT1, —(CH2)vN(T1a)C(O)N(T1b)T1, —(CH2)vN(T1a)SO2T1, —(CH2)vC(O)N(T1a)T1, —(CH2)vC(O)OT1, —(CH2)vOC(O)OT1, —(CH2)vOC(O)T1, —(CH2)vOC(O)N(T1a)T1, —(CH2)vN(T1a)SO2N(T1b)T1, —(CH2)vOT1, —(CH2)vSO2T1, —(CH2)vSO2N(T1a)T1, —(CH2)vC(O)T1, —(CH2)vCH(OH)T1, cycloheteroalkyl, or heteroaryl as defined below, with v being 0-5;

[0033] T1, T1a and T1b are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with 1, 2 or 3 of the following groups, halogen, hydroxyl, —NR8fC(O)NR8gR8i, —C(O)NR8fR8g, —NR8fC(O)R8g, —CN, —N(R8f)SO2R14, —OC(q)R8f, —SO2NR8fR8g, —SOR14, —SO2R14, alkoxy, —COOH, cycloheteroalkyl, or —C(O)OR14; or T1 and T1a or T1 and T1b can together form —(CH2)wXe(CH2)z— where Xe is —C(R8m)(R8i), —O—, —S—, —SO—, —SO2—, —NC(O)OR14a, —NC(O)NR14aR14b, —NC(O)R14a or —N(R6c) where w and z are each independently 1-3; with the proviso that T1 can not be hydrogen when it is connected to carbonyl or sulfur, as in —C(O)T1 or —SO2T1;

[0034] R14, R14a, and R14b are independently C1-C6alkyl, heteroaryl, or aryl, each optionally substituted with —(CH2)SOH, with s being 0-5;

[0035] with the proviso that where Xa is

[0036] (1) where one or both of R7 and R7a, and one or both of R9 and R10 form an alkylene bridge, then where R5 is

[0037] —(CH2)C(O)N(T1a)T1, then at least one of T1a and T≠H; or

[0038] (2) where R1 is arylalkyl and R1a is H and R5 is

[0039] —(CH2)C(O)N(T1a)T1, then T1a or T1 is other than

[0040] (3) where R1 and R7 are each 2-naphthyl-CH2—, then R5≠phenethyl.

[0041] The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in formula I, the more active and thus more preferred configuration is R as determined by the R/S rules when R1a is H. Isomers may be separated by conventional methods, for example, chromatographic or fractional crystallization.

[0042] The pharmaceutically acceptable salts of the compounds of formulae I of the invention include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as phosphate, mandelate, chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.

[0043] In addition, in accordance with the present invention, a method for increasing levels of endogenous growth hormone or increasing the endogenous production or release of growth hormone is provided wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.

[0044] Furthermore, in accordance with the present invention, a method is provided for preventing or treating osteoporosis (improving bone density and/or strength), or treating obesity, or increasing muscle mass and/or muscle strength, or maintenance of muscle strength and function in elderly humans, or reversal or prevention of fraility in elderly humans, wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

[0046] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 6 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 3 substituents including alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, alkanoyl, amino, haloaryl, CF3, OCF3, aryloxy, heteroaryl, cycloalkylalkoxyalkyl, or cycloheteroalkyl.

[0047] Unless otherwise indicated, the term “cycloalkyll” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 7 carbons, forming the ring and which may be fused to 1 aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

[0048] any of which groups may be optionally substituted with 1 to 3 substituents as defined above for alkyl.

[0049] The term “aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to “aryl” (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, oxo, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or preferably any of the aryl substituents as set out above.

[0050] Preferred aryl groups include phenyl, biphenyl or naphthyl.

[0051] The term “aralkyl”, “aryl-alkyl” or “aryllower alkyl” as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.

[0052] The term “lower alkoxyl”, “alkoxyl”, “aryloxyl” or “aralkoxyl” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.

[0053] The term “amino” as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and/or cycloalkyl.

[0054] The term “lower alkylthio”, alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.

[0055] The term “lower alkylamino”, “alkylamino”, “arylamino”, or “arylalkylamino” as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.

[0056] The term “acyl” as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl

[0057] group; examples of acyl groups include alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, and the like.

[0058] The term “alkanoyl”, as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.

[0059] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 2 to 6 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio or any of the substituents for alkyl as set out herein.

[0060] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the substituents for alkyl as set out herein.

[0061] The term “alkylene” as employed herein alone or as part of another group refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for “alkyl”.

[0062] The terms “alkenylene” and “alkynylene” as employed herein alone or as part of another group refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms.

[0063] Examples of (CH2)x, (CH2)y, (CH2)w, (CH2)v, (CH2)s, (CH2)t, (CH2)u or (CH2)z groups (which may include alkylene, alkenylene or alkynylene groups as defined herein, and may optionally include 1, 2, or 3 substituents which may be any of the alkyl substituents set out herein), are as follows:

[0064] The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.

[0065] The term “metal ion” refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

[0066] The term “heterocyclic”, “heterocyclo” or “heterocycle” as employed herein alone or as part of another group refers to “heteroaryl” groups or “cycloheteroalkyl” groups.

[0067] The term “cycloheteroalkyl” as used herein alone or as part of another group refers to a 4-, 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as

[0068] and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0069] The term “heteroaryl” or “heterocyclicaryl” as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as

[0070] and the like.

[0071] The heteroaryl groups may optionally include 1 to 4 substituents such as any of the aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0072] The term “prodrug esters” of the formula I compounds includes esters of hydroxyls and phenols, such as acetate, benzoate, pivolate, stearoylate, isobutyrate, and the like as known in the art.

[0073] General Synthetic Schemes

[0074] The compounds of the present invention may be prepared according to the following general synthetic schemes, as well as relevant published literature procedures that are used by the one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Unless otherwise specified, the various substituents of the compounds are defined in the same manner as the formula I compound of the invention.

[0075] In the following reactions, amide bond forming (peptide coupling) reactions are conducted under standard peptide coupling procedures know in the art. optimally, the reaction is conducted in a solvent such as dimethylformamide (DMF) at 0° C. to room temperature using 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDAC) or (WSC)), 1-hydroxybenzo-triazole hydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) and a base, for example 4-dimethlaminopyridine (DMAP) or Hunig's base.

[0076] Unnatural protected amino acids can be purchased or prepared by standard methods known in the art. Chiral preparations include Meyers, A. G. et al., J. Am. Chem. Soc., 119, 656-673 (1997). O-Alkylated serine derivatives can be formed from serine by known methods, Maligres, P. E. et al., Tetrahedron, 53, 10983-10992 (1997).

[0077] The cyclizations to benzimidazoles or benzoxazoles in Schemes 1, 1a, and 1b can be carried out under standard conditions known in the art. Suitable cyclization procedures are described in Nestor, Jr., J. J., J. Med. Chem., 27, 320-5 (1984) and are optimally heating (60-90° C.) in an acidic solvent, such as acetic acid. Benzothiazoles can be prepared as in Spitulnik, M. J., Synthesis, 730 (1976), and by other methods known in the art.

[0078] Protection and deprotection in the Schemes below may be carried out by procedures generally known in the art. See, for example, T. W. Greene, Protecting Groups in Organic Synthesis, Second Edition, 1991. PG in the Schemes below denotes a nitrogen proItecting group, optimally BOC. The BOC group can be removed under acidic conditions, optimally HCl or trifluoroacetic acid.

[0079] Reduction of nitro groups in Schemes 1c and 1d can be carried out by methods know in the art. Optimally the reduction can be carried out with H2 in the presence of a catalyst (palladium or platinum).

[0080] The arylation reaction covered in Scheme 2 can be performed under the known Suzuki coupling conditions in the literature, or other conditions using the metals zinc or tin known in the art. If the Rx is a chloro, the coupling can be performed as disclosed in Indolese, A. F., Tet. Lett., 38, 3513-3516 (1997) or Shen, W. Tet. Lett., 0.38, 5575-5578 (1997) using a nickel catalyst.

[0081] The tetrazole forming reaction found in Scheme 3 can be carried out under standard conditions known in the art. Suitable procedures are described in Duncia et al. J. Org. Chem., 56, 2395 (1991).

[0082] The triazole forming reaction found in Scheme 4 can be carried out under standard conditions known in the art. Suitable procedures are described in Sung, K et al. Heterocyc. Chem., 29, 1101 (1992), Shukla, J. S. et al. Indian J Chem., 30B—332 (1991), and Wilson, M. W. et al. Molecular Diversity, 3, 95 (1998).

[0083] Other heterocycles can be prepared by methods known to those skilled in the art and by methods found in A. Katritzky, Comprehensive Heterocyclic Chemistry, Volume 1 and Volume 2, Elseveir. Oxazoles can be formed following methods found in Hamada, Y. et al. Tet. Lett., 23, 235-6 (1982). Oxazoles can also be prepared as in Zhang, X. et al. J. Heterocyclic Chem., 34, 1061-4 (1997), and references cited therein. Thiazoles can be prepared following the procedures in Bredenkamp, M. W. et al., Synth. Commun., 2235-2249 (1990) or Aguilar, E., Tet. Lett., 2473-2476 (1994). Oxadiazoles can be prepared as in Borg, S. et al. J. Org. Chem., 60, 3112-3120 (1995).

[0084] The transformation of alcohols 69 to azido 70 and 75 to 76 (Schemes 5 and 5a) can be performed by methods known in the art. A single pot procedure described in Thompson, A. S. et al. J Org Chem., 58, 886 (1993), is the optimal transformation.

[0085] The imidazoles prepared as shown in Scheme 5 and 5a can be carried out following the procedures given in Chadwick, D. J. et al. J. Chem. Soc. Perkin Trans. 1,481 (1984) and Iddon, B., Heterocycles, 23, 117 (1985).

[0086] The tetrazole forming reaction shown in Scheme 6 can be carried out on solid phase resin.

[0087] The solid balls in the schemes and examples below are used to designate a solid phase resin, for example

[0088] The resin may be a Merrifield type resin.

[0089] Intermediates 28 and 42 can be further transformed as shown previously in Schemes 3. Alternatively, intermediates 28 and 42 can be treated with an acid linked to a resin, such as Merrifield or Rink, to give resin bound amides, which can be cleaved to give compounds VI and IX. The carbamate resin linker depicted in Scheme 6 is only one possible candidate (Hernandez, A. et al. J. Org. Chem., 62, 3153 (1997)).

[0090] Compounds in all Schemes except 1b with a terminal —NH—R9 moiety can be transformed by methods known in the art, such as reductive amination or alkylation, to compounds of the form

[0091] The conditions described here for carrying out each step in the general synthetic schemes are conventional and 0.5 capable of wide variation. They are presented for illustrative purpose only and are not intended as a restriction on the scope of invention.

[0092] Final compounds can be easily purified by recrystallization, silica gel chromatography, or reverse phase prep HPLC. In the cases where reverse phase prep HPLC is used, a mixture of solvent A (10% MeOH/90% H2O/0.2% TFA) and solvent B (90% MeOH/10%H2O/0.2% TFA) are used.

[0093] Preferred compounds of formula I of the invention include compounds of the structure wherein Xa is as indicated:

[0094] Preferred are compounds of the present invention of the structure I wherein R1 is arylalkyl, arylalkyloxyalkyl, aryloxyalkyl, cycloheteroalkylalkyl, heteroarylalkyl, for example

[0095] R1a is H or alkyl;

[0096] and (1) Xa is

[0097] where R5 is alkyl, alkenyl or heteroaryloxy-alkyl, each substituted with J1, and J1 is —(CH2)vOC(O)N(T1a)(T1), —(CH2)vCN, or heteroaryl; or

[0098] (2) Xa is where

[0099] is NH, R4 and R4a are H and R3 is J1; or

[0100] (3) Xa is

[0101] where B is —N—; Z is a bond or —S—; R5a is H, or alkyl or arylalkyl each substituted with 1 to 3 J1; R5 is alkyl optionally substituted with J1;

[0102] R6 is H;

[0103] Y is

[0104] where x and y are 0, Xc is a bond, and R7 and R7a are independently alkyl;

[0105] Xb is

[0106] R8j is hydroxy or —OC(O)R8k where R8k is alkyl or aryl;

[0107] R9 and R1 are independently H and substituted alkyl where the substituents may be 1 or 2 hydroxyls;

[0108] J1 is —(CH2)vCN, —(CH2)vN(T1a)SO2T1, —(CH2)vC(O)N(T1a)T1, —(CH2)vN(T1a)C(O)T1, —(CH2)vOC(O)N(T1a)T1, —(CH2)vN(T1a)C(O)N(T1b)T1, or heteroaryl, with v being 0-4;

[0109] T1, T1a and T1b are independently alkyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with —OC(O)R8f, —C(O)NR8R8a, —(CH2)SOH, with s being 0-2, —SO2NR8R8a, —SO2R14, or alkoxy; or T1 and T1a or T1 and T1b can together form —(CH2)wXe(CH2)z— where Xe is C(R8m)(R8l);

[0110] R14 is C1-C6alkyl optionally substituted with —(CH2)vOH, with v being 0-2;

[0111] Preferred compounds of the invention include the following:

[0112] More preferred compounds of the invention include the following:

[0113] The growth hormone releasing compounds of formula I can be administered to animals, including man, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, and to increase milk production in such animals.

[0114] The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula I in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise a growth promoting agent in addition to at least one of the compounds of formula I or another composition which exhibits a different activity, e.g., an antibiotic or other pharmaceutically active material.

[0115] Growth promoting agents include, but are not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890.

[0116] A still further use of the disclosed compounds of formula I of the invention is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 as described in U.S. Pat. No. 4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT920 or growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2. A still further use of the disclosed compounds of formula I of the invention is in combination with parathyroid hormone or a bisphosphonate, such as MK-217 (alendronate), in the treatment of osteoporosis.

[0117] A still further use of the disclosed compounds of formula I is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifene, or a selective androgen receptor modulator, such as disclosed in Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212 (1999), for the treatment of aspects of Metabolic Syndrome, maintenance of muscle strength and function in elderly humans, reversal or prevention of fraility in elderly humans, stimulation and increase in muscle mass and muscle strength, attenuation of protein catabolic response after a major operation or trauma; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; improvement in muscle mobility, and maintenance of skin thickness.

[0118] As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, the administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of growth hormone may be summarized as follows: stimulating growth hormone release in elderly humans; maintenance of muscle strength and function in elderly humans, reversal or prevention of fraility in elderly humans, prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation and increase in muscle mass and muscle strength, stimulation of the immune system, acceleration of wound healing, acceleration of bone fracture repair, treatment of renal failure or insufficiency resulting in growth retardation, treatment of physiological short stature, including growth hormone deficient children, treatment of short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with Prader-Willis syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondrodysplasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic response after a major operation or trauma; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function; treatment of immunosuppressed patients; improvement in muscle mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly; stimulation of osteoblasts, bone remodeling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock; and stimulation of wool growth in sheep.

[0119] In addition, the conditions, diseases, and maladies collectively referenced to as “Syndrome X” or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may be treated employing the compounds of the invention.

[0120] The compounds of the present invention are agents that are growth hormone secretagogues and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc., in need of treatment. These agents can be administered systemically, such as orally or parenterally.

[0121] The compounds of the invention can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation. The above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral intranasal or aerosol forms are quite satisfactory as well.

[0122] The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result. In general, the dosage forms described above may be administered in amounts from about 0.0001 to about 100 mg/kg or body weight or in an amount within the range from about 1 to about 1000 mg per day, preferably, from about 5 to about 500 mg per day in single or divided doses of one to four times daily.

[0123] The following Examples represent preferred embodiments of the invention. All temperatures are in ° C. unless indicated otherwise.

[0124] General Experimental:

[0125] The term HPLCa refers to a Shimadzu high performance liquid chromatograph (HPLC) using a 4 minute gradient of from 0-100% solvent B [MeOH:H2O:0.2% H3PO4] with a 1 min. hold, an ultra violet (UV) detector set at 220 nM, and using a column (4.6×50 mm) packed with YMC C185 micron resin. The term HPLCb refers to a Shimadzu HPLC using a 4 minute gradient of from 0-100% solvent B [MeOH:H2O:0.1% TFA], with a 1 min. hold, an ultra violet (UV) detector set at 220 nM, and using a column (4.6×50 mm) packed with YMC C185 micron resin. A mixture of solvent A (10% MeOH/90% H2O/0.2% TFA) and solvent B (90% MeOH/10%H2O/0.2% TFA) are used for preparative reverse phase HPLC in an automated Shimadzu system. The preparative columns are packed with YMC ODS C185 micron resin.

EXAMPLE 1

[0126]

[0127] To a 0° C. solution of the carboxylic acid

[0128] (5.0 g, 16.9 mmol, Sigma), dianiline

[0129] (2.3 g, 15 mmol, Aldrich), and 1-hydroxy-zazabenzotriazole (HOAt) (2.5 g, 18 mmol) in DMF (48 ml) under nitrogen was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC or EDCI) (3.25 g, 17 mmol) then diisopropylethyl amine (2.95 ml, 17 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight. After 18 hrs, the reaction was diluted with ethyl acetate. The organic layer was extracted with dilute aqueous sodium bicarbonate, water, brine, dried over sodium sulfate, and concentrated in vacuo to give

[0130] as a red colored oil (5.47 g), containing starting dianiline, (referred to here as crude compound). The above crude compound was used in the subsequent reaction without further purification. HPLCb rt=3.19 min.

[0131] A portion of the above crude compound (1.25 g, ≦2.9 mmol) was dissolved in acetic acid (45 mL) and heated at 69° C. for 4.5 h. After stirring at room temperature overnight, the volatiles were removed in vacuo to give crude title compound in the form of a red colored oil, which may be used without further purification. Alternatively, the red colored oil was dissolved in ethyl acetate and the organic layers were extracted three times with 1 N aqueous hydrogen chloride, water, brine, dried over sodium sulfate, and concentrated in vacuo to give pure title compound (0.92 g) as a dark colored oily foam. HPLCa rt 3.99 min.

[0132] Crude Part A compound (≦450 mg, ≦1.04 mmol)) was treated with a solution of hydrogen chloride in dioxane (6 ml, 4N) and after 45 min. a brown solid had fallen from solution. The volatileswere evaporated in vacuo after 2 h. to give a dark colored solid. The residue was triturated three times with hot ethyl acetate to give impure (crude) compound

[0133] as a brown colored solid (338 mg). The crude compound was used without further purification in the next reaction. HPLCa rt=2.93 min.

[0134] To a 0° C. solution of Boc-methylalanine carboxylic acid (256 mg, 1.26 mmol, Aldrich), and the above crude compound (338 mg, ≦0.97 mmol), and HOAt (207 mg, 1.52 mmol) in DMF (5 ml) under nitrogen was added EDAC (245 mg, 1.28 mmol) then diisopropylethyl amine (0.39 ml, 2.25 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight. After 18 h., the reaction was diluted with ethyl acetate. The organic layer was extracted with dilute aqueous sodium bicarbonate, 1N hydrogen chloride, water, brine, dried over sodium sulfate, and concentrated in vacuo to give a dark colored oil (564 mg). The crude residue was combined with material from another reaction (0.10 mmol) and was purified by flash chromatography (SiO2, 40 g), eluting with 3.5% methanol/dichloromethane to give title compound as an orange colored oil (305 mg). HPLCb rt 4.20 min; LC/MS (electrospray, +ions) m/z 498 (M+H).

[0135] A solution of Part B compound (100 mg, 0.2 mmol) in methanol (2 ml) containing 10% palladium on carbon (15 mg) was purged with hydrogen and stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction mixture was filtered through a Nylon frit, washing well with methanol, and the solvents evaporated to give amine compound

[0136] as an orange colored foam (82 mg, 88% crude recovery), 80% pure by HPLCa rt=3.0 min. The amine material was used without further purification in the next reaction. LC/MS (electrospray, +ions) m/z 468 (M+H).

[0137] To a solution of crude amine (82 mg, 0.18 mmol) and triethylamine (35 μl, 0.25 mmol) in dichloromethane (1.8 ml) under nitrogen was added methanesulfonyl chloride (18 μl, 0.23 mmol). After 2 h., the reaction was diluted with ethyl acetate and the organic layer was extracted with water, brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 10 g), eluting with 5.25% methanol/dichloromethane to give title compound as an orange colored solid (30.7 mg). HPLCa rt=3.37 min.

[0138] To neat Part C compound (31 mg, 56.8 μmol) was added hydrogen chloride (0.8 ml, 4N in dioxane) and the mixture stirred for 2.5 h. The volatiles were removed in vacuo and co-evaporated twice with dichloromethane to give a tan colored solid. The crude residue was combined with material from another reaction (39.8 μmol) and neutralized by dissolving in 90 methanol/dichloromethane containing ammonium hydroxide. The resulting suspension was purified by flash chromatography (SiO2, 5 g), eluting with 9% methanol/dichloromethane containing 0.9% ammonium hydroxide to give a glassy solid (35 mg). The residue was dissolved in methanol (2.5 ml) and treated with trifluoroacetic acid (4.5 μl). After 15 min, the volatiles were removed in vacuo to give the title compound (43 mg) as a tan colored solid. HPLCb rt 2.43 min. MS (electrospray, +ions) m/z 446 (M+H).

EXAMPLE 2

[0139]

[0140] N— Methyl morpholine (1.08 mL, 9.83 mmol) and isobutyl chloroformate (1.27 mL, 9.80 mmol) were added to a solution of N-Boc-O-benzyl serine (2.91 g, 9.84 mmol, Sigma) in THF (14.0 mL), cooled at −18° C. After stirring the mixture for 0.5 h. at −18° C., a −14° C. solution of 3-aminopropionitrile (0.73 mL, 9.89 mmol) and N-methyl morpholine (1.08 mL, 9.83 mmol) in THF (6.0 mL) was added and the resulting mixture was allowed to warm up to −6° C. over a period of 5.25 h. The mixture was filtered and the solution was evaporated near to dryness. The residue was taken up in EtOAc (70 mL) and washed with 5% NaHCO3 (2×60 mL), water (60 mL) and brine (60 mL). The organic solution was dried (Na2SO4), evaporated and chromatographed(SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to afford title compound (3.33 g, 97% yield): LC/MS (electrospray, +ions) m/z 348 (M+H).

[0141] Diethylazodicarboxylate (1.51 mL, 9.59 mmol) and azidotrimethylsilane (1.27 mL, 9.57 mmol) were added to a solution of Part A compound (3.33 g, 9.60 mmol), triphenylphosphine (2.52 g, 9.61 mmol) and diisopropylethyl amine (0.42 mL, 2.41 mmol) in THF (30 mL), previously cooled at 0° C. The mixture was stirred at room temperature (rt) overnight and then cooled at 0° C. Another equivalent each of triphenylphosphine (2.52 g), diethylazodicarboxy-late (1.51 mL) and azidotrimethylsilane (1.27 mL) was added and stirring was continued for an additional 28 h at rt. The reaction mixture was cooled at 0° C. and mixed with an aqueous solution of ammonium cerium (IV) nitrate (2.63 g/100 mL). The aqueous mixture was extracted with CH2Cl2 (3×150 mL) and the combined organic phase was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to give the tetrazole (3.5 g, contaminated with 1,2-dicarbethoxyhydrazine) and Part A compound (1.47 g contaminated with triphenylphosphine oxide). The contaminated tetrazole was dissolved in CHCl3 and ether was added to precipitate title compound (2.08 g) as a colorless solid: MS (electrospray, +ions) m/z 373 (M+H).

[0142] To a solution of Part B compound (354 mg, 0.95 mmol) in CH2Cl2 (2.0 mL) was added a 4M HCl/dioxane solution (3.0 mL) and the combined solution was allowed to stand for 1.25 h. The solvents were removed at reduce pressure and the residue was taken up in i-PrOH (1.5 mL). Brine (25.0 mL) was added and the pH of the aqueous solution was adjusted to 10 by addition of 1M K2CO3. The aqueous solution was extracted with CH2Cl2 (3×40 mL) and the combined organic layer was dried (Na2SO4) and evaporated to provide title amine compound (258 mg) as a colorless oil. This material was used without further purification in the subsequent reaction: 1H NMR δ (CDCl3, ppm) 7.31 (m, 5H), 4.80 (m, 2H), 4.54 (m, 3H), 3.88 (m, 2H), 2.99 (m, 2H), 1.82 (broad s, 2H).

[0143] N-Boc-methyl alanine

[0144] (285 mg, 1.40 mmol, Sigma), EDAC (272 mg, 1.42 mmol), HOAt (190 mg, 1.40 mmol), 1,2-dichloroethane (1,2-DCE) (1.6 mL) and DMF (250 μL) were mixed at 0° C. and stirred for 15 min. The resulting cloudy solution was transferred, via syringe, to a 0° C. solution of the crude Part C amine compound (258 mg, 0.95 mmol) in 1,2-DCE (1.4 mL) and the mixture was stirred for 20 h at rt. The reaction mixture was diluted with EtOAc (75 mL) and washed-with saturated NaHCO3 (2×40 mL), water (40 mL) and brine (40 mL). The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to provide title compound (338.5 mg) as a colorless oil: 1H NMR δ (CDCl3, ppm) 7.36 (m, 6H), 5.55 (m, 1H), 5.13 (broad s, 1H), 4.72 (t, J=6.6 Hz, 2H), 4.51 (2d, J=12 Hz, 2H), 4.02 (dd, J=9.2, 5.8 Hz, 1H), 3.86 (t, J=8.3 Hz, 1H), 2.98 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.32 (s, 9H).

[0145] Part D compound (181 mg, 0.40 mmol) was treated with 15% TFA (4.0 mL) for 2.2 h and evaporated in vacuo and the residual TFA was coevaporated with CH2Cl2 (5×6 mL). The oily crude residue was dissolved in CH2Cl2/MeOH (several drops) and ether was added to precipitate the title compound (157 mg) as a white solid: LC/MS (electrospray, +ions) m/z 358 (M+H).

EXAMPLE 3

[0146]

[0147] Diethylazodicarboxylate (1.51 mL, 9.59 mmol) and azidotrimethylsilane (1.27 mL, 9.57 mmol) were added to a solution of Example 2 Part A compound

[0148] (3.33 g, 9.60 mmol), triphenylphosphine (2.52 g, 9.61 mmol) and diisopropylethyl amine (0.42 mL, 2.41 mmol) in THF (30 mL), previously cooled at 0° C. The mixture was stirred at rt. overnight and then cooled at 0° C. Another equivalent each of triphenylphosphine (2.52 g), diethylazodicarboxylate (1.51 mL) and azidotrimethylsilane (1.27 mL) was added and stirring was continued for an additional 28 h at rt. The reaction mixture was cooled at 0° C. and mixed with an aqueous solution of ammonium cerium (IV) nitrate (2.63 g/100 mL). The aqueous mixture was extracted with CH2Cl2 (3×150 mL) and the combined organic phase was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 Hex/EtOAc) to give crude Example 2 Part B compound (3.5 g). The contaminated residue containing Example 2 Part B compound was dissolved in CHCl3, Example 2 Part B compound (2.08 g) precipitated by addition of ether, and the filtrate concentrated. The resulting residue containing more Example 2 Part B compound was dissolved in THF (12 mL) and 1M NaOH and additional volumes of THF were added until disappearence of Example 2 Part B compound, monitoring by TLC (1/1 hexanes/EtOAc). The final reaction mixture was diluted with brine (70 mL), and washed with ether (60 mL) and CHCl3 (2×50 mL). The aqueous layer pH was adjusted to 3, by addition of 1M H3PO4, and the solution was extracted with EtOAc (3×60 mL). The combined organic phase was wa-shed with phosphate buffer (2×40 mL, pH 3) and brine (40 mL), dried (Na2SO4) and evaporated to afford the the title compound (571 mg): LC/MS (electrospray, +ions) m/z 320 (M+H).

[0149] Benzyl bromide (54 μL, 0.45 mmol) was added to a stirred suspension of the Part A compound (115 mg, 0.36 mmol) and cesium carbonate (258 mg, 0.79 mmol) in CH3CN (1.0 mL), and the mixture was stirred for 18 h. at rt. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with water (8 mL). The aqueous phase was back extracted with CH2Cl2 twice and the combined organic phase was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 3/1 hexanes/EtOAc) to give the title compound as a mixture of N-1/N-2 tetrazole isomers (122 mg): LC/MS (electrospray, +ions) m/z 410 (M+H).

[0150] The isomeric mixture of Part B (122.2 mg, 0.30 mmol) was treated with 15% TFA (3.0 mL) for 2.0 h and evaporated. i-PrOH (2 mL) and brine (15.0 mL) were added to the residue and the pH of the aqueous solution was adjusted to 10 by addition of 1M K2CO3. The aqueous solution was extracted with CH2Cl2 (3×25 mL) and the combined organic layer was dried (Na2SO4) and evaporated to provide title amine (94 mg). This amine material was used in the next reaction without further purification. LC/MS (electrospray, +ions) m/z 310 (M+H).

[0151] N-Boc-methyl alanine (79 mg, 0.39 mmol), EDAC (75 mg, 0.39 mmol), HOAT (53 mg, 0.40 mmol), 1,2-DCE (0.7 mL) and DMF (60 μL) were mixed at 0° C. and stirred for 15 min. The resulting cloudy solution was transferred, via syringe, to a 0° C. solution of the crude amine (94 mg, 0.30 mmol) in 1,2-DCE (0.6 mL) and the mixture was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO3 (2×20 mL), water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 7/3 CHCl3/ether) to provide the title compound (44.6 mg). LC/MS (electrospray, +ions) m/z 495 (M+H).

[0152] Part C compound (44.6 mg, 0.09 mmol) was treated with −2M HCl/CH2Cl2, MeOH, MeOAc (3.0 mL, prepared by addition of AcCl to 8/1 CH2Cl2/MeOH) for 2.3 h. and evaporated. The residue was further dried, under high vacuum, to afford the title compound as a colorless solid (41.1 mg): LC/MS (electrospray, +ions) m/z 395 (M+H).

EXAMPLE 4

[0153]

[0154] Benzyl bromide (54 μL, 0.45 mmol) was added to a stired uspesio of the Example 3 Part A compound,

[0155] (115 mg, 0.36 mmol) and cesium carbonate (258 mg, 0.79 mmol) in CH3CN (1.0 mL), and the mixture was stirred for 18 h at rt. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with water (8 mL). The aqueous phase was back extracted with CH2Cl2 twice and the combined organic phase was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 3/1 hexanes/EtOAc) to give the title compound as a mixture of N-1/N-2 tetrazole isomers (122 mg): LC/MS (electrospray, +ions) m/z 410 (M+H).

[0156] The isomeric mixture of, Part A (122.2 mg, 0.30 mmol) was treated with 15% TFA (3.0 mL) for 2.0 h and evaporated. i-PrOH (2 mL) and brine (15.0 mL) were added to the residue and the pH of the aqueous solution was adjusted to 10 by addition of 1M K2CO3. The aqueous solution was extracted with CH2Cl2 (3×25 mL) and the combined organic layer was dried (Na2SO4) and evaporated to provide

[0157] amine (94 mg). The material was used in the next reaction without further purification. LC/MS (electrospray, +ions) m/z 310 (M+H).

[0158] N-Boc-methyl alanine (79 mg, 0.39 mmol), EDAC (75 mg,0.39 mmol), HOAT (53 mg, 0.40 mmol), 1,2-DCE (0.7 mL) and DMF (60 μL) were mixed at 0° C. and stirred for 15 min. The resulting cloudy solution was transferred, via, syringe, to a 0° C. solution of the crude amine (94 mg, 0.30 mmol) in 1,2-DCE (0.6 mL) and the mixture was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO3 (2×20 mL), water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 7/3 CHCl3/ether) to provide the title compound (81.0 mg) as a white solid. LC/MS (electrospray, +ions) m/z 495 (M+H).

[0159] Part B compound (81.0 mg, 0.09 mmol) was treated with −2M HCl/CH2Cl2, MeOH, MeOAc (3.0 mL, prepared by addition of AcCl to 8/1 CH2Cl2/MeOH) for 2.3 h. and evaporated. The residue was further dried, under high vacuum, to afford the title compound (72.4 mg) as a pale yellow solid: LC/MS (electrospray, +ions) m/z 395 (M+H).

EXAMPLE 5

[0160]

[0161] 1M NaOH (0.67 mL) and i-PrOH (0.50 mL) were added to a solution of Example 2 Part D compound

[0162] (308 mg, 0.67 mmol) in 6/1 THF/Dioxane (3.5 mL), and the mixture was stirred at rt. for 13 h. The reaction mixture was diluted with brine (30 mL) and the pH of the aqueous solution was adjusted to 3 by addition of 1M H3PO4. The aqueous solution was extracted with CH2Cl2 (3×50 mL) and the combined organic phase was dried (Na2SO4) and evaporated to yield the title compound (234 mg): LC/MS (electrospray, +ions) m/z 405 (M+H).

[0163] Diisopropylethyl amine (10 μL, 57 mmol) and diethylazodicarboxylate (53 μL, 0.34 mmol) were added to a solution of (+)-methyl-L-mandelate (56 mg, 0.34 mmol, Aldrich), Part A compound (118.5 mg, 0.29 mmol) and triphenylphosphine (87 mg, 0.33 mmol) in CH2Cl2 (0.9 mL), previously cooled at 0° C. After stirring the mixture at rt for 34 h, additional amounts of the reagents, triphenylphosphine (99 mg), of (+)-methyl-L-mandelate (56 mg) and diethylazodicarboxylate (53 μL), were added. The mixture was stirred at rt for an additional 24 h and concentrated in vacuo. The resulting residue was chromatographed (SiO2 230-400 mesh, 4/1 CH2Cl2/Ether) to afford a mixture containing the title compound (57.5 mg) contaminated with 1,2-dicarbethoxyhydrazide. The mixture was purified by chromatography (SiO2 230-400 mesh, 95/5 CHCl3/MeOH) to provide the title compound (49.2 mg, 1/1 mixture of diastereomers) as a colorless oil: LC/MS (electrospray, +ions) m/z 553 (M+H).

[0164] Part B compound (49.2 mg, 89 μmol) was treated with 2M HCl/CH2Cl2, MeOH, MeOAc (3.0 mL, prepared by addition of AcCl to 8/1 CH2Cl2/MeOH) for 2.3 h and evaporated. The residue was further dried, under high vacuum, to afford the title compound (42.7 mg, 1/1 mixture of diastereomers) as a white solid: LC/MS (electrospray, +ions) m/z 453 (M+H).

EXAMPLE 6

[0165]

[0166] Diisopropylethyl amine (10 μL, 57 μmol) and diethylazodicarboxylate (53 μL, 0.34 mmol) were added to a solution of (+)-methyl-L-mandelate (56 mg, 0.34 mmol, Aldrich), compound Example 5 Part A

[0167] (118.5 mg, 0.29 mmol) and triphenylphosphine (87 mg, 0.33 mmol) in CH2Cl2 (0.9 mL), previously cooled at 0° C. After stirring the mixture at rt for 34 h, additional amounts of the reagents, triphenylphosphine (99 mg), of (+)-methyl-L-mandelate (56 mg) and diethylazodicarboxylate.(53 μL), were added. The mixture was stirred at rt for an additional 24 h and concentrated in vacuo. The resulting residue was chromatographed (SiO2 230-400 mesh, 4/1 CH2Cl2/Eter) to afford the title compound (70.6 mg, 1/1 mixture of diastereomers) as a colorless oil: LC/MS (electrospray, +ions) m/z 553 (M+H).

[0168] Part A compound (70.6 mg, 0.13 mmol) was treated with −2M HCl/CH2Cl2, MeOH, MeOAc (3.0 mL, prepared by addition of AcCl to 8/1 CH2Cl2/MeOH); for 2.5 h and evaporated. The residue was further dried, under high vacuum, to afford the title compound (61.9 mg, 1/1 mixture of diastereomers) as a white solid: LC/MS (electrospray, +ions) m/z 453 (M+H).

EXAMPLE 7

[0169]

[0170] To a precooled 160 ml of methanol at 0° C. was added acetyl chloride (log, 128 mmol) slowly. After stirring at 0° C. for 15 min, O-benzyl-D-serine

[0171] (5 g, 25.6 mmol) was added and the solution was heated to reflux for 2 days. The solvent was removed and the residue was dried under high vacuum to give title compound as a white solid (6.29 g, 100%). HPLCa rt=1.90 min.

100

[0172] To a solution of Part A compound (3.65 g, 14.9 mmol) in 100 ml of dry methylene chloride was added di-t-butylcarboxymate (3.89 g, 17.8 mmol) followed by the addition of triethyl amine (2.25 g, 22.3 mmol). The reaction was stirred overnight and quenched with 50 ml of water and extracted with methylene chloride (3×100 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude title product as an oil (5.01 g). HPLCb rt=3.24 min.; LC/MS (electrospray, +ions) m/z 310 (M+H).

101

[0173] To a solution of crude Part B compound (0.98 g, 3.17 mmol) in 10 ml of dry methyl alcohol was added hydrazine (0.447 g, 13.9 mmol). The reaction was stirred at rt for 3 h and heated to reflux for 5 h. The solvent was removed and the residue was dried under high vacuum to give title compound as an oil (0.96 g, 98%). HPLCb rt 3.21 min.; LC/MS (electrospray, +ions) m/z 310 (M+H).

102

[0174] To a solution of crude Part C compound (0.53 g, 1.72 mmol) in 10 ml of dry ethyl alcohol was added benzyl isothiocyanate (307 mg, 2.06 mmol). The reaction was heated to reflux for 4h. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was then treated with 1N NaOH and the resulting mixture was heated to 109° C. for 4 h. After cooling to rt, the resulting white precipitate was isolated by filtration. The solid was rinsed with water and dried under high vacuum to give title compound as a white solid (0.36 g, 62%). HPLCb rt=3.29 min.; LC/MS (electrospray, +ions) m/z 341 (M+H).

103

[0175] To a solution of Part D compound (153 mg, 0.45 mmol) in 4 ml of DMF was added Boc-methylalanine carboxylic acid (96 mg, 0.47 mmol; Sigma), HOAt (64 mg, 0.47 mmol), EDAC (91 mg, 0.47 mmol), and diisopropylethyl amine (61 mg, 0.47 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 20 h, and quenched with water (10 ml). The mixture was extracted with ethyl acetate (3×20 ml), the organic layer dried over sodium sulfate, and concentrated in vacuo to give a crude yellow oil. The crude residue was purified by flash chromatography, eluting with hexane/ethyl acetate (2:1) to give title compound as an oil (153 mg, 65%). HPLCb rt=4.13 min.; LC/MS (electrospray, +ions) m/z 526 (M+H).

104

[0176] Part E compound (133 mg, 0.25 mmol) was treated with 2 ml of TFA/CH2Cl2 (1:3) at room temperature for 1 h, the solvent removed and the residue was purified by preparative HPLC (Shimadzu, 30-100% B, 30 min. gradient, 5 min. hold, 220 nM) to give the title compound (80 mg, 59%). HPLCb rt=3.25 min.; LC/MS (electrospray, +ions) m/z 425 (M+H).

EXAMPLE 8

[0177]

105

[0178] Example 7 Part E, compound (133 mg, 0.25 mmol) was treated with 2 ml of TFA/CH2Cl2 (1:3) at room temperature for 1 h, the solvent removed and the residue was purified by preparative HPLC (Shimadzu, 30-100% B, 30 min. gradient, 5 min. hold, 220 nM) to give the title compound (42 mg, 28%). HPLCb rt=3.80 min.; LC/MS (electrospray, +ions) m/z 481 (M+H).

EXAMPLE 9

[0179]

106

[0180] A solution of Example 7 Part E, compound (78 mg, 0.15 mmol) in 7.5 ml of THF was added to hydrogen peroxide (0.33 ml, 30% w/w). After stirring at rt for 2 days, the solvent was removed. The residue was then treated with 3 ml of TFA/CH2Cl2 (1:3) at room temperature for 1 h, the solvent removed, and the residue was purified by preparative HPLC (Shimadzu, 20-100′-B, 30 min. gradient, 5 min. hold, 220 nM) to give the title compound (59 mg, 79w). HPLCb rt=2.99 min.; LC/MS (electrospray, +ions) m/z 394 (M+H).

Example 10

[0181]

107

[0182] To a suspension of imidazole (19.08 g, 0.28 mol) in 300 ml of dry benzene was added dimethylchlorosulphonamide (26 ml, 0.24 mol) and triethylamine (36 ml, 0.26 mol). The reaction was stirred at rt under nitrogen for 24 h, the mixture filtered, and the filtrate was concentrated. The resulting crude product was distilled under reduced pressure (0.03 mmHg) to yield title compound (36.4 g, 86w). HPLCb rt=0.64 min.; LC/MS (electrospray, +ions) m/z 176 (M+H).

108

[0183] To a suspension of Part A compound (1.88 g, 10.75 mmol) in 100 ml of dry THF at −78° C. was added n-BuLi (4.60 ml, 2.5 M in hexane, 11.51 mmol) dropwise under nitrogen. The reaction was stirred at −78° C. for 1 h and 4-phenyl-butyraldehyde

109

[0184] in 20 ml of dry ether was added in one portion. The mixture was stirred at −78° C. for 5 min. and then allowed to go to rt. After 3 hr at rt, the reaction was quenched with sat. NH4Cl solution. The mixture was extracted with ethyl acetate (3×20 ml), the organic layer dried over sodium sulfate, and concentrated in vacuo to give a crude yellow oil. The crude residue was purified by flash chromatography, eluting with hexane/ethyl acetate (1:3) to give title compound as an oil (3.24 g, 93w). HPLCb rt=3.44 min.; LC/MS (electrospray, +ions) m/z 324 (M+H).

110

[0185] To a mixture of Part B compound (3.2 g, 9.91 mmol) and diphenyl phosphorazide (3.27 g, 11.89 mmol) in 17 ml of dry toluene at 0° C. under nitrogen was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.81 g, 11.89 mmol). The reaction was stirred for 2 h at 0° C. and then 20 h at room temperature. The resulting two phase mixture was quenched with water and extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography using 3:1 hexane/ethyl acetate to afford title compound as an oil (1.64 g, 48%). HPLCb rt=4.15 min.; LC/MS (electrospray, +ions) m/z 349 (M+H).

111

[0186] A mixture of Part C compound (232 mg, 0.67 mmol) and 50 Pd/C (50 mg) in 3 ml of EtOH was hydrogenated under 1 atmosphere of hydrogen. After 9 h, the solid was then filtered off and the filtrate was concentrated in vacuo to afford Part D compound as an oil (200 mg, 93%). HPLCb rt=3.10 min.: LC/MS (electrospray, +ions) m/z 323 (M+H).

112

[0187] To a solution of Part D compound (172 mg, 0.53 mmol) and Boc-methylalanine carboxylic acid (114 mg, 0.56 mmol, Sigma) in 3 ml of acetonitrile was added benzotriazol-1-yloxy-bris(dimethylamine)phoshonium hexafluorophosphate (BOP) (248 mg, 0.56 mmol). After stirring for 20 min at rt, triethylamine (56.6 mg, 0.56 mmol) was added and the reaction was stirred for 5 h at room temperature. The solvent was removed via evaporation and the residue was purified by flash chromatography, eluting with hexane/ethyl acetate (1:1) to give Part E compound as an oil (238 mg, 88%). HPLCb rt=4.13 min.; LC/MS (electrospray, +ions) m/z 508 (M+H).

113

[0188] Part E compound (167 mg, 0.33 mmol) was treated with 2 ml of TFA/CH2Cl2 (1:3) at room temperature for 1 h, the solvent was removed and the residue was purified by preparative HPLC (Shimadzu, 30-100% B, 30 min. gradient, 5 min. hold, 220 nM) to give the title compound (137 mg). HPLCb rt=3.33 min.; LC/MS (electrospray, +ions) m/z 408 (M+H).

[0189] The following compounds were prepared employing the procedures described above and the working Examples.

EXAMPLES 11 TO 45

[0190]

1

Example

M + H positive

No.
Structure
ions

11

114

387

12

115

319

13

116

421

14

117

421

15

118

440

16

119

440

17

120

488

18

121

488

19

122

488

20

123

488

21

124

488

22

125

488

23

126

526

24

127

526

27

128

469

28

129

423

29

130

416

30

131

472

31

132

463

32

133

519

33

134

449

34

135

505

35

136

510

36

137

401

37

138

514

38

139

514

39

140

481

40

141

478

41

142

512

42

143

461

43

144

537

44

145

494

45

146

570

EXAMPLE 46

[0191]

147

[0192] N-Methyl morpholine (2.5 mL) and isobutyl chloroformate (2.88 mL, 22.8 mmol) were added to a solution of N-Boc-O-benzyl-D-serine (6.73 g, 22.8 mmol, Sigma) in THF (35 mL), cooled at −18° C. After stirring the mixture for 0.5 h. at −18° C., a THF (15 mL) and DMF (25 mL) solution of methyl 4-aminobutyrate hydrochloride

148

[0193] (3.53 g, 23 mmol) and N-methyl morpholine (5 mL) was added, keeping the reaction mixture below −10° C. The resulting mixture was stirred for 5 h. at between −10° to −15° C. The mixture was filtered, washing with ethyl acetate, and the solution was evaporated under reduced pressure. The residue was taken up in EtOAc (160 mL) and washed with 5% NaHCO3 (2×40 mL), water (50 mL) and brine (50 mL). The organic solution was dried (MgSO4), evaporated and chromatographed(SiO2 230-400 mesh, 4% methanol/dichloromethane) to afford title compound (8.5 g) as a colorless syrup: LC/MS (electrospray, +ions) m/z 395 (M+H).

149

[0194] Diethylazodicarboxylate (13.4 mL, 21.6 mmol) and azidotrimethylsilane (2.87 mL, 21.6 mmol) were added to a 0° C. solution of Part A compound (8.5 g, 21.6 mmol), triphenylphosphine (5.7 g, 21.6 mmol) and diisopropylethyl amine (1 mL, 5.4 mmol) in THF (70 mL). The mixture was stirred at rt. for 24 h., and then cooled at 0° C. Another equivalent each of triphenylphosphine (5.7 g), diethylazodicarboxylate (13.4 mL) and azidotrimethylsilane (2.87 mL) was added and stirring was continued for an additional 48 h at rt. The reaction mixture was then concentrated in vacuo to one third the original volume, diluted with ethyl acetate (200 mL), then cooled to 0° C. An aqueous solution of ammonium cerium (IV) nitrate (65 g/250 mL) was added and the mixture stirred for 15 min. The organic layer was separated, the aqueous mixture was extracted with ethyl acetate (150mL), and the combined organic phase was dried (Na2SO4). After concentration in vacuo, the residue was chromatographed (SiO2 230-400 mesh, 40% ethyl acetate/hexanes) to give solid title compound (5.5 g, contaminated with a less polar impurity) and recovered Part A compound (5.5 g, contaminated with triphenylphosphine oxide). The contaminated title compound could be used as is in the subsequent reaction. Alternatively, a portion of the impure title compound (4.2 g) was chromatographed (SiO2 230-400 mesh, 25% ethyl ether/dichloromethane) to give solid title compound (3.5 g) as a colorless solid: LC/MS (electrospray, +ions) m/z 420 (M+H).

150

[0195] To a solution of Part B compound (3.5 g, 8.48 mmol) in dichloromethane (20 mL) was added a 4M HCl/dioxane solution (5 mL). After 3 h., more 4M HCl/dioxane solution (4 mL) was added and after a total of 5 h., the volatiles were removed in vacuo to give a syrup. The residue was dissolved in dichloromethane (200 mL), washed with 1N NaOH (75 mL), brine (2×80 mL), dried (sodium sulfate), and concentrated to give title compound (2.46 g) as a syrup. This material was used without further purification in the subsequent reaction: LC/MS (electrospray, +ions) m/z 320 (M+H).

151

[0196] A DMF (30 mL) solution of N-Boc-methyl alanine

152

[0197] (1.88 g, 9.2 mmol, Sigma), Part C compound (2.46 g, 7.7 mmol), HOAT (1.17 g, 8.5 mmol), and EDAC (1.62 g, 8.5 mmol) was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (200 mL). The organic layer was washed with water (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed (SiO2 230-400 mesh) eluting with 40% ether/dichloromethane to give title compound (3.14 g) as a colorless oil: LC/MS (electrospray, +ions) m/z 505 (M+H).

153

[0198] To a solution of Part D compound (1.4 g, 2.78 mmol) in THF (8 mL) was added an aqueous solution of lithium hydroxide (143 mg, 6 mmol, in 2 mL water) and the mixture was allowed to stir for 20 h. at room temperature. The reaction mixture was brought to pH 1-2 with 1N aq. HCl (5 mL) and the aqueous layer was extracted with ethyl acetate (200 mL). The organics were washed with water (60 mL), brine (100 mL), dried (magnesium sulfate), and concentrated in vacuo to give title compound (1.32 g) as a colorless solid. This material was used without further purification in the subsequent reaction: LC/MS (electrospray, +ions) m/z 491 (M+H).

154

[0199] To tryptamine

155

[0200] (24 mg, 0.15 mmol) was added a dichloromethane (1 mL) and DMF (0.5 mL) solution of Part E compound (50 mg, 0.1 mmol), EDAC (28.8 mg, 0.15 mmol), and dimethylamino pyridine (18.3 mg, 0.15 mmol, DMAP). The reaction mixture was shaken for 20 h., then diluted with methanol (5 mL). The resulting solution was passed through a SCX resin column (1 g), eluting with methanol (15 mL), and the eluent was concentrated in vacuo to give the crude intermediate amide:

156

[0201] The resulting residue was dissolved in a dichloromethane/methanol HCl solution (1.5 mL, prepared from dissolving acetyl chloride (10.2 mL) in 3/2 dichloromethane/methanol (40 mL), 3.5 M) and stirred at rt. for 4 h. before removing the volatiles under reduced pressure. The resulting residue was purified by Prep HPLC to give the title compound as a dark colored foam (44 mg): LC/MS (electrospray, +ions) m/z 533 (M+H).

[0202] In a manner analogous to that of preparing the Example 46 compound, compounds of Examples 47 to 91 listed in the table below were prepared from Example 46 Part E compound (0.1 mmol) and the respective amine (0.15 to 0.2 mmol). Examples 47 to 50 were treated with trifluoroacetic acid (0.4 mL) and thioanisole (0.05 mL) in dichloromethane (1 mL) instead of HCl to form the final products. All but Example 70 were purified by preparative HPLC, eluting with a gradient system of methanol and water with 0.2% trifluoroacetic acid. All compounds were isolated as trifluoroacetic acid salts.

[0203] In the tables of compounds which follow, the X1 designation refers to the point of attachment of the particular R moiety shown to the rest of the molecule.

EXAMPLES 47 TO 91

[0204]

157

Example

M + H positive

No.
X1—R
ions

47

158

508

48

159

472

49

160

480

50

161

494

51

162

446

52

163

460

53

164

504

54

165

490

55

166

476

56

167

462

57

168

448

58

169

481

59

170

495

60

171

481

61

172

506

62

173

466

63

174

510

64

175

545

65

176

558

66

177

510

67

178

497

68

179

486

69

180

573

70

181

447

71

182

462

72

183

443

73

184

476

74

185

434

75

186

476

76

187

478

77

188

494

78

189

448

79

190

462

80

191

490

81

192

475

82

193

502

83

194

515

84

195

503

85

196

464

86

197

478

87

198

496

88

199

510

89

200

526

90

201

508

91

202

462

EXAMPLE 92

[0205]

203

[0206] Methyl triflate (1.30 mL, 11.5 mmol) was added to a suspension of resin bound (tert-alkoxycarbonyl)imidazole (8.68 g, loading 0.72 mmol/g)

204

[0207] [Note: this procedure was adapted from Hernandez and Hodges. J. Org. Chem. 1997, 62, 3153] in dry 1,2-DCE (60.0 mL), cooled at 5C. The mixture was stirred for 20 min at this temperature and for 15 min while being warmed to rt. After addition of DMAP (2.96 g, 24.2 mmol), stirring was continued for an additional 10 min.

[0208] N, O-Bis(trimethylsilyl)acetamide (4.48 mL, 18.1 mmol) was added to a suspension of o-benzyl-D-serine (3.54 g, 18.1 mmol) in DMF (21 mL) and the mixture was stirred for 30 min at rt. The resulting solution was transferred via syringe to the stirred resin suspension. The mixture was shaken for 8 h at rt and filtered. The resin bound O-benzyl-D-serine was washed with DMF (3 times), 5% AcOH/DMF, MeOH (3 times, 100 mL total), THF (3 times), and CH2Cl2 (3 times) and dried: 9.58 g; IR 1717 (broad) cm−1; Anal. Found C, 80.78; H, 8.00; N, 0.91. Loading on N content: 0.65 mmol/g.

[0209] A portion of the resin (27 mg) was treated with 10% TPA/CH2Cl2 (1.0 mL) for 4.5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (2 times) and the filtrates were evaporated and dried (vacuum, overnight) to give back O-benzyl-D-serine, as its TFA salt (4.4 mg): LC-MS 100% Area; LC/MS (electrospray, +ions) m/z 196 (M+H). Loading, on cleaved amount, of the resin bound O-benzyl-D-serine: 0.53 mmol/g.

205

[0210] To the Part A resin bound O-benzyl-D-serine (1.75 g, 1.14 mmol) was added a solution of B-alanine methyl ester hydrochloride (315 mg, 2.27 mmol), diisopropylethylamine (0.39 mL, 2.24 mmol) and HOAT (308 mg, 2.26 mmol) in DMF (3.0 mL) and then, a solution of EDAC (433 mg, 2.26 mmol) in DMF (5.5 mL). The mixture was rocked for 24 h at rt and filtered. The polymer was washed 3 times each with DMF, THF and CH2Cl2 to give resin bound O-benzyl-D-serine-2-methoxy-carbonylethyl amide.

[0211] To the resin bound amide was added a solution of triphenylphosphine (955 mg, 3.64 mmol) in 1,2-DCE (3.0 mL) and a solution, previously cooled at 0° C., of trimethylslylazide (0.48 mL, 3.62 mmol) and diethyl azodicarboxylate (DEAD) (0.57 mL, 3.62 mmol) in 1,2-DCE (3.0 mL). The mixture was rocked for 24 h at rt and filtered. The resin was washed with DMF (3 times) and CH2Cl2 (6 times), and resubmitted to the above Mitsunobu reaction conditions twice. The polymer was finally washed with DMF (3 times), THF (3 times) and CH2Cl2 (3 times) to provide the resin bound 1-(2-methoxycarbonylethyl)-tetrazole.

206

[0212] To the Part B resin bound methyl ester resin (307 mg, <0.20 mmol) in n-butyl amine (2.0 mL) was added a solution of tetra-n-butyl ammonium cyanide (40 mg, 0.15 mmol) in MeOH (0.3 mL) and the mixture was heated at 50° C. for 3.6 h. After filtratiion, the polymer was washed 3 times each with DMF, MeOH, THF and CH2Cl2 to give the resin bound amide.

[0213] The resin was treated with −3M HCl/CH2Cl2, MeOH, methyl acetate (4.0 mL, prepared by addition of acetyl chloride (AcCl) to a 3/2 CH2Cl2/MeOH solution) for 4.5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (twice), and the filtrates were evaporated to afford the amine HCl salt intermediate. This material was taken up in isopropanol (1.5 mL) and saturated NaCl (20 mL). The pH of the aqueous phase was adjusted to 10 by addition of 1M K2CO3 and the solution was extracted with CH2Cl2 (3×30 mL). The combined organic phase was dried (Na2SO4) and concentrated to give the free amine contaminated with triphenylphosphine oxide (30.7 mg).

[0214] N-Boc isobutyric acid (36 mg, 0.18 mmol), EDAC (34 mg, 0.18 mmol), HOAT (25 mg, 0.18 mmol), 1,2-DCE (0.3 mL) and DMF (30 uL) were mixed at 0° C. for 15 min. The resulting solution was added to a 0° C. solution of the crude amine (30.7 mg, <0.09 mmol) in 1,2-DCE (0.2 mL). The mixture was stirred for 22 h at rt and diluted with EtOAc (25 mL). The solution was washed with saturated NaHCO3 (2×20 mL), water (20 mL) and saturated NaCl (20 mL), dried and evaporated to give crude Part C compound (44.4 mg). Preparative HPLC (solvent B: start 30t, final 90%; gradient time: 15 min; flow rate 20 mL/min; wavelenght 220 nm; column YMC S5 ODS 20×100 mm) gave the Part C compound (19.0 mg): LC/MS (electrospray, +ions) m/z 532 (M+H).

207

[0215] The Part C compound (19.0 mg, 0.036 mmol) was treated with −3M HCl in CH2Cl2, MeOH, MeOAc (2.0 mL, prepared by addition of AcCl to a 3/2 CH2Cl2/MeOH solution) for 2.2 h and concentrated. The residue was further dried (vacuum, 2 h) to afford the title compound (16.6 mg) as a colorless solid: LC-MS 96% Area; LC/MS (electrospray, +ions) m/z 432 (M+H).

EXAMPLE 93

[0216]

208

209

[0217] Methyl triflate (0.80 mL, 7.11 mmol) was added to a suspension of resin bound (tert-alkoxycarbonyl)imidazole (5.06 g, Loading 0.70 mmol/g)

210

[0218] in dry 1,2-DOCE (30 mL), cooled at 10° C. The mixture was stirred for 15 min at this temperature and for 10 min while being warmed to rt. After addition of Et3N (2.40 mL, 17.2 mmol), stirring was continued for an additional 10 min. A suspension of methyl 2-aminoisobutyrate (1.14 g, 7.42 mmol) and Et3N (0.98 mL, 7.04 mmol) in DMF (13 mL) was filtered and transferred via syringe to the stirred resin suspension. The mixture was shaken for 5.5 h at rt and filtered. The resin bound Part A compound was washed with THF (3 times), 1/1 THF/MeOH, THF (3 times), and CH2Cl2 (3 times) and dried: IR 1728 cm−1; Anal. Found C, 82.02; H, 7.96; N. 0.89. Loading on N content: 0.64 mmol/g.

211

[0219] A 3/2 dioxane/0.25 M KOH solution (40 mL) was added to the Part A compound (2.63 g, Loading 0.64 mmol/g) and the suspension was heated at 75° C. for 4.5 h. After filtration, the polymer was washed with DMF. (3 times), 5% AcOH/DMF (3 times, 50 mL total), MeOH (3 times), THF (3 times) and CH2Cl2 (3 times) and dried to provide the Part B compound (2.50 g).

[0220] A portion of the resin (53 mg) was treated with 10% TFA/CH2Cl2 (1.5 mL) for 5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (2 times) and the filtrates were evaporated and dried (vacuum, overnight) to give pure 2-aminoisobutyric acid, as its TFA salt (6.3 mg): 1H NMR δ (CD3OD, ppm) 1.55 (s, 6H).

[0221] Loading, on cleaved amount, of the resin bound 2-aminoisobutyric acid Part B compound: 0.53 mmol/g.

212

[0222] To a suspension of Example 92, Part B compound in phenethylamine (1.4.0 mL) was added a solution of tetra-n-butyl ammonium cyanide (22 mg, 0.08 mmol) in MeOH (0.3 mL) and the mixture was heated at 60-65° C. for 3 h. After filtration, the polymer was washed 3 times each with DMF, 1/1 THF/MeOH, THF and CH2Cl2 to give the resin bound amide.

[0223] The resin was treated with −3M HCl in CH2Cl2, MeOH, MeOAc (3.0 mL, prepared by addition of AcCl to a 3/2 CH2Cl2/MeOH solution) for 5 h and filtered. The resin was rinsed with CH2Cl2 (3 times) and MeOH (twice), and the filtrates were evaporated to afford the intermediate

213

[0224] (69.3 mg).

[0225] The above intermediate (69.3 mg, 0.18 mmol), Part A compound (400 mg, loading 0.53 mmol/g) and a solution of EDAC (115 mg, 0.60 mmol), HOAT (82 mg, 0.60 mmol) and diisopropylethylamine (0.10 mL, 0.60 mmol) in DMF (3.0 mL) were mixed and the resulting suspension was rocked at rt for 24 h. After filtration, the resin was washed with DMF (3 times) and dioxane (3 times). The resin was swollen with 3/2 dioxane/H2O, rocked overnight, filtered and washed with THF (3 times) and CH2Cl2 (3 times).

[0226] The resin was treated with 3M HCl in CH2Cl2, MeOH, MeOAc (4.0 mL, prepared by addition of AcCl to a 3/2 CH2Cl2/MeOH solution) for 6 h and filtered. The resin was rinsed with CH2Cl2 (2 times) and MeOH and the filtrates were evaporated to give the crude title compound. This crude mixture was dissolved in acetonitrile/MeOH and passed through an anion exchange cartridge (3.0 g, CHQAX) by eluting wit h acetonitrile (18 mL) to provide the amine (22.2 mg). Further elution with 1/1 acetonitrile/MeOH (20 mL) gave an additional amount of amine (29.8 mg). The combined amine was further purified by preparative HPLC %solvent B: start 30%, final 80%; gradient time: 20 min; flow rate 20 mL/min; wavelenght 220 nm; column YMC S5 ODS 20×100 mm) to afford the tittle compound (20.7 mg): HPLC 100% Area; LC/MS (electrospray, +ions) m/z 480 (M+H).

EXAMPLES 94 AND 95

[0227]

214

[0228] Sodium borohydride (110 mg, 2.92 mmol) was added to a solution of cinnamoyl acetonitrile (1.0 g, 5.84 mmol, Maybridge) in 4/1 MeOH/H2O (30 mL), cooled at 0° C., and the mixture was stirred for 1.5 h. After warming to rt, small portions of sodium borohydride were added at 45 min intervals until reaction completion (additional 90 min). After evaporating in vacuo most of the MeOH, potassium phosphate buffer (pH 3, 45 mL) was added and the mixture was stirred for 15 min. 5% NaHCO3 (45 mL) was added and the aqueous mixture was extracted with CH2Cl2. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was chromatographed (SiO2 230-400 mesh, 1/1 Hex/EtOAC) to give the Part A compound (842.5 mg) as a yellow liquid: LC/MS 98% Area; LC/MS (electrospray, +ions) m/z 156 (M-OH).

215

[0229] Diisopropylethylamine (31 μL, 0.18 mol) and diethylazodicarboxylate (0.18 mL, 1.14 mmol) were added to a solution of the Part A alcohol (198 mg, 1.14 mmol), Example 5 Part A compound

216

[0230] (360 mg, 0.89 mmol) and Ph3P (303 mg, 1.15 mmol) in CH2Cl2 (2.6 mL), previously cooled at 0° C. The mixture was stirred at rt for 24 h and evaporated. The residue was chromatographed (SiO2 230-400 mesh, 1/1 Hex/EtOAC) to afford the Part B N-1 substituted tetrazoles (98.3 mg, 20% yield, 2 diastereomers): HPLC 98% diastereomer combined Area; LC/MS (electrospray, +ions) m/z 560 (M+H).

217

[0231] A solution of the Part B compound (72 mg, 0.13 mmol, 2 diastereomers) and thioanisole (45 μL, 0.38 mmol) in CH2Cl2 (1.5 mL) was treated with 4M HCl/dioxane solution (1.5 mL) for 1.2 h and concentrated. Preparative HPLC (solvent, B: start 40%, final 90%; gradient time: 30 min; flow rate 20 mL/min; wavelength 220 nm; column YMC S5 ODS 20×100 mm) afforded Example 94 title compound (23.8 mg, 32% yield, single diastereomer) as a colorless solid: LC/MS 100%. Area; LC/MS (electrospray, +ions) m/z 460 (M+H), and Example 95 title compound (26.7mg, 36% yield, the other diastereomer) as a colorless solid: LC/MS 100% Area; LC/MS (electrospray, +ions) m/z 460 (M+H).

[0232] The following compounds were prepared employing procedures as described in Examples 96 to 101.

3ExampleM + H positiveNo.Structureions96

218

40597

219

40098

220

40599

221

391100

222

446101

223

466

[0233] The following compounds were prepared employing the procedures described in Examples 102 to 117 and general procedures detailed in the working examples.

4ExampleM + H positiveNo.Structureions102

224

460103

225

460104

226

448105

227

448106

228

462107

229

462108

230

462109

231

462110

232

512111

233

530112

234

530113

235

416114

236

372115

237

448116

238

448117

239

384

EXAMPLE 118

[0234]

240

[0235] To a solution of crude

241

[0236] (prepared as described in Example 7 Part C) (7.84 g, 25.37 mmol) in 150 ml of dry ethyl alcohol was added methyl isothiocyanate (2.04 g, 27.91 mmol). The reaction was heated to reflux for 6 h. The reaction was allowed to cool to room temperature and the solvent was removed via the evaporator. The residue was then treated with 1N NaOH (70 ml), the resulting mixture was heated to reflux (113° C. oil bath) for 12 h. The reaction was cooled to room temperature and the solvent was removed via vacuum. The residue was treated with 300 ml of methyl chloride/methanol (100:7.5). The mixture was stirred at room temperature for 1 h and filtered. The filtrate was concentrated and co-evaporated with toluene to give crude title compound (7.54 g). HPLCb retention time (rt) 2.37 min. LC/MS (electrospray, +ions) m/z 265 (M+H).

242

[0237] To a solution of Part A compound (7.54 g, 28.6 mmol) and Boc-methylalanine carboxylic acid (6.96 g, 34.3 mmol, Sigma) in 100 ml of DMF was added HOAt (5.05 g, 37.1 mmol) and EDAC (8.21 g, 42.8 mmol) at room temperature under nitrogen and the reaction mixture was stirred at rt. overnight. The solvent was removed via vacuum and the residue was diluted with water (100 ml). The mixture was extracted with 1/1 ethyl acetate/ether (3×200 ml), the organic layer was dried over magnesium sulfate, and filtered. The filtrate was stored at 0° C. and the resulting solid recovered by filtration to give Part B compound (1.45 g). The resulting filtrate was then concentrated and the residue was purified by flash chromatography, eluting with hexanes/ethyl acetate (2:1) to give further Part B compound as a white solid (6.92 g). HPLCb retention time (rt)=3.19 min. LC/MS (electrospray, +ions) m/z 450 (M+H).

243

[0238] To a solution of Part B compound (67.4 mg, 0.15 mmol) in 1 ml of dry dioxane was added triethyl amine (30.3 mg, 0.3 mmol) and 2-cyanobenzyl bromide (58.8 mg, 0.3 mmol) at rt. The reaction was shaken overnight and the solvent was removed via vacuum to give the intermediate:

244

[0239] The residue was then treated with TFA/dichloro-methane (1 ml, 1:3) at rt for 2 h. The solvent was evaporated and the reaction mixture was purified by a SCX column (2 g) as follows: The column was conditioned by rinsing with methanol (10 mL). The reaction mixture in 1 mL of methanol was loaded onto the column followed by methanol (30 mL). The product was then eluted with 2 N ammonia in methanol (7 mL). The solvent was removed from the sample by the use of a speed vacuum to give the title compound (53 mg, 76%) as an oil: HPLCb rt=3.15 min, LC/MS (electrospray, +ions) m/z 465(M+H).

EXAMPLE 119

[0240]

245

[0241] To a solution of Example 118 Part B compound (67.4 mg, 0.15 mmol) in 1 mL of dry dioxane was added triethyl amine (30.3 mg, 0.3 mmol) and 4-(2-bromoisovaleryl)-morpholine (75 mg, 0.3 mmol) at rt. The reaction was shaken overnight, then potassium carbonate (103 mg, 0.75 mmol) was added and the reaction was continually shaken for another 24 h. The solid was filtered off, the filtrate was collected, and the solvent was removed via vacuum. The residue was then treated with TFA/methylene chloride (1 ml, 1:3) at rt for 2 h. The solvent was evaporated and the reaction mixture was purified by a SCX column (2 g) as follows: The column was conditioned by rinsing with methanol (10 mL). The reaction mixture in 1 ml of methanol was loaded onto the column followed by methanol (30 mL). The product was then eluted with 2 N ammonia in methanol (7 mL). The solvent was removed from the sample by the use of a speed vacuum to give the title compound (41 mg, 53%) as an oil: HPLCb rt 3.06 min, LC/MS (electrospray, +ions) m/z 519(M+H).

EXAMPLE 120

[0242]

246

[0243] To a solution of Example 118 Part B compound (67.4 mg, 0.15 mmol) in 1 ml of dry dioxane was added triethyl amine (30.3 mg, 0.3 mmol) and 2-bromobutyrolactone (49.5 mg, 0.3 mmol) at rt. The reaction was shaken overnight, then potassium carbonate (103 mg, 0.75 mmol) was added and the reaction was continually shaken for another 24 h. The solid was filtered off, the filtrate was collected, and the solvent was removed via vacuum. The reaction mixture was purified by a short silica gel cartridge column (2 g) as follows: The column was conditioned by rinsing with ethyl acetate (10 ml). The reaction mixture in 1 ml of ethyl acetate was loaded onto the column followed by ethyl acetate (7 ml). The solution was collected and the solvent was removed from the sample by the use of a speed vacuum. The residue was then treated with TFA/methyl chloride (1 ml, 1:3) at rt for 2 h. The solvent was removed via vacuum to give the title compound as TFA salt (47.1 mg, 57w): HPLC rt=2.56 min, LC/MS (electrospray, +ions) m/z. 434 (M+H)

[0244] In a manner analogous to that of compounds of Example 118 to 120, compounds of Examples 121 to 172 listed in the table below were prepared from Example 118 Part B compound (0.15 mmol) and the respective bromide (0.3-mmol). Examples 159-172 required further elaboration before deprotection with TFA. A few examples were purified by preparative HPLC, eluting with a gradient system of methanol and water with 0.2% trifluoroacetic acid.

[0245] Examples 121 to 172 were isolated as trifluoroacetic acid salts or as a free base.

EXAMPLES 121 TO 172

[0246]

247

Example

M + H positive

No.
X1—R
ions

121

248

498

122

249

508

123

250

545

124

251

450

125

252

408

126

253

422

127

254

498

128

255

436

129

256

448

130

257

480

131

258

450

132

259

454

133

260

554

134

261

461

135

262

484

136

263

544

137

264

497

138

265

462

139

266

675

140

267

460

141

268

478

142

269

492

143

270

508

144

271

475

145

272

490

146

273

501

147

274

594

148

275

571

149

276

498

150

277

516

151

278

465

152

279

465

153

280

485

154

281

470

155

282

389

156

283

406

157

284

463

158

285

440

159

286

497

160

287

539

161

288

555

162

289

565

163

290

536

164

291

576

165

292

519

166

293

535

167

294

557

168

295

571

169

296

606

170

297

606

171

298

526

172

299

547

[0247] Compounds of Examples 173 to 216 listed in the table below were prepared in a manner analogous to that of compounds of Example 118 to 172.

EXAMPLES 173 TO 216

[0248]

300

Example

M + H positive

No.
X1—R
ions

173

301

472

174

302

531

175

303

562

176

304

574

177

305

585

178

306

556

179

307

567

180

308

660

181

309

651

182

310

564

183

311

636

184

312

582

185

313

531

186

314

551

187

315

551

188

316

564

189

317

529

190

318

536

191

319

531

192

320

558

193

321

531

194

322

517

195

323

474

196

324

560

197

325

491

198

326

564

199

327

473

200

328

574

201

329

611

202

330

516

203

331

488

204

332

574

205

333

620

206

334

546

207

335

610

208

336

563

209

337

528

210

338

585

211

339

741

212

340

624

213

341

628

214

342

526

215

343

544

216

344

564

EXAMPLE 217

[0249]

345

[0250] N-Methyl morpholine (1.86 mL, 16.9 mmol) and isobutyl chloroformate (2.19 mL, 16.9 mmol) were added to a solution of N-Boc-O-benzyl-D-serine (5 g, 16.9 mmol, ChemImpex) in THF (35 mL), cooled at −18° C. under nitrogen. After stirring the mixture for 0.5 h. at −18° C., a solution of N-Cbz-1-3-diaminobutane hydrochloride

346

[0251] (4.14 g, 16.9 mmol) and N-methyl morpholine (1.86 mL, 16.9 mmol) in DMF (10 mL) was added and the resulting mixture was allowed to warm up to −5° C. over a period of 4 h. The mixture was filtered and the solution was evaporated near to dryness. The residue was taken up in EtOAc and washed with 5% NaHCO3 (3×50 mL), water and brine. The organic solution was dried (Na2SO4), and evaporated to afford Part A compound (7.84 g, 97% yield): LC/MS (electrospray, +ions) m/z 486 (M+H)

347

[0252] Diethylazodicarboxylate (2.57 mL, 16.3 mmol) and azidotrimethylsilane (2.16 mL, 16.3 mmol) were added to a solution of Part A compound (7.92 g, 16.3 mmol) and triphenylphosphine (4.28 g, 16.3 mmol) in THF (60 mL), previously cooled at 0° C. under nitrogen. The mixture was stirred at rt overnight and then cooled at 0° C. Another equivalent each of triphenylphosphine (4.28 g), diethylazodicarboxylate,(2.57 mL) and azidotrimethylsilane (2.16 mL) was added and stirring was continued for an additional 24 h at rt. The reaction mixture was cooled at 0° C. and an aqueous solution (75 ml) of ammonium cerium (IV) nitrate (2.63 g/100 mL) was added and stirred for 1 h. The aqueous mixture was extracted with CH2Cl2 and the organic phase was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to give the impure Part B compound. The contaminated tetrazole was dissolved in CHCl3 and ether was added to precipitate Part B compound (2.6 g) as a colorless solid: MS (electrospray, +ions) m/z 511 (M+H).

348

[0253] To a solution of Part B compound (2.5 g, 4.80 mmol) in CH2Cl2 was added a 4M HCl/dioxane solution (14.7 mL) and stirred for 3 h. The solvents were removed at reduce pressure, the residue concentrated from CH2Cl2 and the residue was taken up in minimal i-PrOH. Brine (150 mL) was added and the pH of the aqueous solution was adjusted to 10 by addition of 1M K2CO3. The aqueous solution was extracted with CH2Cl2, dried (Na2SO4), and evaporated to provide the amine intermediate,

349

[0254] used without further purification in the subsequent reaction.

[0255] N-Boc-methyl alanine (1.49 g, 7.35 mmol, Sigma), EDAC (1.14 g, 7.35 mmol), HOAt (1 g, 7.35 mmol), 1,2-DCE and DMF (1.29 mL) were mixed at 0° C. and stirred for 15 min. The resulting solution was transferred to a 0° C. solution of the crude amine intermediate (prepared above) in 1,2-DCE and the mixture was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water and brine. The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to provide Part C compound (1.58 g) as a colorless oil: MS (electrospray, +ions) m/z 596 (M+H).

350

[0256] A methanol (3 mL) solution of Part C compound (100 mg, 0.17 mmol) and 56 palladium on carbon (50 mg) was hydrogenated for 1 h at 45 psi hydrogen. The reaction mixture was filtered through Celite and concentrated affording intermediate compound

351

[0257] (68.1 mg). The resulting residue could be purifired by auto Prep HPLC to give pure intermediate compound (47.6 mg): MS (electrospray, +ions) m/z 462 (M+H).

[0258] A CH2Cl2 (1 mL) and DMF (0.5 mL) solution of hydantoin

352

[0259] (25.3 mg, 0.16 mmol), EDAC (31.3 mg, 0.16 mmol), and dimethylamino pyridine (DMAP) (20.4 mg, 0.16 mmol) was added to a CH2Cl2 (1 mL) solution of the intermediate compound (75 mg, 0.16 mmol) at rt under nitrogen. The reaction mixture was allowed to stir at rt overnight and the volatiles were removed under vacuum. The resulting residue was dissolved in methanol and passed through a SCX resin column to give Part D compound (72 mg): MS (electrospray, +ions) m/z 602 (M+H).

353

[0260] A CH2Cl2 solution of Part D compound (64.3 mg, 0.107 mmol) was treated with an HCl solution (3.0 mL; 10.2 ml of AcCl in 40 ml of 3/2 CH2Cl2/MeOH) for 3 h and evaporated in vacuo. The residue was coevaporated four times with CH2Cl2 to give the title compound (51.4 mg) as a white solid: LC/MS (electrospray, +ions) m/z 502 (M+H).

EXAMPLE 218

[0261]

354

[0262] N-Methyl morpholine (2.23 mL, 20.3 mmol) and isobutyl chloroformate (2.64 mL, 20.3 mmol) were added to a solution of N-Boc-O-benzyl-D-serine (6 g, 20.3 mmol, ChemImpex) in THF (30 mL), cooled at −20° C. under nitrogen. After stirring the mixture for 45 min. at −20° C., a solution of ethanolamine (1.3 g, 21.4 mmol) in THF (20 mL) was added and the resulting mixture was allowed to warm up to rt over a period of 4 h. After stirring overnight, the mixture was filtered and the solution was evaporated near to dryness. The residue was purified by flash column chromatography (silica gel), eluting with hexanes:ethyl acetate (1:4) to afford the Part A compound (7.3 g): LC/MS (electrospray, +ions) m/z 339 (M+H).

355

[0263] To a CH2Cl2 (20 mL) solution of Part A compound (3.60 g, 10.7 mmol) at rt under nitrogen was added pyridine (3.44 mL, 42.6 mmol) and acetic anhydride (1.1 mL, 11.7 mmol). After 14 h, the volatiles were removed under vacuum. The resulting residue was purified by flash column chromatography (silica gel), eluting with hexanes:ethyl acetate (2:1) to afford the Part B compound (3.85 g): LC/MS (electrospray, +ions) m/z 381 (M+H).

356

[0264] To a THF (30 mL) solution of Part B compound (3.83 g, 10.1 mmol) was added triphenylphosphine (2.64 g, 10.1 mmol), diethylazodicarboxylate (1.24 mL, 10.1 mmol) and azidotrimethylsilane (1.34 mL, 10.1 mmol). The mixture was stirred at room temperature (rt) for 24 h and then another equivalent each of triphenylphosphine (2.64 g), diethylazodicarboxylate (1.24 mL) and azidotrimethylsilane (1.34 mL) was added and stirring was continued for an additional 24 h at rt. The volatiles were removed under vacuum and the residue was purified by flash chromatography (SiO2 230-400 mesh, 8/1 hexanes/EtOAc) to give somewhat impure intermediate compound

357

[0265] (2.71 g). The contaminated tetrazole was sufficiently pure for the subsequent reaction.

[0266] A 4M HCl/dioxane solution (10 mL) was added to the above intermediate compound (2.71 g, <6.69 mmol) and stirred for 1.5 h. The solvents were removed at reduce pressure and the residue co-evaporated twice with a mixture of toluene and methanol to provide Part C compound (2.28 g) as a colorless solid: LC/MS (electrospray, +ions) m/z 381 (M+H).

358

[0267] To a CH2Cl2 (25 mL) solution of Part C compound (2.28 g, 6.7 mmol) was added diisopropylethylamine (2.33 mL, 13.4 mmol), N-Boc-methyl alanine (2.04 g, 10 mmol, ChemImpex), HOAt (1.36 g, 10 mmol), and EDAC (1.92 g, 10 mmol) and the mixture was stirred overnight at rt. The reaction mixture was quenched with saturated ammonium chloride, and the aqueous layer was washed three times with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to provide intermediate compound

359

[0268] sufficiently pure for the subsequent reaction.

[0269] The above intermediate compound in a solution of THF/MeOH (20 mL, 20/1) was treated with 2N lithium hydroxide (10 mL) for 1 h. After cooling to 0° C., the reaction mixture was neutralized to pH 7 and the aqueous layer extracted with CH2Cl2 (3 times 100 mL). The combined organics were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to give Part D compound (1.69 g): MS (electrospray, +ions) m/z 449 (M+H).

360

[0270] To a THF (20 mL) solution at 0° C. of Part D compound (1.34 g, 3.0 mmol) was added pyridine (0.53 mL, 6.6 mmol). After 3 min, a THF (10 mL) solution of para-nitrochloro-formate (1.33 g, 6.6 mmol) was added and the mixture was stirred at 0° C. for 1 h and 2, h at rt. The reaction mixture was then filtered and the filtrate concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2, 230-400 mesh) eluting with 1/1 hexanes/EtOAc to give Part E compound (1.52 g): LC/MS (electrospray, +ions) m/z 614 (M+H).

361

[0271] To a THF (20 mL) solution of Part E compound (3.4 g, 5.55 mmol) was added

362

[0272] (0.74 g, 8.32 mmol) and after 3 h at RT, the volatiles were removed under vacuum. The resulting residue was purified by flash chromatography (SiO2 230-400 mesh) eluting with 1/2 hexanes/EtOAc (4/1 to 1/1) to give pure Part F compound (2.325 g), as well as some less pure material (1.03 g): LC/MS (electrospray, +ions) m/z 564 (M+H).

363

[0273] Part F compound (1.59 g, 2.82 mmol) was treated with a 4N HCl/dioxane solution (15 mL) for 1.5 h. The volatiles were evaporated in vacuo to give the title compound (1.44 g) as a colorless solid: LC/MS (electrospray, +ions) m/z 464 (M+H).

[0274] The above intermediate was treated with a 4N HCl/dioxane solution for 3 h and evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound (85 mg) as a white solid: MS (electrospray, +ions) m/z 566 (M+H).

[0275] The intermediate Example 218, Part F can be prepared with the modified conditions as described in Example 219.

EXAMPLE 219

[0276]

364

[0277] To a THF (250 mL) solution of Example 218 Part B compound (47.0 g, 120 mmol) cooled to 1° C. was added triphenylphosphine (32.6 g, 123 mmol) and diisopropylethylamine (5.4 mL, 32 mmol). Diethylazo-dicarboxylate (19.6 mL, 123 mmol, DEAD) was added dropwise over 15 minutes keeping temperature under 5° C. followed by the addition azidotrimethylsilane (16.5 mL, 123 mmol). The mixture was stirred at room temperature (rt) for 24 h and then another equivalent each of triphenylphosphine (32.6 g), DEAD(19.6 mL) and azidotrimethylsilane (16.5 mL) was added as before and stirring was continued for an additional 24 h at rt. Another equivalent each of triphenylphosphine (32.6 g), DEAD (19.6 mL) and azidotrimethylsilane (16.5 mL) was added as before and stirring was continued for an additional 24 h at rt. The reaction was cooled to 1° C. and quenched with a solution of ammonium cerium(IV) nitrate (136 g) in water (500 ml) over 45 minutes. The resulting mixture was filtered through celite and concentrated in vacuo and extracted twice with ethyl acetate (250 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give an orange oil (236 g). This oil was dissolved in methyl t-butyl ether (1 L, MTBE), washed twice with 1N NaOH (500 mL), once with water (500 mL) and once with brine (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow solid (166 g). This solid was purified through a silica gel pad (500 g, 230-400 mesh) eluting with 15-40% ethyl acetate in hexanes to give the acetate intermediate as a yellow oil (20.6 g, 41% yield).

365

[0278] A 4M HCl/dioxane solution (325 mL) was added to a solution of the above intermediate compound (106.6 g, 263 mmol, combined from numerous reactions) in CH2Cl2 (600 mL) and stirred overnight. The solvents were removed in vacuo and the residue co-evaporated twice with a mixture of toluene and methanol to provide desired compound (89.3 g, 100% yield)) as a brown foam: LC/MS (electrospray, +ions) m/z 381 (M+H).

366

[0279] To a CH2Cl2 (1 L) solution of Part A compound (80.0 g, 262 mmol) was added diisopropylethylamine (120 mL, 262 mmol), N-Boc-methyl alanine (80.0 g, 3.93 mmol), HOAt (53.5 g, 393 mmol), and EDAC (75.3 g, 393 mmol) and the mixture was stirred 1 hour at rt. The reaction mixture was washed with water (500 mL), 0.5 M HCl (500 mL) and saturated NaHCO3 (500 mL), dried (MgSO4), and evaporated to provide intermediate compound as a yellow foam (146.8 g)

367

[0280] sufficiently pure for the subsequent reaction.

[0281] The above intermediate compound in a solution of THF/MeOH (1.25 L, 4/1) was placed in a water bath and 2N lithium hydroxide (65, mL) was added over 15 minutes maintaining the internal temperature below 25° C. The reaction stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to an oil/solid mixture which was dissolved in water (500 mL) and the pH was adjusted to 5.5 with 1N HCl (40 mL). Dichloromethane was added (500 mL) and the mixture stirred for 30 minutes. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (250 mL). The combined organics were washed with water (400 mL) and brine (400 mL), dried (MgSO4), filtered, and concentrated under vacuum to give Part D compound (123.2 g) as a light yellow foam: MS (electrospray, +ions) m/z 449 (M+H).

368

[0282] To a CH2Cl2 (350 mL) solution at 0° C. of Part B compound (123 g, 260 mmol) was added pyridine (32.0 mL, 391 mmol). After 10 min, a CH2Cl2 (150 mL) solution of para-nitrochloroformate (63.0 g, 313 mmol) was added over 1 hour, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (300 mL), 1N HCl (300 mL), and brine (300 mL), dried (MgSO4), and concentrated in vacuo to a brown oil (187.3 g). This crude material was purified through a silica gel pad (500 g, 230-400 mesh) eluted with 30-50% ethyl acetate in hexanes to give Part E compound as an off-white foam (130.98 g, 81.9% yield): LC/MS (electrospray, +ions) m/z 614 (M+H).

369

[0283] To a THF (600 mL) solution of Part C compound (117.5 g, 190 mmol) in a water bath was added aminobutanol

370

[0284] (19.4 mL, 210 mmol) dropwise over 30 minutes and after 1 h at RT, an additional aliquot of 4-amino-1-butanol (1.7 mL, 18 mmol) was added. After stirring an additional 30 minutes at rt, the volatiles were removed under vacuum. The resulting residue was dissolved in EtOAc (600 mL) and washed with 1N HCl (200 mL), saturated NaHCO3 (1×400 mL and 2×200 mL, emulsion), and brine (3×200 mL, slow separation), dried (MgSO4), and concentrated in vacuo to give an oil. This oil was dissolved in MTBE (600 mL) and washed with saturated NaHCO3 (1×300 mL), and brine (2×500 mL), dried (Na2SO4), and concentrated in vacuo to give a yellow oil (156.52 g). This oil was dissolved in MTBE (1 L) and washed with 1N NaOH (500 mL) and water. The organic layer was washed again with 1N NaOH (500 mL) and the combined NaOH washes were extracted with MTBE (400 mL). The combined MTBE layers were washed with water (500 mL) and brine (500 mL); dried (MgSO4), and concentrated in vacuo to give pure title Part D compound as a light yellow oil (103.08 g, 95.5% yield): LC/MS (electrospray, +ions) m/z 564 (M+H).

[0285] Examples 220-352 were prepared in a manner analogous to that of compounds described previously in the invention and by methods known in the art.

EXAMPLES 220 TO 352

[0286]

371

Example

M + H positive

No.
X1—R
ions

220

372

466

221

373

478

222

374

505

223

375

505

224

376

418

225

377

415

226

378

434

227

379

433

228

380

482

229

381

476

230

382

475

231

383

590

232

384

474

233

385

544

234

386

518

235

387

462

236

388

442

237

389

447

238

390

434

239

391

464

240

392

448

241

393

502

242

394

479

243

395

511

244

396

574

245

397

485

246

398

462

247

399

463

248

400

349

249

401

524

250

402

496

251

403

448

252

404

434

253

405

462

254

406

498

255

407

496

256

408

466

257

409

498

258

410

497

259

411

542

260

412

512

261

413

512

262

414

511

263

415

462

264

416

511

265

417

547

266

418

404

267

419

390

268

420

418

269

421

518

270

422

510

271

423

496

272

424

510

273

425

391

274

426

524

275

427

489

276

428

543

277

429

492

278

430

506

279

431

513

280

432

527

281

433

582

282

434

553

283

435

520

284

436

476

285

437

448

286

438

462

287

439

476

288

440

450

289

441

464

290

442

480

291

443

478

292

444

432

293

445

510

294

446

510

295

447

524

296

448

562

297

449

562

298

450

630

299

451

512

300

452

475

301

453

524

302

454

524

303

455

462

304

456

524

305

457

462

306

458

573

307

459

552

308

460

478

309

461

492

310

462

506

311

463

520

312

464

482

313

465

524

314

466

504

315

467

539

316

468

553

317

469

532

318

470

518

319

471

518

320

472

554

321

473

468

322

474

553

323

475

526

324

476

386

325

477

372

326

478

567

327

479

508

328

480

478

329

481

474

330

482

553

331

483

440

332

484

498

333

485

540

334

486

537

335

487

528

336

488

450

337

489

462

338

490

480

339

491

536

340

492

540

341

493

563

342

494

507

343

495

556

344

496

494

345

497

549

346

498

542

347

499

531

348

500

549

349

501

377

350

502

439

351

503

508

352

504

477

EXAMPLE 353

[0287]

505

[0288] To a solution of Compound 218 Part F (929 mg, 1.65 mmol) in anhydrous CH2Cl2 (8 mL) was added pyridine (400 μ1,4.95 mmol) and DMAP (40 mg, 0.33 mmol) followed by the addition of benzoyl chloride (287 μl, 2.48 mmol). After stirring for 5 h at room temperature, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (SiO2, 20%-50% EtOAc in hexanes) to give the desired product (1.09 g, 99% yield).

506

[0289] To a solution of Part A compound (580 mg) in CH2Cl2 (3 ml) was added 4N HCl in dioxane (3 ml). The reaction mixture stirred at room temperature for 1.5 h. The solvent was removed in vacuo to give the desired product. (469 mg, 890 yield). LC/MS (electrospray, +ions) m/z 567 (M+H).

EXAMPLE 353,

Alternate Preparation

[0290]

507

[0291] To a solution of Example 219 compound (102.66 g, 1.82 mmol) in anhydrous CH2Cl2 (650 mL) was added pyridine (37.0 mL, 455 mmol) and DMAP (2.23 g, 18.2 mmol). The flask was immersed in a water bath and benzoyl chloride (25 mL, 219 mmol) was added dropwise over 20 minutes. After stirring for 2 h at room temperature, additional benzoyl chloride (6.0 mL, 54 mmol) was added dropwise and the reaction continued to stir at room temperature overnight. The reaction mixture was washed with 1N HCl (300 mL)., saturated NaHCO3 (300 mL), and brine (300 mL), dried (MgSO4), and concentrated in vacuo, and the residue was purified by silica gel pad filtration (SiO2, 650 g, 10%-85% EtOAc in hexanes) to give the desired product (116.34 g, 97% yield) as a colorless foam.

508

[0292] To a solution of Part A compound (116.0 g, 174 mmol) in CH2Cl2 (700 ml) was added 4N HCl in dioxane (218 ml, 870 mmol) dropwise over 30 minutes. The reaction mixture stirred at room temperature for 4 h. The solvent was removed in vacuo. The residue was dissolved in water (500 mL) and washed with MTBE (250 mL). The aqueous layer was mixed with CH2Cl2 (300 mL) and the pH adjusted to 11 with !N NaOH (190 mL). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (300 mL). The combined CH2Cl2 layers were washed with brine (2×300 mL), dried (MgSO4) and concentrated in vacuo to give the desired product (92.8 g, 94% yield) as a yellow oil. LC/MS (electrospray, +ions) m/z 567 (M+H).

EXAMPLE 354

[0293]

509

[0294] To a solution of Compound 219 (100 mg, 0.18 mmol) in 1,2-dichloroethane (250 μl) at 0° C. is added a solution of 2-phenylpropionic acid (50 μl, 0.37 mmol), EDAC (69 mg, 0.36 mmol), and DMAP (44 mg, 0.36 mmol) in 1,2-dichloro-ethane (250 μl). The reaction mixture stirred for 36 hours at room temperature. The reaction was diluted with EtbAc (50 ml) and washed with saturated NaHCO3 (2×25 ml), water (2.5 ml) and brine (25 ml), dried (Na2SO4) and evaporated to give the crude product (128 mg). This material was purified by flash column chromatography eluted with 1:1 hexanes:EtbAc to give the product (122.4 mg, 99% yield).

510

[0295] Part A compound (122 mg, 0.18 mmol) was stirred in a 10%TFA in CH2Cl2 solution (4.0 ml) for 2.5 h. The solvent was removed in vacuo. The residual TFA was removed by coevapoation with CH2Cl2 (4×3 ml) and MeOH (2×3 ml). The residue was dissolved in MeOH and heated at 60° C. for 8 h. The solvent was removed in vacuo, and the residue was purified by prepartive HPLC (20%-100% B. 12 min. gradient, 20 ml/min, YMCS5 ODS 20×100 mm) to give the desired product (115.4 mg, 93% yield). LC/MS (electrospray, +ions) m/z 596 (M+H).

[0296] In a manner analogous to that of compounds of Example 353 and 354, compounds of Examples 355 to 392 listed in the table below were prepared from Example 218 Part F compound and the respective acid or acid chloride.

EXAMPLES 355 TO 392

[0297]

511

Example

No.
X1—R
M + H positive ions

355

512

534

356

513

548

357

514

582

358

515

610

359
X1—CH3
506

360

516

548

361

517

520

362

518

586

363

519

604

364

520

636

365

521

582

366

522

596

367

523

582

368

524

596

369

525

644

370

526

598

371

527

626

372

528

548

373

529

548

374

530

562

375

531

582

376

532

588

377

533

644

378

534

618

379

535

618

380

536

660

381

537

660

382

538

574

383

539

560

384

540

546

385

541

594

386

542

574

387

543

560

388

544

636

389

545

652

390

546

650

391

547

534

392

548

546

[0298] Compounds of Examples 393 to 424 listed in the tables below were prepared in a manner analogous to that of compounds of Example 353 and 354.

EXAMPLES 393 TO 424

[0299]

549

Example No.
X1—R
M + H positive ions

393

550

566

394

551

580

395

552

572

396

553

580

397

554

594

398

555

560

399

556

596

400

557

606

401

558

610

402

559

610

403

560

586

404

561

598

405

562

648

406

563

648

407

564

546

408

565

700

409

566

580

410

567

544

568

Example No.
X1—R
M + H positive ions

411

569

568

412

570

596

413

571

582

414

572

630

415

573

625

416

574

597

417

575

644

418

576

665

419

577

660

420

578

610

421

579

650

422

580

648

423

581

624

424

582

636

EXAMPLE 425

[0300]

583

[0301] To a solution of methyl R-(+)-3-BOC-2,2-dimethyl-4oxazolidine carboxylate

584

[0302] (2.05 g, 7.75 mmol, Aldrich, 98%) in THF (24.0 mL) was added a light suspension of calcium chloride (437 mg, 3.94 mmol) in EtOH (16.5 mL) and the resulting solution was cooled at 0° C. Sodium borohydride was added and the mixture was stirred at 0° C. for 2 h. and for 4 h at rt. The final mixture was cooled at 0° C. and potassium phosphate buffer (pH 3, 40 mL) was added. The aqueous mixture was stirred for 30 min at rt. and then extracted with CH2Cl2 (3×70 mL). The combined organic phase was dried (Na2SO4) and evaporated to a crude which was chromatographed (SiO2 230-400 mesh, 3/2 to 1/1 hexanes/EtOAc) to give the starting ester (409 mg, 20% recovery) and the desired alcohol (1.46 g, 80% yield): 1H NMR ∂ (CDCl3, ppm, rotamers) 4.18-3.56 (4m, 6H), 1.55 and 1.50 (2s, 15H).

585

[0303] To a solution of Part A compound(2.90 g, 12.5 mmol), 2-hydroxypyridine (1.54 g, 15.7 mmol) and triphenyl-phosphine (4.11 g, 15.7 mmol) in THF (27 mL) was added diethylazo-dicarboxylate (2.47 mL, 15.7 mmol) dropwise. The solution was stirred at rt. for 13.5 h. and then partially evaporated. The remaining solution was passed though a SiO2 (230-400 mesh) column, eluting with 7/3 hexanes/EtOAc, to provide the desired compound (1.88 g, 49% yield) as a solid: 1H NMR ∂ (CDCl3, ppm, rotamers) 8.15 (m, 1H), 7.57 (m, 1H), 6.88 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 4.50 (m, 1H), 4.25-3.95 (several m, 4H), 1.61-1.45 (several s, 15H).

586

[0304] A solution of Part B compound (434 mg, 1.41 mmol) and p-toluenesulfonic acid monohydrate (295 mg, 1.55 mmol) in dry MEOH (14.1 mL) was heated at 35° C. for 7 h and then stirred at rt. for 3.8 h. After cooling at 0° C., a 1M K2CO3 solution (0.8 mL) was added and the mixture volume was reduced in vacuo to 4 mL. Brine (50 mL) was added and the pH of the aqueous solution was adjusted to 10 by addition of 1M K2CO3. Extraction with CH2Cl2 (4×50 mL), 10; drying (Na2SO4), evaporation and chromatography (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) of the crude gave starting Part B compound (93 mg, 21% recovery) and the desired alcohol (249 mg, 66% yield) as a colorless solid: LC-MS 99% Area; LC/MS (electrospray, +ions) m/z 269 (M+H).

587

[0305] To a solution of Part C compound (1.34 g, 5.00 mmol) and triphenylphosphine (1.58 g, 6.02 mmol) in CH2Cl2 (34.0 mL), cooled at 0° C., was added diethylazodicarboxylate (0.95 mL, 6.03) dropwise and the mixture was stirred at rt. for 3.75 h. The mixture volume was reduced to 8 mL in vacuo and the remaining solution was passed through a SiO2 (230-400 mesh) column, eluting with 7/3 hexanes/EtOAc to obtain the desired compound (862 mg, 70% yield) as a yellow oil: 1H NMR ∂ (CDCl3, PPM) 8.13 (m, 1H), 7.57 (m, 1H), 6.88 (m, 1H), 6.78 (d, J=8.2 Hz, 1H4), 4.45 (dd, J=11.6, 4 . . . . . 4 Hz, 1H), 4.36 (dd, J=11.6, 5.5 Hz, 1H), 2.88 (m, 1H), 2.35 (d, J=6.0 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.43 (s, 9H).

588

[0306] To a suspension of Part D compound (97 mg, 0.39 mmol) and potassium cyanide (51 mg, 0.78 mmol) in DMSO (2.6 mL) was added water (7 μL) and the mixture was heated at 30-40° C. for 11 h. Stirring was continued for an additional 9 h. at rt. and the mixture was diluted with 9/1 hexanes/EtOAc (60 mL). The solution was washed with water (2×30 mL) and brine (30 mL), dried (Na2SO4) and evaporated to give 92 mg crude. Chromatography (SiO2 230-400 mesh, 7/3 hexanes/EtOAc) provided starting aziridine (8.0 mg, 8?c recovery) and the desired compound (75.6 mg, 72% yield) as a colorless solid: LC-MS 1000% Area; LC/MS (electrospray, +ions) m/z 278 (M+H).

589

[0307] 15% TFA solution (6.0 mL) was added to a flask containing Part E compound(199 mg, 0.72 mmol) and thioanisole (254 μL, 2.16 mmol), and the resulting solution was allowed to stand at rt. for 4 h. The solution was evaporated and the residual TFA was removed by coevaporation with CH2Cl2 (2×5 mL) and MeOH (3×5 mL), and drying under high vacuum for 1 h. The crude amine salt material,

590

[0308] was used without further purification in the subsequent reaction.

[0309] N-Boc-O-benzyl-D-serine (298 mg, 1.00 mmol), EDAC (194 mg, 1.01 mmol), HOAT (137 mg, 1.01 mmol), 1,2-DCE (0.47 mL), and DMF (940 μL) were mixed at 0° C. and stirred for 15 min. The resulting cloudy solution was transferred, via syringe, to a 0° C. solution of the crude amine (from above) in 1,2-DCE (400 μL) and DMF (470 μL), and the mixture was stirred for 10 min. at 0° C. Diisopropylethylamine was added and stirring was continued at rt. for 36 h. The reaction mixture was diluted with EtOAc (80 mL) and washed with saturated NaHCO3 (2×40 mL), water (40 mL) and brine (40 mL). The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 1/1 hexanes/EtOAc) to provide the desired compound (311 mg, 95% yield) as a colorless oil: 1H NMR ∂ (CDCl3, ppm) 8.17 (s, 1H), 7.84 (s, 1H), 7.61 (m, 1H), 7.30 (m, 5H), 6.94 (m, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.37 (s, 1H), 4.52 (m, 5H), 4.31 (broad s, 1H), 3.88 (m, 1H), 3.58 (m, 1H), 2.80 (m, 2H), 1.43 (s, 9H)

591

[0310] Diethylazodicarboxylate (131 μL, 0.83 mmol, DEAD) and azidotrimethylsilane (110 μL, 0.83 mmol) were added to a solution of Part F compound(311 mg, 0.69 mmol) and triphenylphosphine (217 mg, 0.83 mmol) in CH2Cl2 (1.4 mL). The mixture was stirred at rt. for 22 h. and additional amounts of triphenylphosphine (217 mg), DEAD (131 μL) and azidotrimethylsilane (110 μL) were added. Stirring was continued for an additional 24 h at rt. and the final mixture was passed through a SiO2 (230-400 mesh) column, eluting with 3/2 to 1/1 hexanes/EtOAc, to give the desired compound (248 mg, 76%) as a thick colorless oil: 1H NMR ∂ (CDCl3, ppm) 8.11 (m, 1H), 7.55 (m, 1H), 7.33 (m, 3H), 7.20 (m, 2H), 6.92 (t, J=7.9 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 5.45 (d, J=8.3 Hz, 1H), 5.44 (m, 2H), 4.73 (dd, J 11.6, 4.9 Hz, 1H), 4.63 (dd, J=11.6, 8.3 Hz, 1H), 4.50 (d, J=11.0 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 4.00 (dd, J=8.3, 5.5 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.04 (dd, J=17.0, 7.1 Hz, 1H), 2.86 (dd, J=17.0, 7.1 Hz, 1H), 1.43 (s, 9H).

592

[0311] 5% TFA solution (6.2 mL) was added to a flask containing the Part G compound (227 mg, 0.47 mmol) and thioanisole (166 μL, 1.41 mmol), and the resulting solution was allowed to stand at rt. for 4 h. The solution was evaporated and the residual TFA was removed by coevaporation with CH2Cl2 (2×8 mL) and MeOH (3×8 mL), and drying under high vacuum for 1h. The residue was heated at 60° C. in MeOH (25 mL) and the solution concentrated. The crude amine material,

593

[0312] was used without further purification in the subsequent reaction.

[0313] N-Boc-methyl alanine

594

[0314] (125 mg, 0.62 mmol), EDAC (117 mg, 0.61 mmol), HOAT (84 mg, 0.62 mmol), 1,2-DCE (350 μL) and DMF (700 μL) were mixed at 0° C. and stirred for 15 min. The resulting solution was transferred, via syringe, to a 0° C. solution of the crude amine (from above) in 1,2-DCE (300 μL) and DMF (400 μL), and the mixture was stirred at 0° C. for 15 min. Diisopropylethylamine (205 μL, 1.18 mmol) was added and stirring was continued for 25 h at rt. The final mixture was diluted with EtOAc (75 mL) and washed with saturated NaHCO3 (2×30 mL), water (30 mL) and brine (30 mL). The organic layer was dried (Na2SO4), evaporated and chromatographed (SiO2 230-400 mesh, 3/2 to 2/3 hexanes/EtOAc) to provide desired compound (175.4 mg, 66!k yield) as a colorless foam: 1H NMR ∂ (CDCl3, ppm) 8.13 (m, 1H), 7.57 (m, 1H), 7.42 (d, J=8.8H, 1H), 7.31 (m, 3H), 7.19 (m, 2H), 6.93 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 5.75 (m, 1H), 5.49 (m, 1H), 4.97 (s, 1H), 4.73 (dd, J=11.6, 5.5 Hz, 1H), 4.66 (dd, J=11.6, 7.7 Hz, 1H), 4.50 (d, J=11.6 Hz, 1H), 4.43 (d, J=11.5 Hz, 1H), 4.04 (m, 1H), 3.52 (t, J=8.8 Hz, 1H), 3.02 (dd, J=17.1, 6.6 Hz, 1H), 2.85 (dd, J=17.0, 7.7 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.36 (s, 9H)

595

[0315] Part H compound (492 mg, 0.87 mmol) was treated with 15% TFA (14.0 mL) for 2.5 h and the solution concentrated in vacuo. The residual TFA was coevaporated with CH2Cl2 (3×10 mL) and MeOH (2×10 mL), and drying under high vacuum for 1 h. The residue was heated at 60° C. in MeOH (40 mL) for 10 h. and the solution concentrated to give the crude desired compound. Successive precipitation from MeOH/ether provided the desired compound (418 mg). The mother liquor was evaporated and the residue was purified by preparative HPLC (Shimadzu, 10-100% B [MeOH:H20:0.1% TFA], 30 min. gradient, 20 mL/min. flow rate, 220 nm, YMC 55 ODS 20×100 mm) to give an additional amount of the title compound (67.6 mg): Combined yield, 96%; LC-MS 99% Area; LC/MS (electrospray, +ions) m/z 465 (M+H).

[0316] The following compounds were prepared employing the procedures described above and the working Examples.

EXAMPLES 426 TO 477

[0317]

596

10

M + H

Example No.
X1—R
positive ions

426

597

540

427

598

490

428

599

504

429

600

449

430

601

450

431

602

480

432

603

477

433

604

463

434

605

523

435

606

523

436

607

500

437

608

466

438

609

575

439

610

504

440

611

464

441

612

581

442

613

490

443

614

478

444

615

540

445

616

508

446

617

494

447

618

490

448

619

503

449

620

491

450

621

436

451

622

499

452

623

520

453

624

554

454

625

476

455

626

476

456

627

476

457

628

490

458

629

476

459

630

462

460

631

503

461

632

546

462

633

546

463

634

567

464

635

601

465

636

464

466

637

560

467

638

517

468

639

593

469

640

595

470

641

518

471

642

565

472

643

476

473

644

552

474

645

622

475

646

565

476

647

579

477

648

607

EXAMPLES 478 TO 498

[0318]

649

M + H

Exam-

positive

ple No.
X1—R
ions

478

650

566

479

651

566

480

652

552

481

653

519

482

654

532

483

655

572

484

656

510

485

657

523

486

658

574

487

659

573

488

660

460

489

661

516

490

662

545

491

663

488

492

664

501

493

665

474

494

666

523

495

667

574

496

668

473

497

669

544

498

670

508

EXAMPLES 499 TO 530

[0319]

671

Example No.
X1—R
M + H positive ions

499

672

464

500

673

525

501

674

496

502

675

532

503

676

511

504

677

496

505

678

532

506

679

511

507

680

544

508

681

483

509

682

455

510

683

482

511

684

524

512

685

496

513

686

565

514

687

450

515

688

482

516

689

497

517

690

518

518

691

497

519

692

539

520

693

510

521

694

546

522

695

525

523

696

482

524

697

496

525

698

496

526

699

482

527

700

512

528

701

512

529

702

511

530

703

525

EXAMPLES 531 TO 554

[0320]

704

M +

Example No.
X1-R
M ′ H positive ions

531

705

581

532

706

450

533

707

464

534

708

497

535

709

511

536

710

462

537

711

476

538

712

490

539

713

405

540

714

344

541

715

464

542

716

536

543

717

536

544

718

557

545

719

557

546

720

506

547

721

589

548

722

370

549

723

521

550

724

583

551

725

465

552

726

426

553

727

535

554

728

480

EXAMPLES 555 TO 583

[0321]

729

Example No.
X1—R
M + H positive ions

555

730

453

556

731

489

557

732

511

558

733

525

559

734

483

560

735

465

561

736

481

562

737

416

563

738

500

564

739

498

565

740

618

566

741

602

567

742

601

568

743

615

569

744

539

570

745

553

571

746

662

572

747

595

573

748

604

574

749

699

575

750

447

576

751

495

577

752

509

578

753

507

579

754

610

580

755

517

581

756

531

582

757

377

583

758

463

	Number	Date	Country
	60124131	Mar 1999	US
	60154919	Sep 1999	US

	Number	Date	Country
Parent	09506749	Feb 2000	US
Child	10281649	Oct 2002	US

Heterocyclic aromatic compounds useful as growth hormone secretagogues

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (2)

Divisions (1)