FIELD OF THE INVENTION 0001 The present invention relates generally to processes for the conversion of cyano groups into amidines for the purpose of producing compounds which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex. These compounds may be used for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

BACKGROUND 0002 There are several methods to convert cyano groups into amidine groups (S. Patai, Z. Rappoport, The Chemistry of Amidines and Imidates, 1991, John Wiley & Sons Ltd.). One of the most widely used methods for the preparation of amidines is the Pinner synthesis (R. Roger, D. G. Neilson, Chem. Rev. 1961, 61, 179-211), which proceeds in two steps through an imidate intermediate. 0003 Abood et al, in U.S. Pat. No. 5,484,946, discusses formation of the amidine moiety from a nitrile group through an amidoxime intermediate. Jendrall et al, in Tetrahedron 1995, 51, 12047-12068, used a similar process to convert a cyano group into the amidinium functionality. Eloy and Leners, in Chem. Rev., 1962, 62, 155-183, review the preparation of amidoximes from nitrites. Chio and Shine, in J. Heterocyclic Chem., 1989, 26, 125-128, reported that these amidoximes can be transformed into 1,2,4-oxadiazole derivatives. Judkins et al, in Synthetic Commun. 1996, 26, 4351, describe formation of amidine moiety from nitrile through an amidoxime intermediate under acetylation or acylation conditions. 0004 This literature however, does not disclose any regioselectivity between an amidoxime and an isoxazoline. In fact, Mueller et al, Angew. Chem., 1994, 106, 1305-1308, report that hydrogenation with 10%Pd/C will reduce a isoxazoline ring system. There is also no precedent for the transformation of a cyano group into an amidine functionality through a 1,2,4-oxadiazole moiety, and therefore the conversion of a 1,2,4-oxadiazole into amidine directly through catalytic hydrogenation is not taught. 0005 Compounds of generic form (I) are antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex which are currently being evaluated for the inhibition of platelet aggregation, as thrombolytics, and for the treatment of thromboembolic disorders. Consequently, large quantities of these compounds are needed to support drug development studies. 1

0006 The preparation of compounds of generic form (I) have been disclosed in U.S. Pat. No. 5,446,056, PCT international publication WO 95/14683, PCT international publication WO 96/38426, pending and commonly owned U.S. application Ser. No. 08/700,906, and in J. Med. Chem., Xue et al, 1997, 40, 2064-2084. The preparation of (X) has been disclosed by Zhang et al in Tetrahedron Lett. 1996, 37, 4455-4458 and J. Org. Chem. 1997, 62, 2466-2470, which describe amidine formation from a nitrile using the Pinner reaction. Although this process has been able to produce compounds of formula (X) on a multikilogram scale, employing the Pinner reaction on a commercial scale poses several disadvantages. The Pinner approach involves the use of an excess of hydrogen chloride gas which is environmentally unfriendly, and removal of the inorganic salts generated during the Pinner process requires extensive purification protocols. It was therefore necessary to develop an efficient, safer process to produce compounds of formula (I) on large scale.

SUMMARY OF THE INVENTION 0007 The present invention relates generally to processes for the conversion of cyano groups into amidines for the purpose of producing compounds, and intermediates therefore, which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex. These compounds may be used for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders. 0008 There is provided by this invention a process for the preparation of compounds of formula (I), (III), (IV), (V) and (VI): 2

0009 wherein: 0010 R1 is selected from H or NHR1a; 0011 R1a is selected from the group consisting of: 0012 C(O)OR1b, 0013 C(O)R1b, 0014 C(O)N(R1b)2, 0015 C(O)NHSO2R1b, 0016 C(O)NHC(O)R1b, 0017 C(O)NHC(O)OR1b, 0018 C(O)NHSO2NHR1b, 0019 C(S)NHR1b, 0020 NHC(O)OR1b, 0021 NHC(O)R1b, 0022 NHC()NHR1b, 0023 SO2OR1b, 0024 S2R1b, 0025 SO2N(R1b)2, 0026 SO2NHC(O)OR1b, 0027 P(S)(OR1b)2, 0028 P(O)(OR1b)2, 0029 P(S)(R1b)2, 0030 P(O)(R1b)2, and 3

0031 R1b is selected from the group consisting of: 0032 C1-C8 alkyl substituted with 0-2 R1c, 0033 C2-C8 alkenyl substituted with 0-2 R1c, 0034 C2-C8 alkynyl substituted with 0-2 R1c, 0035 C3-C8 cycloalkyl substituted with 0-2 R1c, 0036 aryl substituted with 0-4 R1c, 0037 aryl(C1-C6 alkyl)-substituted with 0-4 R1c, 0038 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and 0039 C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c; 0040 R1c is H, halogen, CF3, CN, NO2, C-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0041 R2 is selected from H or C1-C10 alkyl; 0042 R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a; 0043 R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c; 0044 R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d; 0045 R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0046 R5 is selected from the group consisting of: 0047 hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, 0048 C6-C10 aryloxy, C7-C11 arylalkyloxy, 0049 C3-C10 alkylcarbonyloxyalkyloxy, 0050 C3-C10 alkoxycarbonyloxyalkyloxy, 0051 C3-C10 alkoxycarbonylalkyloxy, 0052 C5-C10 cycloalkylcarbonyloxyalkyloxy, 0053 C5-C10 cycloalkoxycarbonyloxyalkyloxy, 0054 C5-C10 cycloalkoxycarbonylalkyloxy, 0055 C8-C11 aryloxycarbonylalkyloxy, 0056 C8-C12 aryloxycarbonyloxyalkyloxy, 0057 C8-C12 arylcarbonyloxyalkyloxy, 0058 C5-C10 alkoxyalkylcarbonyloxyalkyloxy, 0059 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, 0060 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and 0061 (R5a)HN-(C1-C10 alkoxy)-; 0062 R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl; 0063 R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, aryloxy and aryl substituted with 0-5 R6c; 0064 R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0065 R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0066 n is 0-4; and 0067 a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4; 0068 said process comprising one or more of: 0069 (1): contacting a compound of formula (II) with a salt of hydroxyl amine in the presence of a suitable base to form a compound of formula (III); 0070 (2): contacting a compound of formula (III) with an acylating agent of formula R6COOCOR6 or R6COX, wherein X is fluorine, bromine, chlorine or imidazole, in a suitable solvent to form a compound of formula (IV) or a salt thereof; and 0071 (3): contacting a compound of formula (IV) with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

DETAILED DESCRIPTION OF THE INVENTION 0072 In a first embodiment, the present invention provides a process for the preparation of compounds of formula (I): 4

0073 or a pharmaceutically acceptable salt form thereof; 0074 wherein: 0075 R1 is selected from H or NHR1a; 0076 R1a is selected from the group consisting of: 0077 C(O)OR1b, 0078 C(O)R1b, 0079 C(O)N(R1b)2, 0080 C(O)NHSO2R1b, 0081 C(O)NHC(O)R1b, 0082 C(O)NHC(O)OR1b, 0083 C(O)NHSO2NHR1b, 0084 C(S)NHR1b, 0085 NHC(O)OR1b, 0086 NHC(O)R1b, 0087 NHC()NHR1b, 0088 SO2OR1b, 0089 SO2R1b, 0090 SO2N(R1b)2, 0091 SO2NHC(O)OR1b, 0092 P(S)(OR1b)2, 0093 P(O)(OR1b)2, 0094 P(S)(R1b)2, 0095 P(O)(R1b)2, and 5

0096 R1b is selected from the group consisting of: 0097 C1-C8 alkyl substituted with 0-2 R1c, 0098 C2-C8 alkenyl substituted with 0-2 R1c, 0099 C2-C8 alkynyl substituted with 0-2 R1c, 0100 C3-C8 cycloalkyl substituted with 0-2 R1c, 0101 aryl substituted with 0-4 R1c, 0102 aryl(C1-C6 alkyl)-substituted with 0-4 R1c, 0103 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said hetero cyclic ring being substituted with 0-4 R1c, and 0104 C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c; 0105 R1c is H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0106 R2 is selected from H or C1-C10 alkyl; 0107 R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a; 0108 R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c; 0109 R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d; 0110 R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0111 R5 is selected from the group consisting of: 0112 hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, 0113 C6-C10 aryloxy, C7-C11 arylalkyloxy, 0114 C3-C10 alkylcarbonyloxyalkyloxy, 0115 C3-C10 alkoxycarbonyloxyalkyloxy, 0116 C3-C10 alkoxycarbonylalkyloxy, 0117 C5-C10 cycloalkylcarbonyloxyalkyloxy, 0118 C5-C10 cycloalkoxycarbonyloxyalkyloxy, 0119 C5-C10 cycloalkoxycarbonylalkyloxy, 0120 C8-C11 aryloxycarbonylalkyloxy, 0121 C8-C12 aryloxycarbonyloxyalkyloxy, 0122 C8-C12 arylcarbonyloxyalkyloxy, 0123 C5-C10 alkoxyalkylcarbonyloxyalkyloxy, 0124 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, 0125 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and 0126 (R5a)HN-(C1-C10 alkoxy)-; 0127 R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl; 0128 n is 0-4; 0129 a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4; 0130 said process comprising: 0131 contacting a compound of formula (IV): 6

0132 wherein: 0133 R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, C1-C6 alkyloxy, aryloxy and aryl substituted with 0-5 R6c; 0134 R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0135 R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0136 with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof. 0137 In a preferred embodiment, the present invention provides a process for the preparation of a compound of formula (I), wherein: 0138 said suitable pressure is up to 100 psi, and 0139 said hydrogenation catalyst is selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, palladium on calcium carbonate and platinum on carbon. 0140 In a more preferred embodiment, the present invention provides a process for the preparation of a compound of formula (I), wherein: 0141 R1 is selected from H or NHR1a; 0142 R1a is C(O)OR1b or SO2R1b; 0143 R1b is selected from the group consisting of: 0144 C1-C8 alkyl substituted with 0-1 R1c, 0145 C2-C8 alkenyl substituted with 0-1 R1c, 0146 C2-C8 alkynyl substituted with 0-1 R1c, 0147 C3-C8 cycloalkyl substituted with 0-1 R1c, 0148 aryl substituted with 0-3 R1c, 0149 aryl(C1-C6 alkyl)-substituted with 0-3 R1c, 0150 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and 0151 C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c; 0152 R1c is selected from the group consisting of H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy and C2-C5 alkoxycarbonyl; 0153 R2 is H or C1-C10 alkyl; 0154 R3 and R4 are H or C1-C6 alkyl; 0155 R5 is selected from the group consisting of hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, C6-C10 aryloxy and C7-C11 arylalkyloxy; 0156 R6 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C8 perfluoroalkyl, C7-C10 arylalkyloxy, C1-C6 alkyloxy, aryloxy, aryl substituted with 0-2 R6c; 0157 R6c is H, halogen, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; and 0158 R6d and R6e are independently selected from H or C1-C10 alkyl; 0159 n is 1; 0160 a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4. 0161 In an even more preferred embodiment, the present invention provides a process for the preparation of a compound of formula (I-a): 7

0162 or a pharmaceutically acceptable salt form thereof, wherein: 0163 R1a is C(O)OCH2(CH2)2CH3 or 3,5-dimethyloxazol-4-yl-sulfonyl; 0164 comprising contacting a compound of formula (IV-a): 8

0165 wherein R6 is H, methyl, ethyl, propyl, butyl, pentyl, hexyl C7-C8 arylalkyloxy, C1-C5 alkyloxy, aryloxy or aryl; 0166 with hydrogen under a suitable pressure from about 20 to about 50 psi in the presence of palladium on carbon, in the range of about 1% to about 10% by weight of compound (IV), to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof. 0167 In a second embodiment, the present invention provides a process for the preparation of compounds of formula (IV) or a salt thereof comprising: 0168 contacting a compound of formula (III): 9

0169 with an acylating agent of formula R6COOCOR6 or R6COX, wherein X is fluorine, bromine, chlorine or imidazole, in a suitable solvent to form a compound of formula (IV) or a salt thereof. 0170 In a preferred second embodiment, the present invention provides a process for the preparation of a compound of formula (IV), wherein: 0171 X is chlorine; 0172 R1 is NHR1a; 0173 R1a is C(O)OCH2(CH2)2CH3 or 3,5-dimethyloxazol-4-yl-sulfonyl; 0174 R2 is H; 0175 R3 and R4 are H; 0176 R5 is methyl; 0177 R6 is CH3; 0178 n is 1; 0179 a is a single bond; and 0180 said suitable solvent is acetic acid. 0181 In a third embodiment, the present invention provides a process for the preparation of compounds of formula (III), comprising: 0182 contacting a compound of formula (II): 10

0183 with a salt of hydroxyl amine in the presence of a suitable base to form a compound of formula (III). 0184 In a preferred third embodiment, the present invention provides a process for the preparation of a compound of formula (III), wherein said salts of hydroxyl amine are hydroxylamine hydrochloride and hydroxlyamine sulfate. 0185 In a more preferred third embodiment, the present invention provides a process for the preparation of a compound of formula (III), wherein: 0186 X is chlorine; 0187 R1 is NHR1a; 0188 R1a is C(O)OCH2(CH2)2CH3 or 3,5-dimethyloxazol-4yl-sulfonyl; 0189 R2 is H; 0190 R3 and R4 are H; 0191 R5 is methyl; 0192 R6 is selected from the group consisting of: 0193 H, C1-C6 alkyl, C7-C8 arylalkyloxy, C1-C5 alkyloxy, aryloxy and aryl; 0194 n is 1; 0195 a is a single bond; 0196 said suitable salt of hydroxylamine is hydroxlyamine hydrochloride; and 0197 the suitable base is selected from the group consisting of: 0198 triethylamine, diisopropylethylamine and 4-methyl morpholine. 0199 In a fourth embodiment, the present invention provides a process for the preparation of compounds of formula (I): 11

0200 or a pharmaceutically acceptable salt form thereof, 0201 said process comprising: 0202 (a) heating a compound of the formula (IV): 12

0203 wherein: 0204 R1 is selected from H or NHR1a; 0205 R1a is selected from the group consisting of: 0206 C(O)OR1b, 0207 C(O)R1b, 0208 C(O)N(R1b)2, 0209 C(O)NHSO2R1b, 0210 C(O)NHC(O)R1b, 0211 C(O)NHC(O)OR1b, 0212 C(O)NHSO2NHR1b, 0213 C(S)NHR1b, 0214 NHC(O)OR1b, 0215 NHC(O)R1b, 0216 NHC()NHR1b, 0217 SO2OR1b, 0218 SO2R1b, 0219 SO2N(R1b)2, 0220 SO2NHC(O)OR1b, 0221 P(S)(OR1b)2, 0222 P(O)(OR1b)2, 0223 P(S)(R1b)2, 0224 P(O)(R1b)2, and 13

0225 R1b is selected from the group consisting of: 0226 C1-C8 alkyl substituted with 0-2 R1c, 0227 C2-C8 alkenyl substituted with 0-2 R1c, 0228 C2-C8 alkynyl substituted with 0-2 R1c, 0229 C3-C8 cycloalkyl substituted with 0-2 R1c, 0230 aryl substituted with 0-4 R1c, 0231 aryl(C1-C6 alkyl)-substituted with 0-4 R1c, 0232 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and 0233 C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c; 0234 R1c is H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0235 R2 is selected from H or C1-C10 alkyl; 0236 R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a; 0237 R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c; 0238 R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d; 0239 R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0240 R5 is selected from the group consisting of: 0241 hydroxy, C1-C10 alkyloxy, C3-C1l cycloalkyloxy, 0242 C6-C10 aryloxy, C7-Cl1 arylalkyloxy, 0243 C3-C10 alkylcarbonyloxyalkyloxy, 0244 C3-C10 alkoxycarbonyloxyalkyloxy, 0245 C3-C10 alkoxycarbonylalkyloxy, 0246 C5-C10 cycloalkylcarbonyloxyalkyloxy, 0247 C5-C10 cycloalkoxycarbonyloxyalkyloxy, 0248 C5-C10 cycloalkoxycarbonylalkyloxy, 0249 C8-C11 aryloxycarbonylalkyloxy, 0250 C8-C12 aryloxycarbonyloxyalkyloxy, 0251 C8-C12 arylcarbonyloxyalkyloxy, 0252 C5-C10 alkoxyalkylcarbonyloxyalkyloxy, 0253 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, 0254 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and 0255 (R5a)HN-(C1-C10 alkoxy)-; 0256 R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl; 0257 R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, aryloxy and aryl substituted with 0-5 R6c; 0258 R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0259 R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0260 n is 0-4; 0261 a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4; 0262 for a time sufficient, and to a temperature sufficient to form a compound of formula (V): 14

0263 and (b) contacting said compound of formula (V) with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a salt thereof. 0264 In a preferred fourth embodiment, the present invention provides a process for the preparation of a compound of formula (I), wherein: 0265 said suitable pressure is up to 100 psi; 0266 said hydrogenation catalyst is selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, palladium on calcium carbonate and platinum on carbon; 0267 said sufficient temperature is from about 30 C. to about 120 C.; 0268 said sufficient time is from about 10 minutes to about 24 hours; 0269 wherein an amount of catalyst loaded on carbon is from about 1% to about 10% by weight; and 0270 wherein an amount of a hydrogenation catalyst is from about 1% to about 30% by weight of compound (IV). 0271 In a more preferred fourth embodiment, the present invention provides a process for the preparation of a compound of formula (I), wherein: 0272 R1 is NHR1a; 0273 R1a is C(O)OCH2(CH2)2CH3 or 3,5-dimethyloxazol-4yl-sulfonyl; 0274 R2 is H; 0275 R3 and R4 are H; 0276 R5 is methyl; 0277 R6 is selected from the group consisting of: 0278 H, methyl, ethyl, propyl, butyl, pentyl, hexyl, C7-C8 arylalkyloxy, aryloxy, C1-C5 alkoxy and aryl; 0279 n is 1, and 0280 a is a single bond; 0281 said suitable pressure is from about 20 to about 50 psi; 0282 said sufficient temperature is from about 50 C. to about 120 C.; said sufficient time is from about 10 minutes to about 3 hours; 0283 said hydrogenation catalyst is palladium on carbon; 0284 wherein an amount of catalyst loaded on carbon is from about 3% to about 5% by weight; and 0285 wherein an amount of palladium on carbon is from about 3% to about 7% by weight of compound (IV). 0286 In a fifth embodiment, the present invention provides a process for the preparation of compounds of the formula (I): 15

0287 or a pharmaceutically acceptable salt form thereof; 0288 wherein: 0289 R1 is selected from H or NHR1a; 0290 R1a is selected from the group consisting of: 0291 C(O)OR1b, 0292 C(O)R1b, 0293 C(O)N(R1b)2, 0294 C(O)NHSO2R1b, 0295 C(O)NHC(O)R1b, 0296 C(O)NHC(O)OR1b, 0297 C(O)NHSO2NHR1b, 0298 C(S)NHR1b, 0299 NHC(O)OR1b, 0300 NHC(O)R1b, 0301 NHC()NHR1b, 0302 SO2R1b, 0303 S2N(R1b)2, 0304 SO2NHC(O)OR1b, 0305 P(S)(OR1b)2, 0306 P(O)(OR1b)2, 0307 P(S)(R1b)2, 0308 P(O)(R1b)2, and 16

0309 R1b is selected from the group consisting of: 0310 C1-C8 alkyl substituted with 0-2 R1c, 0311 C2-C8 alkenyl substituted with 0-2 R1c, 0312 C2-C8 alkynyl substituted with 0-2 R1c, 0313 C3-C8 cycloalkyl substituted with 0-2 R1c, 0314 aryl substituted with 0-4 R1c, 0315 aryl(C1-C6 alkyl)-substituted with 0-4 R1c, 0316 a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R1c, and 0317 C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4R1c; 0318 R1c is H, halogen, CF3, CN, NO2, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0319 R2 is selected from H or C1-C10 alkyl; 0320 R3 and R4 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and aryl substituted with 0-2 R3a; 0321 R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, NO2, and NR3bR3c; 0322 R3b and R3c are each independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, aryl (C1-C10 alkyl) sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 R3d; 0323 R3d is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0324 R5 is selected from the group consisting of: 0325 hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, 0326 C6-C10 aryloxy, C7-C11 arylalkyloxy, 0327 C3-C10 alkylcarbonyloxyalkyloxy, 0328 C3-C10 alkoxycarbonyloxyalkyloxy, 0329 C3-C10 alkoxycarbonylalkyloxy, 0330 C5-C10 cycloalkylcarbonyloxyalkyloxy, 0331 C5-C10 cycloalkoxycarbonyloxyalkyloxy, 0332 C5-C10 cycloalkoxycarbonylalkyloxy, 0333 C8-C11 aryloxycarbonylalkyloxy, 0334 C8-C12 aryloxycarbonyloxyalkyloxy, 0335 C8-C12 arylcarbonyloxyalkyloxy, 0336 C5-C10 alkoxyalkylcarbonyloxyalkyloxy, 0337 5-(C5-C10 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, 0338 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)-methyloxy, and 0339 (R5a)HN(C1-C10 alkoxy)-; 0340 R5a is selected from the group consisting of H, C1-C4 alkyl, aryl(C1-C10 alkoxy)carbonyl, C2-C10 alkoxycarbonyl, and C3-C6 alkenyl; 0341 n is 0-4; 0342 a is a single or double bond, with the proviso that if a is a double bond, it is not simultaneously substituted with R3 and R4; 0343 said process comprising: 0344 contacting a compound of formula (VI): 17

0345 wherein: 0346 Z is selected from R6SO2 or (R7)3Si; 0347 R6 is selected from the group consisting of H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, C1-C8 alkyl, C1-C8 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C7-C10 arylalkyloxy, aryloxy and aryl substituted with 0-5 R6c; 0348 R6c is selected from the group consisting of H, halo, CF3, CN, NO2, NR6dR6e, C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C2-C5 alkoxycarbonyl; 0349 R6d and R6e are independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkoxycarbonyl, C2-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C10 alkyl)sulfonyl, arylsulfonyl, heteroaryl(C1-C4 alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, or heteroarylalkylcarbonyl, wherein said aryl and heteroaryl are optionally substituted with 0-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2; 0350 R7 is selected independently from C1-C10 alkyl or aryl substituted 0-3 R7a; and 0351 R7a is C1-C10 alkyl; 0352 with hydrogen under a suitable pressure in the presence of a hydrogenation catalyst to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof. 0353 In a sixth embodiment, the present invention provides a process for the preparation of compounds of formula (VI): 18

0354 comprising: contacting a compound of formula (III): 19

0355 with an agent of formula Z-X, wherein: 0356 X is fluorine, bromine or chlorine; 0357 Z is R6SO2 or (R7)3Si; 0358 R7 is selected independently from C1-C10 alkyl or aryl substituted 0-3 R7a; and 0359 R7a is C1-C10 alkyl; 0360 in the presence of a suitable acid scavenger in a suitable solvent to form a compound of formula (IV) or a salt thereof. 0361 In a seventh embodiment, the present invention provides a compound of formula (III-i): 20

0362 and salt forms thereof. 0363 In a eighth embodiment, the present invention provides a compound of formula (IV-i): 21

0364 and salt forms thereof. 0365 In a ninth embodiment, the present invention provides a compound of formula (V-i): 22

0366 and salt forms thereof.

DEFINITIONS 0367 The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected. 0368 Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2-dichlorotetrafluorethane and hexafluoroethane. 0369 Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or t-butyl methyl ether. 0370 Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. 0371 Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide. 0372 Suitable hydrocarbon solvents include: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene. 0373 Suitable carboxylic acid solvents include acetic acid, trifluoroacetic acid, ethanoic acid, propionic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid. 0374 Suitable pressures range from atmospheric to any pressure obtainable in a laboratory or industrial plant. 0375 Suitable hydrogenation catalysts are those which facilitate the delivery of hydrogen to the NO bond of an N-acylated hydroxylamine. Such hydrogenation catalysts by way of example and without limitation are palladium on carbon, palladium hydroxide on carbon, palladium on calcium carbonate poisoned with lead and platinum on carbon. 0376 As used herein, suitable acid scavengers include those compounds capable of accepting a proton from a hydroxyamidine during either an acylation, sulfonation or silation reaction without reacting with the agent reacting with the oxygen of the hydroxyamidine. Examples include, but are not limited to tertiary bases such as N,N-diisopropylethylamine, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-lutidine, triethylamine, 2-, 3-, or 4-picoline, pyrrole, pyrrolidine, N-methyl morpholine, pyridine and pyrimidine. 0377 As used herein, suitable bases include those soluble in the reaction solvent and capable of free-basing hydroxylamine. Examples include, but are not limited to: lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, imidazole, ethylene diamine, N,N-diisopropylethylamine, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-lutidine, triethylamine, 2-, 3-, or 4-picoline, pyrrole, pyrrolidine, N-methyl morpholine, pyridine, pyrimidine or piperidine. 0378 As used herein, acylating agent refers to an acid halide or anhydride, which, when reacted with a hydroxyamidine results in O-acylation of the hydroxyl amidine. Such acylating agents by way of example and without limitation are of the general structure R6COX or R6COOCOR6, as defined above in the specification. By way of further example, and without limitation, where X is fluorine, chlorine, bromine or imidazole, R6 is H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, methyl, ethyl, propyl, butyl, ethenyl, allyl, ethynyl, cyclopropyl, phenyl, benzyl, C7-C10 arylalkyloxy, C1-C10 alkyloxy or aryloxy. 0379 As used herein, agent refers to a compound of the formula Z-X, which, when reacted with a hydroxyamidine results in placement of the Z group on the oxygen of the hydroxyamidine. By way of further example, and without limitation, where X is fluorine, chlorine, bromine or imidazole, Z is either R6SO2 or (R7)3Si, R6 is H, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, methyl, ethyl, propyl, butyl, ethenyl, allyl, ethynyl, cyclopropyl, phenyl, benzyl, C7-C10 arylalkyloxy, or aryloxy, and R7 is independently selected from C1-C10 alkyl or aryl substituted with 0-3 R7a, and R7a is C1-C10 alkyl. 0380 The compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, CN double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic forms or by synthesis. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended. 0381 When any variable (for example but not limited to R1b, R1c, R3a, R3b, R3c, R6c, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3a, then said group may optionally be substituted with up to two R3a and R3a at each occurrence is selected independently from the defined list of possible R3a. 0382 Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 0383 The term substituted, as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. 0384 As used herein, alkyl, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, C1-C4 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl; for example C1-C10 alkyl includes C1-C4 alkyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomer thereof. 0385 As used herein, any carbon range such as Cx-Cy is intended to mean a minimum of x carbons and a maximum of y carbons representing the total number of carbons in the substituent to which it refers. For example, C3-C10 alkylcarbonyloxyalkyloxy could contain one carbon for alkyl, one carbon for carbonyloxy and one carbon for alkyloxy giving a total of three carbons, or a larger number of carbons for each alkyl group not to exceed a total of ten carbons. 0386 Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl and the like. Alkynyl, is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl and the like. Aryl is intended to mean phenyl or naphthyl. The term arylalkyl represents an aryl group attached through an alkyl bridge; for example aryl(C1-C2)alkyl is intended to mean benzyl, phenylethyl and the like. 0387 As used herin, cycloalkyl is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl. 0388 As used herein, alkyloxy or alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, for example methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy and t-butoxy. The term aryloxy is intended to mean phenyl or naphthyl attached through an oxygen bridge; 0389 As used herein, carbonyl means a carbon double bonded to oxygen and additionally substituted with two groups through single bonds; carbonyloxy means a carbon double bonded to oxygen and additionally bonded through a single bonds to two groups, one of which is an oxygen. As used herein, sulfonyl is intended to mean a sulfur bonded through double bonds to two oxygens and bonded to two additional groups through single bonds. As used herein, hydroxy means a group consisting of an oxygen and a hydrogen bonded to another group through the oxygen. 0390 Halo or halogen as used herein refers to fluoro, chloro, bromo and iodo. 0391 As used herein, the term heterocycle or heterocyclic is intended to mean a stable 5- to 10-membered monocyclic or bicyclic or 5- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. 0392 As used herein, the term heteroaryl refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl. 0393 As used herein, pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the intermediates or final compound are modified by making acid or base salts of the intermediates or final compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 0394 The pharmaceutically acceptable salts of the intermediates or final compounds include the conventional non-toxic salts or the quaternary ammonium salts from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. 0395 The pharmaceutically acceptable salts are generally prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents. 0396 The pharmaceutically acceptable salts of the acids of the intermediates or final compounds are prepared by combination with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like. 0397 As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The present invention is contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers. 0398 The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 1. Scheme 1 details the general synthetic method for synthesis of compounds of formula (I). Compound (II) can be prepared by methods described in J. Org. Chem. 1997, 62, 2466-2470, and Tetrahedron Lett. 1996, 37, 4455-4458. It is understood to one skilled in the art that the anhydride or acid chlorides used in the acylation step can be prepared by conversion of carboxylic acid derivatives as described in Advanced Organic Chemistry, March, 4th edition, John Wiley and Sons, Inc., 1992, p. 401-402 and p. 437-438. 23

0399 In reaction 1, a compound of formula (II) is dissolved in about 10 liters of suitable solvent per kilogram of compound (II). A suitable salt of hydroxyl amine is added. While a wide range of solvents such as halogenated, protic, aprotic, hydrocarbon, or ethers can be used, protic solvents such as methanol, ethanol and isopropanol are preferred, of which methanol is most preferred. Suitable salts of hydroxyl amine include phosphate, sulfate, nitrate and hydrochloride salts; a most preferred salt is hydroxyl amine hydrochloride. The hydroxyl amine salt is free-based with about 1.0 to about 2.0 equivalents of an appropriate base. Preferrable bases are tertiary amines; most preferred is triethyl amine. The reaction mixture can then be heated for a time sufficent to form a compound of form (III). By way of general guidance, compound (II) may be contacted with free-based hydroxyl amine at about 40 C. to about 65 C. for about 1 to about 5 hours to produce compound (III). Preferred temperatures are from about 55 C. to about 65 C. Preferred reaction times are from about 2 to about 4 hours. The product precipitates as a white solid during the course of the reaction. The solids can then be filtered and the cake washed with a solvent, the choice of which is readily understood by one skilled in the art. The product is dried to afford pure compound (III). 0400 In reaction 2, a vessel is charged with compound (III). The solids are dissolved in a suitable solvent followed by the slow charging of the vessel with a second solution made by dissolving a suitable acylating agent in the solvent being used for the reaction. Preferably, the addition of the acylating agent solution should be done over a period of about 15 minutes to about one hour. While a wide range of reaction solvents such as halogenated, aprotic, hydrocarbon, ether, or organic acids are possible, preferred solvents are acetic acid, trifluoroacetic acid, pyridine, chloroform, dichloromethane, dichlorobenzene, acetonitrile, and tetrahydrofuran. Most preferred are carboxylic acids which are structural derivatives of the acylating agent being used. By way of general example, acetic acid would preferably be used as the solvent when acetic anhydride is the acylating agent, whereas triflouroacetic acid would be preferably used when trifluoroacetic anhydride is the acylating agent. Certain solvents such as aprotic, ether, halogenated and hydrocarbon solvents may require the addition of an acid scavenger. Preferred acid scavengers include tertiary bases such as triethyl amine, diisopropyl ethylamine, N-methyl morpholine and pyridine. Most preferred is triethyl amine. Solvents capable of reacting with the acylating agent, such as alcohols, water and the like are not preferred as is readily understood by one skilled in the art. Preferred acylating agents are anhydrides. Most preferred is acetic anhydride. Further, the acylating agent (and preferable solvent) can be strategically chosen to form the desired salt of the reaction product. By way of general example, acetic anhydride would be selected as the acylating agent if the acetate salt of the product is desired. The choice of acylating agent and solvent in this regard is readily understood by one skilled in the art. 0401 After the addition of the acylating agent, the reaction progression can be monitored by HPLC analysis performed on an aliquot of the reaction solution. The acylation reaction is considered finished when compound (III) is completely consumed. Typical reaction times are in the range of about 5 minutes to about 24 hours. Preferred reaction times are about 5 minutes to about 3 hours. The product can be isolated by the removal of the solvent via distillation and precipitation of the product through the addition of a suitable aprotic solvent. Preferred aprotic solvents are ethers. The choice of precipition solvent and the methods of isolation are readily understood by one skilled in the art. Preferably, the product is carried forward without isolation. 0402 Reaction 3, comprises the hydrogenation of the O-substituted hydroxyamidine. This reaction can be carried out without isolation of compound (IV), by the addition of a slurry of a suitable hydrogention catalyst in the solvent used in the preceding reaction. If compound (IV) is isolated, the hydrogenation can be carried out in protic, aprotic, hydrocarbon, ether, or organic acid solvents. The preferred solvents are methanol, ethanol, 2-propanol, dimethylformamide, ethyl acetate, anisole, acetic acid and trifluoroacetic acid. Most preferred is a mixture of methanol and acetic acid. While numerous hydrogenation catalysts are possible, palladium on carbon is most preferred. The amount of catalyst loaded on the carbon ranges from about 0.5% to about 30%. The preferred amount of catalyst on carbon is about 1% to about 10%. Most preferred is about 3% to 5%. The total weight of the catalyst and carbon per gram of starting material is preferably about 1% to about 10%. Most preferred is about 3% to 7%. The total weight of catalyst and carbon is based on the weight of the O-alkylated hydroxyamidine. The reaction solution is then subjected to a hydrogen atmosphere under a suitable pressure. Preferred pressures range from about 1 psi to 100 psi. Most preferred is 20 psi to 50 psi. The reaction time of the hydrogenation is dependent on cumulative factors, including the amount of catalyst present, the reaction temperature and the hydrogen pressure. By way of general example, an acetylation reaction containing 10.0 kilograms of compound (III) required the use of 0.5 kilograms of 3% palladium on carbon, under 5 psi of hydrogen at room temperature to reach completion in about 5 hours. Varying any one of these conditions will effect reaction time which is readily understood by one skilled in the art. 0403 Reaction completion can be monitored by HPLC analysis performed on aliquots of the reaction mixture. The reaction is considered complete when compound (IV) has been completely consumed. After the reaction is judged complete, the catalyst is filtered off and washed with reaction solvent. The filtrate is concentrated, and the product precipitated by the addition of a suitable aprotic solvent. The most preferred solvent for precipitation is acetone. The choice of precipition solvent and the methods of isolation are readily understood by one skilled in the art. The product is then filtered and dried to give pure compound (I). 0404 In reaction 4, the resultant reaction solution of Step 2 is heated to form compound (V). The heating range is from about 30 C. to the reflux temperature of the solvent. Preferred temperatures are from about 30 C. to about 120 C. Preferred solvents for the cyclization are acetic acid, trifluoroacetic acid, pyridine, chloroform, dichloromethane, dichlorobenzene, acetonitrile, and tetrahydrofuran. The most preferred solvent for the cyclization is acetic acid. The preferred time of reflux is solvent dependent due to the limitations of boiling points. By way of general example, the use of acetic acid as the solvent required a heating time of about 3 hours. The product can be isolated by the removal of the solvent via distillation followed by the drying of the solids. Preferably, compound (V) is carried forward without isolation. 0405 In reaction 4, compound (V) is hydrogenated under the identical conditions of Reaction 3 to give compound (I). The present invention may be further exemplified without limitation by reference to Scheme 2. 24

0406 The following examples are meant to be illustrative of the present invention. These examples are presented to exemplify the invention and are not to be construed as limiting the inventors scope.

EXAMPLE 1 0407 (R)-Methyl-3-34amino(hydroxyimino)methyl phenyl-4,5-dihydro-5-isoxazolylacetylamino-N (butoxy-carbonyl)-L-alanine: Compound (III-i) 0408 A 100 gal stainless steel reactor was charged with methanol (87 Kg), compound (II-i) (11 Kg), hydroxylamine hydrochloride (3.6 Kg), and triethylamine (5.2 Kg). The reaction mixture was heated at 60 C. for 3 h and a large amount of solid precipitated during the reaction. After cooling to 0-5 C., the solid was filtered through a Nutsche filter and the cake was washed with a mixture of methanol and water (made from 20 Kg of methanol and 25 Kg of water). After dried the cake, the product (11.8 Kg) was obtained.

EXAMPLE 2 0409 (R)-Methyl-3-3-4-(aminoiminomethyl)phenyl-4,5-dihydro-5-isoxazolylacetylamino-N(butoxy carbonyl)-L-alanine monoacetate: Compound (I-i) 0410 A 50 gal stainless steel reactor was charged with acetic acid(63 Kg) and (R)-Methyl-334amino(hydroxyimino) methylphenyl-4,5-dihydro-5-isoxazolylacetylamino-N (butoxy-carbonyl)-L-alanine (Batch 1: 10.0 Kg; Batch 2: 10.0 Kg.) A solution of acetic anhydride (Batch 1: 2205 g; Batch 2: 1983 g) in acetic acid (21 Kg) was charged into the reactor slowly over 30 min from a pressure cylinder using nitrogen pressure at rt (22 C.). Additional 5.3 Kg of acetic acid was then used to rinse the cylinder. After stirring at 22 C. for 30 min or until a clear solution was attained, a small sample was taken for HPLC analysis. After the reaction was complete as determined by HPLC. A slurry of Pd/C (Batch 1: 3%Pd/C, 0.5 Kg; Batch 2: 5%Pd/C, 0.4 Kg) in acetic acid (5 L) was added and the resulting mixture was hydrogenated under 5 psi hydrogen pressure for 4-5 h. After the reaction was complete as determined by HPLC, the catalyst was filtered off and washed with acetic acid (21 Kg) to give a solution of the product. Anisole (80 Kg) was then added to the filtrate and the resulting mixture was concentrated at about 70 C. under vacuum (40 mm Hg or lower) in a 100 gal reactor. The distillation was stopped until that the distillate was about 148 L or the solid became visible in the batch. Cooled the reactor to 40 C., 72 Kg of acetone was added over 30-90 min. The slurry was stirred at ambient temperature for 1 h and the 0-5 C. for another 1 h. The solid was collected on a Rosenmund filter/dryer and the cake was washed with 10% methanol in acetone (made from 6 Kg of methanol and 57 Kg of acetone). The solid cake was dried until LOD<1%. A hot (80 C.) mixture of acetonitrile (27 Kg) and acetic acid (18 Kg) was charged into the filter to dissolve the cake and the hot solution was then transfer back to 100 gal reactor. The transfer line was washed with a mixture of acetic acid (0.9 Kg) and acetonitrile (1.4 Kg). After the solution was cooled to 40-45 C., acetone (65 Kg) was added within 10 min. The resulting slurry was stirred gently at 25 C. for 1 h and then 0-5 C. for another 1 h. The solid was filtered by the Rosenmund filter/dryer and the cake was washed with 10% methanol in acetone (prepared from 5.5 Kg methanol and 50 Kg of acetone). After drying the cake until LOD<0.1%, the product was obtained (Batch 1: 6.3 Kg. Batch 2: 6.8 Kg). Heels from both batches in the Rosenmund filter/dryer were dissolved in acetonitrile and acetic acid and combined, which was crystallized in the Kilo lab to give additional 2.86 Kg of product.

EXAMPLE 3 0411 (R)-methyl-3-3-4-(acetyloxyimino)aminomethyl phenyl-4,5-dihydro-5-isoxazolylacetylamino-N-(butoxycarbonyl)-L-alanine: Compound (IV-i) 0412 To a suspension of (R)-Methyl-3-3-4-amino (hydroxyimino)methylphenyl-4,5-dihydro-5-isoxazolyl acetylamino-N-(butoxycarbonyl)-L-alanine (11.76 g) in acetic acid (50 mL) was added acetic anhydride (3.6 g) dropwise. After the completion of addition, the reaction mixture was stirred at room temperature 15 min. The reaction mass became clear. Ether (200 mL) was added slowly and a thick slurry formed. The resulting mixture was then stirred for another 1.5 h at room temperature and the solid was filtered. The cake was washed with ether (50 mL) and dried to give (R)-methyl-3-3-4-(acetyloxyimino) aminomethyl phenyl-4,5-dihydro-5-isoxazolyl acetylamino-N-(butoxycarbonyl)-L-alanine (12.3 g).

EXAMPLE 4 0413 (R)-methyl-N-(butoxycarbonyl)-3-4,5-dihydro-3-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl-5-isoxazolylacetyl amino-L-alanine: Compound (V-i) 0414 To a suspension of (R)-Methyl-3-3-4-amino (hydroxyimino)methylphenyl-4,5-dihydro-5-isoxazolyl acetylamino-N-(butoxycarbonyl)-L-alanine (1.05 g) in acetic acid (7 mL) was added acetic anhydride (0.35 g) dropwise. After the completion of addition, the reaction mixture was refluxed for 3 h. The solvent was distilled under vacuum and the solid was dried to give (R)-methyl-N-(butoxycarbonyl)-3-4,5-dihydro-3-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl-5-isoxazolylacetylamino-L-alanine (1.05 g).

EXAMPLE 5 0415 (R) -Methyl-3-3-4-(aminoiminomethyl)phenyl-4,5-dihydro-5-isoxazolylacetylamino-N-(butoxy-carbonyl)-L-alanine monoacetate: Compound (I-i) Method B: 0416 A mixture of (R)-methyl-N-(butoxycarbonyl)-3-4,5-dihydro-3-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl-5-isoxazolyl acetylamino-L-alanine (70 mg) and 3%Pd/C (30 mg) in methanol (3 mL) and acetic acid (0.5 mL) was stirred under hydrogen atmosphere for 3 h. The catalyst was filtered off and washed with methanol (4 mL). The combined filtrate and wash was concentrated to small volume. Acetone (2 mL) was added slowly and a slurry was formed. After stirred for 30 min, the solid was filtered and the cake was washed with 10% methanol in acetone (4 mL) and dried to give the product (25 mg). 1HPLC CONDITIONSColumn:Eclipse XDB-C8 4.6 250 mmMobile Phase:A: 0.1% trifluoroacetic acid/0.1%triethylamine in HPLC grade waterB: tetrahydrofuran (unstabilized-suitablefor liquid chromatography)/0.1%trifluoroacetic acidGradient:t 0 min 85% A 15% Bt 10 min 85% A 15% Bt 32 min 50% A 50% Bt 40 min 50% A 50% BFlow Rate:1.5 mL/minInjection Volume:10 microlitersStop Time:40 minutesPost Time:10 minutesOven Temp.:40 C.Detector:UV (280 nm, 230 nm, 260 nm)

0417 Sample Prep.: Dissolve approximately 0.5 mg of sample (dry solids weight) per mL in 50% tetrahydrofuran 49.9% H20/0.1% acetic acid. Filter any undissolved solids through an Acrodisc 0.45 micron Nylon filter.