Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors

Abstract

In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

Description

FILED OF THE INVENTION

[0002] The present invention relates to pyrazolo[1,5-a]pyrimidine compounds useful as protein kinase inhibitors (such as for example, the inhibitors of the cyclin-dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases. This application claims benefit of priority from U.S. provisional patent applications, Serial No. 60/408,027 filed Sep. 4, 2002, and Ser. No. 60/421,959 filed Oct. 29, 2002.

BACKGROUND OF THE INVENTION

[0003] Protein kinase inhibitors include kinases such as, for example, the inhibitors of the cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), and the like. Protein kinase inhibitors are described, for example, by M. Hale et al in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236. The cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycle progression and can be classified as either G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells, and misregulation of CDK function occurs with high frequency in many important solid tumors. CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E). Many reports have demonstrated that both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over—or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development years, a number of adenosine 5′-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers. U.S. Pat. No. 6,413,974, col. 1, line 23-col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer.

[0004] CDK inhibitors are known. For example, flavopiridol (Formula I) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Sanderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999. 1

[0005] Other known inhibitors of the CDKs include, for example, olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. Pat. No. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors. An illustrative compound from the '305 patent has the Formula II: 2

[0006] K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162 disclose certain aminothiazole compounds as CDK inhibitors.

[0007] Pyrazolopyrimidines are known. For Example, WO92/18504, WO02/50079, WO95/35298, WO02/40485, EP94304104.6, EP0628559 (equivalent to U.S. Pat. Nos. 5,602,136, 5,602,137 and 5,571,813), U.S. Pat. No. 6,383,790, Chem. Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclose various pyrazolopyrimidines. Other publications of interest are: WO 03/101993 (published Dec. 11, 2003), WO 03/091256 (published No. 6, 2003), and DE 10223917 (published Dec. 11, 2003).

[0008] There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with CDKs. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders.

SUMMARY OF THE INVENTION

[0009] In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

[0010] In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in Formula III: 3

[0011] wherein:

[0012] R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR5)n-aryl, —(CHR5)n— 4

[0013] wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, —OR5, —NR5R10, —C(R4R5)p—R9, —N(R5)Boc, —(CR4R5)pOR5, —(CO2)R5, —C(O)R5, —C(O)NR5R10, —SO3H, —SR10, —S(O2)R7, —S(O2)NR5R10, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R10;

[0014] R2 is selected from the group consisting of R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or 5

[0015] wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR5, —SR5, —S(O2)R6, —S(O2)NR5R6, —NR5R6, —C(O)NR5R6, CF3, alkyl, aryl and OCF3;

[0016] R3 is selected from the group consisting of H, halogen, —NR5R6, —OR6, —SR6, —C(O)N(R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, 6

[0017] wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —(CR4R5)pOR5, —OR5, —NR5R6, —(CR4R5)pNR5R6, —C(O2)R5, —C(O)R5, —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6, with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR5 moiety;

[0018] R4 is H, halo or alkyl;

[0019] R5 is H, alkyl, aryl or cycloalkyl;

[0020] R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, —OR5, —NR5R10, —(CR4R5)p—R9, —N(R5)Boc, —(CR4R5)pOR5, —C(O2)R5, —C(O)R5, —C(O)NR5R10, —SO3H, —SR10, —S(O2)R7, —S(O2)NR5R10, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R10;

[0021] R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, —OR5, —NR4R5, —(CR4R5)p—R9, —N(R5)Boc, —(CR4R5)pOR5, —C(O2)R5, —C(O)NR4R5, —C(O)R5, —SO3H, —SR5, —S(O2)R7, —S(O2)NR4R5, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR4R5;

[0022] or optionally (i) R5 and R10 in the moiety —NR5R10, or (ii) R5 and R6 in the moiety —NR5R6, may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups;

[0023] R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R10, —CH2OR5, —C(O2)R5, —C(O)NR5R10, —C(O)R5, —SR10, —S(O2)R10, —S(O2)NR5R10, —N(R5)S(O2)R10, —N(R5)C(O)R10 and —N(R5)C(O)NR5R10;

[0024] R8 is selected from the group consisting of R6, —OR6, —C(O)NR5R10, —S(O2)NR5R10, —C(O)R7, —(C═N—CN)—NH2, —(C═NH)—NHR5, heterocyclyl, and —S(O2)R7;

[0025] R9 is selected from the group consisting of halogen, —CN, —NR5R10, —C(O2)R6, —C(O)NR5R10, —OR6, —SR6, —S(O2)R7, —S(O2)NR5R10, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R10;

[0026] m is 0 to 4;

[0027] n is 1 to 4; and

[0028] p is 1 to 4,

[0029] with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2is aryl, R is not 7

[0030] and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.

[0031] The compounds of Formula III can be useful as protein kinase inhibitors and can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.

DETAILED DESCRIPTION

[0032] In one embodiment, the present invention discloses pyrazolo[1,5-a]pyrimidine compounds which are represented by structural Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.

[0033] In another embodiment, R is —(CHR5)n-aryl, —(CHR5)n-heteroaryl, —(CHR5)n-heteroaryl (with said heteroaryl being substituted with an additional, same or different, heteroaryl), —(CHR5)n-heterocyclyl (with said heterocyclyl being substituted with an additional, same or different, heterocyclyl), or 8

[0034] In another embodiment, R2 is halogen, CF3, CN, lower alkyl, alkyl substituted with —OR6, alkynyl, aryl, heteroaryl or heterocyclyl.

[0035] In another embodiment, R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl, —NR5R6, 9

[0036] wherein said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures shown immediately above for R3 are optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF3, OCF3, lower alkyl, CN, —C(O)R5, —S(O2)R5, —C(═NH)—NH2, —C(═CN)—NH2, hydroxyalkyl, alkoxycarbonyl, —SR5, and OR5, with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR5 moiety.

[0037] In another embodiment, R4 is H or lower alkyl.

[0038] In another embodiment, R5 is H, lower alkyl or cycloalkyl.

[0039] In another embodiment, n is 1 to 2.

[0040] In an additional embodiment, R is —(CHR5)n-aryl, —(CHR5)n-heteroaryl.

[0041] In an additional embodiment, R2 is halogen, CF3, CN, lower alkyl, alkynyl, or alkyl substituted with —OR6.

[0042] In an additional embodiment, R2 is lower alkyl, alkynyl or Br.

[0043] In an additional embodiment, R3 is H, lower alkyl, aryl, 10

[0044] wherein said alkyl, aryl and the heterocyclyl moieties shown immediately above for R3 are optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF3, lower alkyl, hydroxyalkyl, alkoxy, —S(O2)R5, and CN.

[0045] In an additional embodiment, R4 is H.

[0046] In an additional embodiment, R5 is H, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0047] In an additional embodiment, R8 is alkyl or hydroxyalkyl.

[0048] In an additional embodiment, n is 1.

[0049] In an additional embodiment, p is 1 or 2.

[0050] Another embodiment discloses the inventive compounds shown in Table 1, which exhibited CDK2 inhibitory activity of about 0.0001 μM to >about 5 μM. The assay methods are described later (from page 333 onwards).

TABLE 1
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239

[0051] Another embodiment of the invention discloses the following compounds, which exhibited CDK2 inhibitory activity of about 0.0001 μM to about 0.5 μM: 240241242243244245246247248249250251252253254255256

[0052] Another embodiment of the invention discloses the following compounds, which exhibited CDK2 inhibitory activity of about 0.0001 μM to about 0.1 μM: 257258259260261262263264265266267268269270271272273

[0053] As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0054] “Patient” includes both human and animals.

[0055] “Mammal” means humans and other mammalian animals.

[0056] “Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term “substituted alkyl” means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)2, carboxy and —(CO)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substituted alkynyl” means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

[0057] “Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

[0058] “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

[0059] “Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

[0060] “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

[0061] “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.

[0062] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

[0063] “Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl), Y1Y2N—, Y1Y2N-alkyl—, Y1Y2NC(O)—, Y1Y2NSO2— and —SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH3)2— and the like which form moieties such as, for example: 274

[0064] “Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as I defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.

[0065] It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: 275

[0066] there is no —OH attached directly to carbons marked 2 and 5.

[0067] It should also be noted that tautomeric forms such as, for example, the moieties: 276

[0068] are considered equivalent in certain embodiments of this invention.

[0069] “Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

[0070] “Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

[0071] “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

[0072] “Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

[0073] “Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

[0074] “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

[0075] “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

[0076] “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

[0077] “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

[0078] “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

[0079] “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

[0080] “Alkoxycarbonyl” means an alkyl-O-CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0081] “Aryloxycarbonyl” means an aryl-O-C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0082] “Aralkoxycarbonyl” means an aralkyl-O-C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0083] “Alkylsulfonyl” means an alkyl-S(O2)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

[0084] “Arylsulfonyl” means an aryl-S(O2)— group. The bond to the parent moiety is through the sulfonyl.

[0085] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant 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.

[0086] The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

[0087] The term “isolated” or “in isolated form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term “purified” or “in purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

[0088] It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom(s) to satisfy the valences.

[0089] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, N.Y.

[0090] When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula II, its definition on each occurrence is independent of its definition at every other occurrence.

[0091] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0092] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula III or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-rugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

[0093] “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0094] “Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the CDK(s) and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

[0095] The compounds of Formula III can form salts which are also within the scope of this invention. Reference to a compound of Formula III herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula III contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula III may be formed, for example, by reacting a compound of Formula III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0096] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Joumal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

[0097] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0098] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0099] Compounds of Formula III, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

[0100] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[0101] The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula III can be inhibitors of protein kinases such as, for example, the inhibitors of the cyclin-dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and the like. The cyclin dependent kinases (CDKs) include, for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8. The novel compounds of Formula III are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. Many of these diseases and disorders are listed in U.S. Pat. No. 6,413,974 cited earlier, the disclosure of which is incorporated herein.

[0102] More specifically, the compounds of Formula III can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;

[0103] hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkeft's lymphoma;

[0104] hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;

[0105] tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

[0106] tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and

[0107] other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[0108] Due to the key role of CDKs in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.

[0109] Compounds of Formula III may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that CDK5 is involved in the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749).

[0110] Compounds of Formula III may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of Formula III, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

[0111] Compounds of Formula III, as inhibitors of the CDKs, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

[0112] Compounds of Formula III may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.

[0113] Compounds of Formula III may also be useful in inhibiting tumor angiogenesis and metastasis.

[0114] Compounds of Formula III may also act as inhibitors of other protein kinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.

[0115] Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with the CDKs by administering a therapeutically effective amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.

[0116] A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula III. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound.

[0117] The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents selected from the group consisting of cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g. taxotere, taxol); topoisomerase II inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar, or topotecan); tubulin interacting agents (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidilate synthase inhibitors (such as 5-fluorouracil); anti-metabolites (such as methoxtrexate); alkylating agents (such as temozolomide (TEMODAR™ from Schering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide); Farnesyl protein transferase inhibitors (such as, SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide, or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.), tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.); signal transduction inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVEC™ (C-abI kinase inhibitor from Novartis Pharmaceuticals, East Hanover, N.J.); interferons such as, for example, intron (from Schering-Plough Corporation), Peg-Intron (from Schering-Plough Corporation); hormonal therapy combinations; aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine.

[0118] Other anti-cancer (also known as anti-neoplastic) agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaeuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.

[0119] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. For example, the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897. Compounds of Formula III may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of Formula III may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.

[0120] Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/treatments result in desired therapeutic effect.

[0121] The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which are described later have been carried out with the compounds according to the invention and their salts.

[0122] This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.

[0123] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0124] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0125] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0126] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0127] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0128] The compounds of this invention may also be delivered subcutaneously.

[0129] Preferably the compound is administered orally or intravenously.

[0130] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0131] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.

[0132] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0133] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.

[0134] Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0135] Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.

[0136] The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure.

[0137] Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.

[0138] Where NMR data are presented, 1H spectra were obtained on either a Varian VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID; gradient flow: 0 min −10% CH3CN, 5 min −95% CH3CN, 7 min −95% CH3CN, 7.5 min −10% CH3CN, 9 min—stop. The retention time and observed parent ion are given.

[0139] The following solvents and reagents may be referred to by their

[0140] abbreviations in parenthesis:

[0141] Thin layer chromatography: TLC

[0142] dichloromethane: CH2Cl2

[0143] ethyl acetate: AcOEt or EtOAc

[0144] methanol: MeOH

[0145] trifluoroacetate: TFA

[0146] triethylamine: Et3N or TEA

[0147] butoxycarbonyl: n-Boc or Boc

[0148] nuclear magnetic resonance spectroscopy: NMR

[0149] liquid chromatography mass spectrometry: LCMS

[0150] high resolution mass spectrometry: HRMS

[0151] milliliters: mL

[0152] millimoles: mmol

[0153] microliters: μl

[0154] grams: g

[0155] milligrams: mg

[0156] room temperature or rt (ambient): about 25° C.

[0157] dimethoxyethane: DME

EXAMPLES

[0158] In general, the compounds described in this invention can be prepared through the general routes described below in Scheme 1. Treatment of the 277

[0159] starting nitrile with potassium t-butoxide and ethyl formate gives rise to the intermediate enol 2 which upon treatment with hydrazine gives the desired substituted 3-aminopyrazole. Condensation of compounds of type 3 with the appropriately functionalized keto ester of type 5 gives rise to the pyridones 6 as shown in Scheme 3. The keto esters used in this general route are either commercially available or can be made as illustrated in Scheme 2. 278

[0160] The-chlorides of type 9 can be prepared by treatment of the pyridones 8 with POCl3. When R2 is equal to H, substitution in this position is possible on the compounds of type 9 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions.

[0161] Introduction of the N7-amino functionality can be accomplished through displacement of the chloride of compounds of type 9 by reaction with the appropriate amine as shown in Scheme 3. 279

[0162] Condensation of compounds of type 7 with the appropriately functionalized malonate ester of type 11 gives rise to the pyridones 13 as shown in Scheme 4.

[0163] The chlorides of type 14 can be prepared by treatment of the pyridones 13 with POCl3. When R2 is H, substitution in this position is possible on compounds of type 9 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions.

[0164] Incorporation of the N7-amino functionality can be accomplished through regioselective displacement of the chloride of compounds of type 14. Incorporation of the N5-amino functionality by addition of an appropriate amine at higher temperature. 280

[0165] Alternatively, condensations of the aminopyrazoles of type 7 with an appropriately functionalize keto ester as prepared in Scheme 5, leads to compounds of type 13 as shown in Scheme 4. 281

[0166] The chlorides of type 14 can be prepared by treatment of the pyridones 13 with POCl3. When R2 is equal to H, substitution in this position is possible on compounds of type 14 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions.

[0167] Incorporation of the N7-amino functionality can be accomplished through displacement of the chloride of compounds of type 15.

PREPARATIVE EXAMPLES

Preparative Example 1

[0168] 282

[0169] A procedure in German patent DE 19834047 A1, p 19 was followed. To a solution of KOtBu (6.17 g, 0.055 mol) in anhydrous THF (40 mL) was added, dropwise, a solution of cyclopropylacetonitrile (2.0 g, 0.025 mol) and ethyl formate (4.07 g, 0.055 mol) in anhydrous THF (4 mL). A precipitate formed immediately. This mixture was stirred for 12 hr. It was concentrated under vacuum and the residue stirred with Et2O (50 mL). The resulting residue was decanted and washed with Et2O (2×50 mL) and Et2O removed from the residue under vacuum. The residue was dissolved in cold H2O (20 mL) and pH adjusted to 4-5 with 12 N HCl. The mixture was extracted with CH2Cl2 (2×50 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to give the aldehyde as a tan liquid. 283

[0170] The product from Preparative Example 1, Step A (2.12 g, 0.0195 mol), NH2NH2H2O (1.95 g, 0.039 mol) and 1.8 g (0.029 mole) of glacial CH3CO2H (1.8 g, 0.029 mol) were dissolved in EtOH (10 mL). It was refluxed for 6 hr and concentrated under vacuum. The residue was slurried in CH2Cl2 (150 mL) and the pH adjusted to 9 with 1N NaOH. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the product as a waxy orange solid.

Preparative Examples 2-4

[0171] By essentially the same procedure set forth in Preparative Example 1, only substituting the nitrile shown in Column 2 of Table 2, the compounds in Column 3 of Table 2 were prepared:

TABLE 2
Prep.
Ex.	Column 2	Column 3
2	284	285
3	286	287
3.10	288	289

Preparative Example 4

[0172] 290

[0173] 2-Carbomethoxycyclopentanone (6.6 ml, 0.05 mol) in THF (15 ml) was added dropwise to a vigorously stirred suspension of NaH (60% in mineral oil, 4 g, 0.1 mol) in THF (100 ml) at 0-10° C. When bubbling ceased, the reaction mixture was treated at the same temperature with ClCOOMe (7.8 ml, 0.1 mol) in THF (15 ml). The resulted off-white suspension was stirred for 30 minutes at room temperature and 30 minutes under reflux. The reaction was monitored by TLC for disappearance of starting material. The reaction mixture was quenched with water carefully and partitioned between ethyl acetate and saturated solution of ammonium chloride in a funnel. Shaken and separated, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Solvents were removed, and the residue was purified by flash chromatography, eluted with 5% and then 10% ethyl acetate in hexane. 9.4 g colorless oil was obtained with 94% yield. 1H NMR (CDCl3) δ 3.90(s, 3H), 3.73(s, 3H), 2.65(m, 4H), 1.98(m, 2H).

Preparative Example 5

[0174] 291

[0175] To lithium diisopropylamide solution in THF (2.0 N, 0.04 mol) at −65° C., was added dropwise 2,2-dicarbomethoxycyclopentanone (4 g, 0.02 mol) in THF (60 ml). The resulted reaction mixture was stirred at the same temperature before adding methyl chloroformate (1.54 ml, 0.02 mol). Reaction mixture stirred for an hour and poured into saturated ammonium chloride solution with some ice. This solution was extracted three times with ether, and the combined ethearal layers were dried over sodium sulfate. Solvents were removed in vacuo, and the residue was purified by flash chromatography, eluted with 30% increased to 50% ethyl acetate in hexane. 2.3 g yellowish oil was obtained with 58% yield. 1H NMR (CDCl3) δ 3.77(s, 6H), 3.32(t, 1H), 3.60-3.10(m, 4H).

Preparative Example 6

[0176] 292

[0177] The reactions were done as outlined in (K. O. Olsen, J. Org. Chem., (1987) 52, 4531-4536). Thus, to a stirred solution of lithium diisopropylamide in THF at −65 to −70° C. was added freshly distilled ethyl acetate, dropwise. The resulting solution was stirred for 30 min and the acid chloride was added as a solution in THF. The reaction mixture was stirred at −65 to −70° C. for 30 min and then terminated by the addition of 1 N HCl solution. The resulting two-phased mixture was allowed to warm to ambient temperature. The resulting mixture was diluted with EtOAc (100 mL) the organic layer was collected. The aqueous layer was extracted with EtOAc (100 mL). The organic layers were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo to give the crude β-keto esters, which were used in the subsequent condensations.

Preparative Examples 7-19

[0178] By essentially the same procedure set forth in Preparative Example 6 only substituting the acid chlorides shown in Column 2 of Table 3, the β-keto esters shown in Column 3 of Table 3 were prepared:

TABLE 3
Prep.
Ex.	Column 2	Column 3	Data
7	293	294	LCMS: MH+= 223
8	295	296	LCMS: MH+= 253
9	297	298	LCMS: MH+= 261
10	299	300	MH+= 199
11	301	302
12	303	304
13	305	306	LCMS: MH+= 271
14	307	308	Yield = quant MH+= 249
15	309	310	Yield = quant MH+= 237
16	311	312	Yield = quant MH+= 262
17	313	314	Yield = 48 MH+= 195
18	315	316	Yield = 99 MH+= 199
19	317	318	Yield = 77% 1H NMR (CDCl3) δ 7.42 (t, 1H), 6.68 (d, 2H), 4.29 (q, 2H), 3.97 (d, 2H), 3.95 (s, 3H), 1.38 (t, 3H).

Preparative Example 20

[0179] 319

[0180] To a solution of the acid in THF was added Et3N, followed by isobutyl chloroformate at −20 to −30° C. After the mixture was stirred for 30 min at −20 to −30° C., triethylamine hydrochloride was filtered off under argon, and the filtrate was added to the LDA-EtOAc reaction mixture (prepared as outlined in Method A) at 65 to −70° C. After addition of 1 N HCl, followed by routine workup of the reaction mixture and evaporation of the solvents, the crude β-keto esters were isolated. The crude material was used in the subsequent condensations.

Preparative Examples 21-28

[0181] By essentially the same conditions set forth in Preparative Example 20 only substituting the carboxylic acid shown in Column 2 of Table 4, the compounds shown in Column 3 of Table 4 were prepared:

TABLE 4
Prep. Ex.	Column 2	Column 3	CMPD
21	320	321	Yield = 99% MH+= 213
22	322	323	Yield = 70% MH+= 275
23	324	325	Yield = quant MH+= 213
24	326	327	Yield = quant MH+= 211
25	328	329	Yield = 99 MH+= 334
26	330	331	Yield = 99 MH+= 334
27	332	333	Yield = 99 MH+= 334
28	334	335	Yield = 77% 1H NMR (CDCl3) δ4.21 (q, 2H), 3.95 (d, 2H), 3.93-3.79 (m, 4H), 3.52 (s, 2H), 2.65 (m, 1H), 1.25 (t, 3H), 1.23-1.2 (m, 2H).

Preparative Example 29

[0182] 336

[0183] A solution of 3-aminopyrazole (2.0 g, 24.07 mmol) and ethyl benzoylacetate (4.58 mL, 1.1 eq.) in AcOH (15 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was diluted with EtOAc and filtered to give a white solid (2.04 g, 40% yield).

Preparative Examples 30-73

[0184] By essentially the same procedure set forth in Preparative Example 29 only substituting the aminopyrazole shown in Column 2 of Table 5 and the ester shown in Column 3 of Table 5, the compounds shown in Column 4 of Table 5 were prepared:

TABLE 5
Prep.
Ex.	Column 2	Column 3	Column 4	Column 5
30	337	338	339
31	340	341	342
32	343	344	345
33	346	347	348
34	349	350	351
35	352	353	354
36	355	356	357
37	358	359	360
37.10	361	362	363
38	364	365	366
39	367	368	369
40	370	371	372
41	373	374	375
42	376	377	378
43	379	380	381
44	382	383	384
45	385	386	387
46	388	389	390
47	391	392	393
48	394	395	396
49	397	398	399
50	400	401	402
51	403	404	405
52	406	407	408
53	409	410	411
54	412	413	414
55	415	416	417
56	418	EtO2C≡CO2Et	419
57	420	421	422
58	423	424	425	Yield = 68 MH+= 152
59	426	427	428	Yield = 46 MH+= 268
60	429	430	431	Yield = 63 MH+= 255
61	432	433	434	Yield = 80 MH+= 280
62	435	436	437	Yield = 72 MH+= 214
63	438	439	440	Yield = 51 MH+= 218
64	441	442	443	Yield = 82 MH+= 218
65	444	445	446	Yield = 39 MH+= 232
66	447	448	449	Yield = 30 MH+= 230
67	450	451	452	Yield = 80 MH+= 353
68	453	454	455	Yield = 49 MH+= 353
69	456	457	458	Yield = 42 MH+= 353
70	459	460	461
71	462	463	464
72	465	466	467
73	468	469	470

Preparative Example 74

[0185] 471

[0186] Ethyl benzoylacetate (1.76 mL, 1.1 eq.) and 3-amino-4-cyanopyrazole (1.0 g, 9.25 mmol) in AcOH (5.0 mL) and H2O (10 mL) was heated at reflux 72 hours. The resulting solution was cooled to room temperature, concentrated in vacuo, and diluted with EtOAc. The resulting precipitate was filtered, washed with EtOAc, and dried in vacuo (0.47 g, 21% yield).

Preparative Example 75

[0187] 472

[0188] A procedure in U.S. Pat. No. 3,907,799 was followed. Sodium (2.3 g, 2 eq.) was added to EtOH (150 mL) portionwise. When the sodium was completely dissolved, 3-aminopyrazole (4.2 g, 0.05 mol) and diethyl malonate (8.7 g, 1.1 eq.) were added and the resulting solution heated to reflux for 3 hours. The resulting suspension was cooled to room temperature and filtered. The filter cake was washed with EtOH (100 mL) and dissolved in water (250 mL). The resulting solution was cooled in an ice bath and the pH adjusted to 1-2 with concentrated HCl. The resulting suspension was filtered, washed with water (100 mL) and dried under vacuum to give a white solid (4.75 g, 63% yield).

Preparative Examples 76-78

[0189] By essentially the same procedure set forth in Preparative Example 75 only substituting the compound shown in Column 2 of Table 6, the compounds shown in Column 3 of Table 6 are prepared:

TABLE 6
Prep.
Ex.	Column 2	Column 3
76	473	474
77	475	476
78	477	478

Preparative Example 79

[0190] 479

[0191] A solution of the compound prepared in Preparative Example 29 (1.0 g, 4.73 mmol) in POCl3 (5 mL) and pyridine (0.25 mL) was stirred at room temperature 3 days. The resulting slurry was diluted with Et2O, filtered, and the solid residue washed with Et2O. The combined Et2O washings were cooled to 0° C. and treated with ice. When the vigorous reaction ceased, the resulting mixture was diluted with H2O, separated, and the aqueous layer extracted with Et2O. The combined organics were washed with H2O and saturated NaCl, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid (0.86 g, 79% yield). LCMS: MH+=230.

Preparative Example 80-122

[0192] By essentially the same procedure set forth in Preparative Example 79, only substituting the compound shown in Column 2 of Table 7, the compounds shown in Column 3 of Table 7 were prepared:

TABLE 7
Prep.
Ex.	Column 2	Column 3	CMPD
80	480	481	MS: MH+= 248
81	482	483
82	484	485	MS: MH+= 298
83	486	487	MS: MH+= 196
84	488	489	MS: MH+= 210
85	490	491
86	492	493	MS: MH+= 272
87	494	495
87.10	496	497
88	498	499
90	500	501	Yield = 65% MS: MH+= 260
91	502	503	Yield = 35% MS: MH+= 290
92	504	505	Yield = 32% MS: MH+= 298
93	506	507	Yield = 45% MS: MH+= 236
94	508	509	Yield = 100% LCMS: MH+= 250
95	510	511	Yield = 88% MS: MH+= 314
96	512	513	Yield = 43% MS: MH+= 223
97	514	515	Yield = 30% MS: MH+= 295
98	516	517	Yield = 98% MS: MH+= 244
99	518	519
100	520	521
101	522	523
102	524	525
103	526	527
104	528	529
105	530	531
106	532	533
107	534	535	45% yield; MS: MH+= 226
108	536	537	MS: MH+= 308
109	538	539	Yield = quant MH+286
110	540	541	Yield = 50 MH+272
111	542	543	Yield = 85 MH+299
112	544	545	Yield = 97 MH+231
113	546	547	Yield = 45 MH+236
114	548	549	Yield = quant. MH+236
115	550	551	Yield = 57 MH+250
116	552	553	Yield = 89 MH+248
117	554	555	Yield = 96 MH+371
118	556	557	Yield = 99 MH+371
119	558	559	Yield = 50 MH+371
120	560	561	Yield = 57% LCMS: MH+= 224
121	562	563	Yield = 34% LCMS: MH+= 226
122	564	565	Yield = 100% 1H NMR (CDCl3) δ 8.53 (d, 1H), 7.66 (t, 1H), 7.51 (s, 1H), 7.45 (d, 1H), 6.84 (d, 2H).

Preparative Example 123

[0193] 566

[0194] POCl3 (62 mL) was cooled to 5° C. under nitrogen and dimethylaniline (11.4 g, 2.8 eq.) and the compound prepared in Preparative Example 75 (4.75 g, 0.032 mol). The reaction mixture was warmed to 60° C. and stirred overnight. The reaction mixture was cooled to 30° C. and the POCl3 was distilled off under reduced pressure. The residue was dissolved in CH2Cl2 (300 mL) and poured onto ice. After stirring 15 minutes, the pH of the mixture was adjusted to 7-8 with solid NaHCO3. The layers were separated and the organic layer was washed with H2O (3×200 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 50:50 CH2Cl2: hexanes solution as eluent to elute the dimethyl aniline. The eluent was then changed to 75:25 CH2Cl2: hexanes to elute the desired product (4.58 g, 77% yield). MS: MH+=188.

Preparative Examples 124-126

[0195] By essentially the same procedure set forth in Preparative Example 123 only substituting the compound in Column 2 of Table 8, the compounds shown in Column 3 of Table 8 are prepared:

TABLE 8
Prep.
Ex.	Column 2	Column 3
124	567	568
125	569	570
126	571	572

Preparative Example 127

[0196] 573

[0197] A solution of the compound prepared in Preparative Example 79 (0.10 g, 0.435 mmol) in CH3CN (3 mL) was treated with NBS (0.085 g, 1.1 eq.). The reaction mixture was stirred at room temperature 1 hour and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20% EtOAc-in-hexanes solution as eluent (0.13 g, 100% yield). LCMS:MH+=308.

Preparative Examples 128-164

[0198] By essentially the same procedure set forth in Preparative Example 127 only substituting the compounds shown in Column 2 of Table 9, the compounds shown in Column 3 of Table 9 were prepared:

TABLE 9
Prep.
Ex.	Column 2	Column 3	CMPD
128	574	575	MS: MH+= 326
129	576	577	MS: MH+= 342
130	578	579	MS: MH+= 376
131	580	581	MS: MH+= 274
132	582	583	MS: MH+= 288
133	584	585
134	586	587	Yield = 75% MS: MH+= 338
135	588	589	Yield = 52% MS: MH+= 368
136	590	591	Yield = 87% MS: MH+= 376
137	592	593	Yield = 100% MS: MH+= 316
138	594	595	Yield = 92% MS: MH+= 330
139	596	597	Yield = 82% MS: MH+= 395
140	598	599	Yield = 88% MS: MH+= 308
141	600	601	Yield = 100% MS: MH+= 322
142	602	603	MH+= 266
143	604	605
144	606	607
145	608	609
146	610	611
147	612	613
148	614	615
149	616	617
150	618	619
151	620	621	LCMS: MH+= 386
152	622	623	Yield = quant MH+= 364
153	624	625	Yield = quant MH+= 353
154	626	627	Yield = 95 MH+= 378
155	628	629	Yield = 77 MH+= 311
156	630	631	Yield = quant. MH+= 314
157	632	633	Yield = 99 MH+= 328
158	634	635	Yield = 98 MH+= 326
159	636	637	Yield = 99 MH+= 449
160	638	639	Yield = 95 MH+= 449
161	640	641	Yield = 72 MH+= 449
162	642	643	Yield = 98% LCMS: MH+= 302
163	644	645	Yield = 95% LCMS: MH+= 305
164	646	647	Yield = 50% 1H NMR (CDCl3) δ8.36 (s, 1H), 7.72 (d, 1H), 7.20 (s, 1H), 6.82 (d, 1H), 3.99 (s, 3H), 3.90 (s, 3H);

Preparative Example 165

[0199] 648

[0200] A solution of the compound prepared in Preparative Example 80 (0.3 g, 1.2 mmol) in CH3CN (15 mL) was treated with NCS (0.18 g, 1.1 eq.) and the resulting solution heated to reflux 4 hours. Additional NCS (0.032 g, 0.2 eq.) added and the resulting solution was stirred at reflux overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue purified by flash chromatography using a 20% EtOAc in hexanes solution as eluent (0.28 g, 83% yield). LCMS: MH+=282.

Preparative Example 166-167

[0201] By essentially the same procedure set forth in Preparative Example 165 only substituting the compound shown in Column 2 of Table 10, the compound shown in Column 3 of Table 10 was prepared:

TABLE 10
Prep. Ex.	Column 2	Column 3	CMPD
166	649	650	Yield = 82% LCMS: MH+= 286
167	651	652

Preparative Example 167.10

[0202] 653

[0203] By essentially the same procedure set forth in Preparative Example 165 only substituting N-iodosuccinimide, the above compound was prepared.

Preparative Example 168

[0204] 654

[0205] To a solution of the compound from Preparative Example 79 (1.0 g, 4.35 mmol) in DMF (6 mL) was added POCl3 (1.24 mL, 3.05 eq.) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and the excess POCl3 was quenched by the addition of ice. The resulting solution was neutralized with 1N NaOH, diluted with H2O, and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% MeOH in CH2Cl2 solution as eluent (0.95 g, 85% yield). LCMS: MH+=258.

Preparative Example 169

[0206] 655

[0207] By essentially the same procedure set forth in Preparative Example 168 only substituting the compound prepared in Preparative Example 80, the above compound was prepared (0.45 g, 40% yield).

Preparative Example 170

[0208] 656

[0209] To a solution of the product of Preparative Example 169 (0.25 g, 0.97 mmol) in THF was added NaBH4 (0.041 g, 1.1 eq.) and the resulting solution was stirred at room temperature overnight. The reaction mixture was quenched by the addition of H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 60: 40 hexanes: EtOAc mix as eluent (0.17 g, 69% yield). MS: MH+=260.

Preparative Example 171

[0210] 657

[0211] A solution of the compound prepared in Preparative Example 170 (0.12 g, 0.462 mmol), dimethyl sulfate (0.088 mL, 2.0 eq), 50% NaOH (0.26 mL) and catalytic Bu4NBr in CH2Cl2 (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 30% EtOAc-in-hexanes solution as eluent (0.062 g, 48% yield).

Preparative Example 172

[0212] 658

[0213] To a solution of PPh3 (4.07 g, 4.0 eq.) and CBr4 (2.57 g, 2.0 eq.) in CH2Cl2 (75 mL) at 0° C. was added the compound prepared in Preparative Example 168 (1.0 g, 3.88 mmol). The resulting solution was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The residue was purified by flash chromatography using a 20% EtOAc in hexanes solution as eluent (1.07 g, 67% yield).

Preparative Example 173

[0214] 659

[0215] By essentially the same procedure set forth in Preparative Example 172 only substituting the compound prepared in Preparative Example 169 the above compound was prepared (0.5 g, 70% yield).

Preparative Example 174

[0216] 660

[0217] The compound prepared in Preparative Example 127 (3.08 g, 10.0 mmol), 2.0 M NH3 in 2-propanol (50 mL, 100.0 mmol), and 37% aqueous NH3 (10.0 mL) were stirred in a closed pressure vessel at 50° C. for 1 day. The solvent was evaporated and the crude product was purified by flash chromatography using 3:1 CH2Cl2:EtOAc as eluent. Pale yellow solid (2.30 g, 80%) was obtained. LCMS: M+=289.

Preparative Examples 175-180

[0218] By essentially the same procedure set forth in Preparative Example 174 only substituting the compound shown in Column 2 of Table 11, the compounds shown in Column 3 of Table 11 were prepared.

TABLE 11
Prep.
Ex.	Column 2	Column 3
175	661	662
176	663	664
177	665	666
178	667	668
179	669	670
180	671	672

Preparative Example 181

[0219] 673

[0220] The compound prepared in Preparative Example 80 (0.3 g, 1.2 mmol), K2CO3 (0.33 g, 2 eq.), and 4-aminomethylpyridine (0.13 mL, 1.1 eq.) was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and, concentrated. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent (0.051 g, 40% yield). LCMS: MH+=320.

Preparative Example 182

[0221] 674

[0222] By essentially the same procedure set forth in Preparative Example 181 only substituting the compound described in Preparative Example 92, the above compound was prepared. LCMS: MH+=370.

Preparative Example 183

[0223] 675

[0224] To a solution of the compound prepared in Preparative Example 123 (0.25 g, 1.3 mmol) in dioxane (5 mL) was added iPr2NEt (0.47 mL, 2.0 eq.) and 3-aminomethylpyridine (0.15 ml, 1.1 eq.). The resulting solution was stirred at room temperature 72 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O and saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% MeOH in CH2Cl2 solution as eluent (0.29 g, 83% yield). MS: MH+=260.

Preparative Examples 184-187

[0225] By essentially the same procedure set forth in Preparative Example 183 only substituting the compound shown in Column 2 of Table 12, the compounds shown in Column 3 of Table 12 are prepared.

TABLE 12
Prep.
Ex.	Column 2	Column 3
184	676	677
184.1	678	679
185	680	681
186	682	683
187	684	685
187.1	686	687
187.11	688	689

Preparative Example 188 and Preparative Example 189

[0226] 690

[0227] To a solution of the compound prepared in Preparative Example 185 (1.18 g, 3.98 mmol) in THF (35 mL) at −78° C. was added LAH (4.78 mL, 1M in Et2O, 1.0 eq.) dropwise. The reaction mixture was stirred at −78° C. for 3 hours at which time additional LAH (2.0 mL, 1 M in Et2O, 0.42 eq.) was added dropwise. The reaction mixture was stirred an additional 1.25 hours and quenched by the addition of saturated Na2SO4 (8.5 mL). The reaction mixture was diluted with EtOAC (23 mL), H2O (2 mL), and CH3OH (50 mL). The resulting slurry was filtered through a plug of Celite. The Celite was washed with CH3OH and the filtrate dried with Na2SO4, filtered, and concentrated. The product was purified by flash chromatography using a CH2Cl2: CH3OH (93:7) solution as eluent to yield aldehyde as the first eluting product and alcohol as the second eluting product.

[0228] Preparative Example 188: (aldehyde): 0.4 g, 39% yield. MS: MH+=254.

[0229] Preparative Example 189: (alcohol): 0.25 g, 24% yield. MS: MH+=256.

Preparative Example 190

[0230] 691

[0231] To a solution of the compound prepared in Preparative Example 188 (0.075 g, 0.30 mmol) in THF (2.0 mL) at 0° C. was added CH3MgBr (0.3 mL, 3.0M solution in Et2O, 3.0 eq.) dropwise. The resulting solution was stirred at 0° C. an additional 1.5 hours, warmed to room temperature, and stirred overnight. Additional CH3MgBr (0.15 mL, 3.0M in Et2O, 1. eq.) was added and the resulting solution stirred an additional 1.5 hours. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated NH4Cl. The resulting solution was diluted with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organics were washed with saturated NaCl and dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a CH2Cl2: CH3OH (90:10) solution as eluent (0.048 g, 60% yield). MS: MH+=270.

Preparative Example 191

[0232] 692

[0233] By essentially the same procedure set forth in Preparative Example 190 only substituting the compound prepared in Preparative Example 185 and using excess MeMgBr (5 eq.), the above compound was prepared.

Preparative Example 192

[0234] 693

[0235] The compound prepared in Preparative Example 181 (0.29 g, 0.91 mmol), BOC2O (0.22 g, 1.1 eq), and DMAP (0.13 g, 1.1 eq.) in dioxane (10 mL) was stirred at room temperature 3 days. Additional BOC2O (0.10 g, 0.5 eq.) was added and the reaction mixture was stirred 4 hours. The reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 (15 mL), and extracted with CH2Cl2 (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduce pressure. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent (0.35 g, 91% yield). LCMS: MH+=420.

Preparative Example 193

[0236] 694

[0237] By essentially the same procedure set forth in Preparative Example 192 only substituting the compound prepared in Preparative Example 183, the above compound was prepared. MS: MH+=360.

Preparative Example 193.10

[0238] 695

[0239] By essentially the same procedure set forth in Preparative Example 192 only substituting the compound prepared in Preparative Example 184.1, the above compound was prepared. MS: MH+=454.

Preparative Example 194

[0240] 696

[0241] By essentially the same procedure set forth in Preparative Example 192 only substituting the above compound prepared in Preparative Example 187.11, the above compound was prepared (0.223 g, 88% yield). MS: MH+=528.

Preparative Example 195

[0242] 697

[0243] By essentially the same procedure set forth in Preparative Example 127 only substituting the compound prepared in Preparative Example 192, the above compound was prepared (0.38 g, 95% yield). LCMS: MH+=498.

Preparative Example 196

[0244] 698

[0245] By essentially the same procedure set forth in Preparative Example 195, only substituting the compound prepared in Preparative Example 193, the above compound was prepared (0.3 g, 83% yield). MS: MH+=438.

Preparative Example 197

[0246] 699

[0247] A solution of the compound prepared in Preparative Example 195 (0.15 g, 0.3 mmol), phenylboronic acid (0.073 g, 2.0 eq.), K3PO4 (0.19 g, 3.0 eq.), and Pd(PPh3)4 (0.017 g, 5 mol %) was heated at reflux in DME (16 mL) and H2O (4 mL) 7 hours. The resulting solution was cooled to room temperature, diluted with H2O (10 mL), and extracted with CH2Cl2 (3×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 2.5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent (0.16 g, 100% yield).

Preparative Example 198

[0248] 700

[0249] To a solution of 4-aminomethylpyridine (1.41 mL, 13.87 mmol) in CH2Cl2 (50 mL) was added BOC2O (3.3 g, 1.1 eq.) and TEA and the resulting solution was stirred a room temperature 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5% (10% NH4OH in MeOH) solution in CH2Cl2 as eluent to give a yellow solid (2.62 g, 91% yield). LCMS: MH+=209.

Preparative Example 199

[0250] 701

[0251] By essentially the same procedure set forth in Preparative Example 198 only substituting 3-aminomethylpyridine, the above compound was prepared as a yellow oil (2.66 g, 92% yield). LCMS: MH+=209.

Preparative Example 200

[0252] 702

[0253] To a solution of the compound prepared in Preparative Example 198 (0.20 g, 0.96 mmol) in CH2Cl2 (5 mL) at 0° C. was added m-CPBA (0.17 g, 1.0 eq) and the resulting solution stirred at 0° C. 2 hours and stored at 4° C. overnight at which time the reaction mixture was warmed to room temperature and stirred 3 hours. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 10% (10% NH4OH in MeOH) solution as eluent: LCMS: MH+=255.

Preparative Example 201

[0254] 703

[0255] A solution of oxone (58.6 g) in H2O (250 mL) was added dropwise to the compound prepared in Preparative Example 199 (27 g, 0.13 mol) and NaHCO3 (21.8 g, 2.0 eq.) in MeOH (200 mL) and H2O (250 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (500 mL) and filtered. The layers were separated and the aqueous layer extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid (21.0 g, 72% yield). MS: MH+=255.

Preparative Example 202

[0256] 704

[0257] The compound prepared in Preparative Example 200 (0.29 g, 1.29 mmol) was stirred at room temperature in 4M HCl in dioxane (0.97 mL) 2 hours. The reaction mixture was concentrated in vacuo and used without further purification. LCMS: MH+=125.

Preparative Example 203

[0258] 705

[0259] By essentially the same procedure set forth in Preparative Example 202 only substituting the compound prepared in Preparative Example 201, the compound shown above was prepared. LCMS: MH+=125.

Preparative Example 204

[0260] 706

[0261] To 4-N-t-Butoxycarbonylaminopiperidine (0.8 g, 4.0 mmol) in CH2Cl2 (10 mL) at 0° C. was added TEA (1.40 mL, 2.5 eq.) and 3-trifluoromethyl benzoyl chloride (1.05 g, 1.25 eq.). The resulting solution was stirred 15 minutes and warmed to room temperature and stirred 3 hours. The reaction mixture was diluted with CH2Cl2 and washed with 5% Na2CO3 (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a pale yellow solid (quantitative crude yield).

Preparative Example 205

[0262] 707

[0263] To a solution of the compound prepared in Preparative Example 204 (1.0 g, 2.76 mmol) in CH2Cl2 (15 mL) at 0° C. was added TFA (8 mL) and the resulting solution was stirred at 0° C. for 30 minutes and room temperature 1 hour. The reaction mixture was poured onto Na2CO3 (40 g) and H2O (400 mL) added and the resulting mixture was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20% (7N NH3 in MeOH) solution in CH2Cl2 as eluent (0.6 g, 82% yield).

Preparative Examples 206

[0264] 708

[0265] Step A:

[0266] To a solution of 6-chloronicotinamide (1 g, 6.39 mmol) in isoamyl alcohol (15 mL) at rt was added Na2CO3 (0.81 g, 7.67 mmol) followed by methoxyethylamine (0.67 mL, 7.67 mmol). The mixture was heat at 130° C. for 16 h, cooled to rt, and was filtered thru a medium glass-fritted filter. The resulting filtrate was concentrated under reduced pressure and the resultant solid was triturated with Et2O (2×10 mL). The crude solid was placed under high vacuum to afford 1.2 g (96%) of a light yellow solid. M+H=196.

[0267] Step B:

[0268] To a solution of amide (1.2 g, 6.12 mmol) from Preparative Example 206, Step A THF (5 mL) at 0° C. was added a solution of BH3-THF (43 mL; 43 mmol) dropwise over 10 min. The resultant solution was warmed to rt and stirred for 14 h. The mixture was cooled to 0° C. and was sequentially treated with 6M HCl (35 mL), water (30 mL), and MeOH (150 mL). The mixture was stirred for 8 hand was concentrated under reduced pressure. The crude residue was triturated with MeOH, concentrated under reduced pressure, and placed under high vaccum to afford 1.6 g (82%) of a white solid as the dihydrochloride salt, M+H (free base)=182.0. This material was used crude in the coupling with 7-Cl adducts.

Preparative Examples 207-211

[0269] By essentially the same known procedure set forth in Preparative Example 206 only by utilizing the amines shown in Column 2 of Table 13 and the amines shown in Column 3 of Table 13 were prepared:

TABLE 13
			CMPD
	Column 2	Column 3	M + H (free
Prep. Ex.	(Amine)	(Amine)	base)
207	709	710	M + H = 138
208	711	712	M + H = 152
209	713	714	M + H = 178
210	715	716	M + H = 195
211	717	718	M + H = 207

Preparative Example 212

[0270] 719

[0271] The above compound was prepared accordingly to the methods described in WO 91/18904.

Preparative Example 213

[0272] 720

[0273] The above compound was prepared accordingly to the methods described in U.S. Pat. No. 6,180,627 B1.

Preparative Example 214

[0274] 721

[0275] The known amine was prepared as described in J. Med. Chem. (2001), 44, 4505-4508.

Preparative Example 215

[0276] 722

[0277] The known amine was prepared as described in J. Med. Chem. (1997), 40, 3726-3733.

Preparative Example 216

[0278] 723

[0279] A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH (300 mL) was cooled to 0° C. and carefully treated with NaBH4 (20 g, 0.53 mol in 6 batches) over 20 minutes. The reaction was then allowed to warm to 20° C. and was stirred for 4 hours. The mixture was again cooled to 0° C., carefully quenched with saturated aqueous NH4Cl, and concentrated. Flash chromatography (5-10% 7N NH3—MeOH/CH2Cl2) provided the primary alcohol (31 g, 62%) as a light yellow solid.

[0280] Step B:

[0281] A slurry of alcohol (31 g, 0.25 mol) from Preparative Example 216, Step A in CH2Cl2 (500 mL) was cooled to 0° C. and slowly treated with SOCl2 (55 mL, 0.74 mol over 30 minutes). The reaction was then stirred overnight at 20° C. The material was concentrated, slurried in acetone, and then filtered. The resulting beige solid was dried overnight in vacuo (38.4 g, 52%, HCl salt).

[0282] Step C:

[0283] To a 15 mL pressure tube charged with a stir bar was added chloride (150 mg, 0.83 mmol) from Preparative Example 216, Step B followed by 7 M NH3/MeOH (10 mL). The resulting solution was stirred for 48 hat rt where upon the mixture was concentrated under reduced pressure to afford a light yellow solid (0.146 g, 83%). M+H (free base)=140.

Preparative Example 217

[0284] 724

[0285] The above compound was prepared accordingly to methods described in WO 00/26210.

Preparative Example 218

[0286] 725

[0287] The above compound was prepared accordingly to methods described in WO 99/10325.

Preparative Example 219

[0288] 726

[0289] The known amine dihydrochloride was prepared according to methods described in WO 02/64211.

Preparative Example 220

[0290] 727

[0291] The above compound was prepared according to methods described in WO 02/64211.

Preparative Example 221

[0292] 728

[0293] The known primary alcohol was prepared according to WO 00/37473 and was converted to the desired amine dihydrochloride in analogous fashion as Preparative Example 220 according to WO 02/064211.

Preparative Example 222

[0294] 729

[0295] Step A:

[0296] To a solution of aldehyde (WO 02/32893) (0.46 g, 2.07 mmol) in MeOH/THF (2 mL/2 mL) at 0° C. was added NaBH4 (94 mg, 2.48 mmol) in one portion. The resulting mixture was stirred for 12 hat rt and was diluted with sat. aq. NH4Cl (3 mL). The mixture was concentrated under reduced pressure and the resultant aqueous layer was extracted with CH2Cl2 (3×5 mL). The organic layers were combined, washed with brine (1×5 mL), dried (Na2SO4), and filtered. The organic layer was concentrated under reduced pressure to afford 417 mg (90% yield) of a white solid. M+H=225.

[0297] Step B:

[0298] The crude alcohol from Preparative Example 222, step A (0.4 g, 1.78 mmol) in CH2Cl2 (4 mL) was added SOCl2 (0.65 mL, 8.91 mmol) and the mixture was stirred for 2 hat rt. The mixture was concentrated under reduced pressure to afford 407 mg (94%) of a light yellow solid. M+H=243. The crude product was taken on without further purification.

[0299] Step C:

[0300] To a solution of crude chloride from Preparative Example 222, Step B (0.33 g, 1.36 mmol) in a pressure tube charged with 7M NH3/MeOH (35 mL) and the mixture was stirred for 72 h. The mixture was concentrated under reduced pressure to afford 257 mg (85%) of a yellow semisolid. M+H (free base)=224.

Preparative Example 223

[0301] 730

[0302] To a round bottom flask charged with amine hydrochloride (0.24 g, 1.1 mmol) from Preparative Example 222 and a stir bar was added 4N HCl/dioxane (10 mL). The resulting solution was stirred for 12 h at rt, concentrated under reduced pressure, and triturated with CH2Cl2 (3×5 mL). The crude product was filtered, washed with Et2O (2×5 mL), and dried under high vacuum to afford 0.19 g (91%) as the dihydrochloride salt. M+H (free base)=124.

Preparative Example 224

[0303] 731

[0304] Pd(PPh3)4 (0.404 gm, 0.35 mmol) was added to a degassed solution of 4-cyanobenzene boronic acid (1.029 g, 7 mmol) and 2-bromopyridine (1.11 g, 7 mmol) in 75 mL acetonitrile. 0.4 M sodium carbonate solution (35 mL) was added to the reaction mixture and the resulting solution was refluxed at 90° C. under Ar for 24 hours (progress of reaction was monitored by TLC). The reaction mixture was cooled and aqueous layer was separated. The organic layer containing the product and spent catalyst was mixed with silica gel (15 g) and concentrated to dryness. The 4-(2-pyridyl)-benzonitrile was isolated by column chromatography (0.850 g, 68%). LCMS: MH+=181; 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H).

Preparative Examples 225-228

[0305] By following essentially same procedure described in Preparative Example 224, only substituting the bromides in column 2 of Table 14, compounds in column 3 of Table 14 were prepared.

TABLE 14
Prep.
Ex.	Column 2	Column 3	Column 4
226	732	733	Yield = 70% LCMS: MH+= 187
226	734	735	Yield = 60% LCMS: MH+= 187
227	736	737	Yield = 70% LCMS: MH+= 186
228	738	739	Yield = 70% LCMS: MH+= 200

Preparative Example 229

[0306] 740

[0307] BH3-THF solution (1 M, 24 mL, 5 eq) was added slowly to a stirring solution of 4-(2-pyridyl)-benzonitrile (0.85 g, 4.72 mmol) in anhydrous THF (25 mL) under Ar, and the resulting solution was refluxed for about 12 hr. The solution was cooled to 0° C. using ice-water. Methanol (15 mL) was added drop-wise to the cold reaction mixture and stirred for 1 h to destroy excess BH3. Added HCl-methanol (1M, 10 mL) slowly to the reaction mixture and refluxed for 5 h. Concentrated the solution to dryness and the residue was dissolved in 25 mL water and extracted with ether to remove any un-reacted material. The aqueous solution was neutralized with solid potassium carbonate to pH 10-11. The free amine, thus formed was extracted with ether, dried over potassium carbonate (0.45 g, 50%). LCMS: MH+=185; 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H), 3.7 (t, 2H), 1.7 (t, 2H).

Preparative Examples 230-233

[0308] By following essentially the same procedure set forth in Preparative Example 229, compounds in column 3 of Table 15 were prepared.

TABLE 15
Prep.
Ex.	Column 2	Column 3	Column 4
230	741	742	Yield = 60% LCMS: MH+= 191
231	743	744	Yield = 60% LCMS: MH+= 191
232	745	746	Yield = 70% LCMS: MH+= 190
233	747	748	Yield = 70% LCMS: MH+= 204

Preparative Example 234

[0309] 749

[0310] Step A:

[0311] A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl sodium (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80° C. under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2×50 mL). Combined EtOAc extracts was dried over anhydrous MgSO4, concentrated, and the 4-(1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78%). LCMS: MH+=170; 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)

[0312] Step B:

[0313] 4-(1-imidazolyl)-benzonitrile (1 g, 5.92 mmol) was dissolved in anhydrous THF (10 mL) and added drop-wise to a stirring solution of LAH-THF (1 M in THF, 18 mL) at room temperature. The reaction mixture was refluxed under Ar for 2 h and the progress was monitored by TLC. The mixture was cooled to 0° C. and quenched by drop-wise addition of a saturated Na2SO4-H2O solution. The mixture was stirred for 1 h and filtered to remove lithium salts. The filtrate was dried over anhydrous MgSO4 and concentrated to obtain 4-(1-imidazolyl)-benzylamine (0.8 g, 80%). LCMS: MH+=174.

Preparative Example 235

[0314] 750

[0315] A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and CICOOi-Bu (745 mg, 5.46 mmol) was added dropwise. After the addition was over, the reaction mixture was stirred for additional 5 min and then aq NH4OH (0.63 mL of 28% solution, 10.46 mmol) was added. After overnight stirring, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to provide 500 mg (48%) of the 4-(5-oxazolyl)-benzamide: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.20-7.80 (m, 5H).

Preparative Example 236

[0316] 751

[0317] A suspension of 4-(5-oxazolyl)benzamide (500 mg, 2.657 mmol) in 10 mL of dry THF was cooled to 0° C. and 10 mL of 1 M BH3.THF (10.00 mmol) was added. The contents were refluxed overnight and the excess borane was destroyed by dropwise addition of methanol. The solvent was evaporated and the residue was treated with methanolic HCl to decompose the amine-borane complex. After evaporation of the methanol, the residue was taken in water, basified to pH 10 and the product was extracted in to DCM. The DCM layer was dried (K2CO3) and the solvent was removed to provide 150 mg (32%) of 4-(5-oxazolyl)benzylamine: 1H NMR (CDCl3) δ 7.90 (s, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 7.30 (s, 1H), 3.90 (s, 2H).

Preparative Examples 237-239

[0318] By essentially the same procedures set forth above, the compounds in Column 2 of Table 16 were reduced using the method indicated in Column 3 of Table 16 to give the amine indicated in Column 4 of Table 16.

TABLE 16
Prep.
Ex.	Column 2	Column 3	Column 4	CMPD
237	752	BH3	753	1H NMR (CDCl3) δ7.15-6.90 (m, 3H), 3.85 (s, 2H), 1.45 (s, 2H)
238	754	H2	755	1H NMR (CDCl3) δ8.40 (s, 1H), 7.55 (dd, 1H), 7.10 (d, 1H), 3.85 (s, 2H), 2.50 (s, 3H), 1.70 (bs, 2H)
239	756	BH3	757

Preparative Example 240

[0319] 758

[0320] Prepared by the literature procedure (PCT Int. Appl, WO 0105783): 1H NMR (CDCl3) δ 7.35 (d, 1H), 7.24-7.10 (m, 2H), 7.02 (d, 1H), 3.95 (t, 1H), 3.70 (d, 1H), 3.37 (d, 1H), 2.65 (m, 2H), 2.45 (s, 3H), 1.90 (bs, 2H)

Preparative Example 241

3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE

[0321] 759

[0322] A. 3-(tert-BUTOXYCARBONYLAMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE 760

[0323] 3 (R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3 g, 14.0 mmoles) was dissolved in anhydrous dichloromethane (50 mL) and trimethylsilylisocyanate (9.68 g, 11.4 mL, 84.0 mmoles) was added. The mixture was stirred under argon at 25° C. for 68 h. Additional trimethylsilylisocyanate (4.84 g, 5.7 mL, 42.0 mmoles) was added and the mixture was stirred at 25° C. for a total of 90 h. The mixture was evaporated to dryness and chromatographed on a silica gel column (30×5 cm) using 2% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(tert-butoxycarbonylaminomethyl)piperidine-1-carboxamide (3.05 g, 85%): FABMS: m/z 258.1 (MH+); HRFABMS: m/z 258.1816 (MH+). Calcd. for C12H24O3N3: m/z 258.1818; δH (CDCl3) 1.22 91H, m, CH2), 1.42 (9H, s, —COOC(CH3)3), 1.48 (1H, m, CH2), 1.67 (2H, m, CH2), 1.78 (1H, m, CH), 2.80 (1H, m, CH2), 2.99, 3H, m, CH2), 3.59 (1H, m, CH20 3.69 (1H, m, CH2), 4.76 (2H, bm, CONH2) and 4.98 ppm (1H, bm, NH); δc (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 24.0, 28.3, 43.2, 45.1, 47.8; CH: 36.5; C: 79.4, 156.3, 158.5.

[0324] B. 3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE 761

[0325] 3 -(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide (150 mg, 0.583 mmoles) (prepared as described in Preparative Example 241, Step A above) was dissolved in methanol (3 mL). 10% conc. sulfuric acid in 1,4-dioxane (7.9 mL) was added and the mixture was stirred at 25° C. for 1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (15×2 cm) using dichloromethane followed by 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%): FABMS: m/z 158.1 (MH+); HRFABMS: m/z 158.1294 (MH+). Calcd. for C7H16N3O: m/z 158.1293; δH (CDCl3+drop CD3OD) 1.20 (1H, m, CH2), 1.48 (1H, m, CH2), 1.60 (1H, m, CH), 1.68 (1H, m, CH2), 1.83 (1H, m, CH2), 2.64 (bm, 2H, —CH2NH2), 2.82 (1H, m, CH2), 3.02 (1H, m, CH2), 2.98 (2H, m, CH2), 3.70 (1H, m, —CH2NH2), 3.78 (1H, m, —CH2NH2) and 5.24 ppm (1H, bs, NH); δc (CDCl3+drop CD3OD) CH2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C: 159.0.

Preparative Example 242

3 -(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

[0326] 762

[0327] A. 3-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE 763

[0328] 3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.35 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (417.7 mg, 70%): FABMS:

[0329] m/z 272.0 (MH+); HRFABMS: m/z 272.1979 (MH+). Calcd. for C13H26O3: m/z 272.1974; δH (CDCl3) 1.16 (1H, m, CH2), 1-30-1.60 (5H, m, CH/CH2), 1.46 (9H, s, —COOC(CH3)3), 1.68 (1H, m, CH2), 1 84 (1H, m, CH2), 2.54 (1H, dd, CH2), 2.73 (1H, m, CH2), 3.08 (1H, m, CH2), 3.42 (1H, m, CH2), 4.02 (1H, m, CH2), 410 (1H, m, CH2), 4.84 (1H, m, NH) and 4.96 ppm (2H, bm, CONH2); δc (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5, 156.4, 158.2.

[0330] B. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE 764

[0331] 3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7 mg, 1.45 mmoles) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5 mL) and 10% conc. sulfuric acid in 1,4-dioxane (19.5 mL) was added. The mixture was stirred at 25° C. for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z 172.1 (MH+); HRFABMS: m/z 172.1444(MH+). Calcd for C8H18N3O requires: m/z 172.1450; δH (CDCl3+3% CD3OD) 1.14 (1H, m, CH2), 1.40 (2H, m, CH2), 1.49 (1H, m, CH), 1.58 (1H, m, CH2), 1.69 (1H, m, CH2), 1.85 (1H, m, CH2), 2.55 (1H, m, CH2), 2.67 (5H, m, CH2/NH2), 2.76 (1H, bm, CH2), 2.84 (1H, m, CH2) and 3.82 ppm (2H, m, CONH2); δc (CDCl3+3% CD3OD) CH2: 24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH: 33.4.

Preparative Example 243:

4 -(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE

[0332] 765

[0333] A. 4-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE 766

[0334] 4 -(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.25 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (308.2 mg, 52%): FABMS: m/z 272.0 (MH+); HRFABMS: m/z 272.1965 (MH+). Calcd. for C13H26O3N3: m/z 272.1974; δH (CDCl3) 1.20 (2H, m, CH2), 1.47 (9H, s, —COOC(CH3)3), 1.45-1.5 (3H, m, CH/CH2), 1.75 (2H, m, CH2), 2.82 (2H, m, CH2), 3.19 (2H, m, CH2), 3.96 (2H, m, CH2), 4.64 (2H, m, CH2) and 4.70 ppm (1H, bm, NH); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 31.8, 31.8, 36.7, 38.0, 44.5, 44.5; CH: 33.4; C: 79.2, 156.7, 158.1.

[0335] A. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE 767

[0336] 4-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (283.3 mg, 1.04 mmoles) (prepared as described in Preparative Example 243, Step A above) was dissolved in methanol (5.4 mL) and 10% conc. sulfuric acid in 1,4-dioxane (14.2 mL) was added and the mixture was stirred at 25° C. for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give the 3-(2-aminoethyl)piperidine-1-carboxamide (170 mg, 95%): FABMS: m/z 172.1 (MH+); HRFABMS: m/z 172.1442. Calcd for C8H18N3O requires: m/z 172.1450; δH (CDCl3+3% CD3OD) 1.16 (2H, m, CH2), 1.43 (2H, m, CH2), 1.52 (1H, m, CH), 1.70 (2H, m, CH2), 2.70-2.85 (8H, m, CH2) and 3.92 ppm (2H, m, CONH2); δC (CDCl3+3% CD3OD) CH2: 31.9, 31.9, 39.0, 39.7, 44.4, 44.4; CH: 33.5; C: 158.7.

Preparative Example 244:

3 -(AMINOMETHYL)-1-METHYLPIPERIDINE

[0337] 768

[0338] A. 3-(BROMOMETHYL)-1-METHYLPIPERIDINE 769

[0339] 3-(Hydroxymethyl)-1-methylpiperidine (2 g, 15.5 mmoles) was dissolved in anhydrous acetonitrile (32 mL) and anhydrous pyridine (2.02 mL, 24.8 mmoles) was added and the solution was cooled to 0° C. Dibromotriphenylphosphorane (8.49 g, 20.2 mmoles) was added at 0° C. and the mixture was allowed to warm up to 25° C. and was stirred for 94 h. The mixture was evaporated to dryness and the residue was chromatographed on a silica gel column (30×5 cm) using gradient elution with dichloromethane, 35% diethyl ether in dichloromethane and 5-10% methanol in dichloromethane as the eluant to give 3-(bromomethyl)-1-methylpiperidine (3.13 g, 100%): FABMS: m/z 192.1 (MH+); δH (CDCl3) 1.52 (1H, m, CH2), 1.99 (2H, m, CH2), 2.43 (1H, m, CH2), 2.75 (2H, m, CH2), 2.82 (1H, m CH), 2.86/2.88 (3H, s, NCH3), 3.42/3.49 (2H, dd, —CH2Br) and 3.56 ppm (2H, m, CH2); δC (CDCl3) CH3: 44.3; CH2: 22.1, 26.6, 35.4, 54.8, 58.2; CH: 34.6.

[0340] A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)-1-METHYLPIPERIDINE 770

[0341] 3-(Bromomethyl)-1-methylpiperidine (1.5 g, 7.81 mmoles) (from Preparative Example 244, Step A above) and di-tert-butyliminodicarboxylate (1.697 g, 7.81 mmoles) were dissolved in anhydrous acetonitrile (25 mL). Cesium carbonate (5.1 g, 15.6 mmoles) and lithium iodide (52 mg, 0.391 mmoles) were added and the mixture was stirred at 70° C. for 20 h. The mixture was evaporated to dryness and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. the residue was chromatographed on a silica gel column (30×5 cm) using 3% methanol in dichloromethane as the eluant to give 3-(di-tert-butoxycarbonylamino)-1-methylpiperidine (1.331 g, 52%): FABMS: m/z 329.2 (MH+); HRFABMS: m/z 329.2438 (MH+). Calcd. for C17H33N2O4: m/z 329.2440; δH (CDCl3) 1.10 (1H, m, CH2), 1.54 (18H, s, —COOC(CH3)3), 1.86 (2H, m, CH2), 2.01 (1H, m, CH2), 2.19 (1H m, CH), 2.34 (2H, bm, CH2), 2.59 (3H, —NCH3), 3.19 (2H, m, CH2) and 3.52/3.52 ppm (2H, —CH2N—); δC (CDCl3) CH3: 28.5, 28.5, 28.5, 28.5, 28.5, 28.5, 47.2; CH2: 25.4, 28.3, 50.4, 56.8, 60.8; CH: 37.2; C: 83.0, 83.0,153.5, 153.5.

[0342] A. 3-(AMINOMETHYL)-1-METHYLPIPERIDINE 771

[0343] 3-(Di-tert-butoxycarbonylamino)-1-methylpiperidine (500 mg, 1.52 mmoles) (from Preparative Example 244, Step B above) was dissolved in methanol (7.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (1 9.75 mL) was added. The solution was stirred at 25° C. for 0.5 h. Methanol (300 mL) was added, followed by BioRad AG1-X8 resin (OH− form) until the pH was ˜10. The resin was filtered off and washed with methanol (2×200 mL). The combined eluates were evaporated to dryness and the residue was chromatographed on a silica gel column (30×2.5 cm) using 10% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(aminomethyl1-methylpiperidine (69.2 mg, 35%): FABMS: m/z 129.1 (MH+); HRFABMS: m/z 129.1392 (MH+). Calcd. for C7H17N2: m/z 129.1392; δH (CDCl3) 0.90 (2H, m, CH2), 1.65 (2H, m, CH2), 1.72 (1H, m, CH), 1.79 (1H, m, CH2), 1.91 (1H, m, CH2), 2.30 (3H, s, —NCH3), 2.64 (2H, m, CH2), 2.82 (1H, m, —CH2NH2) and 2.92 ppm (1H, m, —CH2NH2); δC (CDCl3) CH3: 46.7; CH2: 25.2, 28.0, 46.3, 56.4, 60.3; CH: 39.9.

Preparative Example 245:

4-(AMINOMETHYL)-1-METHYLPIPERIDINE

[0344] 772

[0345] A. 1-METHYLISONIPECOTAMIDE 773

[0346] Isonipecotamide (10 g, 78.0 mmoles) was dissolved in distilled water (100 mL) and 37% aqueous formaldehyde (7.6 mL, equivalent to 2.81 g HCHO, 93.6 mmoles) was added. Wet 10% Pd-C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25° C. and 50 psi for 43 h. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60×5 cm) using 8%-10%-20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 1-methylisonipecotamide (7.15 g, 64%): FABMS: m/z 143.1 (MH+); HRFABMS: m/z 143.1184 (MH+). Calcd. for C7H15N2O : m/z 143.1184; δH (d6-DMSO) 1.50/1.57 (4H, m, CH2),1.76/1.94 (4H, m, CH2), 2.10 (3H, s, —NCH3), 2.72 (1H, m, CH) and 6.68/7.18 ppm (2H, m, CONH2); δC (d6-DMSO) CH3: 41.2; CH2: 28.5, 28.5, 54.9, 54.9; CH: 46.2; C: 176.7.

[0347] B. 4-(AMINOMETHYL)-1-METHYLPIPERIDINE 774

[0348] 1 -Methylisonipecotamide (6.75 g, 47.5 mmoles) (prepared as described in Preparative Example 245, Step A above) was dissolved in anhydrous THF (350 mL) and the resulting mixture was added in portions to a stirred slurry of lithium aluminum hydride (1.8 g, 47.5 mmoles) in anhydrous THF (100 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min and then heated at 66° C. for 25 h under nitrogen. Distilled water (1.88 mL) was added dropwise to the stirred mixture at 0° C., followed by 20% aqueous sodium hydroxide (1.42 mL) and then distilled water (6.75 mL) and the mixture was stirred for 15 min. The mixture was filtered and the solids were washed with THF and dichloromethane. The combined filtrates were evaporated to dryness and chromatographed on a silica gel column (30×5 cm) using 15%-20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)-1-methylpiperidine (0.678 g, 11%): FABMS: m/z 129.1 (MH+); HRFABMS: m/z 129.1389 (MH+). Calcd. for C7H17N2: m/z 129.1392; δH (d6-DMSO): 2.08 ppm (3H, s, —NCH3); δ C (d6-DMSO): CH3: under DMSO peaks; CH2: 29.6, 29.6,46.7, 55.2, 55.2; CH: 46.2.

Preparative Example 246:

3-(AMINOMETHYL)BENZONITRILE

[0349] 775

[0350] A. 3-(Di-tert-BUTOXYCARBONYLAMINO)BENZONITRILE 776

[0351] 3-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) and di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) and lithium iodide (1 70.5 mg, 1.275 mmoles) were added. The mixture was stirred at 70° C. for 22 h and the reaction was worked up as described in Preparative Example 89, Step B above. The residue was chromatographed on a silica gel column (60×5 cm) using 5% ethyl acetate in hexane as the eluant to give 3-(di-tert-butoxycarbonylamino)benzonitrile (7.39 g, 87%): FABMS: m/z 333.2 (MH+); HRFABMS: m/z 333.1815 (MH+); Calcd. for C18H25N2O4: m/z 333.1814; δH (CDCl3) 1.52 (18H, s, —COOC(CH3)3), 4.84 (2H, s, CH2), 7.48 (1H, m, Ar-H), 7.60 (2H, m, Ar-H) and 7.65 ppm (1H, m, Ar-H); δC (CDCl3) CH3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 48.4; CH: 129.2, 131.0, 131.0, 131.9; C: 83.2, 83.2, 112.5, 118.8, 140.1,152.5, 152.5.

[0352] B. 3-(AMINOMETHYL)BENZONITRILE 777

[0353] 3-(Di-tert-butoxycarbonylamino)benzonitrile (2 g, 6.0 mmoles) (prepared as described in Preparative Example 246, Step A above) was dissolved in methanol (30 mL) and 10%(v/v) (10% conc. sulfuric acid in 1,4-dioxane) (79 mL) was added. The solution was stirred at 25° C. for 0.25 h and worked up as described in Preparative Example 89, Step C above). The residue was chromatographed on a silica gel column (15×5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (651.4 mg, 82%): FABMS: m/z 133.1 (MH+); HRFABMS: m/z 133.0762 (MH+). Calcd. for C8H9N2: m/z 133.0766; δH (CDCl3) 2.57 (2H, s, —CH2NH2), 3.92 (2H, s, —CH2NH2), 7.46 (1H, m, Ar-H), 7.57 (2H, m, Ar-H) and 7.64 ppm (1H, m, Ar-H); δC (CDCl3) CH2: 45.2; CH: 129.4, 130.7, 130.7, 131.8; C: 112.4, 118.8, 143.8.

Preparative Example 247:

4-(AMINOMETHYL)BENZONITRILE

[0354] 778

[0355] A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)BENZONITRILE 779

[0356] 4-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) and di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) and lithium iodide (1 70.5 mg, 1.275 mmoles) were added. The mixture was stirred at 70° C. for 23 h and the reaction was worked up as described in Preparative Example 244, Step B above. The residue was chromatographed on a silica gel column (50×5 cm) using 5% ethyl acetate in hexane as the eluant to give 4-(di-tert-butoxycarbonylaminomethyl)benzonitrile (7.07 g, 83%): FABMS: m/z 333.2 (MH+); HRFABMS: m/z 333.1816 (MH+). Calcd. for C18H25N2O4: m/z 333.1814; δH (CDCl3) 1.45 (18H, s, —COOC(CH3)3), 4.81 (2H, s, CH2), 7.37 (2H, d, Ar-H) and 7.62 ppm (2H, d, Ar-H); δC (CDCl3) CH3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 49.2; CH: 127.8, 127.8, 132.3, 132.3; C: 83.2, 83.2, 111.1, 118.9, 144.1, 152.4, 152.4.

[0357] B. 4-(AMINOMETHYL)BENZONITRILE 780

[0358] 4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0 mmoles) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4 mL) and the solution was stirred at 25° C. for 0.25 h. The reaction mixture was diluted with dichloromethane and extracted with 1N sodium hydroxide. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (15×5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1 (MH+); HRFABMS: m/z133.0764 (MH+). Calcd. for C8H9N2: m/z 133.0766; δH (CDCl3) 2.04 (2H, s, —CH2NH2), 3.89 (2H, s, —CH2NH2), 7.40 (2H , d, Ar-H) and 7.59 ppm (2H, d, Ar-H); δC (CDCl3)CH2: 45.7; CH: 127.8, 127.8, 132.4, 132.4; C: 110.6, 118.9, 148.0.

Preparative Example 248

[0359] 781

[0360] To a solution of (1S,2S)-2-benzyloxycyclopentyl amine (1.5 g, 7.84 mmol) in MeOH (50 mL) at rt was added 10% Pd/C (50% wet, 1.0 g) followed by dropwise addition of conc. HCl (0.7 mL). The mixture was stirred under a balloon of H2 for 14 h and the catalyst was filtered off thru a pad of Celite. The pad of Celite was washed with MeOH (2×10 mL) and the resulting filtrate was concentrated under reduced pressure to afford 0.97 g (90%) of a yellow semisolid; M+H (free base)=102

Preparative Examples 249-251

[0361] In an analogous fashion to Preparative Example 248, the benzyl protected cycloalkyl amines (Column 2) were converted to the desired aminocycloalkanol hydrochloride derivatives (Column 3) as listed in Table 17.

TABLE 17
	Column 2	Column 3	CMPD
Ex.	(Amine)	(Cleavage method)	M + H
249	782	783	M + H = 102 (free base)
250	784	785	M + H = 116 (free base)
251	786	787	M + H = 116 (free base)

Preparative Example 252

[0362] 788

[0363] To a solution of ester (prepared according to J. Org. Chem. (1999), 64, 330) (0.5 g, 2.43 mmol) in THF (8 mL) at 0° C. was added LiAlH4 (0.37 g, 9.74 mmol) in one portion. The resulting mixture was heated at reflux for 12 h and was cooled to 0° C. The mixture was treated sequentially with H2O (1 mL), 1 M NaOH (1 mL), and H2O (3 mL). CH2Cl2 (10 ml) was added to the mixture which was stirred vigorously for 30 min. The mixture was filtered thru a pad of Celite which was washed generously with CH2Cl2 (3×5 mL). The resulting filtrate was concentrated under reduced pressure to afford 0.41 g (85%) of a yellow/orange solid. M+H=142.

Preparative Example 253

[0364] 789

[0365] Step A:

[0366] To a solution of L-proline methyl ester hydrochloride (0.50 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. was added Et3N (1.1 mL, 7.55 mmol) followed by TFAA (0.56 mL, 3.92 mmol). The mixture was stirred for 12 h at rt and 1N HCl (25 mL) was added. The layers were separated and the organic layer was washed sequentially with sat. aq. NaHCO3 (1×25 mL), and brine (1×25 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 0.72 g (100%) of a yellow oil. M+H=226. The crude material was taken onto Step B without further purification.

[0367] Step B:

[0368] To a solution of the compound prepared in Preparative Example 253, Step A (0.68 g, 3.0 mmol) in THF (20 mL) at 0° C. was added MeMgl (5.1 mL, 3.0 M in Et2O) dropwise over 10 min. The resulting solution was stirred for 16 h at rt whereupon the mixture was quenched by addition of sat. aq. NH4Cl. The mixture was concentrated to dryness and the resultant residue was stirred with EtOAc (100 mL) for 45 min and filtered. The filtrate was concentrated under reduced pressure to afford 0.68 g (100%) of a yellow/orange oil. M+H=226. The crude material was taken onto Step C without further purification.

[0369] Step C:

[0370] To a solution of the compound prepared in Preparative Example 253, Step B (0.68 g, 3.0 mmol) in MeOH (5 mL) was added a solution of KOH (0.68 g, 12.1 mmol) in MeOH (5 mL). The mixture was stirred at reflux for 12 h and rt for 72 h whereupon the mixture was concentrated to dryness. The crude residue was suspended in EtOAc (50 mL) and was stirred vigorously for 30 min and was filtered. This procedure was repeated 2X more and the resultant filtrate was concentrated under reduced pressure to afford 128 mg (33%) of a maroon/orange oil. M+H=130. This material was used without purification in the subsequent coupling step.

Preparative Example 254

[0371] 790

[0372] The aldehyde was prepared according to the procedure of Gupton (J. Heterocyclic Chem. (1991), 28, 1281).

Preparative Example 255

[0373] 791

[0374] Using the aldehyde from Preparative Example 254, the procedure of Gupton (J. Heterocyclic Chem. (1991), 28, 1281) was employed to prepare the title aldehyde.

Preparative Example 256

[0375] 792

[0376] The title aldehyde was prepared according to the procedure of Ragan et. al Synlett (2000), 8, 1172-1174.

Preparative Example 257

[0377] 793

[0378] The reaction of known cyclopentyl guanidine hydrochloride (Org. Lett. (2003), 5, 1369-1372) under the conditions of Ragan (Synlett (2000), 8, 1172-1174) afforded the title aldehyde.

Preparative Example 258

[0379] 794

[0380] The title compound was prepared according to known literature Monatshefte fur Chemie (1973), 104, 1372-1382.

EXAMPLES

Example 1

[0381] 795

[0382] A solution of the product from Preparative Example 127 (0.27 g, 0.875 mmol), 4-aminomethylpyridine (0.12 g, 1.3 eq.), and K2CO3 (0.24 g, 2 eq.) in CH3CN (5 mL) was stirred at room temperature 48 hours. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 4% MeOH in CH2Cl2 solution as eluent (0.28 g, 93% yield). LCMS: MH+=380; mp=>205° C. (dec).

Examples 2-210

[0383] By following essentially the same procedure set forth in Example 1 only substituting the chlorides shown in Column 2 of Table 18 and the amines shown in Column 3 of Table 18, the compounds in Column 4 of Table 18 were prepared:

TABLE 18
Ex.	Column 2	Column 3
2	796	797
3	798	799
4	800	801
5	802	803
6	804	805
7	806	807
8	808	809
9	810	811
10	812	813
11	814	815
12	816	817
13	818	819
14	820	821
15	822	823
16	824	825
17	826	827
17.1	828	829
18	830	831
19	832	833
20	834	835
21	836	837
22	838	839
23	840	841
24	842	843
25	844	845
26	846	847
27	848	849
28	850	851
30	852	853
31	854	855
32	856	857
33	858	859
34	860	861
35	862	863
36	864	865
37	866	867
38	868	869
39	870	871
40	872	873
41	874	875
42	876	877
43	878	879
44	880	881
45	882	883
46	884	885
47	886	887
48	888	889
49	890	891
50	892	893
51	894	895
52	896	897
54	898	899
55	900	901
56	902	903
57	904	905
58	906	907
59	908	909
60	910	911
61	912	913
62	914	915
63	916	917
64	918	919
65	920	921
66	922	923
67	924	925
68	926	927
69	928	929
70	930	931
71	932	933
72	934	935
73	936	937
74	938	939
75	940	941
76	942	943
77	944	945
78	946	947
79	948	949
80	950	951
81	952	953
82	954	955
83	956	957
84	958	959
85	960	961
86	962	963
87	964	965
88	966	967
89	968	969
90	970	971
91	972	973
92	974	975
93	976	977
94	978	979
95	980	981
96	982	983
97	984	985
98	986	987
99	988	989
100	990	991
101	992	993
102	994	995
103	996	997
104	998	999
105	1000	1001
106	1002	1003
107	1004	1005
108	1006	1007
109	1008	1009
110	1010	1011
111	1012	1013
112	1014	1015
113	1016	1017
114	1018	1019
115	1020	1021
116	1022	1023
117	1024	1025
118	1026	1027
121	1028	1029
126	1030	1031
127	1032	1033
128	1034	1035
129	1036	1037
130	1038	1039
131	1040	1041
132	1042	1043
133	1044	1045
134	1046	1047
135	1048	1049
136	1050	1051
137	1052	1053
138	1054	1055
139	1056	1057
140	1058	1059
141	1060	1061
142	1062	1063
143	1064	1065
144	1066	1067
145	1068	1069
146	1070	1071
147	1072	1073
148	1074	1075
149	1076	1077
150	1078	1079
151	1080	1081
152	1082	1083
153	1084	1085
154	1086	1087
155	1088	1089
156	1090	1091
157	1092	1093
158	1094	1095
159	1096	1097
160	1098	1099
161	1100	1101
162	1102	1103
163	1104	1105
164	1106	1107
165	1108	1109
166	1110	1111
167	1112	1113
168	1114	1115
169	1116	1117
170	1118	1119
171	1120	1121
172	1122	1123
173	1124	1125
174	1126	1127
175	1128	1129
176	1130	1131
177	1132	1133
178	1134	1135
179	1136	1137
180	1138	1139
181	1140	1141
182	1142	1143
183	1144
184	1145	1146
185	1147	1148
186	1149	1150
187	1151	1152
188	1153	1154
189	1155	1156
190	1157	1158
191	1159	1160
192	1161	1162
193	1163	1164
194	1165	1166
195	1167	1168
196	1169	1170
197	1171	1172
198	1173	1174
199	1175	1176
200	1177	1178
201	1179	1180
202	1181	1182
203	1183	1184
204	1185	1186
204.10	1187	1188
204.11	1189	1190
205	1191	1192
206	1193	1194
207	1195	1196
208	1197	1198
209	1199	1200
210	1201	1202
	Ex.	Column 4	Data
	2	1203	LCMS: MH+= 380; mp = 175-176° C.
	3	1204	LCMS: MH+= 398; mp = 156-157° C.
	4	1205	LCMS: MH+= 398; mp = 45-49° C.
	5	1206	LCMS: MH+= 354; mp = 43-46° C.
	6	1207	LCMS: MH+= 354; mp = 149-150° C.
	7	1208	LCMS: MH+= 414; mp = 86-92° C.
	8	1209	LCMS: MH+= 414; mp = 185-186° C.
	9	1210	LCMS: MH+= 448; mp = 167-168° C.
	10	1211	LCMS: MH+= 346; mp = 57-58° C.
	11	1212	LCMS: MH+= 347; mp = 122.9-125.3° C.
	12	1213	LCMS: MH+= 360; mp = 127-128° C.
	13	1214	LCMS: MH+= 342; mp = 133-135° C.
	14	1215	LCMS: MH+= 344; mp = 152-155° C.
	15	1216	LCMS: MH+= 362; mp = 164-167° C.
	16	1217	LCMS: MH+= 327; mp = 146-155° C.
	17	1218	LCMS: MH+= 332; mp = 71-82° C.
	17.1	1219	MS: MH+= 332.
	18	1220	LCMS: MH+= 346; mp = 58-65° C.
	19	1221	LCMS: MH+= 414; mp = 211-213° C.
	20	1222	LCMS: MH+= 414; mp = 194-197° C.
	21	1223	MS: MH+= 414 m.p. 211-216° C.
	22	1224	LCMS: MH+= 544; mp = 104-107° C.
	23	1225	Yield = 83% LCMS: MH+= 410.
	24	1226	Yield = 84% LCMS: MH+= 410.
	25	1227	Yield = 96% LCMS: MH+= 440.
	26	1228	Yield = 99% LCMS: MH+= 440.
	27	1229	Yield = 89% LCMS: MH+= 448.
	28	1230	Yield = 78% LCMS: MH+= 448.
	30	1231	Yield = 96% LCMS: MH+= 483.
	31	1232	Yield = 35% LCMS: MH+= 483.
	32	1233	Yield = 77% LCMS: MH+= 515.
	33	1234	Yield = 100% m.p. 179° C. LCMS: MH+= 388
	34	1235	Yield = 99% m.p. 186° C. LCMS: MH+= 456
	35	1236	Yield = 98% m.p. 181° C. LCMS: MH+= 401
	36	1237	Yield = 63% m.p. 192° C. LCMS: MH+= 480
	37	1238	Yield = 75% m.p. 126-127° C. LCMS: MH+= 400
	38	1239	Yield = 94% m.p. 132-133° C. LCMS: MH+= 400
	39	1240	Yield = 95% m.p. 121-122° C. LCMS: MH+= 400
	40	1241	Yield = 98% LCMS: MH+= 460
	41	1242	Yield = 87% m.p. 170-171° C. LCMS: MH+= 464
	42	1243	Yield = 84% m.p. 126-217° C. LCMS: MH+= 464
	43	1244	Yield = 96% m.p. 214° C. LCMS: MH+= 464
	44	1245	Yield = 95% m.p. 158° C. LCMS: MH+= 522
	45	1246	Yield = 90% LCMS: MH+= 278
	46	1247	Yield = 100%; LCMS: MH+= 394
	47	1248	LCMS: MH+= 473 m.p. 84-87° C.
	48	1249	MS: MH+= 396 m.p. 91.5-93.3° C.
	49	1250	MS: MH+= 396 m.p. 196-199° C.
	50	1251	MS: MH+= 430 m.p. 242-244° C.
	51	1252	MS: MH+= 430 m.p. 218° C.
	52	1253	MS: MH+= 430 m.p. 230-233° C.
	54	1254	MS: MH+= 405 m.p. 185-188° C.
	55	1255	MS: MH+= 370 m.p. 229-232° C.
	56	1256	MS: MH+= 370 m.p. 85-90° C.
	57	1257	MS: MH+= 386 m.p. 227-230° C.
	58	1258	MS: MH+= 372 m.p. 212-215° C.
	59	1259	MS: MH+= 318 m.p. 169-171° C.
	60	1260	MS: MH+= 332 m.p. 170-173° C.
	61	1261	MS: MH+= 346 m.p. 156-159° C.
	62	1262	MS: MH+= 360 m.p. 114-116° C.
	63	1263	MS: MH+= 348 m.p. 197-200° C.
	64	1264	1. mp = 230-232 2. M + H = 396
	65	1265	1. mp = 205-207 2. M + H = 402
	66	1266	1. mp = 220-223 2. M + H = 414
	67	1267	1. mp = 191-193 2. M + H = 431
	68	1268	1. mp = 235-237 2. M + H = 397
	69	1269	1. mp = >250 2. M + H = 403
	70	1270	1. mp = 230-232 2. M + H = 415
	71	1271	1. mp = 235-238 2. M + H = 431
	72	1272	1. mp = 186-188 2. M + H = 410
	73	1273	1. mp = 136-138 2. M + H = 424
	74	1274	1. mp = 192-195 2. M + H = 450
	75	1275	1. mp = 88-90 2. M + H = 454
	76	1276	1. mp = 230-232 2. M + H = 467
	77	1277	1. mp = 131-133 2. M + H = 479
	78	1278	1. mp = 85-88 2. M + H = 376
	79	1279	1. mp = 131-133 2. M + H = 388
	80	1280	1. mp = 206-208 2. M + H = 408
	81	1281	1. mp = 108-110 2. M + H = 502
	82	1282	1. mp = 83-85 2. M + H = 402
	83	1283	1. mp = 220 2. M + H = 414
	84	1284	1. mp = 154-156 2. M + H = 426
	85	1285	1. mp = 152-153 2. M + H = 438
	86	1286	1. mp = 159-161 2. M + H = 420
	87	1287	1. mp = >220 2. M + H = 455
	88	1288	1. mp = 223-225 2. M + H = 425
	89	1289	1. mp = 199-201 2. M + H = 419
	90	1290	1. mp = 184-186 2. M + H = 426
	91	1291	1. mp = 196-198 2. M + H = 420
	92	1292	1. mp = 156-159 2. M + H = 440
	93	1293	1. mp = 173-176 2. M + H = 434
	94	1294	1. mp = 173-175 2. M + H = 452
	95	1295	1. mp = 174-176 2. M + H = 469
	96	1296	1. mp = 230-234 2. M + H = 434
	97	1297	1. mp = 191-193 2. M + H = 441
	98	1298	1. mp = 202-205 2. M + H = 434
	99	1299	1. mp = 209-212 2. M + H = 453
	100	1300	1. mp = 219-221 2. M + H = 469
	101	1301	1. mp = 64-66 2. M + H = 403
	102	1302	1. mp = 168-170 2. M + H = 420
	103	1303	1. mp = 213-216 2. M + H = 411
	104	1304	1. mp = 98-100 2. M + H = 561
	105	1305	1. mp = 70-72 2. M + H = 608
	106	1306	1. mp = 168-170 2. M + H = 538
	107	1307	1. mp = 189-191 2. M + H = 592
	108	1308	LCMS: MH+= 458;
	109	1309	Yield = 89 LCMS: MH+= 418 m.p. = 131-132° C.
	110	1310	Yield = 95% LCMS: MH+= 347
	111	1311	Yield = 91% 3H); LCMS: MH+ 484
	112	1312	Yield = 87% LCMS: MH+= 427
	113	1313	Yield = 80% LCMS: MH+= 427
	114	1314	Yield = 91% LCMS: MH+= 378
	115	1315	Yield = 92%, 3H); LCMS: MH+= 520
	116	1316	Yield = 98% LCMS: MH+= 536
	117	1317	Yield = 82% LCMS: MH+= 410
	118	1318	Yield = 95% LCMS: MH+= 347
	121	1319	Yield = 65% LCMS: MH+= 481.02
	126	1320	Yield = 71% MH+= 486
	127	1321	Yield = 71% MH+= 495.1
	128	1322	Yield = 55% MH+= 463
	129	1323	Yield = 77% LCMS: MH+= 455
	130	1324	1H NMR (Yield = 75% LCMS: MH+= 379
	131	1325	Yield = 75% LCMS: MH+= 407
	132	1326	Yield = 75% LCMS: MH+= 421
	133	1327	Yield = 70% LCMS: MH+= 421
	134	1328	Yield = 78% LCMS: MH+= 475
	135	1329	Yield = 75% LCMS: MH+= 476
	136	1330	Yield = 65% LCMS: MH+= 455
	137	1331	Yield = 55% LCMS: MH+= 473)
	138	1332	Yield = 60% LCMS: MH+= 439
	139	1333	Yield = 65% LCMS: MH+= 441
	140	1334	Yield = 80% LCMS: MH+= 432
	141	1335	Yield = 60% LCMS: MH+= 429
	142	1336	LCMS: MH+= 330 mp = 109-111° C.
	143	1337	LCMS: MH+= 346 mp = 186-188° C.
	144	1338	LCMS: MH+= 384 mp = 148-150° C.
	145	1339	LCMS: MH+= 400 mp = 186-188° C.
	146	1340	LCMS: M2H+= 390; mp = 192-194° C.
	147	1341	LCMS: M+= 404; mp = 220-222° C.
	148	1342	LCMS: MH+= 369; mp > 230° C.
	149	1343	LCMS: MH+= 364; mp = 186-188° C.
	150	1344	LCMS: MH+= 312; mp = 138-140° C.
	151	1345	LCMS: M+= 380; mp = 172-174° C.
	152	1346	LCMS: MH+= 352; mp = 201-203° C.
	153	1347	LCMS: MH+= 348; mp = 166-168° C.
	154	1348	LCMS: M2H+= 153; mp = 78-80° C.
	155	1349	LCMS: M2H+= 474; mp = 161-163° C.
	156	1350	LCMS: M+= 444; mp = 48-51° C.
	157	1351	MH+= 542.1
	158	1352	MH+= 520.1
	159	1353	MH+= 542.1
	160	1354	MH+= 480.1
	161	1355	MH+= 506.1
	162	1356	MH+= 480.1
	163	1357	MH+= 494.1
	164	1358	MH+= 466.1
	165	1359	MH+= 494.1
	166	1360	MH+= 508.1
	167	1361	MH+= 520.1
	168	1362	MH+= 528.1
	169	1363	MH+= 520.1
	170	1364	MH+= 528.1
	171	1365	LCMS: MH+= 474;
	172	1366	LCMS: MH+= 437;
	173	1367	LCMS: MH+= 472;
	174	1368	LCMS: MH+= 428.1
	175	1369	LCMS: MH+= 426.2
	176	1370	LCMS: MH+= 442.0
	177	1371	LCMS: MH+= 452.0
	178	1372	Yield = 90 MH+= 436 m. pt. = 89.1° C.
	179	1373	MH+= 424 m. pt. = 188.2° C.
	180	1374	MH+= 448 m. pt. = 211.3° C.
	181	1375	Yield = quant. MH+= 464
	182	1376	MH+= 382 m. pt. = 185.8° C.
	183	1377	MH+= 387 m. pt. = 181-182° C.
	184	1378	MH+= 453
	185	1379	MH+= 401 m. pt. = 178.3° C.
	186	1380	MH+= 402
	187	1381	Yield = 91 MH+= 386 m. pt. = 148.3° C.
	188	1382	Yield = 65 MH+= 402 m. pt. = 174.5° C.
	189	1383	MH+= 379 m. pt. = 82-83° C.
	190	1384	MH+= 379 m. pt. = 50.7° C.
	191	1385	Yield = 89 MH+= 469 m. pt. = 186.7° C.
	192	1386	Yield = 93 MH+= 410 m. pt. = 86.7° C.
	193	1387	Yield = 76 MH+= 333 m. pt. = 120.3° C.
	194	1388	Yield = 86 MH+= 353 m. pt. = 188.9° C.
	195	1389	Yield = 11% LCMS: 374 MH+= 390
	196	1390	Yield = 88% LCMS: 374 MH+= 346
	197	1391	Yield = 88% LCMS: 374 MH+= 346
	198	1392	Yield = MH+= 400 m. pt. = 111.5-112.2° C.
	199	1393	MH+= 416
	200	1394	MH+= 415
	201	1395	MH+= 398 m.p. = 156.5° C.
	202	1396	MH+= 414 m.p. = 89.5° C.
	203	1397	MH+= 413
	204	1398	Yield = 86 MH+= 521 m.p. = 79.9° C.
	204.10	1399
	204.11	1400	Yield = 87 MH+= 521 m.p. = 128.6° C.
	205	1401	Yield = 99 MH+= 537 m.p. = 83.5° C.
	206	1402	Yield = 94 MH+= 598 m.p. = 110.8° C.
	207	1403	Yield = quant. MH+= 545
	208	1404	Yield = 96 MH+= 468 m.p. = 69.2° C.
	209	1405	MH+= 498 m.p. = 226.5° C.
	210	1406	MH+= 564 m.p. = 174.2° C.

[0384] Additional data for select examples given below.

Example 23

[0385] 1 H NMR (CD3OD) δ 8.63 (d, J=5.7Hz, 2H), 8.18 (s, 1H), 7.81 (dd, J=8.1 Hz, 2.1 Hz, 1H), 7.58 (d, J=6.0 Hz, 2H), 7.48 (m, 1H), 7.15-7.10 (m, 2H), 6.50 (s, 1H), 4.86 (s, 2H), 3.70 (s, 3H)

Example 24

[0386] 1 H NMR (CDCl3) δ 8.82 (s, 1H), 8.73 (d, J=4.2 Hz, 1H), 8.11 (s, 1H), 8.06 (dd, J=7.8 Hz, 1.8 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.20 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.75 (s, I H), 4.81 (d, J=4.5 Hz, 2H), 3.86 (s, 3H)

Example 25

[0387] 1 H NMR (CDCl3) δ 8.75 (d, J=5.7 Hz, 2H), 8.12 (s, 1H), 7.81 (d, J=2.1Hz, 1H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 7.45 (d, J=6.0 Hz, 2H), 6.96 (t, j=6.0 Hz, 2H), 6.33 (s, 1H), 4.85 (d, J=6.0 Hz, 2H), 4.09 (s, 3H), 4.03 (s, 3H)

Example 26

[0388] 1 H NMR (CDCl3) δ 8.82 (s, 1H), 8.72 (s, 1H), 8.09 (m, 1H), 7.87-7.83 (m, 2H), 7.60 (m, 1H), 7.45 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.43 (s, 1H), 4.83 (d, J=4.5 Hz, 2H), 4.11 (s, 3H), 4.04 (s, 3H)

Example 27

[0389] 1 H NMR (CDCl3) δ 8.75 (d, J=4.5 Hz, 2H), 8.19 (s, 1H), 7.63 (d, J=7.8Hz, 2H), 7.44-7.40 (m, 3H), 7.07 (m, 1H), 6.26 (s, 1H), 4.83 (d, J=5.1 Hz, 2H)

Example 28

[0390] 1 H NMR (CDCl3) δ 8.86 (s, 1H), 8.74 (m, 1H), 8.17 (s, 1H), 7.97 (m, 1H), 7.66-7.63 (m, 2H), 7.62 (m, 1H), 7.41 (m, 1H), 7.07 (m, 1H), 6.35 (s, 1H), 4.87 (d, J=6.0 Hz, 2H)

Example 30

[0391] 1 H NMR (CDCl3) δ 8.16 (s, 1H), 7.66-7.62 (m, 2H), 7.41 (m, 1H), 7.33-7.22 (m, 3H), 6.96 (t, J=6.0 Hz, 1H), 6.33 (s, 1H), 4.73 (d, J=6.0Hz, 2H)

Example 31

[0392] 1 H NMR (CDCl3) δ 8.13 (s, 1H), 7.66 (d, J=7.8 Hz, 2H), 7.45-7.40 (m, 2H), 7.10-7.04 (m, 2H), 6.93 (t, J=6.6 Hz, 1H), 6.60 (s, 1H), 4.84 (d, J=6.6 Hz, 2H)

Example 32

[0393] 1 H NMR (CDCl3) δ 8.16 (s, 1H), 7.66-7.62 (m, 2H), 7.57-7.55 (m, 2H), 7.41 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.8, 1.8 Hz, 1H), 6.99 (t, J=6.0 Hz 1H), 6.32 (s, 1H), 4.73 (d, J=6.0 Hz, 2H)

Example 40

[0394] 1 H NMR (CDCl3) δ 8.01 (s, 1H), 7.31-7.24 (d, J=8.2 Hz, 1H), 6.72-6.64 (br t, J=5.4 Hz, 1H), 6.62-6.52 (m, 2H), 6.05-6.01 (s, 1H), 5.56-4.64 (d, J=6.0 Hz, 2H), 4.03-3.93 (s, 3H), 3.94-3.86 (s, 3H), 2.79-2.70 (d, J=8.1 Hz, 2H), 2.02-1.66 (m, 6H), 1.43-1.22 (m, 3H), 1.20-1.02 (m, 2H)

Example 45

[0395] 1 H NMR (CDCl3) δ 8.73(d, 2H), 8.54(s, 1H), 7.41(d, 2H), 7.02(br, 1H), 5.90(s, 1H), 4.80(s, 2H), 4.48(q, 2H), 2.75(s, 2H), 1.50(t, 2H), 1.06(s, 9H;

Example 46

[0396] 1 H NMR (CDCl3) δ 8.79(s, 1H), 8.72(d, 1H), 8.14(s, 1H), 7.84(d, 1H), 7.54-7.33(m, 4H), 6.97(t, 1H), 6.18(s, 1H), 4.79(d, 2H), 2.47(s, 3H)

Example 108

[0397] 1 H NMR (CDCl3) δ 8.79 (s, 1H), 8.72 (d, J=3.0 Hz, 1H), 8.16 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.5 Hz, 2H), 7.55-7.35 (m, 3H), 6.92 (t, J=6.3 Hz, 1H), 6.42 (s, 1H), 4.81 (d, J=6.3 Hz, 2H)

Example 110

[0398] 1 H NMR (CDCl3) δ 8.18(t, 1H), 8.03(s, 1H), 7.44(m, 1H), 7.30(t, 1H), 7.17(q, 1H), 6.66(s, 1H), 6.56(br, 1H), 4.28(d, 2H), 2.38(s, 1H)

Example 111

[0399] 1 H NMR (CDCl3) δ 8.72(br, 1H), 8.59(d, 1H), 8.11 (t, 1H), 8.06(s, 1H), 7.73(d, 1H), 7.44(d, 1H), 7.42-7.21(m, 3H), 7.07(q, 1H), 6.39(d, 1H), 5.21 (q, 1H), 4.16(q, 2H), 3.08(d, 2H), 1.22(t, 3H)

Example 112

[0400] 1 H NMR (CDCl3) δ 8.22(t, 1H), 8.15(s, 1H), 7.51-7.33(m, 7H), 7.21(q, 1H), 6.82(d, 1H), 6.51(s, 1H), 4.68(q, 1H), 2.18(m, 2H), 1.17(t, 3 H)

Example 113

[0401] 1 H NMR (CDCl3) δ 8.22(t, 1H), 8.14(s, 1H), 7.51-7.33(m, 7H), 7.21(q, 1H), 6.82(d, 1H), 6.51 (s, 1H), 4.68(q, 1H), 2.18(m, 2H), 1.17(t, 3)

Example 114

[0402] 1 H NMR (CDCl3) δ 8.81(s, 1H), 8.75(d, 1H), 8.21(s, 1H), 7.84(d, 1H), 7.47(q,1H), 6.96(s, 1H), 6.94(t, 1H), 4.85(d, 2H), 4.60(q, 2H), 1.58(t, 3H

Example 115

[0403] 1 H NMR (CDCl3) δ 8.77(s, 1H), 8.72(d, 1H), 8.14(s, 1H), 7.83(d, 1H), 7.65(d, 1H), 7.44(q, 1H), 7.80(t, 1H), 7.6(d, 1H), 6.18(s, 1H), 4.75 (d, 2H), 3.91(s, 3H), 3.81 (s, 3H)

Example 116

[0404] 1 H NMR (CDCl3) δ 8.67(s, 1H), 8.55(d, 1H), 8.50(s, 1H), 7.92(d, 1H), 7.90(d, 1H), 7.78(t, 1H), 7.10(d, 1H), 6.97(s, 1H), 5.11(s, 2H), 3.77(s, 6H)

Example 117

[0405] 1 H NMR (CDCl3) δ 8.38(s, 1H), 8.30(d, 1H), 8.17(s, 1H), 7.52-7.37(m, 6H), 6.97(t, 1H), 6.13(s, 1H), 4.77(d, 2H), 2.50(s, 3H)

Example 118

[0406] 1 H NMR (CDCl3) δ 8.18(t, 1H), 8.03(s, 1H), 7.44(m, 1H), 7.30(t, 1H), 7.17(q, 1H), 6.66(s, 1H), 6.56(br, 1H), 4.28(d, 2H), 2.38(s, 1H);

Example 121

[0407] 1 H NMR (CDCl3) δ 8.6 (S, 1H), 8.15 (dt,1H), 8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (dd, 1H), 7.2 (d, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.75 (d, 2H).

Example 126

[0408] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.5 (d, 1H), 7.42-7.35(m, 2H), 7.3-7.2 (m, 2H), 7.15 (dd, 1H), 7.1 (dd, 1H), 7.0 (t, 1H), 6.6 (s, 1H), 4.8(d, 2H).

Example 127

[0409] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (dd, 1H), 7.3-7.25 (m, 3H), 7.1 (dd, 1H), 6.9-6.85 (m, 2H), 6.7 (t, 1H), 6.6 (s, 1H), 4.6 (d, 2H), 3.2 (m, 4H), 2.6 (m, 4H), 2.3 (s, 3H)

Example 128

[0410] 1 H NMR (CDCl3) δ 8.15 (dt,1H), 8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 2H), 7.25 (d, 1H), 7.2 (s, 1H), 7.15 (dd, 1H), 7.0 (s, 1H), 6.8 (t, 1), 6.6 (s, 1H), 4.75 (d, 2H).

Example 129

[0411] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.05 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.15 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.75 (d, 2H), 3.85 (s, 3H)

Example 130

[0412] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (dd, 1H), 7.3(dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.4 (s, 1H), 4.2 (d, 2H), 3.8 (s, 3H).

Example 131

[0413] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 1.2 (t, 3H)

Example 132

[0414] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 2.05 (m, 2H) 1.2 (t, 3H)

Example 133

[0415] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd 1H), 7.2 (dd, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 3.7 (s, 3H), 3.5 (dd,2H),2.4 (t, 2H), 1.8 (m, 4H)

Example 134

[0416] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.95 (d, 2H), 7.6 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.8 (d, 2H), 3.0 (s, 3H)

Example 135

[0417] 1 H NMR (DMSO d6) δ 9.1 (bs, 2H), 8.4 (s, 1H), 8.0 (t, 1H), 7.85 (d, 2H), 7.7 (d, 2H), 7.6 (m, 1H), 7.4 (m, 2H), 6.6 (s, 1H), 4.8 (bs, 2H)

Example 136

[0418] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (m, 3H), 6.7 (t, 1H), 6.5 (s, 1H), 4.5 (d, 2H), 4.2 (s, 4H)

Example 137

[0419] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.9 (dd, 1H), 6.8 (t, 1H), 6.7 (m, 1H), 6.6 (s, 1H), 5.3 (s, 2H, 4.85 (s, 2H), 4.6 (d, 2H).

Example 138

[0420] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.4 (m, 2H), 7.3 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H)

Example 139

[0421] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.2 (dd, 1H), 7.1 (dd, 1H), 6.8 (d, 1H), 6.7 (t, 1H), 6.6(s, 1H), 4.6 (m, 4H), 3.2 (t, 2H)

Example 140

[0422] 1 H NMR (CDCl3) δ 8.45 (s, 1H), 8.2 (dt, 1H), 8.0 (s, 1H), 7.7 (dd, 1H), 7.4-7.3 (m, 3H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.7 (d, 2H)

Example 141

[0423] 1 H NMR (CDCl3) δ 8.2 (dt, 1H), 8.0 (s, 1H), 7.45-7.1 (m, 7H), 6.6 (s, 1H), 4.4 (dt, 2H), 2.6 (t, 2H), 1.8 (m, 2H), 1.4 (m, 2H)

Example 171

[0424] 1 H NMR (CD3OD) δ 8.41 (s, 1H), 8.25 (d, J=6.3 Hz, 1H), 8.15 (s, 1H), 7.67 (d, J=7.8Hz, 2H), 7.55-7.48 (m, 2H), 7.45 (dd, J=7.5, 1.2 Hz, 1H), 7.34 (dd, J=7.5, 1.8 Hz, 1H), 6.28 (s, 1H), 4.79 (s, 2H).

Example 172

[0425] 1 H NMR (CDCl3) δ 8.64 (s, 1H), 7.68-7.64 (m, 2H), 7.52 (m, 1H), 7.43 (t, J=7.8 Hz, 1H), 6.89 (t, J=6.0Hz, 1H), 6.51 (s, 1H), 6.48 (m, 2H), 4.74 (d, J=6.0 Hz, 2H).

Example 173

[0426] 1 H NMR (DMSO-d6) δ 8.86 (s, 1H), 8.46 (s, 1H), 8.32-8.28 (m, 2H), 7.97 (m, 1H), 7.87 (m, 1H), 7.52 (m, 1H), 7.35-7.24 (m, 2H), 6.57 (s, 1H), 6.46 (m, 1H), 3.65 (m, 4H).

Example 174

[0427] 1 H NMR (CDCl3) d 8.37 (s, 1H), 8.16 (t, J=7.5 Hz, 1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 3H), 7.17-7.07 (m, 1H), 6.92 (t, J=6 Hz, 1H), 6.48 (s, 1H), 4.65 (d, 2H), 2.50 (s, 3H).

Example 175

[0428] 1 H NMR (CDCl3) d 8.16 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.49 (d, J=9 Hz, 1H), 7.46-7.36 (m, 1H), 7.18-7.08 (m, 1H), 7.00 (d, J=9 Hz, 1H), 6.62-6.50 (m, 2H), 2.60 (s, 3H), 2.55 (s, 3H).

Example 176

[0429] 1 H NMR (CDCl3) d 8.15 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 1H), 7.20-7.05 (m, 3H), 6.80 (t, 1H), 6.50 (s, 1H), 4.65 (d, 2H), 2.65 (s, 3H), 2.50 (s, 3H).

Example 177

[0430] 1 H NMR (CDCl3) d 8.20 (t, 1H), 7.90 (s, 1H), 7.50-7.05 (m, 8H), 6.80 (s, 1H), 5.054.90 (m, 2H), 3.80 (d, 1H), 3.45 (d, 1H), 3.00 (dd,1H), 2.90 (dd, 1H), 2.50 (s, 3H).

Example 181

[0431] 1 H NMR (300 MHz, CDCl3)□ 8.41 (s, 1H), 8.28-8.23 (d, 1H), 8.15 (s, 1H), 7.69-7.60 (d, 1H), 7.62-7.50 (m, 3H), 7.50-7.47 (dd, 1H), 6.35 (s, 1H), 5.36 (s, 1H), 4.80 (s, 2H).

Example 184

[0432] 1 H NMR (300 MHz, CDCl3)□□8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H), 7.72 (d, 1H), 7.70-7.61 (dd, 1H), 7.24-7.20 (dd, 1H), 6.92-6.84 (t, 1H), 6.36 (s, 1H), 4.96-4.89 (d, 2H).

Example 186

[0433] 1 H NMR (300 MHz, CDCl3)□□8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.44 (s, 1H), 8.27-8.24 (d, 1H), 8.02 (s, 1H), 7.78-7.76 (d, 1H), 7.73-7.70 (d, 1H), 7.58-7.51 (m, 2H), 7.13-7.08 (dd,1H), 5.51 (s, 2H).

Example 195

[0434] 1 H NMR (CD3OD) δ 8.40(s, 1H), 8.27(d, 1H), 8.03(s, 1H), 7.75-7.50(m, 2H), 6.10(s, 1H), 4.76(s, 2H), 4.05(m, 2H), 3.88(m, 2H), 3.52(m, 1H), 2.33(m, 1H), 2.20(m, 1H).

Example 196

[0435] 1 H NMR (CD3OD) δ 8.73(d, 1H), 8.58(q, 1H), 8.12(s, 1H), 8.00(d, 1H), 7.54(q, 1H), 6.19(s, 1H), 4.86(s, 2H), 4.224.08(m, 2H), 4.03-3.93(m, 2H), 3.63(m, 1H), 2.50-2.39(m, 1H), 2.32-2.21 (m, 1H).

Example 197

[0436] 1 H NMR (CD3OD) δ 8.73(d, 1H), 8.58(q, 1H), 8.12(s, 1H), 8.00(d, 1H), 7.54(q, 1H), 6.19(s, 1H), 4.86(s, 2H), 4.22-4.08(m, 2H), 4.03-3.93(m, 2H), 3.63(m, 1H), 2.50-2.39(m, 1H), 2.32-2.21 (m, 1H).

Example 199

[0437] 1 H NMR (300 MHz, CDCl3) □□ 8.29 (s, 1H), 8.15 (brs, 1H), 7.95 (s, 1H), 7.28 (d, 1H), 7.05-6.95 (appt t,1H), 5.70 (s, 1H), 4.62 (d, 2H), 2.90 (m, 1H), 2.30 (m, 1H), 1.9-1.2 (m, 8H), 0.65 (d, 3H).

Example 200

[0438] 1 H NMR (300 MHz, CDCl3) □□ 8.71 (s, 2H), 8.00 (s, 1H), 6.13 (s, 1H), 3.59 (s, 2H), 3.01-2.58 (m, 1H), 2.51-2.45 (m, 1H), 2.44-2.30 (m, 1H), 2.20 (s, 3H), 2.09-1.95 (m, 2H), 1.85-1.70 (m, 2H), 0.80-0.76 (d, 3H).

Example 203

[0439] 1 H NMR (300 MHz, CDCl3) □□ 8.10 (s, 1H), 8.08 (s, 1H), 6.27 (s, 2H), 4.95 (s, 2H), 3.00-2.90 (dd, 2H), 2.60 (m, 2H), 2.48 (br s, 1H), 2.39 (s, 3h), 2.25 m, 1H), 1.95-1.70 (m, 3H).

Example 211

[0440] 1407

[0441] To a solution of the compound prepared in Example 156 (100 mg, 0.23 mmol) in dry THF (4 mL) was added LiAlH4 (1.0 M in THF, 0.110 mL, 0.110 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for 1 hr, warmed to 25° C., then additional LiAlH4 (1.0 M in THF, 0.400 mL) was added, the mixture was stirred for 20 min and then quenched with MeOH (2.0 mL). The solvent was evaporated and the crude product was purified by flash chromatography using 10:1 CH2Cl2:MeOH as eluent. White solid (46 mg, 49%) was obtained. LCMS: M+=416. Mp=71-72° C.

Example 212

[0442] 1408

[0443] To a solution of the compound prepared in Example 156 (70 mg, 0.16 mmol) in dry THF (3 mL) was added MeMgBr (3.0 M in Et2O, 1.10 mL, 3.20 mmol) under N2. The mixture was stirred at 25° C. for 45 min and then quenched with saturated aqueous NH4Cl (5.0 mL). The mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with CH2Cl2 (3×20 mL). The extracts were dried over Na2SO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography using 20:1 CH2Cl2:MeOH as eluent. White solid (25 mg, 36%) was obtained. LCMS: M+=444. Mp=76-80° C.

Example 213

[0444] 1409

[0445] Anhydrous DMF (40 mL) was added under N2 to the compound prepared in Preparative Example 174 (2.50 g, 8.65 mmol) and 60% NaH in mineral oil (346 mg, 8.65 mmol). The mixture was stirred at 25° C. for 1 hr, then 2-chloro-5-chloromethylpyridine N-oxide (1.54 g, 8.65 mmol) in anhydrous DMF (20 mL) was added slowly. The mixture was stirred at 25° C. for 18 hr, the solvent was evaporated and the crude product was purified by flash chromatography using 30:1 CH2Cl2:MeOH as eluent. So obtained solid was triturated by 50 mL of 1:1 EtOAc: hexane. Pale yellow solid (1.25 g, 34%) was obtained. LCMS: MH+=432. Mp=224-226° C.

Examples 214-217

[0446] By essentially the same procedure set forth in Example 213 combining the compounds shown in Column 2 of Table 19 with compounds in Column 3 of Table 19, the compounds shown in Column 3 of Table 19 were prepared.

TABLE 19
Ex.	Column 2	Column 3	Column 4	CMPD
214	1410	1411	1412	LCMS: MH+ = 380; mp = ° C.
215	1413	1414	1415	LCMS: MH+ = 450; mp = 218-222° C.
216	1416	1417	1418	LCMS: MH+ = 466; mp = 126-128° C.
217	1419	1420	1421	LCMS: M+ = 523

Example 218

[0447] 1422

[0448] CF3CH2OH (3.0 mL) was added under N2 to 60% NaH in mineral oil (40 mg, 1.0 mmol), the mixture was stirred for 20 min, then the product prepared in Example 213 (50 mg, 0.12 mmol) was added. The mixture was refluxed for 20 hr, the solvent was evaporated, and the residue was purified by flash chromatography using 20:1 CH2Cl2:MeOH as eluent to yield pale yellow solid (35 mg, 61%). LCMS: M2H+=496. Mp=208-210° C.

Examples 219-225

[0449] By essentially the same procedure set forth in Example 218 combining the compounds shown in Column 1 of Table 20 with the appropriate alcohol, the compounds shown in Column 2 of Table 20 were prepared.

TABLE 20
Ex.	Column 1	Column 2	Data
219	1423	1424	LCMS: M+ = 426; mp = 126-128° C.
220	1425	1426	LCMS: M+ = 483; mp = 89-91° C.
221	1427	1428	LCMS: M2H+ = 442; mp = 112-114° C.
222	1429	1430	LCMS: MH+ = 462; mp = 121-123° C.
223	1431	1432	LCMS: MH+ = 444; mp = 112-114° C.
224	1433	1434	LCMS: M+ = 376; mp = ° C.
225	1435	1436	LCMS: MH+ =; mp = ° C.

Example 226

[0450] 1437

[0451] A mixture of the product prepared in Example 213 (100 mg, 0.23 mmol) and KOH (95 mg, 1.70 mmol) in 1,2-dimethoxyethane (3 mL) and H2O (1.5 mL) was refluxed under N2 for 20 hr, quenched with acetic acid (0.30 mL), and the solvent was evaporated. The residue was suspended in H2O (15 mL), filtered and the solid was washed with H2O (15 mL) and Et2O (10 mL). Then it was mixed with CH2Cl2 (2 mL) and Et2O (2 mL) and filtered. Et2O (5 mL) was added to the filtrate and the mixture was allowed to stand overnight. The solid was removed by filtration, washed with Et2O and then dissolved in MeOH (5 mL). The solution was filtered and the solvent from the filtrate was evaporated. Off-white solid (5 mg, 5%) was obtained. LCMS: M+=412. Mp=206-208° C.

Example 227

[0452] 1438

[0453] A mixture of the product prepared in Example 213 (129 mg, 0.30 mmol), N,N-dimethylethylenediamine (0.165 mL, 1.50 mmol), and diisopropylethylamine (0.10 mL) in anhydrous N-methylpyrrolidinone (1.0 mL) was stirred at 100° C. for 24 hr. The solvent was evaporated, and the residue was purified by flash chromatography using 20:1 CH2Cl2: 7N NH3 in MeOH as eluent to yield pale yellow solid (110 mg, 76%). LCMS: M+=482. Mp=76-78° C.

Examples 28-233

[0454] By essentially the same procedure set forth in Example 227 combining the compounds shown in Column 1 of Table 21 with the appropriate amine, the compounds shown in Column 2 of Table 21 were prepared.

TABLE 21
Ex.	Column 1	Column 2	Data
228	1439	1440	LCMS: M2H+ = 467; mp 126-128° C.
229	1441	1442	LCMS: M+ = 481; mp = 128-130° C.
230	1443	1444	LCMS: M+ = 494; mp = 108-110° C.
231	1445	1446	LCMS: M2H+ 482; mp = 129-133° C.
232	1447	1448	LCMS: M2H+ 482; mp = 124-126° C.
233	1449	1450	LCMS: M2H+ 471; mp = 88-90° C.

Example 234

[0455] 1451

[0456] A mixture of the product prepared in Example 213 (80 mg, 0.19 mmol) and 2.0 M methylamine in THF was stirred in a closed pressure vessel at 50° C. for 72 hr. The solvent was evaporated, and the residue was purified by flash chromatography using 10:1 CH2Cl2: MeOH as eluent to yield pale yellow solid (40 mg, 51%). LCMS: M2H+=427. Mp=217-219° C.

Example 235:

[0457] 1452

[0458] By essentially the same procedure set forth in Example 234, the compound shown above was prepared. LCMS: M2H+=441. Mp=98-101° C.

Example 236

[0459] 1453

[0460] The compound prepared in Preparative Example 174 (140 mg, 0.48 mmol) and the aldehyde (71 mg, 0.58 mmol) were stirred in anhydrous THF (4 mL) at 50° C. under N2. Ti(OiPr)4 (0.574 mL, 1.92 mmol) was added, the mixture was stirred at 50° C. 3 hr, and cooled to 25° C. NaBH3CN (181 mg, 2.88 mmol) was added, the mixture was stirred for 2 more hr, then poured into 10% aqueous Na2CO3 (100 mL), and extracted with CH2Cl2 (3×50 mL). Combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 15:1 CH2Cl2:MeOH as eluent to yield pale yellow solid (40 mg, 21%). LCMS: MH+=398. Mp>230° C.

Examples 237-256

[0461] By essentially the same procedure set forth in Example 236 combining the compounds shown in Column 2 and 3 of Table 22, the compounds shown in Column 4 of Table 22 were prepared.

TABLE 22
Ex.	Column 2	Column 3	Column 4	Data
237	1454	1455	1456	LCMS: M+ = 381; mp >200° C.
238	1457	1458	1459	LCMS: M+ = 387; mp = ° C.
239	1460	1461	1462	LCMS: MH+ = 413; mp = 157-159° C.
240	1463	1464	1465	LCMS: M2H+ = 419; mp = 77-79° C.
241	1466	1467	1468	LCMS: M2H+ = 385; mp = 214-216° C.
242	1469	1470	1471	LCMS: MH+ =; mp = ° C.
243	1472	1473	1474	LCMS: M+ = 416; mp = 80-82° C.
244	1475	1476	1477
245	1478	1479	1480
246	1481	1482	1483	LCMS: M+ = 452; mp = 54-56° C.
247	1484	1485	1486	LCMS: MH+ = 401; mp >200° C.
248	1487	1488	1489	LCMS: M2H+ = 474; mp >200.0.° C. dec.
249	1490	1491	1492	LCMS: MH+ = 377; mp = 65-67° C.
250	1493	1494	1495	LCMS: M2H+ = 421; mp = 87-93° C.
251	1496	1497	1498	LCMS: MH+ = 361; mp >225° C.
252	1499	1500	1501	LCMS: MH+ = 346; mp = 270-271° C.
253	1502	1503	1504	LCMS: MH+ = 402; mp = 250-255° C.
254	1505	1506	1507	LCMS: MH+ = 416; mp = 210-215° C.
255	1508	1509	1510	LCMS: MH+ = 428; mp = 145° C.
256	1511	1512	1513	LCMS: MH+ =; mp = ° C.

[0462] 1514

[0463] A mixture of the compound prepared in Example 242 (100 mg, 0.24 mmol), conc. aqueous HCl (1.0 mL) and acetic acid (2.0 mL) were stirred at 100° C. under N2for 2 hr, then poured onto Na2CO3 (15 g), and extracted with 1:1 acetone:CH2Cl2 (3×30 mL). Combined extracts were filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 10:1 CH2Cl2:MeOH as eluent to yield pale yellow solid (36 mg, 37%). LCMS: M2H+=398.

Examples 258-260

[0464] By essentially the same procedure set forth in Example 257 starting from the compounds shown in Column 1 of Table 23, the compounds shown in Column 2 of Table 23 were prepared.

TABLE 23
Ex.	Column 1	Column 2	Data
258	1515	1516	LCMS: M+ = 402; mp = 229-231° C.
259	1517	1518	LCMS: MH+ = 416; mp = 215-218° C.
260	1519	1520	LCMS: M2H+ = 398; mp > 230° C.

Example 261

[0465] 1521

[0466] To a stirred solution of the compound prepared in Example 239 (41 mg, 0.10 mmol) in CH2Cl2 was added 1.0 M BBr3 (0.30 mL, 0.30 mmol) in CH2Cl2 at −78° C. The mixture was stirred at −78° C. for 5 min, then at 24° C. for 3 hr, then MeOH (2.0 mL) was added and the mixture was stirred for 10 min. The solvent was evaporated and the residue was purified by flash chromatography using 5:1:0.1 CH2Cl2:MeOH:conc. NH4OH as eluent to yield white solid (39 mg, 99%). LCMS: M+=397. Mp>230° C.

Example 262

[0467] 1522

[0468] A mixture of the product prepared in Example 217 (40 mg, 0.077 mmol) and 5.0 M aqueous NaOH (0.8 mL) in MeOH (3.0 mL) was refluxed under N2 for 1 hr. NaHCO3 (700 mg) was added, the solvent evaporated, and the residue was purified by flash chromatography using 10:1:0.1 CH2Cl2: MeOH: conc. NH4OH as eluent to yield white solid (10 mg, 35%). LCMS: M2H+=371. Mp=237-239° C.

Examples 263-264

[0469] By essentially the same procedure set forth in Example 262 starting from the compounds shown in Column 1 of Table 24, the compounds shown in Column 2 of Table 24 were prepared.

TABLE 24
Ex.	Column 1	Column 2	Data
263	1523	1524	LCMS: M2H+ = 370; mp = 166-168° C.
264	1525	1526	LCMS: M2H+ = 371; mp = 180-182° C.

Example 265

[0470] 1527

[0471] TFA (0.5 mL) was added to a solution of the compound prepared in Preparative Example 197 (0.08 g, 0.16 mmol) in CH2Cl2 (2.0 mL) at 0° C. and the resulting solution stirred 2.5 hours and stored at 4° C. overnight at which time additional TFA (0.5 mL) was added. The resulting solution was stirred 4 hours and concentrated in vacuo. The residue was neutralized with 1N NaOH and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 2.5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent (0.009 g, 15% yield). LCMS: MH+=396; mp=53-54° C.

Example 266

[0472] 1528

[0473] A solution of the compound prepared in Preparative Example 182 (26 mg, 0.070 mmol) and potassium thiocyanate (13 mg, 0.14 mmol) in MeOH (1 mL) was cooled in a cold water bath. To it was added a solution of bromine (22 mg, 0.14 mmol) in MeOH (0.7 mL) dropwise. The resulting reaction mixture was stirred for 4 h at room temperature and the volatiles were removed under reduced pressure. The residue obtained was suspended in a small amount of CH2Cl2. The potassium bromide was filtered off and pH of the filtrate was adjusted to about 7 by the addition of aqueous ammonia. It was concentrated under reduced pressure and the residual oil was purified by preparative thin-layer chromatography using 15% MeOH in CH2Cl2 as eluent (26 mg, 87% yield). 1H NMR (CDCl3) δ 8.75 (d, J=4.2 Hz, 2H), 8.38 (s, 1H), 7.68-7.64 (m, 2H), 7.46-7.39 (m, 3H), 7.22 (t, J=6.3 Hz, 1H), 6.43 (s, 1H), 4.84 (d, J=6.3 Hz, 2H); LCMS: MH+=427.

Example 267

[0474] 1529

[0475] Boron tribromide (1 M in CH2Cl2, 0.60 mL, 0.60 mmol) was added dropwise to an ice-cold stirred solution of the compound prepared in Example 24 (50 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) under an argon atmosphere. The resulting reaction mixture was stirred at 0° C. for 30 minutes, allowed to warm up to room temperature, and stirred overnight. The mixture was quenched by the addition of a small amount of water and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and concentrated in vacuo (45 mg, 94% yield). 1H NMR (CD3OD) δ 9.16 (s, 1H), 8.95 (s, 1H), 8.88 (d, J=8.1 Hz, 1H), 8.24 (t, J=6.9 Hz, 1H), 8.18 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.00-6.96 (m, 2H), 6.86 (s, 1H), 5.28 (s, 2H); LCMS: MH+=396.

Example 268

[0476] 1530

[0477] A solution of the compound from Preparative Example 184 (0.05 g, 0.15 mmol), N-methylpiperazine (20 μL, 1.2 eq.) and iPr2Et (52 μL, 2.0 eq.) in dioxane (1 mL) was heated to 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with H2O and saturated NaHCO3. The resulting mixture was extracted with CH2Cl2, the combined organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Preparative TLC using a 5% (10% NH4OH in MeOH) in CH2Cl2 solution as eluent (0.028 g, 47% yield). MS: MH+=402. mp=210° C. (dec.)

Examples 269-275

[0478] By essentially the same procedure set forth in Example 268 only substituting the amine in Column 2 of Table 25 and the chlorides in Column 3 of Table 25, the compounds shown in Column 4 of Table 25 are prepared:

TABLE 25
Ex.	Column 2	Column 3	Column 4	CMPD
269	1531	1532	1533	MS: MH+ = 387 m.p. 182-183° C.
270	1534	1535	1536	MS: MH+ = 373 m.p. 190-191° C.
271	1537	1538	1539	MS: MH+ = 403 m.p. 227-230° C.
272	1540	1541	1542	MS: MH+ = 388 m.p. 198-201° C.
273	1543	1544	1545	MS: MH+ = 430 m.p. 100-103° C.
274	1546	1547	1548	MS: MH+ = 456 m.p. 175-178° C.
275	1549	1550	1551	MS: MH+ = 403 m.p. 218° C.

Example 276

[0479] Step A: 1552

[0480] 4-Fluorophenyl magnesium bromide (0.68 mL, 1.2 eq.) was added to the compound prepared in Preparative Example 193 (0.20 g, 0.55 mmol) and PdCl2(dppf)2 (0.037 g, 10 mol %) in THF and the resulting solution was stirred at room temperature 72 hours. The reaction mixture was dilute with saturated NH4Cl and extracted with EtOAc. The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using neat EtOAc as eluent (0.15 g, 65% yield). MS: MH+=420.

[0481] Step B: 1553

[0482] By essentially the same procedure set forth in Preparative Example 127 only substituting the compound prepared in Example 276, Step A, the above compound was prepared (0.17 g, 94% yield).

[0483] Step C: 1554

[0484] By essentially the same procedure set forth in Preparative Example 200 only substituting the compound prepared in Example 276, Step B, the above compound was prepared (0.1 g, 100% yield).

[0485] Step D: 1555

[0486] By essentially the same procedure set forth in Example 265 only substituting the compound prepared in Example 276, Step C, the above compound was prepared (0.049 g, 62% yield). MS: MH+=414; mp=110-115° C.

Example 277

[0487] Step, A: 1556

[0488] Pd(PPh3)4 (0.065 g, 10 mol %) was added to 3-cyanophenyl zinc iodide (2.2 mL, 0.5 M solution in THF, 2 eq.) and the compound prepared in Preparative Example 193 (0.2 g, 0.56 mmol) in DMF (2.0 mL) and the resulting solution heated to 80° C. g for 144 hours. The reaction mixture was cooled to room temperature, diluted with saturated NH4Cl and extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a neat EtOAC solution as eluent (0.07 g, 29% yield). MS: MH+=427.

[0489] Step B Through Step D: 1557

[0490] By essentially the same procedures set forth in Example 276, Step B through Step D, the above compound was prepared (0.023 g, 53% yield). MS: MH+=421; mp=230° C. (dec.)

Example 278

[0491] 1558

[0492] By essentially the same procedure set forth in Example 276 only substituting the appropriate cyclopropylmagnesium bromide in Step A, the compound was prepared. MS: MH+=372; m. p.=96-98° C.

Example 279

[0493] 1559

[0494] The palladium-catalyzed zinc cross-coupling reaction was carried out in a manner similar to the procedure described in J. Org. Chem. (1999), 453. A solution of the chloropyrazolopyrimidine (200 mg, 0.458 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol), and exo-2-norbonylzinc bromide (0.5 M in THF, 0.95 mL, 0.47 mmol) in DMF (2 mL) was refluxed at 100° C. (oil bath temp.) overnight. The reaction mixture was quenched with half-saturated NH4Cl and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography using a 50% EtOAc in hexanes solution as eluent. A solution of the obtained N-Boc-protected product (121 mg, 53% yield, LCMS: MH+=498) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2, neutralized with saturated NaHCO3, and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated in vacuo (96 mg, 99% yield). LCMS: MH+=398; 1H NMR (CDCl3) δ 8.78 (s, 1H), 8.71 (d, J=4.2 Hz, 1H), 8.04 (d, J=3.9 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.44 (m, 1H), 6.73 (m, 1H), 5.98 (d, J=7.5 Hz, 1H), 4.74 (d, J=5.4 Hz, 2H), 3.40-1.00 (m, 11H).

Examples 280-294

[0495] By following essentially the same procedure set forth in Example 279 only substituting the chlorides shown in Column 2 of Table 26 and the organozinc reagents shown in Column 3 of Table 26, the compounds in Column 4 of Table 26 were prepared:

TABLE 26
Ex.	Column 2	Column 3	Column 4	Data
280	1560	1561	1562	LCMS: MH+ = 395
281	1563	1564	1565	LCMS: MH+ = 400
282	1566	1567	1568	LCMS: MH+ = 412
283	1569	1570	1571	LCMS: MH+ = 452
284	1572	1573	1574	LCMS: MH+ = 422
285	1575	1576	1577	LCMS: MH+ = 408
286	1578	1579	1580	LCMS: MH+ = 404
287	1581	1582	1583	LCMS: MH+ = 404
288	1584	1585	1586	LCMS: MH+ = 408
289	1587	1588	1589	LCMS: MH+ = 386
290	1590	1591	1592	LCMS: MH+ = 464
291	1593	1594	1595	LCMS: MH+ = 480
292	1596	1597	1598	LCMS: MH+ = 424
293	1599	1600	1601	LCMS: MH+ = 424
294	1602	1603	1604	LCMS: MH+ = 426

[0496] Additional data for select compounds is shown below.

Example 280

[0497] 1 H NMR (CDCl3) δ 8.65 (s, 1H), 8.57 (d, J=4.2 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 8.01 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.31-7.22 (m, 2H), 6.77 (m, 2H), 4.71 (d, J=5.4 Hz, 2H), 2.68 (s, 3H).

Example 281

[0498] 1 H NMR (CDCl3) δ 8.80 (s, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.08 (s, 1H), 7.85-7.40 (m, 3H), 7.02 (d, J=5.1 Hz, 1H), 6.90 (t, J=6.0 Hz, 1H), 6.29 (s, 1H), 4.79 (d, J=6.0 Hz, 2H), 2.61 (s, 3H).

Example 282

[0499] 1 H NMR (CDCl3) δ 8.67 (s, 1H), 8.61 (d, J=3.9 Hz, 1H), 8.03 (s, 1H), 7.72-7.31 (m, 3H), 7.22-7.00 (m, 2H), 6.81 (t, J=6.0 Hz, 1H), 6.03 (s, 1H), 4.68 (d, J=6.0 Hz, 2H), 2.28 (s, 3H).

Example 283

[0500] 1 H NMR (CDCl3) δ 8.68 (s, 1H), 8.63 (d, J=4.0 Hz, 1H), 8.00 (s, 1H), 7.80-7.72 (m, 2H), 7.54-7.47 (m, 3H), 7.35 (m, 1H), 6.74 (t, J=6.0 Hz, 1H), 6.19 (s, 1H), 4.67 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H).

Example 284

[0501] 1 H NMR (CDCl3) δ 7.97 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.33-7.15 (m, 5H), 6.73 (t, J=5.4 Hz, 1H), 5.99 (s, 1H), 4.61 (d, J=5.4 Hz, 2H), 309 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H).

Example 285

[0502] 1 H NMR (CDCl3) δ 8.56-8.55 (m, 2H), 7.94 (s, 1H), 7.54 (m, 1H), 7.30-7.22 (m, 6H), 6.59 (t, J=5.7 Hz, 1H), 5.66 (s, 1H), 4.47 (d, J=5.7 Hz, 2H), 4.26 (q, J=7.2 Hz, 1H), 1.68 (d, J=7.2 Hz, 3H).

Example 286

[0503] 1 H NMR (CDCl3) δ 8.67 (m, 2H), 7.94 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.34 (m, 1H), 6.63 (t, J=5.7 Hz, 1H), 5.87 (s, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.82 (m, 1H), 1.22 (m, 3H).

Example 287

[0504] 1 H NMR (CDCl3) δ 8.66 (m, 2H), 7.94 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.34 (m, 1H), 6.62 (t, J=6.0 Hz, 1H), 5.87 (s, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.81 (m, 1H), 1.22 (m, 3H).

Example 288

[0505] 1 H NMR (CDCl3) δ 8.64 (s, 1H), 8.60 (d, J=3.6 Hz, 1H), 8.04 (s, 1H), 7.68 (m, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 7.07-7.05 (m, 2H), 6.80 (t, J=6.3 Hz, 1H), 5.93 (s, 1H), 4.64 (d, J=6.3 Hz, 2H), 2.08 (s, 6H).

Example 289

[0506] 1 H NMR (CDCl3) δ 8.72 (s, 1H), 8.62 (d, J=4.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.73-7.69 (m, 2H), 7.40-7.33 (m, 2H), 6.67 (t, J=6.0 Hz, 1H), 6.29 (s, 1H), 4.71 (d, J=6.0 Hz, 2H).

Example 290

[0507] 1 H NMR (CDCl3) δ 8.73 (s, 1H), 8.62 (d, J=4.5 Hz, 1H), 8.01 (s, 1H), 7.76 (m, 1H), 7.41 (d, J=5.1 Hz, 1H), 7.34 (dd, J=8.1,5.1 Hz, 1H), 7.05 (d, J=5.1 Hz, 1H), 7.01 (s, 1H), 6.79 (t, J=6.0 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H).

Example 291

[0508] 1 H NMR (DMSO-d6) δ 9.12 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.13 (m, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (d, J=5.1H, 1H), 6.86 (s, 1H), 4.86 (s, 2H).

Example 292

[0509] 1 H NMR (CDCl3) δ 8.23 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.06 (s, 1H), 7.31-7.05 (m, 5H), 6.86 (m, 1H), 5.87 (s, 1H), 4.62 (d, J=6.3 Hz, 2H), 2.09 (s, 6H).

Example 293

[0510] 1 H NMR (CDCl3) δ 8.14 (s, 1H), 8.12 (d, J=6.3 Hz, 1H), 7.94 (s, 1H), 7.29-7.16 (m, 6H), 7.07 (m, 1H), 6.78 (t, J=6.0 Hz, 1H), 5.54 (s, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.24 (t, J=7.2 Hz, 1H), 1.68 (d, J=7.2 Hz, 3H).

Example 294

[0511] 1 H NMR (CDCl3) δ 8.67 (s, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.01 (s, 1H), 7.71 (m, 1H), 7.52 (dd, J=7.8, 1.8 Hz, 1H), 7.40-7.19 (m, 4H), 6.78 (t, J=6.0 Hz, 1H), 6.32 (s, 1H), 4.67 (d, J=6.0 Hz, 2H), 2.38 (s, 3H).

Example 295

[0512] 1605

[0513] To a suspension of lithium aluminum hydride (10 mg, 0.26 mmol) in anhydrous THF (2 mL) at 0° C. was added dropwise a solution of the compound prepared in Example 283 (20 mg, 0.044 mmol) in anhydrous THF (2 mL). The resulting mixture was refluxed for 1 hr and stirred at room temperature overnight, neutralized with dilute sulfuric acid, and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography using a 5% MeOH in EtOAc solution as eluent (15 mg, 83% yield). LCMS: MH+=410; 1H NMR (CDCl3) δ 8.69 (s, 1H), 8.61 (d, J=3.9 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.52-7.31 (m, 5H), 6.97 (t, J=6.3 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H), 6.20 (s, 1H), 4.71 (d, J=6.3 Hz, 2H), 4.52 (s, 2H).

Example 296

[0514] 1606

[0515] To a solution of the N-Boc-protected compound prepared in Example 294 (45 mg, 0.085 mmol) in CH2Cl2 (4 mL) at −50° C. was added m-CPBA (18 mg, 0.10 mmol). After stirring for 1 hr at −50° C. more m-CPBA (4 mg, 0.02 mmol) was added. The mixture was stirred for a further 2 hr, diluted with CH2Cl2 (20 mL), and washed with saturated NaHCO3 (20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using a 2.5% MeOH in CH2Cl2 solution as eluent. A solution of the obtained N-Boc-protected product (37 mg, 80% yield, LCMS: MH+=542) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2, neutralized with saturated NaHCO3, and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography using a 5% MeOH in EtOAc solution as eluent (26 mg, 89% yield). LCMS: MH+=442; 1H NMR (CDCl3) δ 8.71 (s, 1H), 8.64 (d, J=3.9 Hz, 1H), 8.41 (m, 1H), 8.03 (s, 1H), 7.75-7.54 (m, 4H), 7.36 (dd, J=8.1, 5.1 Hz, 1H), 6.81 (t, J=6.0 Hz, 1H), 6.34 (s, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.25 (s, 3H).

Example 297

[0516] 1607

[0517] To a solution of the N-Boc-protected compound prepared in Example 294 (56 mg, 0.11 mmol) in CH2Cl2 (4 mL) at 0° C. was added m-CPBA (42 mg, 0.24 mmol). After stirring for 2 hr at room temperature more m-CPBA (13 mg, 0.075 mmol) was added. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (20 mL), and washed with saturated NaHCO3 (20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using a 2.5% MeOH in EtOAc solution as eluent. A solution of the obtained N-Boc-protected product (29 mg, 49% yield, LCMS: MH+=558) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2, neutralized with saturated NaHCO3, and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography using a 2.5% MeOH in EtOAc solution as eluent (21 mg, 90% yield). LCMS: MH+=458; 1H NMR (CDCl3) δ 8.64 (s, 2H), 8.20 (m, 1H), 8.01 (s, 1H), 7.73-7.60 (m, 3H), 7.46 (m, 1H), 7.35 (s, 1H), 6.82 (t, J=5.9 Hz, 1H), 6.17 (s, 1H), 4.65 (d, J=5.7 Hz, 2H), 3.60 (s, 3H).

Example 298

[0518] 1608

[0519] By essentially the same procedure set forth in Preparative Example 127 only substituting the compound prepared in Preparative Example 189, the above compound was prepared. MS: MH+=334; mp=170-173° C.

Examples 299-300

[0520] By essentially the same procedure set forth in Example 298 only substituting the compound shown in Table 27, Column 2, the compounds shown in Table 27, Column 3 were prepared:

TABLE 27
Ex.	Column 2	Column 3	CMPD
299	1609	1610	MS: MH+ = 348 m.p. = 73-83° C.
300	1611	1612	MS: MH+ = 362 m.p. = 165-175° C.

Example 301

[0521] 1613

[0522] To a solution of the compound prepared in Preparative Example 186 (0.1 g, 0.21 mmol) in THF (4.0 mL) at −78° C. was added nBuLi (0.57 mL, 2.16M in hexanes, 5.0 eq.) at −78° C. The reaction mixture was stirred 2 hours at −78° C., quenched with H20, warmed to room temperature, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Preparative TLC using a 2.5% (10%NH4OH in CH3OH) solution in CH2Cl2 as eluent (0.013 g, 20% yield). MS: MH+=326; mp=71-72° C.

Example 302

[0523] 1614

[0524] By essentially the same procedure set forth in Example 301 only substituting the compound from Preparative Example 187, the above compound was prepared (0.049 g, 68% yield).MS: MH+=344; mp=69-71° C.

Example 303

[0525] 1615

[0526] To a solution of 3-H adduct from Preparative Example 187.1 (0.70 g, 2.32 mmol) in DMF (4.2 mL) at 0° C. was added POCl3 (0.67 mL, 7.2 mmol) dropwise. The mixture was stirred for 14 h at rt, cooled to 0° C., and was quenched by addition of ice. 1 N NaOH was carefully added to adjust pH to 8 and the mixture was extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was recrystallized from EtOAc to afford 0.43 g (56%) of a yellow solid. mp 181-183° C.; M+H=330.

Example 304

[0527] 1616

[0528] STEP A:

[0529] To a solution of aldehyde (100 mg, 0.30 mmol) from Example 303 in THF (1 mL) at 0° C. was added cyclohexyl magnesium bromide (0.46 mL, 2.0M in Et2O) dropwise over 5 min. The resulting mixture was stirred at 0° C. for 2 h and at rt for 12 h. The mixture was cooled to 0° C. and was treated with sat. aq. NH4Cl (3 mL) and CH2Cl2 (5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×5 mL). The organic layers were combined, washed with brine (1×5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 110 mg (89%) of a light yellow semisolid. M+H=414. This material was carried on crude to Step B without further purification.

[0530] STEP B:

[0531] To a solution of alcohol (53 mg, 0.13 mmol) in CH2Cl2 (0.5 mL) at 0° C. was added Et3SiH (24 μL, 0.15 mmol) followed by TFA (24 μL, 0.30 mmol). The mixture was stirred for 2 h at 0° C. and rt for 2 h whereupon additional portions of Et3SiH (24 μL, 0.15 mmol) and TFA (24 μL, 0.30 mmol) were added and the mixture was stirred for 3 h at rt (until complete by TLC). The mixture was concentrated under reduced pressure and the crude residue was partitioned between CH2Cl2 (5 mL) and sat. aq. NaHCO3 (2.5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×5 mL). The organic layers were combined, washed with brine (1×5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by prep TLC (8×1000 mM) eluting with CH2Cl2/MeOH (22:1) to afford 29 mg (56%) of a yellow semisolid. M+H=398.

Examples 305-312

[0532] By essentially the same procedure set forth in Example 304, utilizing the aldehyde from Example 303 and substituting the Grignard or organolithium reagents shown in Column 2 of Table 28, the compounds in Column 3 of Table 28 were prepared:

TABLE 28
			CMPD
	Column 2	Column 3	1. mp (° C.)
Ex.	(Organometallic)	(Final Structure)	2. M + H
305	1617	1618	1. yellow oil 2. M + H = 392
306	1619	1620	1. red oil 2. M + H = 353
307	1621	1622	1. red oil 2. M + H = 398
308	1623	1624	1. yellow oil 2. M + H = 406
309	1625	1626	1. yellow semisolid 2. M + H = 384
310	1627	1628	1. semisolid 2. M + H = 340
311	1629	1630	1. mp = 141-143 2. M + H = 358
312	1631	1632	1. mp = 148-150 2. M + H = 372

Example 313

[0533] 1633

[0534] To solution of aldehyde (81 mg, 0.25 mmol) from Example 303 in benzene (2.5 mL) was added carboethoxymethylene triphenyl phosphorane (0.12 g, 0.33 mmol) in one portion. The mixture was heated at reflux for 24 h, cooled to rt, and concentrated under reduced pressure. The mixture was diluted CH2Cl2 (5 mL), brine (2 mL) was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 98 mg (100%) of white solid. mp 151-153° C.; M+H=400.

Example 314

[0535] 1634

[0536] To a mixture of benzyltriphenylphosphonium bromide (0.59 g, 1.37 mmol) in THF (3 mL) was added NaH (55 mg, 1.37 mmol) and the mixture was stirred for 30 min. The aldehyde (0.15 g, 0.46 mmol) from Example 303 was added in a single portion and the mixture was heated at reflux for 36 h. The mixture was cooled to rt and was concentrated under reduced pressure. The mixture was diluted CH2Cl2 (5 mL), brine (2 mL) was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 58 mg (32%) of yellow solid. mp 138-141° C.; M+H=404.

Example 315

[0537] 1635

[0538] To a solution of aldehyde (0.20 g, 0.60 mmol) from Example 303 in THF (3 mL) was added Ti (i-OPr)4 (0.36 mL, 1.21 mmol) dropwise followed by addition of (S)-(−)-2-methyl-2-propanesulfinamide (74 mg, 0.61 mmol). The resulting mixture was stirred for 18 h at reflux, cooled to rt, and quenched with brine (2 mL). The mixture was filtered thru a pad of Celite which was washed with EtOAc (2×2 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 0.21 g (80%) of yellow solid. mp 108-110° C.; M+H=433.

Example 316

[0539] 1636

[0540] Prepared in the same fashion as Example 315 except substituting (R)-(−)-2-methyl-2-propanesulfinamide to afford 0.25 g (94%) as a yellow solid. mp 107-109° C.; M+H=433.

Example 317

[0541] 1637

[0542] STEP A:

[0543] To a solution of sulfinimine (50 mg, 0.12 mmol) from Example 316 in CH2Cl2 (2.5 mL) at 40° C. was added MeMgBr (96 mL, 0.29 mmol) dropwise. The mixture was stirred for 5 h at −40° C. and was stirred at rt for 12 h. An additional portion of MeMgBr (96 mL, 0.29 mmol) and the mixture was stirred for 12 h. Sat. aq. NH4Cl (2 mL) was added and the mixture was extracted with EtOAc (3×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 30 mg (58%) of crude residue. This material was taken onto the next step without purification.

[0544] STEP B:

[0545] The crude material from Step A (30 mg, 0.067 mmol) in MeOH (2 mL) was added conc. HCl (2 mL). The mixture was stirred at rt for 12 h and the mixture was concentrated to dryness. The crude material was partitioned between CH2Cl2 (3 mL) and sat. aq. NaHCO3 (2 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×3 mL) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 6 mg (24%) of the title compound as a light yellow solid. mp 100-102° C.; M+H=345.

Example 318

[0546] 1638

[0547] To a solution of aldehyde (75 mg, 0.23 mmol) from Example 300 in THF/CH2Cl2 (5 mL/1 mL) at rt was added MeONH2.HCl (38 mg, 0.46 mmol) followed by dropwise addition of pyridine (46 lL, 0.57 mmol). The mixture was stirred for 72 h at rt whereupon the mixture was concentrated to dryness. The crude material was partitioned between CH2Cl2 (3 mL) and sat. aq. NaHCO3 (2 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×3 mL) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (3×1000 μM) eluting with CH2Cl2/MeOH (22:1) to afford 90 mg (100%) of light yellow solid. mp 173-175° C.; M+H=359.

Example 319

[0548] 1639

[0549] To solution of aldehyde (60 mg, 0.18 mmol) from Example 303 at EtOH (2.5 mL) was added oxindole (48 mg, 0.37 mmol) followed by piperidine (3 drops). The mixture was heated at reflux for 14 h and the mixture was cooled to rt. The resultant precipitate was filtered and washed with cold EtOH (2×2 mL). The product was dried under high vacuum to afford 81 mg (100%) of the title compound as an orange/brown solid. mp 182-185° C.; M+H=445.

Example 320

[0550] 1640

[0551] To a solution of 3-H analog (106 mg, 0.35 mmol) from Preparative Example 187.10 in AcOH (2 mL) was added 37% aqueous formaldehyde (1.5 ml; 1.40 mmol) followed by piperidine (100 μL; 0.37 mmol). The resulting mixture was stirred at rt for 24 h and the AcOH was removed under reduced pressure. The mixture was diluted with water (2 mL) and neutralized with 2M NaOH until pH=8. The aqueous layer was extracted with CH2Cl2 (3×7 mL) and the organic layers were combined. The organic layer was washed with brine (1×4 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 96 mg (69%) of an off-white solid. mp 88-90° C.; M+H 399.

Examples 321-322

[0552] By essentially the same procedure set forth in Example 320 only substituting the amines in Column 2 of Table 29 and employing the 3-H adduct from Preparative Example 187.10, the compounds in Column 3 of Table 29 were prepared:

TABLE 29
			CMPD
	Column 2	Column 3	1. mp (° C.)
Ex.	(Amine)	(Final Structure)	2. M + H
321	1641		1. mp = 178-180 2. M + H = 401
		1642
322	1643	1644	1. mp = 102-104 2. M + H = 414

Example 323

[0553] 1645

[0554] To a solution of 3-H analog (113 mg, 0.38 mmol) from Preparative Example 187.10 in CH2Cl2 (5 mL) at rt was added AICl3 (215 mg, 1.61 mmol) followed by AcCl (100 mL, 1.40 mmol). The mixture was heated at reflux for 12h and was cooled to rt. The mixture was treated sequentially with 3M HCl (3 mL) followed by sat. aq. NaHCO3 (until pH=8). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×5 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 mM) eluting with CH2Cl2/MeOH (20:1) to afford 68 mg (52%) of white solid. mp 220-221° C.; M+H=344.

Example 324

[0555] 1646

[0556] Utilizing the method described in Example 323, except employing benzoyl chloride, the title compound was prepared in 61% yield as a white solid. mp 172-175° C.; M+H=406.

Example 325

[0557] 1647

[0558] To a solution of ketone (100 mg, 0.29 mmol) from Example 323 in CH2Cl2 (2.5 mL) at 0° C. was added MeMgBr (0.35 mL, 3.0M in Et2O) dropwise. The resulting mixture was stirred for 18 h at rt and was carefully quenched by addition of sat. aq. NH4Cl (2 mL) and CH2Cl2 (2 mL) were added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 lM) eluting with CH2Cl2/MeOH (10:1) to afford 68 mg (52%) of a yellow solid. mp 160-162° C.; M+H=360.

Example 326

[0559] 1648

[0560] To a solution of ketone (84 mg, 0.24 mmol) from Example 323 in MeOH/THF (1:1; 2 mL total) at 0° C. was added NaBH4 (12 mg, 0.30 mmol) in one portion. The resulting mixture was stirred for 18 h at rt whereupon and additional portion of NaBH4 (12 mg, 0.30 mmol) was added. The mixture was stirred for 12 h whereupon the mixture was quenched with ice followed by addition of 1 M NaOH to adjust the pH=9. The mixture was diluted with CH2Cl2 (5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×4 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 μM) eluting with CH2Cl2/MeOH (10:1) to afford 25 mg (30%) of a yellow solid. mp 148-150° C.; M+H=346.

Example 327

[0561] 1649

[0562] Using the same procedure as outlined in Example 326, the ketone (84 mg, 0.21 mmol) was converted to 53 mg (62%) as a light yellow solid. mp 78-80° C.; M+H=408.

Example 328

[0563] 1650

[0564] To a solution of 3-H adduct (1.3 g, 4.31 mmol) from Preparative Example 187.10 in CH2Cl2 (50 mL) was added Eschenmoser's salt (0.79 g, 4.31 mmol) followed by dropwise addition of TFA (0.56 mL, 7.33 mmol). The mixture was stirred at rt for 48 h and was diluted with CH2Cl2 (250 mL). The organic layer was washed with sat. aq. NaHCO3 (2×125 mL) to afford 1.41 h (92%) of a yellow solid. mp 231-233° C.; M+H=359.

Example 329

[0565] 1651

[0566] To a solution of tertiary amine adduct (100 mg, 0.28 mmol) from Example 328 in 50% aq. DMF (5 mL) in a pressure tube was added KCN (0.15 g, 2.32 mmol). The tube was capped and heated at 100° C. for 96 h. The mixture was cooled to rt and was diluted with EtOAc (25 mL). The organic layer was washed with brine (1×5 mL) and water (1×5 mL). The organic layers was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (4×1000 μM) eluting with EtOAc to afford 21 mg (30%) of brown solid. mp 152-155° C.; M+H=341.

Example 330

[0567] 1652

[0568] To a solution of alcohol (45 mg, 0.14 mmol) from Example 17.10 in CH2Cl2 (0.7 mL) at 0° C. was added Et3SiH (26 μL, 0.16 mmol) followed by TFA (25 μL, 0.33 mmol). The mixture was stirred for 2 h at 0° C. and rt for 2 h whereupon additional portions of Et3SiH (26 μL, 0.16 mmol) and TFA (25 μL, 0.33 mmol) were added and the mixture was stirred for 4 h at rt (until complete by TLC). The mixture was concentrated under reduced pressure and the crude residue was partitioned between CH2Cl2 (3 mL) and sat. aq. NaHCO3 (1.5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×4 mL). The organic layers were combined, washed with brine (1×5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by prep TLC (4×1000 mM) eluting with CH2Cl2/MeOH (20:1) to afford 21 mg (48%) of a yellow solid. mp 146-148° C.; M+H=316.

Example 331

[0569] 1653

[0570] To a solution of 3-H adduct (90 mg, 0.30 mmol) from Preparative Example 187.10 in conc. H2SO4 (2 mL) at 0° C. was added fuming HNO3 (30 μL, 0.72 mmol) dropwise. The resulting mixture was stirred for 1 h at 0° C. whereupon ice (˜1 g) was added to the mixture. The resulting precipitate was collected and was washed with water (2×2 mL) and CH2Cl2 (2×2 mL). The crude product was dried under high vacuum to afford 67 mg (60%) of the monosulfate salt as a yellow/orange solid. mp 250° C.; M+H (free base)=392.

Example 332

[0571] Step A: 1654

[0572] To a solution of aldehyde (0.10 g, 0.39 mmol) from Preparative Example 168 in THF (2.5 mL) at 0° C. was added CF3TMS (64 mL, 0.43 mmol) followed by CsF (10 mg). The resulting mixture was stirred for 2 h at 0° C. and 2 h at rt. 1M HCl (5 mL) was added and the mixture was diluted with CH2Cl2 (10 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (2×10 mL), and the organic layers were combined. The organic layer was washed with brine (1×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 127 mg (99%) of a yellow semisolid. M+H=328. The crude product was carried on without further purification.

[0573] Step B: 1655

[0574] By utilizing the general procedure set forth in Example 1, the 7-Cl adduct (127 mg, 0.39 mmol) from Example 332, Step A was reacted with 3-(aminomethyl)pyridine (73 μL, 0.43 mmol) to afford 80 mg (51%) of the title compound as a light yellow solid. mp 68-72° C.; M+H=400.

Example 333

[0575] 1656

[0576] To a solution of aniline (200 mg, 0.69 mmol) from Preparative Example 174 in THF (6 mL) at rt was added aldehyde (114 mg, 0.83 mmol) from Preparative Example 256 followed by dropwise addition of Ti(i-OPr)4 (0.82 mL, 2.77 mmol). The mixture was stirred at reflux for 4 h and was cooled to rt. NaCNBH3 (347 mg, 5.53 mmol) was added and the mixture was stirred for 2 h at rt. The mixture was cooled to 0° C., treated with 1 M NaOH (4 mL) and brine (1 mL) and stirred for 30 min. The mixture was extracted with CH2Cl2 (3×10 mL) and the organic layers were combined. The organic layer was washed with brine (1×7 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (8×1000 υM plates) eluting with CH2Cl2/MeOH (25:1) to afford 89 mg (31%) of the title compound as a yellow solid. mp 210-213° C. ; M+H=411.

Examples 334-337

[0577] By essentially the same procedure set forth in Example 333 only by utilizing the anilines shown in Column 2 of Table 30 and the aldehydes shown in Column 3 of Table 30, the compounds in Column 4 of Table 30 were prepared.

TABLE 30
				CMPD
	Column 2	Column 3	Column 4	1. mp (° C.)
Ex.	(Aniline)	(Aldehyde)	(Final Structure)	2. M + H
334	1657	1658	1659	1. mp = 87-87 2. M + H = 425
335	1660	1661	1662	1. mp = 160-162 2. M + H = 451
336	1663	1664	1665	1. mp = 117-119 2. M + H = 382
337	1666	1667	1668	1. mp = 171-175 2. M + H = 400

Example 338

[0578] 1669 1670

[0579] STEP A:

[0580] Reaction of aniline (0.20 g, 0.69 mmol) with aldehyde (0.13 g, 0.83 mmol) under the reaction conditions described in Example 333 afforded 70 mg (23%) of thiomethyl derivative as a yellow solid. M+H=428.

[0581] STEP B:

[0582] To a solution of thiomethyl derivative (60 mg, 0.14 mmol) from Example 338, Step A in dioxane (2 mL) was added Boc2O (61 mg, 0.28 mmol) followed by DMAP (21 mg, 0.17 mmol). The mixture was stirred for 14 h at rt and was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (6×1000 μM plates) eluting with hexanes/EtOAc (4:1) to afford 61 mg (83%) of the title compound as a yellow solid. M+H=528.

[0583] STEP C:

[0584] To a solution of thiomethyl derivative from Example 338, Step B (41 mg, 0.078 mmol) in CH2Cl2 (2 mL) was added MCPBA (33 mg, 0.19 mmol) in one portion. The resulting mixture was stirred for 3 h at rt and the mixture was diluted with CH2Cl2 (5 mL) and sat. aq. NaHCO3 (2.5 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (2×5 mL), and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 40 mg (92%) of the sulfone adduct as a light yellow solid. M+H=560.

[0585] STEP D:

[0586] To a flask charged with sulfone from Example 338, Step C (75 mg, 0.13 mmol) and a stir bar was added morpholine (2 ml; 22 mmol). The mixture was heated at reflux for 12 h, cooled to rt, and concentrated to dryness under high vacuum. The crude product was purified by preparative thin-layer chromatography (6×1000 μM plates) eluting with CH2Cl2/MeOH (40:1) to afford 41 mg (68%) of the title compound as a yellow solid. mp 209-210° C.; M+H=466.

Example 339

[0587] 1671

[0588] The title compound was prepared according to the procedure outlined in Example 338 except using benzyl amine to afford 12 mg (70%) of a white solid. mp 194-196; M+H=487.

Example 340

[0589] 1672

[0590] STEP A:

[0591] To a solution of 5-chloro adduct (0.15 g, 0.34 mmol) in dioxane/DIPEA (2.5mL/l.OmL) at rt was added cyclopentylamine (0.041 μL, 0.41 mmol) dropwise. The resulting solution was stirred at reflux for 16 h, cooled to rt, and concentrated under reduced pressure. The crude material was purified by preparative thin-layer chromatography (8×1000 μM) eluting with CH2Cl2/MeOH (25:1) to afford 148 mg (89%) of a yellow oil. M+H=489.

[0592] STEP B: Removal of the t-butoxvcarbonyl Protecting Group with TFA

[0593] To a solution of the compound prepared in Example 340, Step A (135 mg, 0.28 mmol) in CH2Cl2 (2 mL) at rt was added TFA (0.54 mL, 7.0 mmol) dropwise. The resulting solution was stirred for 18 h at rt and was concentrated under reduced pressure. The crude material was redissolved in CH2Cl2 (5 mL) and the organic layer was sequentially washed with sat. aq. NaHCO3 (2×2 mL) and brine (1×2 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin-layer chromatography (8×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 105 mg (97%) of white solid. mp 120-122° C.; M+H=389.

Example 341

[0594] 1673

[0595] Step A:

[0596] By essentially the same procedure set forth in Example 340 only substituting the appropriate amine, the above compound was prepared. MS: MH+=431.

[0597] Step B: Removal to t-butoxvcarbonyl Protecting Group with KOH. 1674

[0598] To a mixture of the compound prepared in Example 341, Step A (0.14 g, 0.26 mmol) in EtOH:H2O (3 mL, 2:1) was added KOH (0.29 g, 20 eq.) in one portion. The resulting solution was stirred at reflux 14 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in CH2Cl2 (5 mL) and diluted with saturated NaHCO3 (2 mL). The layers were separated and the aqueous layer extracted with CH2Cl2 (2×4 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (8×1000 μM) eluting with 5% MeOH in CH2Cl2 solution (0.066 g, 59% yield). MS: MH+=432; mp=219-221° C.

Examples 342-397

[0599] By essentially the same procedure set forth in Example 340 only substituting the chlorides in Column 2 of Table 31 and removing the t-butoxycarbonyl protecting group by the method shown in Column 3 of Table 31, the compounds shown in Column 4 of Table 31 were prepared.

TABLE 31
Ex.	Column 2	Column 3	Column 4	CMPD
342	1675	HCl	1676	MS: MH+ = 403 m.p. 151-157° C.
343	1677	HCl	1678	MS: MH+ = 466 m.p. 212-217° C.
344	1679	HCl	1680	MS: MH+ = 405 m.p. 53-58° C.
345	1681	HCl	1682	MS: MH+ = 405 m.p. 63-69° C.
346	1683	HCl	1684	MS: MH+ = 363 m.p. 170-171° C.
347	1685	HCl	1686	MS: MH+ = 407 m.p. 148-151° C.
348	1687	HCl	1688	MS: MH+ = 435 m.p. 56-59° C.
349	1689	HCl	1690	MS: MH+ = 445 m.p. 66-68° C.
350	1691	KOH	1692	MS: MH+ = 417 m.p. 149-151° C.
351	1693	KOH	1694	MS: MH+ = 431 m.p. 111-114° C.
352	1695	KOH	1696	MS: MH+ = 417 m.p. 53-58° C.
353	1697	KOH	1698	MS: MH+ = 456 m.p. 186-189° C.
354	1699	KOH	1700	MS: MH+ = 416 m.p. 210-213° C.
355	1701	TFA	1702	1. mp = 68-70 2. M + H = 494
356	1703	KOH	1704	1. mp = 181-183 2. M + H = 404
357	1705	TFA	1706	1. mp = 69-71 2. M + H = 494
358	1707	KOH	1708	1. mp = 182-184 2. M + H = 404
359	1709	KOH	1710	1. mp = 202-204 2. M + H = 418
360	1711	TFA	1712	1. mp = 160-162 2. M + H = 402
361	1713	TFA	1714	1. mp = 151-153 2. M + H = 416
362	1715	KOH	1716	1. mp = 140-143 2. M + H = 418
363	1717	KOH	1718	1. mp = 139-142 2. M + H = 418
364	1719	KOH	1720	1. mp = 115-117 2. M + H = 418
366	1721	TFA	1722	1. mp = 102-104 2. M + H = 445
367	1723	TFA	1724	1. mp = 118-120 2. M + H = 474
368	1725	TFA	1726	1. mp = 106-108 2. M + H = 474
369	1727	TFA	1728	1. mp = 160-161 2. M + H = 464
370	1729	TFA	1730	1. mp = 93-95 2. M + H = 432
371	1731	KOH	1732	1. mp = 108-110 2. M + H = 432
372	1733	KOH	1734	1. mp = 180-182 2. M + H = 418
373	1735	TFA	1736	1. mp = 169-170 2. M + H = 417
374	1737	TFA	1738	1. mp = 77-79 2. M + H = 479
375	1739	TFA	1740	1. mp = 76-79 2. M + H = 479
376	1741	TFA	1742	1. mp = 105-107 2. M + H = 389
377	1743	TFA	1744	1. mp = 105-107 2. M + H = 389
378	1745	TFA	1746	1. mp = 130-133 2. M + H = 389
379	1747	TFA	1748	1. mp = 132-135 2. M + H = 431
380	1749	TFA	1750	1. mp = 135-137 2. M + H = 372
381	1751	KOH	1752	1. mp = 78-82 2. M + H = 432
382	1753	TFA	1754	1. mp = 101-103 2. M + H = 432
383	1755	TFA	1756	1. mp = 92-95 2. M + H = 472
384	1757	TFA	1758	1. mp = 107-111 2. M + H = 444
384.10	1759	TFA	1760	1. mp =2. M + H = 417
384.11	1761	TFA	1762	1. mp = 210-212 2. M + H = 391
385	1763	TFA	1764	1. mp = 122-124 2. M + H = 403
386	1765	TFA	1766	1. mp = 186-188 2. M + H = 491
387	1767	TFA	1768	1. mp = 173-175 2. M + H = 483
388	1769	TFA	1770	1. mp = 167-169 2. M + H = 450
389	1771	TFA	1772	1. mp = 90-92 2. M + H = 374
390	1773	TFA	1774	1. mp = 113-115 2. M + H = 404
391	1775	TFA	1776	1. mp = 114-116 2. M + H = 404
392	HNMe2	TFA	1777	LCMS: MH+ = 347;
393	H2NMe	TFA	1778	LCMS: MH+ = 333;
394	1779	TFA	1780	LCMS: MH+ = 359;
395	1781	TFA	1782	LCMS: MH+ = 405;
396	1783	TFA	1784	LCMS: MH+ = 405;
397	1785	TFA	1786	LCMS: MH+ = 391;

[0600] Additional data for select example shown below:

Example 392

[0601] 1 H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.46 (d, J=3.3 Hz, 1H), 8.21 (t, J=6.6 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.46 (s, 1H), 4.61 (d, J=6.9 Hz, 2H), 3.01 (s, 6H).

Example 393

[0602] 1 H NMR (CDCl3) δ 8.65 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.70 (m, 1H), 7.32 (dd, J=8.1, 4.8 Hz, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.08 (s, 1H), 4.80 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 2.96 (d, J=5.1 Hz, 3H).

Example 394

[0603] 1 H NMR (CDCl3) δ 8.68 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.72 (m, 1H), 7.32 (dd, J=7.8, 5.4 Hz, 1H), 6.55 (t, J=5.7 Hz, 1H), 5.53 (s, 1H), 5.35 (s, 1H), 4.62 (d, J=5.7 Hz, 2H), 2.49 (m, 1H), 0.75 (m, 2H), 0.51 (m, 2H).

Example 395

[0604] 1 H NMR (CDCl3) δ 8.65 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.33 (dd, J=8.1, 5.1 Hz, 1H), 6.45 (t, J=6.0 Hz, 1H), 5.07 (s, 1H), 4.69 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.98 (m, 1H), 3.79 (dd, J=10.8, 2.4 Hz, 1H), 3.59 (dd, J=11.1, 7.2 Hz, 1H), 1.59-1.36 (m, 4H), 0.94 (t, J=6.9 Hz, 3H).

Example 396

[0605] 1 H NMR (CDCl3) δ 8.60 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 7.73 (s, 1H), 7.66 (m, 1H), 7.31 (dd, J=7.8, 4.8 Hz, 1H), 6.51 (t, J=6.0 Hz, 1H), 5.05 (s, 1H), 4.86 (d, J=6.6 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 3.94 (m, 1H), 3.78 (dd, J=11.1, 2.4 Hz, 1H), 3.57 (dd, J=11.1, 7.2 Hz, 1H), 1.57-1.34 (m, 4H), 0.91 (t, J=7.2 Hz, 3H).

Example 397

[0606] 1 H NMR (CDCl3) δ 8.65 (s, 1H), 8.59 (d, J=4.5 Hz, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.31 (m, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.06 (s, 1H), 4.88 (m, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.70 (m, 2H), 3.38 (m, 2H), 1.79-1.61 (m, 4H).

Examples 398-416

[0607] By essentially the same conditions set forth in Example 341, Steps A and B only substituting the compound prepared in Preparative Example 193.10, the compounds in Column 4 of Table 32 were prepared.

TABLE 32
Ex.	Column 2	Column 3	Column 4	CMPD
398	1787		1788	MS: MH+ = 419 m.p. 102-105° C.
399	1789		1790	MS: MH+ = 421 m.p. 79-81° C.
400	1791		1792	MS: MH+ = 421 m.p. 78-79° C.
401	1793		1794	MS: MH+ = 433 m.p. 228-231° C.
402	1795		1796	MS: MH+ = 447 m.p. 97-102° C.
403	1797		1798	MS: MH+ = 421 m.p. ° C.
404	1799		1800	MS: MH+ = 421 m.p. ° C.
405	1801		1802	MS: MH+ = 386 m.p. ° C.
407	1803	KOH	1804	1. mp = 98-100 2. M + H = 390
408	1805	TFA	1806	1. mp = 170-173 2. M + H = 404
409	1807	KOH	1808	1. mp = 219-221 2. M + H = 420
410	1809	KOH	1810	1. mp = 110-112 2. M + H = 448
411	1811	TFA	1812	1. mp = 81-83 2. M + H = 448
412	1813	TFA	1814	1. mp = 136-138 2. M + H = 448
413	NaOMe	KOH	1815	1. mp = 107-110 2. M + H = 351
414	1816		1817	LCMS: MH+ = 375;

[0608] Additional data for select examples shown below:

Example 414

[0609] 1 H NMR (DMSO-d6) δ 8.26 (s, 1H), 8.23 (m, 1H), 8.13 (m, 1H), 7.90 (s, 1H), 7.40-7.27 (m, 3H), 5.34 (s, 1H), 4.49 (d, J=6.3 Hz, 2H), 2.56 (m, 1H), 0.67 (m, 2H), 0.35 (m, 2H).

Example 403

[0610] 1 H NMR (DMSO-d6+CDCl3) δ 8.08 (s, 1H), 7.90 (d, J=6.3 Hz, 1H), 7.49 (s, 1H), 7.34 (t, J=6.3 Hz, 1H), 7.16-7.09 (m, 2H), 5.65 (d, J=6.6 Hz, 1), 4.97 (s, 1H), 4.90 (s, 1H), 4.29 (d, J=6.3 Hz, 2H), 3.70 (m, 1H), 3.46 (m, 1H), 3.34 (m, 1H), 1.35-1.17 (m, 4H), 0.71 (t, J=7.2 Hz, 3H).

Example 404

[0611] 1 H NMR (DMSO-d6) δ 8.21 (s, 1H), 8.12 (d, J=6.6 Hz, 1H), 8.06 (m, 1H), 7.86 (s, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 5.28 (s, 1H), 4.70 (t, J=5.1 Hz, 1H), 4.41 (d, J=6.6 Hz, 2H), 4.00 (s, 1), 3.39 (m, 1H), 1.53 (m, 1H), 1.36-1.25 (m, 3H), 0.86 (t, J=7.0 Hz, 3H).

Examples 417-421

[0612] By the procedure set forth in Chem. Pharm. Bull. 1999, 47, 928-938. utilzing the oxygen or sulfur nucleophiles shown in Column 2 as described of Table 33 and by employing the cleavage method listed in Column 3 of Table 33, the compounds in Column 4 of Table 33 were prepared:

TABLE 33
		Column 3		CMPD
	Column 2	(Cleavage	Column 4	1. mp.
Ex.	(Nucleophile)	method	(Final Structure)	2. M + H
417	NaSMe	TFA	1818	1. mp = 172-175 2. M + H = 351
418	NaSt-Bu	TFA	1819	1. mp = 165-168 2. M + H = 392
419	NaSPh	TFA	1820	1. mp = 154-156 2. M + H = 412
420	NaOMe	TFA	1821	1. mp = 161-163 2. M + H = 335
421	NaOPh	TFA	1822	1. mp = 64-66 2. M + H = 397

Example 422

[0613] 1823

[0614] To a solution of amino compound (18 mg, 0.043 mmol) from Example 373 in CH2Cl2 (1 mL) at rt was added DIPEA (10 μL, 0.056 mmol) followed by MeSO2Cl (4 mL, 0.052 mmol). The mixture was stirred at rt for 12 h and was diluted with CH2Cl2 (2 mL) and sat. aq. NaHCO3 (2 mL). The layers were separated and the organic layer was extracted with brine (1×2 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin-layer chromatography (4×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 16 mg (75%) of white solid. mp 152-154° C.; M+H=495.

Examples 423-424

[0615] Utilizing the procedure outlined in Example 422, the amino compounds (Column 2) were converted to the corresponding methylsulfonamides (Column 3) in Table 34.

TABLE 34
			CMPD
	Column 2	Column 3	1. mp.
Ex.	(Amine)	(Final Structure)	2. M + H
423	1824	1825	1. mp = 166-168 2. M + H = 467
424	1826	1827	1. mp = 165-168 2. M + H = 467

Example 425

[0616] STEP A: 1828

[0617] A mixture of the compound prepared in Preparative Example 194 (132 mg, 0.25 mmol), tributylvinyltin (95 mg, 0.30 mmol) and tetrakis(triphenylphospine) palladium (29 mg, 0.025 mmol) in anhydrous dioxane (5 mL) was refluxed under N2 for 24 hr. The solvent was evaporated and the residue was purified by flash chromatography using 2:1 CH2Cl2:EtOAc as eluent to yield yellow waxy solid (53 mg, 50%). LCMS: MH+=428.

[0618] STEP B: 1829

[0619] A mixture of the compound prepared in Example 425, Step A (50 mg, 0.12 mmol) and KOH (100 mg, 1.80 mmol) in ethanol (3 mL) and H2O (0.6 mL) was stirred at 70° C. under N2 for 24 hr. NaHCO3 (1.0 g), Na2SO4 (2.0 g), and CH2Cl2 (20 mL) were added, the mixture was shaken and then filtered. The solvent was evaporated and the residue was purified by flash chromatography using 20:1:0.1 CH2Cl2:MeOH:conc.NH4OH as eluent to yield yellow waxy solid (17 mg, 45%). LCMS: MH+=328. Mp=48-51° C.

Example 426

[0620] STEP A: 1830

[0621] By essentially the same procedure set forth in Example 425, Step A only using tributylmethylethynyltin, the compound shown above was prepared.

[0622] STEP B: 1831

[0623] A mixture of the compound prepared in Example 426, Step A (150 mg, 0.34 mmol) and PtO2 (30 mg, 0.13 mmol) in glacial acetic acid (5 mL) was stirred under 1 atmosphere of H2 for 20 hr. The mixture was filtered, fresh PtO2 (30 mg, 0.13 mmol) was added and the mixture was stirred under 1 atmosphere of H2 for 2.5 hr. The mixture was poured onto Na2CO3 (20 g) and H2O (200 mL) and it was extracted with CH2Cl2 (4×20 mL). The combined extracts were dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography using 1:1 CH2Cl2:EtOAc as eluent to yield yellow waxy solid (68 mg, 45%).

[0624] STEP C: 1832

[0625] By essentially the same procedure set forth in Example 425, Step B only substituting the compound prepared in Example 426, Step B, the compound shown above was prepared, MS: MH+=344. Mp=110-112° C.

Example 427

[0626] STEP A: 1833

[0627] A mixture of the compound prepared in Preparative Example 194 (527 mg, 1.00 mmol), triethyl(trifluoromethyl)silane (666 mg, 3.60 mmol), potassium fluoride (210 mg, 3.60 mmol), and Cul (850 mg, 4.46 mmol) in anhydrous DMF (4 mL) was stirred in a closed pressure vessel at 80° C. for 72 hr. CH2Cl2 (80 mL) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by flash chromatography using 2:1 CH2Cl2: EtOAc as eluent to yield pale orange waxy solid (70 mg, 15%). LCMS: M+=470.

[0628] STEP B: 1834

[0629] TFA (0.70 mL) was added at 0° C. under N2 to a stirred solution of the compound prepared in Example 427, Step A (70 mg, 0.15 mmol), in anhydrous CH2Cl2 (3 mL). The mixture was stirred at 0° C. for 10 min, then at 25° C. for 2 hr. It was poured into 10% aqueous Na2CO3 (50 mL), extracted with CH2Cl2 (3×15 mL), dried over Na2SO4, and filtered. The solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to yield off-white solid (40 mg, 73%). LCMS: M+=370. Mp=156-158° C.

Example 428

[0630] STEP A: 1835

[0631] A mixture of the compound prepared in Preparative Example 193 (100 mg, 0.28 mmol), tetracyclopropylltin (91 mg, 0.32 mmol), Pd2dba3 (8.0 mg, 0.009 mmol) and Pd(Pt-Bu3)2 (9.0 mg, 0.017 mmol) in anhydrous dioxane (3 mL) was refluxed under N2 for 27 hr. The solvent was evaporated and the residue was purified by flash chromatography using 1:1 CH2Cl2:EtOAc as eluent to yield colorless waxy solid (38 mg, 38%). LCMS: MH+=366.

[0632] STEP B: 1836

[0633] A mixture of the compound prepared in Example 428, Step A (36 mg, 0.10 mmol) and KOH (300 mg, 5.40 mmol) in ethanol (3 mL), 1,2-dimethoxyethane (3.0 mL0 and H2O (0.8 mL) was refluxed under N2 for 4 hr. It was poured into saturated aqueous NaHCO3 (100 mL), extracted with CH2Cl2 (5×10 mL), dried over Na2SO4, and filtered. The solvent was evaporated and the residue was purified by flash chromatography using 30:1 EtOAc:MeOH as eluent to yield colorless waxy (18 mg, 69%). LCMS: MH+=266.

[0634] STEP C: 1837

[0635] N-bromosuccinimide (12 mg, 0.068 mmol) in anhydrous CH3CN (2 mL). was added under N2 to a stirred solution of the compound prepared in Example 428, Step B (18 mg, 0.068 mmol), in anhydrous CH3CN (2 mL). The mixture was stirred at 25° C. for 2 hr. The solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to yield 5 mg (17%) of the dibromo compound (white solid, LCMS: MH+=370, mp=150-152° C.) and 8 mg (34%) of the monobromo compound (colorless solid, LCMS: M+=344, mp=196-198° C.).

Example 429

[0636] STEP A: 1838

[0637] 1,3-propanesultam (72 mg, 0.60 mmol) in anhydrous DMF (3 mL) was added under N2 to 60% NaH in mineral oil (36 mg, 0.90 mmol). The mixture was stirred for 20 min, then the compound prepared in Preparative Example 196 (200 mg, 0.46 mmol) was added. The mixture was stirred at 100° C. for 30 min, the solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to yield colorless solid (150 mg, 63%). LCMS: M+=523.

[0638] STEP B: 1839

[0639] TFA (1.5 mL) was added at 0° C. under N2 to a stirred solution of the compound prepared in Preparative Example 196 (140 mg, 0.27 mmol), in anhydrous CH2Cl2 (5 mL). The mixture was stirred at 0° C. for 10 min, then at 25° C. for 2 hr. It was poured onto Na2CO3 (10 g), extracted with CH2Cl2 (3×50 mL), and filtered. The solvent was evaporated and the residue was purified by flash chromatography using 40:1 EtOAc:MeOH as eluent to yield white solid (32 mg, 28%). LCMS: M+=423. Mp=218-220° C.

Example 430

[0640] 1840

[0641] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (1 equivalent) (prepared as described in Preparative Example 129), or 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (1 equivalent) (prepared as described in Preparative Example 127), R1NH2 (1.2 equivalents) and diisopropyl ethylamine (2 equivalents) were dissolved in anhydrous 1,4-dioxane and the mixture was heated at 75° C. for the time given in Table 97. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column as described in Table 97, to give the title compound.

[0642] Using the appropriate reactants and essentially the same procedure as described above, the products of Examples 431 to 438 were prepared. Variations in the reaction conditions are noted in Table 35.

TABLE 35
			FABMS	Reaction		Chromatographic
Ex.	Structure	MW	MH+	Conditions	Yield	Data
431	1841	463.8	463.0	75° C./26 h	52%	15 × 2.5 cm 0.5-2% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
432	1842	429.3	429.2	75° C./26 h 25° C./39 h	53%	15 × 5 cm Dichloromethane; 1.5% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
433	1843	477.8	477.1	75° C./26 h	48%	15 × 5 cm Dichloromethane; 3.5-15% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
434	1844	477.8	477.0	75° C./26 h	50%	15 × 5 cm Dichloromethane; 3.5-15% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
435	1845	434.8	434.1	75° C./24 h 25° C./65 h	53%	15 × 2.5 cm 3% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
436	1846	434.8	434.2	75° C./27 h	31%	15 × 2.5 cm 3% (10% Conc. ammonium hydroxide in methanol)-dichloromethane
437	1847	438.7	438.1	75° C./21 h 25° C./46 h	97%	15 × 2.5 cm 0.25% (10% Conc. ammonium hydroxide in methanol)- dichloromethane
438	1848	438.7	438.1	75° C./28 h −20° C./72 h	95%	60 × 2.5 cm 20% Ethyl acetate in hexane

[0643] Additional physical data for the compounds are given below:

Example 431

[0644] Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (110 mg, 0.318 mmoles) (prepared as described in Preparative Example 129); 3-(aminomethyl)piperidine-1-carboxamide (60 mg, 0.382 mmoles) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.111 mL, 0.636 mmoles); anhydrous 1,4-dioxane (2.5 mL). Physical properties: HRFABMS: m/z 463.0628 (MH+). Calcd. for C19H21N6OBrCl: m/z 463.0649: δH (CDCl3) 1.38 (1H, m, CH2), 1.52 (1H, m, CH2), 1.73 (1H, m, CH), 1.93 (1H, m, CH2), 2.02 (1H, m, CH2), 2.98 (1H, m, CH2), 3.06 (1H, m, CH2), 3.37 (2H, m, CH2), 3.58 (1H, m, CH2), 3.82 (1H, m, CH2), 4.87 (2H, bm, COHN2), 6.28 (1H, s, H6), 7.02 (1H, m, NH), 7.36 (2H, m, Ar—H), 7.45 (1H, m, Ar—H), 7.68 (1H, m, Ar—H) and 8.00 ppm (1H, s, H2); δC (CDCl3) CH2: 23.7, 28.1,44.6, 45.5, 47.2; CH: 35.2, 87.4, 127.2, 130.1, 130.3, 131.6, 143.9: C: 83.1, 132.1, 138.6, 145.5, 146.5, 158.0, 158.4.

Example 432

[0645] Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (500 mg, 1.62 mmoles) (prepared as described in Preparative Example 127); 3-(aminomethyl)piperidine-1-carboxamide (306 mg, 1.944 mmoles) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.566 mL, 3.24 mmoles); anhydrous 1,4-dioxane (13 mL). Physical properties: HRFABMS: m/z 429.1031 (MH+). Calcd. for C19H22N6OBr: m/z 429.1038; δH (CDCl3) 1.44 (1H, m, CH2), 1.59 (1H, m, CH2), 1.79 (1H, m, CH), 2.01 (1H, m, CH2), 2.08 (1H, m, CH2), 3.03 (1H, m, CH2), 3.13 (1H, m, CH2), 3.39 (1H, m, CH2), 3.47 (1H, m, CH2), 3.63 (1H, m, CH2), 3.90 (1H, m, CH2), 4.88 (2H, bm, CONH2), 6.40 (1H, s, H6), 6.90 (1H, m, NH), 7.53 (2H, m, Ar—H), 8.02 (1H, s, H2) and 8.12 (1H, m, Ar—H); δ (CDCl3) CH2: 23.7, 28.2, 44.7, 45.5, 47.3; CH: 35.2, 82.9, 127.5, 127.5, 128.7, 128.7, 130.0, 143.9; C: 83.0, 138.5, 145.8, 147.1, 158.3, 158.5.

Example 433

[0646] Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (347 mg, 1.01 mmoles) (prepared as described in Preparative Example 129); 3-(aminoethyl)piperidine-1-carboxamide (208 mg, 1.21 mmoles) (prepared as described in Preparative Example 242 above); diisopropyl ethylamine (0.393 mL, 2.02 mmoles); anhydrous 1,4-dioxane (9 mL). Physical properties: δH (CDCl3) 1.24 (1H, m, CH2), 1.55 (1H, m, CH), 1.72 (4H, m, CH2), 1.93 (1H, m, CH2), 2.69 (1H, m, CH2), 2.94 (1H, m, CH2), 3.55 (2H, m, CH2), 3.73 (1H, m, CH2), 3.98 (1H, m, CH2), 4.83 (2H, bm, CONH2), 6.55 (1H, s, H6), 6.78 (1H, m, NH), 7.41 (2H, m, Ar—H), 7.50 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH2: 24.6, 30.7, 32.6, 39.9, 45.3, 49.3; CH: 33.3, 87.5, 127.4, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.8, 145.7, 146.2, 158.1, 158.1.

Example 434

[0647] Reactants: 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (275 mg, 0.803 mmoles) (prepared as described in Preparative Example 129); 4-(aminoethyl)piperidine-1-carboxamide (165 mg, 0.963 mmoles) (prepared as described in Preparative Example 243 above); diisopropyl ethylamine (0.311 mL, 0.963 mmoles); anhydrous 1,4-dioxane (7.2 mL). Physical properties: δH (d6-DMSO) 1.00 (2H, m, CH2), 1.50 (1H, m, CH), 1.59 (2H, m, CH2), 1.67 (2H, m, CH2), 2.60 (2H, m, CH2), 3.48 (2H, m, CH2), 3.70 (2H, m, CH2), 5.84 (2H, bs, CONH2), 6.43 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.30 (1H, s, H2) and 8.36 ppm (1H, m, NH); δC (d6-DMSO) CH2: 31.5, 31.5, 34.8, 43.5, 43.5, 43.5; CH: 32.8, 86.8, 127.1, 129.7, 130.3, 131.0, 143.3; CH: 81.3, 131.0, 138.7, 145.1, 146.4, 157.3, 157.8.

Example 435

[0648] Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (174 mg, 0.507 mmoles) (prepared as described in Preparative Example 129) and 3-(aminomethyl)-1-methylpiperidine (65 mg, 0.507 mmoles) (prepared as described in Preparative Example 244 above); diisopropyl ethylamine (0.178 mL, 1.014 mmoles); anhydrous 1,4-dioxane (2.5 mL). Physical properties: HRFABMS: m/z 434.0742 (MH+). Calcd. for C19H22N5BrCl: m/z 434.0747; δ (CDCl3) 1.18 (1H, m, CH2), 1.68 (1H, m, CH2), 1.80 (1H, m, CH2), 1.87 (1H, m, CH2), 1.96 (1H, m, CH), 2.14 (2H, m, CH2), 2.32 (3H, s, NCH3), 2.75 (1H, m, CH2), 2.29 (1H, m, CH2), 3.42 (2H, m, —NHCH2CH), 6.36 (1H, s, H6), 6.64 (1H, bm, NH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.74 (1H, m, Ar—H) and 8.06 ppm (1H, s, H2); δC (CDCl3) CH3: 46.6; CH2: 24.4, 27.9, 46.1, 56.1, 59.6; CH: 36.0, 87.4, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.2.

Example 436

[0649] Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (111.4 mg, 0.325 mmoles) (prepared as described in Preparative Example 129); 4-(aminomethyl)-1-methylpiperidine (50 mg, 0.39 mmoles) (prepared as described in Preparative Example 245 above); diisopropyl ethylamine (0.1135 mL, 0.65 mmoles); anhydrous 1,4-dioxane (1.5 mL). Physical data: HRFABMS: m/z 434.0735 (MH+). Calcd. for C19H22N5BrCl: m/z 434.0747; 5H (CDCl3) 1.42 (2H, m, CH2), 1.72 (1H, m, CH), 1.82 (2H, m, CH2), 1.93 (2H, m, CH2), 2.20 (3H, s, NCH3), 2.89 (2H, m, CH2), 3.34 (2H, m, —NHCH2CH), 6.31 (1H, s, H6), 6.46 (1H, m, NH), 7.36 (2H, m, Ar—H), 7.46 (1H, m, Ar—H), 7.70 (1H, m, Ar—H) and 8.00 ppm (1H, s, H2); δC (CDCl3) CH3: 46.4; CH2: 30.2, 30.2, 48.0, 55.3, 55.3; CH: 35.4, 87.5, 127.2, 130.2, 130.2, 131.6, 143.8; C: 83.3, 132.2, 138.9, 145.7, 146.4, 158.1.

Example 437

[0650] Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (191 mg, 0.557 mmoles) (prepared as described in Preparative Example 129); 3-(aminomethyl)benzonitrile (88.3 mg, 0.668 mmoles) (prepared as described in Preparative Example 246 above); diisopropyl ethylamine (0.192 mL, 1.114 mmoles); anhydrous 1,4-dioxane (4.5 mL). Physical data: HRFABMS: m/z 438.0125 (MH+). Calcd. for C19H12N5BrCl: m/z 438.0121; δH (CDCl3) 4.76 (2H, d, —CH2NH—), 6.32 (1H, s, H6), 7.00 (1H, m, —CH2NH—), 7.40 (2H, m, Ar—H), 7.46 (1H, m, Ar—H), 7.55 (1H, m, Ar—H), 7.67 (2H, m, Ar—H), 7.71 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.10 ppm (1H, s, H2); δC (CDCl3) CH2: 45.5; CH: 88.2, 127.2, 130.0, 130.2, 130.4, 130.6, 131.4, 131.6, 131.9, 144.1; C: 83.8, 113.4, 118.3, 132.0, 137.8, 138.3, 145.6, 145.9, 158.0.

Example 438

[0651] Reactants: 3-Bromo-7-chloro-5-phenylpyrazolo[1 ,5-a]pyrimidine (233.5 mg, 0.681 mmoles) (prepared as described in Preparative Example 129); 4-(aminomethyl)benzonitrile (108 mg, 0.817 mmoles) (prepared as described in Preparative Example 247 above); diisopropyl ethylamine (0.235 mL, 1.362 mmoles); anhydrous 1,4-dioxane (5.3 mL). Physical data: HRFABMS: m/z 438.0117 (MH+) Calcd. for C20H14N5BrCl: m/z 438.0121; δH (CDCl3) 4.80 (2H, d, CH2), 6.30 (1H, s, H6), 7.01 (1H, m, NH), 7.40 (2H, m, Ar—H), 7.47 (1H, m, Ar—H), 7.70 (2H, m, Ar—H), 7.72 (2H, m, Ar—H), 7.80 (1H, m, Ar—H) and 8.10 ppm (1H, s, H2); δC (CDCl3) CH2: 45.8; CH: 88.2, 127.2, 127.7, 127.7, 130.2, 130.4, 131.6, 132.9, 132.9, 144.1; C: 83.8, 112.2, 118.4, 132.0, 138.2, 141.5, 145.5, 146.0, 158.0.

Example 439

[0652] 1849

[0653] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1 ,5-a]pyrirmidine (50 mg, 0.146 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac Technologies carousel reaction tube. PS-diisopropyl ethylamine resin (161 mg, 0.5828 mmoles) was added to each tube. A freshly prepared 1 M solution of the appropriate amine R1NH2in anhydrous 1,4-dioxane (0.2185 mL, 0.2185 mmoles) was added to each tube and the tubes were sealed and heated at 70° C. for 78 h with magnetic stirring in the reaction block. Each tube was filtered and the resin was washed with anhydrous 1,4-dioxane and then dichloromethane. The combined individual filtrates from each tube were evaporated to dryness and the residues were each re-dissolved in anhydrous 1,4-dioxane (5 mL) and placed in GeneVac reaction tubes. To each tube was added PS-isocyanate resin (594 mg, 0.8742 mmoles) and PS-trisamine resin (129 mg, 0.4371 mmoles) and the tubes were stirred at 25° C. for 20 h in the reaction block. The resins were filtered off and washed with anhydrous 1,4-dioxane and dichloromethane. The filtrates from each tube were evaporated to dryness and the residues were each chromatographed on a silica gel column using the column size and the eluant shown in Table 36, to give the title compounds.

TABLE 36
			FABMS		Chromatographic
Ex.	Structure	MW	MH+	Yield	Data
440	1850	428.7	428.0	81%	15 × 2.5 cm Dichloromethane; 0.5% Methanol in dichloromethane
441	1851	428.7	428.0	48%	20 × 2 cm Dichloromethane; 1.5% Methanol in dichloromethane
442	1852	428.7	428.0	24%	15 × 2.5 cm Dichloromethane; 1.5% Methanol in dichloromethane
443	1853	463.8	463.0	44%	15 × 2.2 cm Dichloromethane; 5% Methanol in dichloromethane
444	1854	434.8	434.1	63%	15 × 2.5 cm 5% Methanol in dichloromethane
445	1855	448.8	448.2	65%	15 × 2.5 cm 5% Methanol in dichloromethane
446	1856	448.8	448.1	40%	15 × 2.5 cm Dichloromethane; 0.5% Methanol in dichloromethane
447	1857	436.7	436.1	72%	15 × 2.5 cm 0.5% Methanol in dichloromethane
448	1858	450.8	450.0	53%	20 × 2 cm Dichloromethane; 0.5% Methanol in dichloromethane
449	1859	381.7	381.0	44%	20 × 2 cm 1.5% Methanol in dichloromethane

[0654] Additional physical data for the compounds are given below:

Example 440

[0655] Physical properties: HRFABMS: m/z 428.0272 (MH+). Calcd. for C19H16N5BrCl: m/z 428.0278; δH (CDCl3) 3.28 (2H, dd, C5H4NCH2CH2NH—), 3.94 (2H, ddd, C5H4NCH2CH2NH—), 6.40 (1H, s, H6), 7.22-7.29 (3H, m, Ar—H), 7.38-7.44 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.68 (1H, ddd, Ar—H), 7.73 (1H, Ar—H), 8.18 (1H, s, H2) and 8.68 ppm (1H, NH); δC (CDCl3) CH2: 36.4, 41.5; CH: 87.3, 122.1, 123.6, 127.1, 130.1, 130.1, 131.6, 137.0, 143.8, 149.5; C: 83.1, 132.1, 138.9, 145.7, 146.3, 158.0, 158.1.

Example 441

[0656] Physical properties: HRFABMS: m/z 428.0272 (MH+). Calcd. for C19H16N5BrCl: m/z 428.0278; δH (CDCl3) 3.12 (2H, dd, C5H4NCH2CH2NH—), 3.77 (2H, ddd, C5H4NCH2CHH2NH—), 6.40 (1H, s, H6), 6.59 (1H, m, Ar—H), 7.34 (1H, bm, Ar—H), 7.39-7.45 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.62 (1H, m, Ar—H), 7.75 (1H, m, Ar—H), 8.05 (1H, s, H2) and 8.63 ppm (1H, m, NH); δC (CDCl3) CH2: 32.7, 43.1; CH: 87.5, 127.2, 130.2, 130.3, 131.6, 136.4, 142.9, 148.3, 149.8; C: 83.5, 132.0, 138.6, 145.6, 145.9, 158.1.

Example 442

[0657] Physical properties: HRFABMS: m/z 428.0275 (MH+). Calcd. for C19H16N5BrCl: m/z 428.0278; δH (CDCl3) 3.13 (2H, dd, C5H4NCH2CH2NH—), (2H, ddd, C5H4NCH2CH2NH—), 6.42 (1H, s, H6), 6.53 (1H, m, Ar—H), 7.23 (2H, m, Ar—H), 7.40-7.46 (2H, m, Ar—H), 7.62 (1H, m, Ar—H), 7.76 (1H, m, Ar—H), 8.07 (1H, s, H2) and 8.63 ppm (1H, m, NH); δC (CDCl3) CH2: 34.7, 42.5; CH: 87.4, 124.5, 124.5, 127.2, 130.2, 130.3, 131.6, 144.0, 150.2, 150.2; C: 83.5, 132.0, 138.6, 145.6, 145.9, 146.6, 158.1.

Example 443

[0658] Physical properties: HRFABMS: m/z 463.1003 (MH+). Calcd. for C20H25N6BrCl: m/z 463.1013; δH (CDCl3) 1.98 (2H, m, ═NCH2CH2CH2NH—), 2.443 (3H, s, NCH3), 2.67 (2H, m, ═NCH2CH2CH2NH—), 2.70 (8H, piperazine CH2), 3.58 (2H, m, ═NCH2CH2CH2NH—), 6.32 (1H, s, H6), 7.37-7.43 (2H, m, Ar—H), 7.50 (1H, m, Ar—H), 7.73 (1H, m, Ar—H), 8.06 (1H, s, H2) and 8.60 ppm (1H, m, NH); 67C (CDCl3) CH3: 46.1; CH2: 24.1, 42.8, 53.3, 54.6, 54.6, 57.5, 57.5; CH: 87.1, 127.0, 130.0, 130.1, 131.5, 143.4; C: 82.7, 132.1, 139.2, 145.7, 146.7, 158.0.

Example 444

[0659] Physical properties: HRFABMS: m/z 434.0742 (MH+). Calcd. for C19H22N5BrCl: m/z 434.0747; δH (CDCl3) 1.72 (1H, m, CH/CH2), 1.78-1.90 (2H, m, CH/CH2), 2.02 (3H, m, CH/CH2), 2.50 (1H, m, CH/CH2), 2.45 (3H, s, NCH3), 2.51 (1H, m, CH/CH2), 3.23 (1H, m, CH/CH2), 3.54 (1H, m, CH/CH2), 3.60 (1H, m, CH/CH2), 6.32 (1H, s, H6), 7.38-7.44 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H), 7.96 (1H, bm, NH) and 8.05 ppm (1H, s, H2); δC (CDCl3) CH3: 40.7; CH2: 22.7, 29.3, 30.1, 39.4, 57.0; CH: 64.2, 87.1, 127.1, 130.0, 130.1, 131.6, 143.8; C: 82.8, 132.1, 139.1, 145.7, 146.4, 158.0.

Example 445

[0660] Physical properties: HRFABMS: m/z 448.0910 (MH+). Calcd. for C20H24N5BrCl: m/z 448.0904; δH (CDCl3) 1.90 (4H, m, CH2), 2.00 (4H, m, CH2), 2.84 (2H, m, CH2), 2.95 (4H, m, CH2), 3.51 (2H, m, CH2), 6.32 (1H, s, H6), 7.05 (1H, bm, NH), 7.37-7.43 (2H, m, Ar—H), 7.50 (1H, m, Ar—H), 7.73 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH2: 23.4, 23.4, 24.8, 26.4, 41.8, 53.9, 53.9, 55.2; CH: 87.3, 127.1, 130.1, 130.2, 131.6, 143.7; C: 83.0, 132.0, 138.9, 145.7, 146.3, 158.1.

Example 446

[0661] Physical properties: HRFABMS: m/z 448.0548 (MH+). Calcd. for C19H20N5OBrCl: m/z 448.0540; δH (CDCl3) 1.94 (2H, m, CH2), 2.09 (2H, m, CH2), 2.49 (2H, m, CH2), 3.45 (2H, m, CH2), 3.51 (4H, m, CH2), 6.32 (1H, s, H6), 7.37-7.44 (3H, m, Ar—H/NH), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.10 ppm (1H, s, H2); δC (CDCl3) CH2: 18.0, 26.3, 30.8, 39.2, 39.9, 47.5; CH: 87.0, 127.1, 130.1, 130.1, 131.6, 144.1; C: 82.9, 132.1, 138.9, 145.6, 146.2, 157.9, 176.2.

Example 447

[0662] Physical properties: HRFABMS: m/z 436.0532 (MH+). Calcd. for C18H20N5OBrCl: m/z 436.0540; δH (CDCl3) 2.60 (4H, bm, —N(CH2CH2)2O), 2.83 (2H, m, ═NCH2CH2NH—), 3.57 (2H, m, ═NCH2CH2NH—), 3.83 (4H, m, —N(CH2CH9)2O), 6.37 (1H, s, H6), 6.99 (1H, bm, NH), 7.38-7.45 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.09 ppm (1H, s, H2); δC (CDCl3) CH2: 38.2, 53.3, 53.3, 56.2, 66.9, 66.9; CH: 87.6, 127.1, 130.1, 130.2, 131.6, 143.9; C; 83.1, 132.1, 138.9, 145.7, 146.2, 158. 1.

Example 448

[0663] Physical properties: HRFABMS: m/z 450.0688 (MH+). Calcd. for C19H22N5OBrCl: m/z 450.0696; δH (CDCl3) 1.98 (2H, m, ═NCH2CH2CH2NH—), 2.58 (4H, m, —N(CH2CH2)2O), 2.67 (2H, m, ═NCH2CH2CH2NH—), 3.59 (2H, m, ═NCH2CH2CH2NH—), 3.94 (4H, m, —N(CH2CH2)2O), 6.31 (1H, s, H6), 7.37-7.44 (2H, Ar—H), 7.51 (1H, m, Ar—H), 7,78 (1H, m, Ar—H), 8.08 (1H, s, H2) and 8.60 ppm (1H, bm, NH); δC (CDCl3) CH2: 23.7, 42.7, 52.9, 52.9, 58.0, 66.6, 66.6; CH: 87.0, 127.1, 130.0, 130.1, 131.5, 143.6; C: 82.8, 132.1, 139.1, 145.7, 146.7, 158.0.

Example 449

[0664] Physical properties: HRFABMS: m/z 381.0114 (MH+). Calcd. for C15H15N4OBrCl: m/z 381.0118; δH (CDCl3) 1.39 (3H, d, CHCH3), 2.76 (1H, bm, —OH), 3.71 (1H, m, ═CHCH2OH), 3.81 (1H, m, ═CHCH2OH), 3.88 (1H, m, ═CHCH2OH), 6.38 (1H, s, H6), 7.38 (2H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.68 (1H, m, Ar—H) and 8.02 ppm (1H, s, H2); δ (CDCl3) CH3: 16.9; CH2: 65.0; CH: 50.0, 88.0, 127.1, 130.1, 130.3, 131.4, 143.8; C: 83.0, 132.0, 138.5, 145.6, 146.0, 158.2.

Example 450

[0665] 1860

[0666] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.146 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac Technologies carousel reaction tube. PS-diisopropyl ethylamine resin (161 mg, 0.5828 mmoles) was added to each tube. A freshly prepared solution of the appropriate amine RINH2 (0.219 mmoles) in anhydrous 1,4-dioxane (0.3 mL) was added to each tube, with the exception of Example 99-5 in which the amine was dissolved in 10% MeOH in 1,4-dioxane (0.3 mL), and the tubes were sealed and heated at 70° C. for 74 h with magnetic stirring in the reaction block. Each tube was filtered and the resin was washed with anhydrous 1,4-dioxane and then dichloromethane. The combined individual filtrates from each tube were evaporated to dryness and the residues were each re-dissolved in anhydrous 1,4-dioxane (5 mL) and placed in GeneVac reaction tubes. To each tube was added PS-isocyanate resin (594 mg, 0.8742 mmoles) and PS-trisamine resin (129 mg, 0.4371 mmoles) and the tubes were stirred at 25° C. for 20 h in the reaction block. The resins were filtered off and washed with anhydrous 1,4-dioxane and dichloromethane. The filtrates from each tube were evaporated to dryness and the residues were each chromatographed on a silica gel column using the column size and the eluant shown in Table 37, to give the title compounds.

TABLE 37
			FABMS		Chromatographic
Ex.	Structure	MW	MH+	Yield	Data
451	1861	381.7	380.9	66%	15 × 2.5 cm; 0.5% Methanol in dichloromethane
452	1862	381.7	380.9	60%	20 × 2 cm; 0.5% Methanol in dichloromethane
453	1863	381.7	380.9	69%	15 × 2.5 cm; 0.35% Methanol in dichloromethane
454	1864	381.7	380.9	75%	15 × 2.5 cm; 0.35% Methanol in dichloromethane
455	1865	397.7	397.2	84%	15 × 2.5 cm; 1.5% Methanol in dichloromethane
456	1866	397.7
457	1867	395.7	395.0	60%	15 × 2.5 cm; 0.35% Methanol in dichloromethane
458	1868	395.7	396.3	50%	15 × 2.5 cm; 0.35% Methanol in dichloromethane
459	1869	395.7	396.0	76%	15 × 2.5 cm; 0.35% Methanol in dichloromethane

[0667] Additional physical data for the compounds are given below:

Example 451

[0668] Physical properties: HRFABMS: m/z 381.0115 (MH+). Calcd. for C15H15N4OBrCl: m/z 381.0118; [α]D25° C.+1.4° (c=0.25, MeOH); 5H (CDCl3) 1.44 (3H, d, —CHCH3), 3.77 3.89 (1H, dd, CHCH2OH), (1H, dd, CHCH2OH), 3.94 (1H, m, CHCH2OH), 6.41 (1H, s, H6), 6.58 (1H, d, NH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.74 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH3: 17.1; CH2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.7, 145.6, 145.8, 158. 1.

Example 452

[0669] Physical properties: HRFABMS: m/z 381.0115 (MH+). Calcd. for C15H15N4OBrCl: m/z 381.0118; [α]D25° C.+6.5° (c=0.32, MeOH); 8H (CDCl3) 1.44 (3H, d, —CHCH3), 3.78 (1H, dd, CHCH2OH), 3.89 (1H, dd, CHCH2OH), 3.96 (1H, m, CHCH2OH), 6.41 (1H, s, H6), 6.58 (1H, d, NH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH3: 17.1; CH2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.3, 131.6, 143.8; C: 83.2, 132.1, 138.6, 145.6, 145.8, 158.1.

Example 453

[0670] Physical properties: HRFABMS: m/z 381.0115 (MH+). Calcd. for C15H15N4OBrCl: m/z 381.0118; [α]D25° C.+9.40 (c=0.27, MeOH); 5H (CDCl3) 1.33 (3H, d, CH3), 2.25 (1H, bs, OH), 3.37 (1H, dd, CH2), 3.51 (1H, m, CH2), 4.16 (1H, m, CHOH), 6.35 (1H, s, H6), 6.93 (1H, m, NH), 7.40 (2H, m, Ar—H), 7.50 (1H, m, Ar—H), 7.70 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH3: 20.8; CH2: 49.2; CH: 65.7, 87.8, 127.1, 130.1, 130.2, 131.2, 143.9; C: 83.1, 132.1, 138.5, 145.6, 146.6, 158.3.

Example 454

[0671] Physical properties: HRFABMS: m/z 381.0112 (MH+). Calcd. for C15H15N4OBrCl: m/z 381.0118; [α]D25° C.−3.20 (c=0.29, MeOH); δH (CDCl3) 1.32 (3H, d, CH3), 2.48 (1H, bs, OH), 3.35 (1H, dd, CH2), 3.49 (1H, m, CH2), 4.15 (1H, m, CHOH), 6.34 (1H, s, H6), 6.93 (1H, m, NH), 7.39 (2H, m, Ar—H), 7.49 (1H, m, Ar—H), 7.68 (1H, m, Ar—H) and 8.03 ppm (1H, s, H2); δC (CDCl3) CH3: 20.8; CH2: 49.2; CH: 65.7, 87.7, 127.1, 130.1, 130.3, 131.4, 143.9; C: 83.0, 132.0, 138.6, 145.6, 146.6, 158.3.

Example 455

[0672] Physical properties: HRFABMS: m/z 397.0054 (MH+). Calcd. for C15H15N4O2BrCl: m/z 397.0067; [α]D25° C.−9.50 (c=0.28, MeOH); 8H (CDCl3) 3.18 (2H, bs, OH), 3.47 (1H, dd, CH2), 3.58 (1H, dd, CH2), 3.63 (1H, dd, CH2OH), 3.70 (1H, dd, CH2OH), 3.98 (1H, m, CH), 6.35 (1H, s, H6), 7.10 (1H, m, NH), 7.37 (2H, m, Ar—H), 7.46 (1H, m, Ar—H), 7.64 (1H, m, Ar—H) and 8.01 ppm (1H, s, H2); δC (CDCl3) CH2: 44.7, 64.0; CH: 69.7, 87.7,:127.0, 130.1, 130.3, 131.3, 143.9; C: 82.9, 132.0, 138.4, 145.4, 146.7, 158.3.

Example 456

[0673] This enantiomer may be prepared by essentially the same manner as described above.

Example 457

[0674] Physical properties: HRFABMS: m/z 395.0260 (MH+). Calcd. for C16H17N4OBrCO: m/z 395.0274; [α]D25° C.−34.3° (c=0.28, MeOH); 8H (CDCl3) 1.08 (3H, dd, CH3), 1.78 (1H, m, CH2), 1.86 (1H, m, CH2), 2.35 (1H, bs, CH2OH), 3.71 (1 H, m, CHNH), 3.81 (1H, dd, CH2OH), 3.90 (1H, dd, CHOOH), 6.42 (1H, s, H6), 6.53 (1H, m, NH), 7.41 (2H, m, Ar—H), 7.51 (1H, Ar—H), 7.75 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH3: 10.5; CH2: 24.5, 63.7; CH: 55.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.6, 145.6, 146.3, 158.1.

Example 458

[0675] Physical properties: HRFABMS: m/z 395.0274 (MH+). Calcd. for C16H7N4OBrCO: m/z 395.0274; [α]D25° C.+27.5° (c=0.25, MeOH); 5H (CDCl3) 1.05 (3H, dd, CH3), 1.76 (1H, m, CH2), 1.85 (1H, m, CH2), 2.28 (1H, bs, CHH2OH), 3.67 (1H, m, CHNH), 3.77 (1H, dd, CH2OH), 3.84 (1H, dd, CH2OH), 6.49 (1H, s, H6), 6.66 (1H, m, NH), 7.39 (2H, m, Ar—H), 7.49 (1H, Ar—H), 7.71 (1H, m, Ar—H) and 8.04 ppm (1H, s, H2); δC (CDCl3) CH3: 10.5; CH2: 24.3, 63.3; CH: 56.1, 88.0, 127.1, 130.1, 130.3, 131.5, 143.8; C: 83.0, 132.1, 138.6, 145.6, 146.3, 158.2.

Example 459

[0676] Physical properties: HRFABMS: m/z 395.0264 (MH+). Calcd. for C16H17N4OBrCl: m/z 395.0274; δH (CDCl3) 1.77 (2H, m, —NHCH2CH2CH2CH2OH 1.90 (1H, bm, —NHCH2CH2CH2CH2OH), 1.93 (2H, m, —NHCH2CH2CH2CH2OH), 3.54 (2H, m, —NHCH2CH2CH2CH2OH), 3.77 (2H, m, —NHCH2CH2CH2CH2OH), 6.37 (1H, s, H6), 6.72 (1H, m, —NHCH2CH2CH2CH2OH), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.75 (1H, m, Ar—H) and 8.06 ppm (1H, S, H2); δC (CDCl3) CH2: 25.7, 29.7, 42.2, 62.2; CH: 87.4, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.1, 132.1, 138.8, 145.6, 146.3, 158.1.

Example 460

4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1 ,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLIC ACID AMIDE

[0677] 1870

[0678] A. 4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLIC ACID tert-BUTYL ESTER: 1871

[0679] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg, 0.875 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL). 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) were added and the mixture was heated at 75° C. for 24 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (1 5×5 cm) using dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%):

[0680] FABMS: m/z 520.1 (MH+); HRFABMS: m/z 520.1111 (MH+). Calcd. for C23H28N5O2BrCl: m/z 520.1115; δH (CDCl3) 1.30 (2H, m, CH2), 1.51 (9H, s, —COOC(CH3)3), 1.85 (2H, d, CH2), 1.95 (1H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1H, s, H6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.07 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.

[0681] B. [3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]PIPERIDIN-4-YLMETHYLAMINE: 1872

[0682] 4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (441 mg, 0.847 mmoles) (prepared as described in Example 460, Step A above) was dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (11.46 mL) was added. The mixture was stirred at 25° C. for 0.5 h. The product was worked up as described in Preparative Example 241, step B and chromatographed on a silica gel column (15×5 cm) using 8% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give [3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-yl methylamine (314.4 mg, 88%): FABMS: m/z 420.0 (MH+); HRFABMS: m/z 420.0585 (MH+).

[0683] Calcd. for C18H20N5BrCl: m/z 420.0591; δH (CDCl3) 1.34 (2H, m, CH2), 1.86 (2H, m, CH2), 1.91 (1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67 (2H, m, CH2), 3.18 (2H, m, CH2), 3.38 (2H, m, CH2), 6.37 (1H, s, H6), 6.53 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.06 ppm (1H, s Ar—H); δC (CDCl3) CH2: 31.2, 31.2, 46.2, 46.2,48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.1.

[0684] C. 4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PIPERIDINE-1-CARBOXYLIC ACID AMIDE: 1873

[0685] [3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine (57 mg, 0.136 mmoles) (prepared as described in Example 460, Step B above) was dissolved in anhydrous dichloromethane (1.2 mL) and trimethylsilylisocyanate (0.091 mL, 0.679 mmoles) was added. The mixture was stirred at 25° C. for 2.5 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30×2.5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl )pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid amide (53.7 mg, 86%): FABMS: m/z 463.1 (MH+); HRFABMS:

[0686] m/z 463.0647 (MH+). Calcd. for C19H21N6OBrCl: m/z 463.0649; δH (d6-DMSO) 1.09 (2H, m, CH2), 1.63 (2H, m, CH2), 1.87 (1H, m, CH), 2.60 (2H, m, CH2), 3.53 (2H, bm, CONH2), 3.91 (2H, d, CH2), 6.52 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.33 (1H, s, H2) and 8.52 ppm (1H, m, NH); δC (d6-DMSO) CH2: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1, 158.8.

Example 461

2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLIC ACID AMIDE:

[0687] 1874

[0688] A. 2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLIC ACID tert-BUTYL ESTER: 1875

[0689] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.1 66 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL). 2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were added and the mixture was heated at 75° C. for 48 h. Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was added and the heating was continued for a total of 58 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane followed by 0.3% (10% cbnc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH+);

[0690] HRESIMS: m/z 534.12797 (MH+). Calcd. for C24H30N5O2BrCl: m/z 534.12714; δH (CDCl3) 1.50 (1H, m, CH2), 1.51 (9H, s, COOC(CH3)3), 1.57 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76 (2H, m, CH2), 2.24 (1H, bm, CH2), 2.82/3.40/3.5414.08/4.51 (5H, m, CH/CH2), 6.34 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H2); δC (CDCl3) CH3; 28.5, 28.5, 28.5; CH2: 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH: ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.

[0691] B. [3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]-(2-PIPERIDIN-2-YLETHYL)AMINE: 1876

[0692] 2-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (465 mg, 0.869 mmoles) (prepared as described in Example 461, Step A above) was dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (11.76 mL) was added. The mixture was stirred at 25° C. for 1.5 h. The product was worked up as described in Preparative Example 241, step B and chromatographed on a silica gel column (15×5 cm) using 3.5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give [3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-ylethyl )amine (365.6 mg, 97%): FABMS: m/z 434.1 (MH+); HRFABMS: m/z 434.0726 (MH+). Calcd. for C19H22N5BrCl: m/z 434.0747; δH (CDCl3) 1.24 (1H, m, CH2), 1.41 (1H, m, CH2), 1.49 (1H, m, CH2), 1.66 (1H, m, CH2), 1.73 (1H, m, CH2), 1.81 (1H, m, CH2), 1.88 (2H, m, CH2), 2.68 (1H, m, CH2), 2.78 (1H, m, CH2), 3.20 (1H, m, CH), 3.55 (1H, m, CH2), 3.60 (1H, m, CH2), 6.32 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.74 (1H, m, Ar—H), 7.78 (1H, m, NH) and 8.05 ppm (1H, s, H2); δC (CDCl3) CH2: 24.7, 26.8, 33.1, 35.2, 40.3, 47.0; CH: 55.7, 87.2, 127.1, 130.0, 130.1, 131.5, 143.8; C: 82.9, 132.1, 139.0, 145.7, 146.5, 158.1.

[0693] C. 2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDI N-7-YLAMINO]ETHYL}PIPERIDINE-1-CARBOXYLIC ACID AMIDE: 1877

[0694] [3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimid in-7-yl]piperidin-2-ylethyl)amine (200 mg, 0.46 mmoles) (prepared as described in Example 461, Step B above) was dissolved in anhydrous dichloromethane (2 mL) and trimethylsilylisocyanate (0.31 mL, 2.3 mmoles) was added. The mixture was stirred at 25° C. for 1.25 h. Additional trimethylsilylisocyanate (0.155 mL, 1.15 mmoles) was added and the stirring was continued for a total of 3 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30×2.5 cm) using 2% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{2-[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid amide (1 06.3 mg, 48%): FABMS: m/z 477.0 (MH+); HRFABMS: m/z 477.0804 (MH+). Calcd. for C20H23N6OBrCl: m/z 477.0805; 5H (d6-DMSO) 1.29 (1H, m, CH2), 1.52 (5H, m, CH2), 1.72 (1H, m, CH2), 2.05 (1H, m, CH2), 2.51 (2H, s, CONH2), 2.79 (1H, dd, CH), 3.31 (1H, m, CH2), 3.34 (1H, m, CH2), 3.76 (1H, m, CH2), 4.30 (1H, bm, CH2), 6.42 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.60 (1H, m, Ar—H), 7.63 (1H, m, Ar—H), 8.29 (1H, s, H2) and 8.38 ppm (1H, dd, NH); δC (d6-DMSO) CH2: 18.6, 25.2, 28.2, 38.4, 38.6, 54.8; CH: 46.7, 86.6, 127.1, 129.7, 130.3, 131.0, 143.4; C: 81.2, 131.0, 138.7, 145.1, 146.4, 158.2.

Example 462

[0695] 1878

[0696] To a solution of the compound prepared in Example 204 (1.11 g, 2.12 mmol) in anhydrous acetonitrile (20 mL) was added TMSI (1.70 g, 8.52 mmol), dropwise at ambient temperature. After 10 minutes the acetonitrile was removed in vacuo. The resulting yellow foam was treated with 2 N HCl solution (7 mL) and then washed immediately with Et2O (5×). The pH of the aqueous was adjusted to 10 with 50% NaOH (aq) and the product was isolated by saturation of the solution with NaCl (s) followed by extraction with CH2Cl2 (5×) to give the crystalline product (733 mg, 89% yield). MH+=387; m. p. 207.5° C.

Examples 463-472

[0697] By essentially the same procedure set forth in Example 462 only substituting the compounds shown in Column 2 of Table 38, the compounds shown in Column 3 of Table 38 were prepared.

TABLE 38
Ex.	Column 2	Column 3	CMPD
463	1879	1880	MH+ = 403 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.38 (d, 1H), 8.04 (s, 1H), 7.78 (d, 1H), 7.65 (t, 1H), 6.18 (s, 1H), 4.89 (s, 2H), 3.26-3.21 (d, 2H), 2.96-2.70 (m, 3H), 2.05-1.78 (m, 4H).
464	1881	1882	MH+ = 454 m.p. = 175.4° C.
465	1883	1884	Yield = 87 MH+ = 470 m.p. = 220° C. m. pt (hydrochloride salt) = 164.3° C.
466	1885	1886	MH+ = 464 m.p. = 206° C.
467	1887	1888	MH+ = 411 m.p. = 169.5° C.
468	1889	1890	MH+ = 334 m.p. = 176.2° C.
469	1891	1892	MH+ = 465 m.p. = 250.4° C.
470	1893	1894	MH+ = 387 m.p. = 68.5° C.
471	1895	1896	MH+ = 387 m.p. = 59.4° C.
472	1897	1898	1. mp = 230-232 2. M + H = 396
472.10	1899	1900	1. mp = 157-160 2. M + H = 427

Example 473

[0698] Step A: 1901

[0699] A solution of the sulfonic acid (560 mg, 1.17 mmol) in 5 mL of dry DMF was cooled to 0° C. and SOCl2 (278 mg, 2.34 mmol) was added. The reaction mixture was brought to RT and stirred overnight. The next day the contents were poured on ice and the pH was carefully adjusted to 8. The product was extracted in to EtOAc and the solvent was removed after drying (Na2SO4) to provide 240 mg (41%) of the crude sulfonyl chloride which was used for the next step without further purification. 1H NMR (CDCl3) δ 8.20-8.10 (m, 1H), 8.10-7.95 (m, 3H), 7.65 (d, 2H), 7.45-7.35 (m, 1H), 7.35-7.20 (m, 1H), 7.15-7.05 (m, 1 H), 6.95 (t, 1H), 4.85 (d, 2H).

[0700] Step B: 1902

[0701] A solution of compound prepared in Example 473, Step A (120 mg, 0.24 mmol) in 10 mL of THF was treated with 2 mL of 1 M MeNH2 (2.00 mmol) in THF at RT overnight. The solvent was removed and the residue was purified by chromatography (silica, hexane:EtOAc (4:1→1:1)) to provide 56 mg (48%) of the sulfonamide. 1H NMR (DMSO-d6) δ 9.05 (t, J=9 Hz, 1H), 8.35 (s, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 7.55-7.46 (m, 1H), 7.45-7.38 (m, 1H), 7.38-7.25 (m, 1H), 6.50 (s, 1H), 4.80 (d, 2H), 3.30 (s, 3H)

[0702] LCMS: MH+=492.1

Example 474

[0703] 1903

[0704] By essentially the same procedure set forth in Example 473, only substituting dimethylamine, the above compound was prepared. 1H NMR (CDCl3) δ 8.14 (t, J=9 Hz, 1H), 8.00 (s, 1H), 7.76 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.34-7.44 (m, 1H), 7.26 (t, J=9 Hz, 1H), 7.14-7.04 (m, 1H), 6.93 (t, J=6 Hz, 1H), 6.45 (s, 1H), 4.75 (d, 2H), 2.70 (s, 6H)

[0705] LCMS: MH+=504.2

Example 475

[0706] 1904

[0707] A mixture of the compound prepared in Example 129 (300 mg, 0.66 mmol), NaOH (5 g), CH3OH—H2O (100 mL, 90:10) was stirred at 25 C for about 15 h. Progress of hydrolysis was checked by TLC. Reaction mixture was concentrated to remove methanol. The concentrate was diluted with 50 mL water, and extracted with ether to remove any un-reacted ester. Aqueous solution, thus obtained, was neutralized with 3 N HCl to pH 4 to obtain free acid, filtered and washed repeatedly with water. The acid was dried under vacuum (270 mg, 93% ) and used without further purification.

Example 476-479

[0708] By essentially the same procedure set forth in Example 475 only substituting the compounds in Column 2 of Table 39, the compounds in Column 3 of Table 39 were prepared.

TABLE 39
Ex.	Column 2	Column 3	CMPD
476	1905	1906	Yield = 82% LCMS: MH+ = 365
477	1907	1908	Yield = 82% LCMS: MH+ = 379
478	1909	1910	Yield = 72% LCMS: MH+ = 393
479	1911	1912	Yield = 70% LCMS: MH+ = 407
+Additional data for select examples shown below:

Example 476

[0709] 1 H NMR (CDCl3) δ 8.15 (m, 2H), 8.0 (m, 1H), 7.6 (m, 1H), 7.3 (m, 2H), 6.6 (s, 1H), 4.2 (d, 2H).

Example 477

[0710] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (dt, 2H), 2.6 (t, 2H).

Example 479

[0711] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 3.5 (dt, 2H), 2.4 (t, 2H), 1.8 (m, 4H).

Example 480

[0712] 1913

[0713] A mixture of the acid from Example 475 (85 mg, 0.193 mmol) and Et3N (20 mg, 0.193 mmol) in THF (20 mL) was stirred at 25 C for 15 min. Isobutyryl chloroformate (28 mg, 0.205 mmol) was added to the reaction mixture and stirred for 10 min followed by addition of NH4OH solution (0.5 mL ). The reaction mixture was stirred for 1 hr and concentrated to dryness. The dry mass was purified by column chromatography.

Examples 481-509

[0714] By essentially the same procedure set forth in Example 480 only substituting the carboxylic acid shown in Column 2 of Table 40 and the amine shown in Column 3 of Table 40, the compounds shown in Column 4 of Table 40 were prepared.

TABLE 40
Ex.	Column 2	Column 3	Column 4	CMPD
481	1914	CH3NH2	1915	Yield = 88% LCMS: MH+ = 454
482	1916	(CH3)2NH	1917	Yield = 80% LCMS MH+ = 468
483	1918	CH3NH2	1919	Yield = 70% LCMS MH+ = 454.
484	1920	1921	1922	Yield = 75% LCMS MH+ = 482.1
485	1923	1924	1925	Yield = 71% LCMS MH+ = 480.1
486	1926	1927	1928	Yield = 75% LCMS MH+ = 494.1
487	1929	1930	1931	Yield = 75% MH+ = 494.1
488	1932	1933	1934	Yield = 75% MH+ = 496.1
489	1935	1936	1937	Yield = 75% LCMS MH+ = 508.1
490	1938	1939	1940	Yield = 78% LCMS MH+ = 524.1
491	1941	1942	1943	Yield = 73% LCMS MH+ = 508.1
492	1944	1945	1946	Yield = 73% LCMS MH+ = 510.1
493	1947	1948	1949	Yield = 76% LCMS MH+ = 526.1
494	1950	1951	1952	Yield = 76% MH+ = 523.1
495	1953	1954	1955	Yield = 76% MH+ = 523.1
496	1956	1957	1958	Yield = 51% LCMS MH+ = 484.1
497	1959	1960	1961	Yield = 66% MH+ = 537.1
498	1962	1963	1964	Yield = 76% LCMS MH+ = 551.2
499	1965	1966	1967	Yield = 79% LCMS MH+ = 552.1
500	1968	1969	1970	Yield = 80% MH+ = 549.1
501	1971	1972	1973	Yield = 80% LCMS MH+ = 478.1
502	1974	1975	1976	Yield = 80% LCMH+ = 468.1
503	1977	1978	1979	Yield = 80% MH+ = 522.1
504	1980	1981	1982	Yield = 82% LCMS MH+ = 528.1
505	1983	CH3NH2	1984	Yield = 60% MH+ = 392
506	1985	1986	1987	Yield = 60% LCMH+ = 448.1
507	1988	1989	1990	Yield = 70% MH+ = 464.1
508	1991	1992	1993	Yield = 50% LCMS MH+ = 436.1
508.10	1994	CH3NH2	1995	Yield = 92 MH+ = 577

[0715] Additional data for select examples given below:

Example 481

[0716] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (s, 1H), 7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.95 (t, 1H), 6.5 (s, 1H), 6.25 (bs, 1H), 4.7 (d, 2H), 3.0 (d, 3H).

Example 482

[0717] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 4H), 7.25 (d, 2H), 7.15 (dd, 1H), 6.7 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.1 (s, 3H), 3.0 (s, 3H).

Example 483

[0718] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (bs, 1H), 7.7 (d, 1H), 7.5-7.3 (m, 3H), 7.25 (d, 1H), 7.15 (dd, 1H), 6.75 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1H), 4.7 (d, 2H), 3.0 (d, 3H).

Example 484

[0719] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H), 4.7 (d, 2H), 4.25 (m, 1H), 1.2 (d, 6H).

Example 485

[0720] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (s, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.3 (t, 1H), 4.7 (d, 2H), 2.9 (m, 1H), 0.8 (bt, 2H), 0.6 (bt, 2H).

Example 486

[0721] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (d, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.2 (t, 1H), 4.7 (d, 2H), 3.3 (dd, 2H), 1.05 (m, 1H), 0.5 (m, 2H), 0.25 (m, 2H).

Example 487

[0722] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1H), 4.7 (d, 2H), 4.6 (m, 1H), 2.4 (m, 2H), 1.95 (m, 1H), 1.75 (m, 2H).

Example 488

[0723] 1 H NMR (CDCl3) δ 8.5 (t, 1H), 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 5.9 (bs, 1H), 4.7 (d, 2H), 1.4 (s, 9H).

Example 489

[0724] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H), 4.7 (d, 2H), 4.4 (m, 1H), 2.05 (m, 2H), 1.7 (m, 4H), 1.4 (m, 2H).

Example 490

[0725] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.5 (bs, 2H), 4.7 (d, 2H), 4.1 (m, 1H), 3.9-3.7 (m, 3H), 3.3 (m, 1H), 2.0-1.9 (m, 5H).

Example 491

[0726] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (m, 5H), bs, 2H), 1.7 (bs, 4H), 1.5 (bs, 2H).

Example 492

[0727] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.8-3.4 (bm, 8H).

Example 493

[0728] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 4.0 (m, 2H), 3.6 (m, 2H), 2.8-2.45 (m, 4H).

Example 494

[0729] 1 H NMR (CH3OD) δ 8.15 (s, 1H), 8.0 (dt, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.4 (bs, 2H), 2.5-2.4 (m, 4H), 2.2 (s, 3H).

Example 495

[0730] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.75 (bs, 2H), 3.35 (bs, 2H), 2.4 (bs, 2H), 2.3 (s, 3H), 2.2 (bs, 2H).

Example 496

[0731] 1 H NMR (CDCl3) δ 7.95 (s, 1H), 7.9 (dt, 1H), 7.8 (t, 1H), 7.7 (d, 2H), 7.15 (m, 4H), 7.05 (dd, 1H), 6.9 (dd, 1H), 6.2 (s, 1H), 4.5 (d, 2H), 3.6 (t, 2H), 3.3 (dt, 2H).

Example 497

[0732] 1 H NMR (CH3OD) δ 8.1 (s, 1H), 7.9 (dt, 1H), 7.8 (d, 2H), 7.5 (d, 2H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.4 (s, 1H), 4.7 (d, 2H), 3.5 (t, 2H), 2.7 (m, 2H), 2.6 (bs, 4H), 1.8 (bs, 4H).

Example 498

[0733] 1 H NMR (CDCl3) δ 8.5 (t, 1H), 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7-2.5 (m, 4H), 2.35 (s, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 6H).

Example 499

[0734] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (m, 4H), 3.5 (dt, 2H), 2.6 (t, 2H), 2.5 (m, 4H).

Example 500

[0735] 1 H NMR (CH3OD) δ 8.15 (s, 1H), 7.9 (dt, 1H), 7.8 (d, 2H), 7.45 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.4 (s, 1H), 4.75 (d, 2H), 4.2 (m, 1H), 3.4-2.8 (m, 7H), 1.9-1.6 (m, 4H).

Example 501

[0736] 1 H NMR (CDCl3) δ 8.05 (dt, 1H), 8.0 (s, 1H), 7.6 (d, 2H), 7.4 (s, 1H), 7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 4.7 (d, 2H), 4.2 (d, 2H), 2.3 (bs, 1H).

Example 502

[0737] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.75 (d, 2H), 7.45 (s, 1H), 7.4 (d, 2H), 7.3 (dd, 1H), 7.1(dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.1(bs, 1H), 4.7 (d, 2H), 3.5 (dq, 2H), 1.2 (t, 3H).

Example 503

[0738] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 4.75 (d, 2H), 4.1 (m, 2H).

Example 504

[0739] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.45 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.6 (t, 1H), 6.5 (s, 1H), 4.7 (d, 1H), 3.6 (m, 2H), 2.8 (t, 2H), 2.6 (q, 2H), 1.3 (t, 3H).

Example 505

[0740] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (m, 2H), 2.7 (t, 2H), 3.0 (d, 3H).

Example 506

[0741] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (m, 2H), 3.6 (m, 6H), 3.4 (m, 2H), 2.7 (t, 2H).

Example 507

[0742] 1 H NMR (CDCl3) δ 8.15 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.9 (t, 2H), 3.8 (dt, 2H), 3.7 (t, 2H), 2.7 (t, 2H), 2.6 (m, 4H).

Example 508

[0743] 1 H NMR (CH3OD ) δ 8.1 (s, 1H), 7.95 (dt, 1H), 7.5 (m, 1H), 7.35-7.2 (m, 2H), 6.5 (s, 1H), 3.6 (m, 4H), 3.25 (m, 4H), 2.4 (t, 2H), 2.05 (dt, 2H).

Example 509

[0744] 1996

[0745] A solution of NaOH (59 mg, 1.47 mmol) in 1 mL of water was added to a suspension of NH2OH.HCl (102 mg, 1.47 mmol) in 10 mL of methanol at 0° C. After 5 min, the compound prepared in Example 210.10 (208 mg, 0.49 mmol) was added and the reaction mixture was refluxed overnight. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The EtOAc layer was dried (Na2SO4) and the solvent was evaporated. The resulting crude amidoxime was suspended in trimethyl orthoformate containing catalytic amount of PTS acid and refluxed overnight. The solvent was removed and the residue was taken up in EtOAc. The EtOAc layer was washed with aq NaHCO3 followed by water and brine. The solvent was evaporated and the residue was purified by chromatography (silica, hexane:EtOAc (1:1)) to provide 80 mg (35%) of the oxadiazole. 1H NMR (CDCl3) δ 8.75 (s, 1H), 8.20-8.10 (m, 3H), 8.03 (s, 1H), 7.53 (d, J=9 Hz, 2H), 7.45-7.36 (m, 1H), 7.30-7.22 (m, 2H), 7.16-7.08 (m, 1H), 6.80 (t, J=5 Hz, 1H), 6.56 (s, 1H). LCMS: MH+=465.2

Example 510

[0746] 1997

[0747] By essentially the same procedure set forth in Example 509 only substituting the compound prepared in Preparative Example 192, the above compound was prepared. yield=75; MH+=453; m. p.=79.3° C.

Example 511

[0748] 1998

[0749] A mixture of the nitrile (235 mg, 0.56 mmol) and Me3SnN3 (343 mg, 1.67 mmol) in 20 mL of dry toluene was refluxed for 2 days under Ar. The solvent was removed in vacuo and the residue was dissolved in dry methanol. HCl gas was bubbled through the solution for 15 min and the reaction mixture allowed to stand at overnight at RT. The next day, the solvent was removed, the residue was taken in water and the pH was adjusted to 5. The precipitated product was extracted into EtOAc. Evaporation of the EtOAc layer after drying (Na2SO4) provided the residue which was purified by chromatography (silica, DCM:MeOH (98:2-95:5)) to yield 50 mg (19%) of the pure tetrazole. 1H NMR (CD3OD) δ 8.10 (s, 1H), 8.00 (d, J=9 Hz, 2H), 7.90 (t, J=7 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.50-7.40 (m, 1H), 7.30-7.10 (m, 2H), 6.45 (s, 1H), 4.80 (s, 2H); LCMS: MH+=465.0

Example 512

[0750] 1999

[0751] By essentially the same procedure set forth in Example 511 only substituting the compound prepared in Example 192, the above compound was prepared. Yield=64; MH+=453; m. p.=238.9° C.

Example 513

[0752] 2000

[0753] The compound prepared in Example 157 was dissolved in dioxane (30 mL) and a HCl-dioxane solution (4 M, 30 mL) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure and ethyl acetate (200 mL) was added. The organic solution was washed with 1 N sodium hydroxide followed by saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. MH+=442.1

Example 514-526

[0754] By essentially the same procedure set forth in Example 513, only substituting the compounds shown in Column 2 of Table 41, the compounds shown in Column 3 of Table 41 were prepared.

TABLE 41
Ex.	Column 2	Column 3	CMPD
514	2001	2002	MH+ = 420.1
515	2003	2004	MH+ = 442.1
516	2005	2006	MH+ = 380.1
517	2007	2008	MH+ = 406.1
518	2009	2010	MH+ = 380.1
519	2011	2012	MH+ = 394.1
520	2013	2014	MH+ = 366
521	2015	2016	MH+ = 394
522	2017	2018	MH+ = 408.1
523	2019	2020	MH+ = 420.1
524	2021	2022
525	2023	2024	MH+ = 420.1
526	2025	2026	MH+ = 428.1
526.10	2027	2028

Examples 528-564

General Procedure for 5-piperidinyl Parallel Library Formation

[0755] To a mixture of the starting material (80 mg, 0.21 mmol) shown in Column 2 of Table 42 in anhydrous CH2Cl2 (1.5 mL) was added DIPEA (75 μL, 0.42 mmol) and the appropriate capping reagent (1.1 equiv., 0.23 mmol). After 1 to 2 h, the reaction mixture was applied to 1000 micron preparatory TLC plate and was subsequently developed using a 8-10% EtOH—CH2Cl2 as eluent to afford the compounds shown in Column 3 of Table 42.

TABLE 42
Ex.	Column 2	Column 3	CMPD
528	2029	2030	MH+=608 m.p. =230.1° C.
529	2031	2032	Yield =82 MH+=614 m.p. =235.4° C.
530	2033	2034	MH+=486 m.p. =60.5° C.
531	2035	2036	MH+=500 m.p. =113.6° C.
532	2037	2038	MH+=430 m.p. =159.2° C.
533	2039	2040	MH+=531 m.p. =105.9° C.
534	2041	2042	MH+=486
535	2043	2044	MH+=500
536	2045	2046	MH+=430
537	2047	2048	MH+=531
538	2049	2050	MH+=486 m.p. =69.6° C.
539	2051	2052	MH+=500 m.p. =82.3° C.
540	2053	2054	MH+=430 m.p. =223.6° C.
541	2055	2056	MH+=531 m.p. =118.1° C.
542	2057	2058	MH+=455 m.p. =109-110° C.
543	2059	2060	MH+=429 m.p. =111.5° C.
544	2061	2062	MH+=455
545	2063	2064	MH+=429
546	2065	2066	MH+=455 m.p. =80.1° C.
547	2067	2068	MH+=429 m.p. =64.7° C.
548	2069	2070	MH+=494 m.p. =76.5° C.
549	2071	2072	MH+=493 m.p. =83.6° C.
550	2073	2074	MH+=465 m.p. =207.5° C.
551	2075	2076	MH+=494
552	2077	2078	MH+=493
553	2079	2080	MH+=465
554	2081	2082	MH+=481 m.p. =102.7° C.
555	2083	2084	MH+=494 m.p. =85.3° C.
556	2085	2086	MH+=493 m.p. =89.1° C.
557	2087	2088	MH+=465 m.p. =83.8° C.
558	2089	2090	Yield =quant. MH+=443 98.3° C. (HCl salt)
559	2091	2092	MH+=454
560	2093	2094	Yield quant. MH+=429 m.p. =111.5-112.6° C.
561	2095	2096	MH+=460 122.7° C.
562	2097	2098	MH+=460 m.p. =95.4° C.
563	2099	2100	MH+=460
564	2101	2102	MH+=460 m.p. =95.4° C.

[0756] Additional data for select examples given below.

Example 534

[0757] 1 H NMR (300 MHz, CDCl3) δ 8.66-8.62 (s, 1H), 8.62-8.58 (d, 1 H), 7.95 (s, 1H), 7.72-7.68 (d, 1H), 7.36-7.31 (dd, 1H), 6.66-6.62 (t, 1H), 5.93 (s, 1H), 4.65-4.62 (d, 2H), 3.86-3.82 (d, 1H), 3.65-3.58 (m, 1H), 3.26-3.12 (dd, 4H), 3.02-2.80 (m, 3H), 2.10-2.00 (m, 1H), 1.67-1.57 (m, 3H)

Example 535

[0758] 1 H NMR (300 MHz, CDCl3) δ 8.66-8.62 (s, 1H), 8.62-8.58 (d, 1H), 7.95 (s, 1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd, 1H), 6.70-6.64 (t, 1H), 5.90 (s, 1H), 4.63-4.61 (d, 2H), 3.93-3.86 (m, 1H), 3.69-3.61 (m, 4H), 327-3.23 (m, 4H), 3.10-3.01 (dd,1 H), 2.93-2.84 (m, 2H), 2.08-2.03 (m,1 H), 1.90-1.57 (m, 4H).

Example 536

[0759] 1 H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.62-8.58 (d, 1H), 7.96 (s, 1H), 7.72-7.68 (d, 1H), 7.36-7.30 (dd, 1H), 6.79-6.72 (t, 1H), 596(s, 1H), 4.86 (br s, 2H), 4.66-4.63 (d, 2H), 3.89-3.73 (m, 2H), 3.55-3.32(m, 2H), 3.00-2.89 (m, 1H), 2.10-1.97 (m, 2H), 1.70-1.53 (m, 2H).

Example 537

[0760] 1 H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.62-8.58 (d, 1H), 7.98 (s, 1H), 7.77-7.76 (t, 1H), 7.72-7.69 (d, 1H), 7.63-7.59 (m, 1H), 7.56 (s, 1H), 7.36-7.29 (dd, 1H), 6.83-6.79 (t, 1H), 5.96 (s, 1H), 4.67-4.64 (d, 2H), 3.98-3.93 (dd, 1H), 3.79-3.68 (m, 2H), 3.37-3.28 (m, 1H), 3.03-2.94 (m, 1H), 2.12-1.99 (m, 1H),1.76-1.56 (m, 3H).

Example 544

[0761] 1 H NMR (300 MHz, CDCl3) δ 8.66-8.62 (d, 1H), 8.61-8.58 (dd, 1H), 7.95 (s, 1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd, 1H), 6.80-6.62 (br s, 1H), 5.88 (s, 1H), 4.63 (s, 2H), 3.08-2.95 (m, 2H), 2.87-2.80 (m, 2H), 2.04 (m, 1H), 1.85-1.78 (m, 4H), 1.52-1.44 (m, 1H), 0.87-0.82 (m, 2H), 0.72-0.66(m, 2H).

Example 545

[0762] 1 H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.62-8.58 (br t, 1H), 7.97 (s, 1H), 7.73-7.68 (d, 1H), 7.36-7.30 (br t, 1H), 6.79-6.72 (br t, 1H), 5.96 (s, 1H), 4.64 (br s, 2H), 4.59-4.46 (br d, 1H), 3.95-3.74 (br m, 1H), 3.57-3.49 (dd,1H), 3.10-3.01 (dd, 1H), 2.86-2.70 (m, 2H), 2.13 (s, 3H), 2.06-2.00 (m, 2H), 1.65-1.48 (m, 2H).

Example 551

[0763] 1 H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.63-8.59 (d, 1H), 7.96 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.30 (dd, 1H), 6.69-6.64 (t, 1H), 5.95(s, 1H), 4.67-4.63 (d, 2H), 3.85 3.65 (m,1H), 3.75-3.65 (m, 1H), 3.25-3.18 (dd, 1H), 3.03-2.90 (m, 2H), 2.81 (s, 6H), 2.03-1.95 (m, 1H), 1.89-1.68 (m, 3H).

Example 552

[0764] 1 H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.62-8.59 (d, 1H), 7.95 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.31 (dd, 1H), 6.67-6.60 (t, 1H), 5.98 (s, 1H), 4.67-4.63 (d, 2H), 3.92-3.86 (m, 1H), 3.85-3.75 (m, 1H), 3.40-3.30 (dd,1H), 3.27-3.16 (m, 1H), 3.10-2.86 (m, 2H), 2.10-1.78(m, 3H), 1.40-1.30 (d, 6H).

Example 553

[0765] 1 H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.62 (br s, 1H), 7.96 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.31 (dd, 1H), 6.70-6.66 (t, 1H), 5.98 (s, 1H) 4.67-4.63 (d, 2H), 3.88-3.81 (m, 1H), 3.71-3.65 (m, 1H), 3.20-3.11 (dd, 1H), 3.02-2.91 (m, 1H), 2.90-2.80 (m, 4H), 2.01-1.80 (m, 3H).

Example 559

[0766] 1 H NMR (300 MHz, CDCl3) δ 8.66-8.60 (d, 1H), 8.50-8.44 (dd, 1H), 8.01 (s, 1H), 7.93 (m, 1H), 7.48-7.40 (dd, 1H), 6.08 (s, 1H), 4.80-7.74 (s, 2H), 4.32-4.19 (br d, 2H), 3.10-2.86 (m, 2H), 1.95-1.68 (m, 4H).

Example 563

[0767] 1 H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.62-8.58 (d, 1H), 7.96 (s, 1H), 7.73-7.68 (d, 1H), 7.36-7.30 (dd, 1H), 6.96-6.86 (br s, 1H) 6.79-6.74 (t, 1H), 6.00 (s, 1H), 4.67-4.64 (d, 2H), 4.37-4.30 (dd, 1H), 4.22-4.13 (m, 1H), 3.97-3.86 (dd, 1H), 3.73-3.64 (m, 1H), 3.17-3.14 (d, 3H), 3.07-2.99 (m, 1H), 2.20-1.97 (m, 2H), 1.68-1.48 (m, 2H).

[0768] General Procedure 1: Procedure for the Amide Formation Parallel Synthesis: 2103

[0769] Parallel synthesis was conducted in polypropylene 96-well reaction blocks with removable top seal and fixed bottom seal. Each reaction well was fitted with a 20 micron polypropylene bottom frit and the maximum volume was 3 mL. Collection block was not fitted with bottom frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a DMF-THF-MeCN mixture (4:3:3 v/v, 0.95 mL), EDC resin (P-EDC, Polymer Laboratories Ltd., 43 mg, 0.063 mmol), 1-hydroxybenzotriazole (HOBt, 5.67 mg, 0.042 mmol) and a solution of a carboxylic acid in dimethylformamide (1 M, 0.0315 mL, 0.0315 mmol). The reaction mixture was agitated at room temperature for 16 h. The crude product solution was filtered into a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanate resin (P-NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was agitated at room temperature for 16 h and filtered into the collection block. The product solution was evaporated under reduced pressure to afford the desired amide product.

[0770] General Procedure 2: Procedure for the Sulfonamide Formation Parallel Synthesis 2104

[0771] Parallel synthesis was conducted in polypropylene 96-well reaction blocks with removable top seal and fixed bottom seal. Each reaction well was fitted with a 20 micron polypropylene bottom frit and the maximum volume was 3 mL. Collection block was not fitted with bottom frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a DMF-THF-MeCN mixture (3:2:2 v/v, 0.95 mL), DIEA resin (P-DIEA, Argonaut Tech. Inc., 18 mg, 0.063 mmol) and a solution of a sulfonyl chloride in dimethylformamide (1 M, 0.0315 mL, 0.0315 mmol). The reaction mixture was agitated at room temperature for 16 h. The crude product solution was filtered into a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanate resin (P-NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was agitated at room temperature for 16 h and filtered into the collection block. The product solution was evaporated under reduced pressure to afford the desired sulfonamide product.

[0772] General Procedure 3: Procedure for the Urea Formation Parallel Synthesis 2105

[0773] Parallel synthesis was conducted in polypropylene 96-well reaction blocks with removable top seal and fixed bottom seal. Each reaction well was fitted with a 20 micron polypropylene bottom frit and the maximum volume was 3 mL. Collection block was not fitted with bottom frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a DMF-MeCN mixture (1:1 v/v, 0.95 mL) and a solution of an isocyanate in dichloromethane (0.33 M, 0.126 mL, 0.042 mmol). The reaction mixture was agitated at room temperature for 16 h. The crude product solution was filtered into a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanate resin (P-NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was agitated at room temperature for 16 h and filtered into the collection block. The product solution was evaporated under reduced pressure to afford the desired urea product.

[0774] General Procedure 4: Procedure for the Reductive Alkylation Parallel Synthesis 2106

[0775] Parallel synthesis was conducted in polypropylene 96-well reaction blocks with removable top seal and fixed bottom seal. Each reaction well was fitted with a 20 micron polypropylene bottom frit and the maximum volume was 3 mL. Collection block was not fitted with bottom frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in AcOH-DCE mixture (1:99 v/v, 0.5 mL), a solution of an aldehyde or ketone in dichloroethane (1 M, 0.147 mL, 0.147 mmol), and a solution of tetramethylammonium triacetoxyborohydride (11 mg, 0.042 mmol) dissolved in AcOH-DCE mixture 1:99 v/v, 0.5 mL). The reaction mixture was agitated at room temperature for 3 days. The crude product solution was filtered into a reaction well loaded with sulfonic acid resin Lanterns (P-SO3H, MimotopesPty Ltd., 0.3 mmol). The reaction mixture was agitated at room temperature for 2 h and decanted. The product resin Lanterns were washed with methanol (1 mL) for three times. A solution of ammonia in methanol (2 M, 1.2 mL) was added. The reaction mixture was agitated at room temperature for 30 min. and filtered into the collection block. The product solution was evaporated under reduced pressure to afford the desired tertiary amine product.

[0776] General Procedure 5: Procedure for the Parallel Synthesis of 7, N-Substituted Pyrazolo[1,5a]Pyrimidines 2107

[0777] To 3-bromo-7-chloro-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (9.0 mg, 0.03 mmol) in tetrahydrofuran were added di-iso-propylethylamine (12 μL, 0.07), followed by cyclopropylmethylamine (70 μL, 0.07 mmol; 1M solution in DMF). The reaction mixture was heated to 70°0 C. for 36 h and then cooled to rt. The mixture was treated with (P-NCO, Argonaut Tech. Inc 70 mg, 0.12 mmol), and P-CO3− (Argonaut Tech. Inc 70 mg, 0.24 mmol) and shaken at rt for 12-18 h. The solution was filtered and evaporated to dryness to provide the product. observed m/z 375.21.

[0778] General Procedure 6: Procedure for the Parallel Synthesis of 5, N-Substituted Pyrazolo[1,5a]Pyrimidines

[0779] General Protocols:

[0780] Parallel synthesis was performed in a 96 well polypropylene blocks as described elsewhere. In the instance that heating was required, reactions were conducted in 2.5 mL glass tubes individually sealed with a polypropylene mat and heating achieved by a 96 well heat transfer block. 2108

[0781] Step A:

[0782] To the 3-bromo-5-chloro-7-N-Boc-alkylamino-pyrazolo[1,5-a]pyrimidine (17 mg, 0.04 mmol) in p-dioxane were added DIEA (9 μL, 0.05), followed by cyclopropyl-methylamine (80 μL, 0.08 mmol; 1M solution in isopropanol). The reaction mixture was heated to 90° C. for 36 h and then cooled to rt. The mixture was treated with P-NCO (Argonaut Tech. Inc. 70 mg, 0.12 mmol) and P-CO3−(Argonaut Tech. Inc. 70 mg, 0.24 mmol) and shaken at rt for 12-18 h. The solution was filtered and evaporated to dryness to provide the product.

[0783] Step B(acidic):

[0784] The product from STEP A was taken up in 35% TFA/DCM and agitated for 4 h followed by concentration under high vacuum. The residue was treated with 10% HCl(aq) in MeOH agitated for 2 h and then concentrated to give the desired product. . observed m/z 375.21.

[0785] Step B(basic):

[0786] The product from step A was taken up in EtOH and treated with Ambersep® 900-OH ion exchange resin (Acros, 100mg), heated at reflux for 48 h with gently stirring. The reaction mixture was cooled to rt, filtered and concentrated to provide the desired product.

Example 565

[0787] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 462 shown below, the compounds with the observed m/z shown in Table 43 were prepared. 2109

Example 566

[0788] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 471 shown below, the compounds shown in Table 44 with the observed m/z were prepared. 2110

Example 567

[0789] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 515 shown below, the compounds shown in Table 45 with the observed m/z were prepared. 2111

Example 568

[0790] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 513 shown below, the compounds shown in Table 46 with the observed m/z were prepared. 2112

Example 569

[0791] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 526 shown below, the compounds shown in Table 47 with the observed m/z were prepared. 2113

Example 570

[0792] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 524 shown below, the compounds shown in Table 48 with the observed m/z were prepared. 2114

Example 571

[0793] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 525 shown below, the compounds shown in Table 49 with the observed m/z were prepared. 2115

Example 572

[0794] By utilizing the procedure set forth in General Procedure. 1 and the compound from Example 526.10 shown below, the compounds shown in Table 50 with the observed m/z were prepared. 2116

Example 573

[0795] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 518 shown below, the compounds shown in Table 51 with the observed m/z were prepared. 2117

Example 574

[0796] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 519 shown below, the compounds shown in Table 52 with the observed m/z were prepared. 2118

Example 575

[0797] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 520 shown below, the compounds shown in Table 53 with the observed m/z were prepared. 2119

Example 576

[0798] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 522 shown below, the compounds shown in Table 54 with the observed m/z were prepared. 2120

Example 577

[0799] By utilizing the procedure set forth in General Procedure 1 and the compound from Example 523 shown below, the compounds shown in Table 55 with the observed m/z were prepared. 2121

Example 578

[0800] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 462 shown below, the compounds shown in Table 56 with the observed m/z were prepared. 2122

Example 579

[0801] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 471 shown below, the compounds shown in Table 57 with the observed m/z were prepared. 2123

Example 580

[0802] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 515 shown below, the compounds shown in Table 58 with the observed m/z were prepared. 2124

Example 581

[0803] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 513 shown below, the compounds shown in Table 59 with the observed m/z were prepared. 2125

Example 582

[0804] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 513 shown below, the compounds shown in Table 60 with the observed m/z were prepared. 2126

Example 583

[0805] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 524 shown below, the compounds shown in Table 61 with the observed m/z were prepared. 2127

Example 584

[0806] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 525 shown below, the compounds shown in Table 62 with the observed m/z were prepared. 2128

Example 585

[0807] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 526.10 shown below, the compounds shown in. Table 63 with the observed m/z were prepared. 2129

Example 586

[0808] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 518 shown below, the compounds shown in Table 64 with the observed m/z were prepared. 2130

Example 587

[0809] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 519 shown below, the compounds shown in Table 65 with the observed m/z were prepared. 2131

Example 588

[0810] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 520 shown below, the compounds shown in Table 67 with the observed m/z were prepared. 2132

Example 589

[0811] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 521 shown below, the compounds shown in Table 68 with the observed m/z were prepared. 2133

Example 590

[0812] By utilizing the procedure set forth in General Procedure 2 and the compound from Example 523 shown below, the compounds shown in Table 69 with the observed m/z were prepared. 2134

Example 591

[0813] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 462 shown below, the compounds shown in Table 70 with the observed m/z were prepared. 2135

Example 592

[0814] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 471 shown below, the compounds shown in Table 71 with the observed m/z were prepared. 2136

Example 593

[0815] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 513 shown below, the compounds shown in Table 72 with the observed m/z were prepared. 2137

Example 594

[0816] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 524 shown below, the compounds shown in Table 73 with the observed m/z were prepared. 2138

Example 595

[0817] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 524 shown below, the compounds shown in Table 74 with the observed m/z were prepared. 2139

Example 596

[0818] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 519 shown below, the compounds shown in Table 75 with the observed m/z were prepared. 2140

Example 597

[0819] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 520 shown below, the compounds shown in Table 76 with the observed m/z were prepared. 2141

Example 598

[0820] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 521 shown below, the compounds shown in Table 77 with the observed m/z were prepared. 2142

Example 599

[0821] By utilizing the procedure set forth in General Procedure 3 and the compound from Example 523 shown below, the compounds shown in Table 78 with the observed m/z were prepared. 2143

Example 600

[0822] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 462 shown below, the compounds shown in Table 79 with the observed m/z were prepared. 2144

Example 601

[0823] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 471 shown below, the compounds shown in Table 80 with the observed m/z were prepared. 2145

Example 602

[0824] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 525 shown below, the compounds shown in Table 81 with the observed m/z were prepared. 2146

Example 603

[0825] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 526.10 shown below, the compounds shown in Table 82 with the observed m/z were prepared. 2147

Example 604

[0826] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 521 shown below, the compounds shown in Table 83 with the observed m/z were prepared. 2148

Example 605

[0827] By utilizing the procedure set forth in General Procedure 4 and the compound from Example 523 shown below, the compounds shown in Table 84 with the observed m/z were prepared. 2149

Example 606

[0828] By utilizing the procedure set forth in General Procedure 5 and the compound from Preparative Example 81 shown below, the compounds shown in Table 85 with the observed m/z were prepared. 2150

Example 607

[0829] By utilizing the procedure set forth in General Procedure 6 and the compound from Preparative Example 196, the compounds shown in Table 86 with the observed m/z were prepared. 2151

Preparative Example 500

[0830] 2152

[0831] Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to (S)-(+)-camphorsulfonic acid (228.7 g, 1.0 eq.) in 95% EtOH (150 mL) and the resulting solution was warmed to reflux. To the warm solution was added Et2O (600 mL) and the solution cooled to room temperature and let stand 3 days. The resulting crystals were filtered and dried in vacuo (25 g): mp 173-173° C. (lit. 168° C.). The salt was then dissolved in NaOH (3M, 100 mL) and stirred 2 hours and the resulting solution was extracted with CH2Cl2 (5 ×100 mL). The combined organics were dried over Na2SO4, filtered, filtered and concentrated under reduced pressure to give (S)-piperidine-2-ethanol (7.8 g) a portion of which was recrystallized from Et2O: mp=69-70° C. (lit. 68-69° C.); [α]D=14.09° (CHCl3, c=0.2).

Preparative Example 501

[0832] 2153

[0833] Bye essentially the same procedure set forth in Preparative Example 500 only substituting (R)-(−)-camphorsulfonic acid, (R)-piperidine-2-ethanol was prepared. (1.27 g): [α]D=11.3° (CHCl3, c=0.2).

Preparative Example 502

[0834] 2154

[0835] To pressure bottle charged with a solution of cis-(1R,2S)-(+)-2-(Benzylamino) cyclohexanemethanol (1 g, 4.57 mmol) in MeOH (35 mL) was added 20% wt Pd(OH)2 (0.3 g, >50% wet) in one portion. The mixture was shaken under 50 psi of H2 in a Parr hydrogenation apparatus for 12 h. The mixture was purged to N2 and was filtered through a pad of Celite. The pad was generously washed with MeOH (2×25 mL) and the resulting filtrate was concentrated under reduces pressure to afford 0.57 g (97%) of a white solid. M+H=130.

Preparative Example 503

[0836] 2155

[0837] Step A:

[0838] To a solution of 3-Br adduct (1.1 g, 4.1 mmol) from Preparative Example 142 in THF (40 mL) at 0° C. was added CH3SNa (0.32 g, 4.53 mmol) in one portion. The heterogenous mixture was stirred for 72 h at rt and the mixture was concentrated under reduced pressure. The crude product was partitioned between water (10 mL) and EtOAc (30 mL) and the layers were separated. The organic layer was washed with brine (1×10 mL) and dried (Na2SO4). The organic layer was filtered and concentrated under reduced pressure to afford 1.0 g (88%) of a yellow solid. mp 150-152° C.; M+H=280. This material was taken onto Step B without further purification.

[0839] Step B:

[0840] To a solution of thiomethyl derivative (1.5 g, 5.37 mmol) from Step A in dioxane/DI PEA (15 mU4 mL) at rt was added amino alcohol (1.3 g, 8.06 mmol) from Preparative Example 10. The mixture was heated at reflux for 48 h, cooled to rt, and concentrated under reduced pressure. The crude product was purified by flash chromatography using CH2Cl2/MeOH (30:1) as eluent to afford 1.8 g of product (90%) as a yellow crystalline solid. mp 167-169° C.; M+H=373.

[0841] Step C:

[0842] To a solution of thiomethyl derivative (2.2 g, 5.92 mmol) from Step B in CH2Cl2 (20 mL) at 0° C. was added MCPBA (1.53 g, 8.9 mmol) in one portion. The resulting mixture was stirred for 2h at 0° C. whereupon the mixture was diluted with CH2Cl2 (20 mL) and sat. aq. NaHCO3 (15 mL). The layers were separated and the organic layer was washed with sat. aq. NaHCO3 (15 mL) and brine (1×15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 2.0 g of a brown solid (87%). mp 181-183° C.; M+H=388.

Preparative Example 504

[0843] 2156

[0844] The title compound (racemic) was prepared according to the procedure set forth in Preparative Example 503 except substituting the commercially available cis-hydroxymethyl-1-cyclohexylamine hydrochloride in Step B.

Preparative Example 505

[0845] 2157

[0846] Step A:

[0847] Treatment of thiomethyl derivative (2.0 g, 7.2 mmol) from Step A of Preparative Example 503 with (S)-piperidine-2-ethanol (1.2 g, 9.3 mmol) from Preparative Example 500 under the identical conditions as described in Step B of Preparative Example 503, 0.90 g (34%) of the title compound was prepared semisolid. mp 173-175° C. M+H=372.

[0848] Step B:

[0849] Following the procedure from Step C in Preparative Example 503, the thiomethyl derivative (0.30 g, 0.81 mmol) was treated with MCPBA (0.21 g, 1.2 mmol) to afford 0.31 g (99%) the title compound as a yellow viscous oil. M+H=388.

Preparative Example 506

[0850] 2158

[0851] The title compound (racemic) was prepared according to the procedure set forth in Preparative Example 505 except substituting the commercially available piperidine-2-ethanol. M+H=388.

Preparative Example 507

[0852] 2159

[0853] t-BuOK (112.0 g, 1.00 mol) was stirred under N2 in dry Et2O (3.0 L) in a 5 L flask equipped with an addition funnel. A mixture of butyronitrile (69.0 g, 1.00 mol) and ethylformate (77.7 g, 1.05 mol) was added dropwise during 3 hrs, the reaction mixture was then stirred overnight at room temperature. The mixture was cooled to 0° C., AcOH (57 mL) was added, the mixture was filtered, and the solid was washed with Et2O (500 mL). The combined filtrates were evaporated at room temperature on a rotovap to give pale yellow oil (95.1 g). The oil was dissolved in dry EtOH (100 mL), 99% hydrazine monohydrate (48 mL) was added, then AcOH (14 mL) was added, and the mixture was refluxed under N2 overnight. The solvents were evaporated and the resulting oil was chromatographed on silicagel with CH2Cl2:7N NH3 in MeOH. 22.4 g (20%) of 3-amino4-ethylpyrazole was obtained as clear oil that solidified upon standing.

Preparative Example 508

[0854] 2160

[0855] Step A:

[0856] The pyrazole from Preparative Example 507 (9.80 g) and dimethylmalonate (45 mL) were stirred and refluxed under N2 for 3 hrs. The excess of dimethylmalonate was evaporated in a vacuum and the residue was chromatographed with 15:1 CH2Cl2:MeOH to yield pale yellow solid (10.6 g, 57%). LCMS: MH+=212.

[0857] Step B: 2161

[0858] Dry MeOH (200 mL) was added under N2 to a mixture of the amide from Setp A (11.9 g, 56.4 mmol) and sodium methoxide (4.57 g, 84.6 mmol). The mixture was stirred and refluxed under N2 for 5 hrs, cooled to rt, and conc. HCl (20 mL) was added. The solvents were evaporated and the residue was suspended in H2O (300 mL). The solid was filtered off, washed on filter with 2×300 mL of H2O, and dried in a vacuum at 100° C. 7.40 g (73%) of cream-colored solid was obtained. LCMS: MH+=180.

[0859] Step C: 2162

[0860] POCl3 (100 mL) and N, N-dimethylaniline (20 mL) were added under N2 to the diketone from Step B (7.70 g), and the mixture was stirred and refluxed for 20 hrs under N2. Then it was cooled to rt, carefully poured onto 1 L of crushed ice, and extracted with EtOAc (2×500 mL). The extracts were washed with H2O (500 mL), dried over Na2SO4, filtered, and the solvent was evaporated. The residue was chromatographed with CH2Cl2 to yield pale yellow solid (8.20 g, 90%). LCMS: MH+=216.

Preparative Example 508.10

[0861] 2163

[0862] By essentially the same procedure set forth in Preparative Example 508, only substituting the compound from Preparative Example 1, the above compound was prepared. LCMS: MH+=228.

Preparative Example 509

[0863] 2164

[0864] A mixture of the dichloride from Preparative Example 508 (3.13 g, 14.5 mmol), the amine.HCl from Preparative Example (3.00 g, 18.9 mmol), DIPEA (7.5 mL), and dry NMP (40 mL) plus dry dioxane (40 mL) was stirred at 60° C. for 4 days under N2. The solvents were then distilled off in a vacuum and the residue was chromatographed with 6:1 EtOAc: MeOH and then rechromatographed with 12:1 CH2Cl2:MeOH. So obtained solid was suspended in H2O (100 mL), filtered, washed on filter with H2O (2×100 mL), and dried in a vacuum. Pale rose solid (2.37 g, 54%) was obtained. M+H=304.

Preparative Examples 510-516

[0865] By essentially the same procedure set forth in Preparative Example 509 only substituting the amines in Column 2 of Table 500 and the chlorides shown in Column 3 of Table 500, the compounds shown in Column 4 of Table 500 were prepared.

TABLE 500
Prep. Ex.	Column 2	Column 3	Column 4	CMPD
510	2165	2166	2167	M + H = 316
512	2168	2169	2170	M + H = 318
513	2171	2172	2173	M + H = 318
514	2174	2175	2176
515	2177	2178	2179	M + H = 332
516	2180	2181	2182

Preparative Example 517

[0866] By essentially the same procedure set forth in Preparative Example 184 only substituting the amines in Column 2 of Table 501, the compounds shown in Column 3 of Table 501 were prepared.

TABLE 501
Prep. Ex.	Column 2	Column 3	CMPD
518	2183	2184	M + H = 422.1
519	2185	2186

Preparative Example 520-521

[0867] By essentially the same procedure set forth in Preparative Example 192 only substituting the compounds in Column 2 of Table 502, the compounds shown in Column 3 of Table 502 were prepared.

TABLE 502
Prep. Ex.	Column 2	Column 3	CMPD
520	2187	2188	M + H = 522.1
521	2189	2190	M + H = 539.1

Example 1000

[0868] 2191

[0869] A mixture of the compound prepared in Preparative Example 509 (1.50 g, 4.94 mmol) with the aminoalcohol from Preparative Example 500 (1.91 g, 14.8 mmol) in dry NMP (3 mL) was stirred under N2 at 160° C. for 48 hr. The NMP was distilled off in a vacuum and the residue was chromatographed first with 5:1 EtOAc:MeOH, then the crude product was rechromatographed with 10:1 CH2Cl2:MeOH. White solid (460 mg, 24%) was obtained. LCSM: MH+=397; mp=113-115° C

Example 1001

[0870] Major side product isolated (540 mg, 29%) was deoxygenated product (LCMS: MH+=381; mp=49-52° C.: 2192

Examples 1002-1014

[0871] By essentially the same procedure set forth in Example 1000 only substituting the amines in Column 2 of Table 1000 and the chlorides in Column 3 of Table 1000 the compounds in column 4 of Table 1000 were prepared.

TABLE 1000
Ex.	Column 2	Column 3	Column 4	CMPD
1002	2193	2194	2195	MH+= 409; mp = 165-171° C.
1003	2196	2197	2198	MH+= 397; mp = 219-221° C.
1004	2199	2200	2201	MH+= 409; mp = 138-142° C.
1005	2202	2203	2204	MH+= 411; mp = 194-196° C.
1006	2205	2206	2207	MH+= 411; mp = 118-120° C.
1007	2208	2209	2210	MH+= 411; mp = 85-87° C.
1008	2211	2212	2213	MH+= 411; mp = 105-108° C.
1009	2214	2215	2216	MH+= 397; mp = 173-177° C.
1010	2217	2218	2219	MH+= 397; mp = 169-173° C.
1011	2220	2221	2222	MH+= 425
1012	2223	2224	2225	MH+= 425; mp = 232-234° C.
1013	2226	2227	2228
1014	2229	2230	2231

Example 1015

[0872] 2232

[0873] To a solution of sulfoxide from Preparative Example 505 (0.10 g, 0.28 mmol) in n-BuOH in a sealed tube was added Et3N (0.13 mL, 1.0 mmol) followed by the amine dihydrochloride (0.13 g, 0.65 mmol) from Preparative Example 216. The tube was sealed and was heated to 100° C., cooled to room temperature, and was concentrated under reduced pressure. The crude residue was purified by preparative TLC (6×1000 μM) eluting with CH2Cl2/MeOH (20:1) to afford 50 mg (40%) of a pale white solid. mp 182-185° C.; M+H=446.

Examples 1016-1026

[0874] By essentially the same procedure set forth in Example 1015 only substituting the sulfoxide shown in Column 2 of Table 1001 and the amine in Column 3 of Table 1001, the compounds shown in Column 4 of Table 1001 were prepared.

TABLE 1001
Ex.	Column 2	Column 3	Column 4	CMPD
1016	2233	2234	2235	mp = 182-185° C.; M + H = 448
1017	2236	2237	2238	mp = 187-189° C.; M + H = 445
1018	2239	2240	2241	mp = 139-143° C.; M + H = 453
1020	2242	2243	2244	mp = 186-189° C.; M + H = 485
1021	2245	2246	2247	mp = 154-157° C.; M + H = 448
1022	2248	2249	2250	mp = 103-105° C.; M + H = 485
1023	2251	2252	2253	mp = 203-205° C.; M + H = 432
1024	2254	2255	2256	mp = 210-212° C.; M + H = 395
1025	2257	2258	2259	mp = 82-84° C.; M + H = 446
1026	2260	2261	2262	mp = 86-90° C.; M + H = 462

Examples 1027-1038

[0875] By essentially the same conditions set forth in Example 341, Steps A and B only substituting the amines in Column 2 of Table 1002 and the compound prepared in Preparative Example 193.10, the compounds in Column 4 of Table 1002 were prepared.

TABLE 1002
Ex.	Column 2	Column 4	CMPD
1027	2263	2264	mp = 160-163° C.; M + H = 434
1028	2265	2266	mp = 122-124° C.; M + H = 434
1029	2267	2268	mp = 153-156° C.; M + H = 408
1030	2269	2270	mp = 170-174° C.; M + H = 448
1031	2271	2272	mp = 166-169° C.; M + H = 434
1032	2273	2274	mp = 167-168° C.; M + H = 434
1033	2275	2276	MH+= 393
1034	2277	2278	mp = 157-160° C.; M + H = 447
1035	2279	2280	mp = 164-168° C.; M + H = 448
1036	2281	2282	mp = 165-168° C.; M + H = 448
1037	2283	2284	mp = 131-135° C.; M + H = 447
1038	2285	2286

Examples 1039-1041

[0876] By essentially the same procedure set forth in Example 340 only substituting the amines in Column 2 of Table 1003, the compounds shown in column 4 of Table 1003 were prepared.

TABLE 1003
Ex.	Column 2	Column 4	CMPD
1039	2287	2288	mp = 210-212° C.; M + H = 392
1040	2289	2290	mp = 128-130° C.; M + H = 432
1041	2291	2292	mp = 148-151° C.; M + H = 18

Examples 1042-1057

[0877] By essentially the same procedure set forth in Example 340 only using the appropriate 5-chloroderivative and substituting the amines in Column 2 of Table 1004, the compounds shown in Column 4 of Table 1004 were prepared.

TABLE 1004
Ex.	Column 2	Column 4	CMPD
1042	2293	2294	M + H = 500.3
1043	2295	2296	M + H = 514.1
1044	2297	2298	M + H = 460.3
1045	2299	2300	M + H = 477.1
1046	2301	2302	M + H = 505.1
1047	2303	2304	M + H = 505.1
1048	2305	2306	M + H = 531.1
1049	2307	2308	M + H = 477.1
1050	2309	2310	M + H = 505.1
1051	2311	2312	M + H = 505.1
1052	2313	2314	M + H = 531.1
1053	2315	2316	M + H = 514.1
1054	2317	2318	M + H = 488.3
1055	2319	2320	M + H = 488.3
1056	2321	2322	M + H = 488.1
1057	2323	2324	M + H = 488.1

Assay

[0878] BACULOVIRUS CONSTRUCTIONS: Cyclins A and E were cloned into pFASTBAC (Invitrogen) by PCR, with the addition of a GluTAG sequence (EYMPME) at the amino-terminal end to allow purification on anti-GluTAG affinity columns. The expressed proteins were approximately 46 kDa (cyclin E) and 50 kDa (cyclin A) in size. CDK2 was also cloned into pFASTBAC by PCR, with the addition of a haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS). The expressed protein was approximately 34 kDa in size.

[0879] ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclins A, E and CDK2 were infected into SF9 cells at a multiplicity of infection (MOI) of 5, for 48 hrs. Cells were harvested by centrifugation at 1000 RPM for 10 minutes. Cyclin-containing (E or A) pellets were combined with CDK2 containing cell pellets and lysed on ice for 30 minutes in five times the pellet volume of lysis buffer containing 50 mM Tris pH 8.0, 0.5% NP40, 1 mM DTT and protease/phosphatase inhibitors (Roche Diagnostics GmbH, Mannheim, Germany). Mixtures were stirred for 30-60 minutes to promote cyclin-CDK2 complex formation. Mixed lysates were then spun down at 15000 RPM for 10 minutes and the supernatant retained. 5ml of anti-GluTAG beads (for one liter of SF9 cells) were then used to capture cyclin-CDK2 complexes. Bound beads were washed three times in lysis buffer. Proteins were competitively eluted with lysis buffer containing 100-200 ug/mL of the GluTAG peptide. Eluate was dialyzed overnight in 2 liters of kinase buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 10 mM MgCl2, 100 uM sodium orthovanadate and 20% glycerol. Enzyme was stored in aliquots at −70° C.

[0880] IN VITRO KINASE ASSAY: CDK2 kinase assays (either cyclin A or E-dependent) were performed in low protein binding 96-well plates (Corning Inc, Corning, N.Y.). Enzyme was diluted to a final concentration of 50 μg/ml in kinase buffer containing 5OmM Tris pH 8.0, 10 mM MgCl2, mM DTT, and 0.1 mM sodium orthovanadate. The substrate used in these reactions was a biotinylated peptide derived from Histone H1 (from Amersham, UK). The substrate was thawed on ice and diluted to 2 μM in kinase buffer. Compounds were diluted in 10% DMSO to desirable concentrations. For each kinase reaction, 20 μl of the 50 μg/ml enzyme solution (1 μg of enzyme) and 20 μl of the 1 μM substrate solution were mixed, then combined with 10 μl of diluted compound in each well for testing. The kinase reaction was started by addition of 50 μl of 4 μM ATP and 1 μCi of 33P-ATP (from Amersham, UK). The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 200 μl of stop buffer containing 0.1% Triton X-100, 1mM ATP, 5mM EDTA, and 5 mg/ml streptavidine coated SPA beads (from Amersham, UK) for 15 minutes. The SPA beads were then captured onto a 96-well GF/B filter plate (Packard/Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard/Perkin Elmer Life Sciences.). Non-specific signals were eliminated by washing the beads twice with 2M NaCl then twice with 2 M NaCl with 1% phosphoric acid. The radioactive signal was then measured using a TopCount 96 well liquid scintillation counter (from Packard/Perkin Elmer Life Sciences).

[0881] IC50 DETERMINATION: Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against % kinase activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis. The thus-obtained IC50 values for the compounds of the invention are shown in Table 87. These kinase activities were generated by using cyclin A or cyclin E using the above-described assay.

TABLE 87
CMPD	Example	IC50 (μM)
2325	1	0.020 0.029
2326	3	0.032 0.024
2327	4	0.011
2328	5	0.021
2329	8	0.003
2330	6	0.064 0.029
2331	7	0.01 0.006
2332	10	0.042
2333	12	0.17
2334	16	0.62
2335	1	5.6
2336	3	0.14

[0882] As demonstrated above by the assay values, the compounds of the present invention exhibit excellent CDK inhibitory properties.

[0883] While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

TABLE 43
Ex.	Compound	m/z
4301	2337	457.25
4302	2338	471.26
4303	2339	477.26
4304	2340	483.27
4305	2341	487.27
4306	2342	487.27
4307	2343	487.27
4308	2344	494.27
4309	2345	499.27
4310	2346	500.27
4311	2347	503.28
4312	2348	505.28
4313	2349	509.28
4314	2350	512.28
4315	2351	513.28
4316	2352	513.28
Ex.	Product	m/z
4317	2353	518.28
4318	2354	518.28
4319	2355	519.29
4320	2356	521.29
4321	2357	523.29
4322	2358	523.29
4323	2359	523.29
4324	2360	525.29
		1. Ex.
	Product	2. m/z
	2361	1.4325 2.527.29
	2362	1.4326 2.527.29
	2363	1.4327 2.532.29
	2364	1.4328 2.532.29
	2365	1.4329 2.532.29
	2366	1.4330 2.533.29
	2367	4331
	2368	1.4332 2.533.29
	2369	1.4333 2.533.29
	2370	1.4334 2.537.3
	2371	1.4335 2.537.3
	2372	1.43362. 537.3
	2373	1.4337 2.539.3
	2374	1.4338 2.539.3
	2375	1.4339 2.539.3
	2376	1.4340 2.541.3
	2377	1.4341 2.543.3
	2378	1.434.2 2.546.3
	2379	1.4334 2.547.3
	2380	1.4344 2.547.3
	2381	1.4345 2.549.3
	2382	1.4346 2.550.3
	2383	1.4347 2.551.3
	2384	1.4348 2.551.3
	2385	1.4349 2.551.3
	2386	1.4350 2.553.3
	2387	1.4351 2.557.31
	2388	1.4352 2.557.31
	2389	1.4353 2.558.31
	2390	1.4354 2.561.31
	2391	1.4355 2.561.31
	2392	1.4356 2.561.31
	2393	1.4357 2.561.31
	2394	1.4358 2.561.31
	2395	1.4359 2.569.31
	2396	1.4360 2.569.31
	2397	1.4361 2.574.32
	2398	1.4362 2.573.32
	2399	1.4363 2.573.32
	2400	1.4364 2.575.32
	2401	1.43652. 575.32
	2402	1.436662. 575.32
	2403	1.43672. 574.32
	2404	1.436882. 583.32
	2405	1.43692. 583.32
	2406	1.437002. 585.32
	2407	1.43712. 583.32
	2408	1.43722. 585.32
	2409	1.43732. 585.32
	2410	1.43742. 597.33
	2411	1.4375 2.499.27
	2412	1.4375 2.493.27
	2413	1.4377 2.535.29

[0884]

TABLE 44
        1. Ex.
Product 2. m/z
2414    1.4401 2.471.3
2415    1.4402 2.475.26
2416    1.4403 2.483.27
2417    1.4404 2.481.26
2418    1.4405 2.485.27
2419    1.4406 2.487.27
2420    1.4407 2.487.27
2421    1.4408 2.487.27
2422    1.4409 2.494.3
2423    1.4410 2.496.27
2424    1.4411 2.499.27
2425    1.4412 2.499.27
2426    1.4413 2.500.27
2427    1.4414 2.503.28
2428    1.4415 2.505.28
2429    1.4416 2.507.28
2430    1.4417 2.509.3
2431    1.4418 2.512.28
2432    1.4419 2.513.28
2433    1.4420 2.513.28
2434    1.4421 2.513.28
2435    1.4422 2.513.28
2436    1.4423 2.518.28
2437    1.4424 2.518.28
2438    1.4425 2.519.3
2439    1.4426 2.521.29
2440    1.4428 2.521.29
2441    1.4428 2.523.29
2442    1.4429 2.523.29
2443    1.4430 2.523.29
2444    1.4431 2.523.29
2445    1.4432 2.525.29
2446    1.4433 2.525.3
2447    1.4434 2.527.29
2448    1.4435 2.527.29
2449    1.4436 2.527.29
2450    1.4437 2.532.29
2451    1.4438 2.532.29
2452    1.4439 2.532.29
2453    1.4440 2.531.29
2454    1.4441 2.533.3
2455    1.4442 2.531.29
2456    1.4443 2.533.29
2457    1.4444 2.535.29
2458    1.4445 2.537.3
2459    1.4446 2.537.3
2460    1.4447 2.537.3
2461    1.4448 2.539.3
2462    1.4449 2.539.3
2463    1.4450 2.539.3
2464    1.4451 2.541.3
2465    1.4452 2.543.3
2466    1.4453 2.546.3
2467    1.4454 2.547.3
2468    1.4455 2.547.3
2469    1.4456 2.549.3
2470    1.4457 2.550.3
2471    1.4458 2.550.3
2472    1.4459 2.551.3
2473    1.4460 2.551.3
2474    1.4461 2.549.3
2475    1.4462 2.553.3
2476    1.4463 2.557.3
2477    1.4464 2.557.31
2478    1.4465 2.558.31
2479    1.4466 2.561.31
2480    1.4467 2.561.31
2481    1.4468 2.561.31
2482    1.4469 2.561.31
2483    1.4470 2.562.3
2484    1.4471 2.569.31
2485    1.4472 2.569.31
2486    1.4473 2.572.31
2487    1.4474 2.572.31
2488    1.4475 2.575.32
2489    1.4476 2.572.31
2490    1.4477 2.573.32
2491    1.4478 2.574.32
2492    1.4479 2.576.32
2493    1.4480 2.583.32
2494    1.4481 2.583.32
2495    1.4482 2.583.32
2496    1.4483 2.585.32
2497    1.4484 2.585.32
2498    1.4485 2.585.3
2499    1.4486 2.585.32
2500    1.4487 2.597.33
2501    1.4488 2.499.27

[0885]

TABLE 45
        1. Ex.
Product 2. m/z
2502    1.4501 2.512.28
2503    1.4502 2.526.39
2504    1.4503 2.532.29
2505    1.4504 2.538.3
2506    1.4505 2.538.3
2507    1.4506 2.540.3
2508    1.4507 2.542.3
2509    1.4508 2.542.3
2510    1.4509 2.542.3
2511    1.4510 2.549.3
2512    1.4511 2.551.3
2513    1.4512 2.554.3
2514    1.4513 2.554.3
2515    1.4514 2.555.31
2516    1.4515 2.558.31
2517    1.4516 2.560.31
2518    1.4517 2.562.31
2519    1.4518 2.564.31
2520    1.4519 2.567.31
2521    1.4520 2.568.31
2522    1.4521 2.568.31
2523    1.4522 2.568.31
2524    1.4523 2.568.31
2525    1.4524 2.573.32
2526    1.4525 2.573.32
2527    1.4526 2.574.32
2528    1.4527 2.576.32
2529    1.4528 2.576.32
2530    1.4529 2.578.32
2531    1.4530 2.578.32
2532    1.4531 2.578.32
2533    1.4532 2.578.32
2534    1.4533 2.580.32
2535    1.4534 2.580.32
2536    1.4535 2.582.32
2537    1.4536 2.582.32
2538    1.4537 2.582.32
2539    1.4538 2.587.32
2540    1.4539 2.587.32
2541    1.4540 2.587.32
2542    1.4541 2.588.32
2543    1.4542 2.588.32
2544    1.4543 2.588.32
2545    1.4544 2.588.32
2546    1.4545 2.590.32
2547    1.4546 2.588.32
2548    1.4547 2.588.32
2549    1.4548 2.588.32
2550    1.4549 2.588.32
2551    1.4550 2.590.32
2552    1.4551 2.592.33
2553    1.4552 2.592.33
2554    1.4553 2.592.33
2555    1.4554 2.594.33
2556    1.4555 2.594.33
2557    1.4556 2.593.33
2558    1.4557 2.596.33
2559    1.4558 2.596.33
2560    1.4559 2.598.33
2561    1.4560 2.601.33
2562    1.4561 2.602.33
2563    1.4562 2.602.33
2564    1.4563 2.604.33
2565    1.4564 2.603.3
2566    1.4565 2.605.33
2567    1.4565 2.605.33
2568    1.4567 2.606.33
2569    1.4568 2.606.33
2570    1.4569 2.606.33
2571    1.4570 2.608.33
2572    1.4571 2.612.34
2573    1.4572 2.612.34
2574    1.4573 2.613.34
2575    1.4574 2.616.34
2576    1.4575 2.616.34
2577    1.4576 2.616.34
2578    1.4577 2.616.34
2579    1.4578 2.616.34
2580    1.4579 2.616.34
2581    1.4580 2.624.34
2582    1.4581 2.624.34
2583    1.4582 2.629.35
2584    1.4583 2.629.35
2585    1.4584 2.630.35
2586    1.4585 2.630.35
2587    1.4586 2.630.35
2588    1.4587 2.630.35
2589    1.4588 2.630.35
2590    1.4589 2.631.35
2591    1.4590 2.638.35
2592    1.4591 2.638.35
2593    1.4592 2.640.35
2594    1.4593 2.640.35
2595    1.4594 2.640.35
2596    1.4595 2.640.35
2597    1.4596 2.652.36
2598    1.4597 2.486.27
2599    1.4598 2.554.3
2600    1.4599 2.548.3
2601    1.451002.

[0886]

TABLE 46
        1. Ex.
Product 2. m/z
2602    1.4601 2.512.28
2603    1.4602 2.526.29
2604    1.4603 2.532.29
2605    1.4604 2.538.3
2606    1.4605 2.536.3
2607    1.4606 2.540.3
2608    1.4607 2.542.3
2609    1.4608 2.542.3
2610    1.4609 2.542.3
2611    1.4610 2.547.3
2612    1.4611 2.551.3
2613    1.4612 2.552.3
2614    1.4613 2.552.3
2615    1.4614 2.555.31
2616    1.4615 2.558.31
2617    1.4616 2.560.31
2618    1.4617 2.562.31
2619    1.4618 2.562.3
2620    1.4619 2.567.31
2621    1.4620 2.568.31
2622    1.4621 2.568.31
2623    1.4622 2.568.31
2624    1.4623 2.568.31
2625    1.4624 2.573.32
2626    1.4625 2.573.32
2627    1.4626 2.574.32
2628    1.4627 2.576.32
2629    1.4628 2.576.32
2630    1.4629 2.578.32
2631    1.4630 2.578.32
        1. Ex.
Product 2. m/x
2632    1.4631 2.578.32
2633    1.4632 2.578.32
2634    1.4633 2.580.32
2635    1.4634 2.580.32
2636    1.4635 2.582.32
2637    1.4636 2.582.32
2638    1.4637 2.582.32
2639    1.4638 2.587.32
2640    1.4639 2.585.3
2641    1.4640 2.585.3
        1. Ex.
Product 2. m/z
2642    1.4641 2.588.32
2643    1.4642 2.588.32
2644    1.4643 2.588.32
2645    1.4644 2.588.32
2646    1.4645 2.590.32
2647    1.4646 2.592.33
2648    1.4647 2.592.33
2649    1.4648 2.592.33
2650    1.46492.
2651    1.4650 2.594.33
2652    1.4651 2.594.33
2653    1.4652 2.596.33
2654    1.4653 2.596.3
2655    1.4654 2.598.33
2656    1.4655 2.601.33
2657    1.4656 2.602.33
2658    1.4657 2.602.33
2659    1.4658 2.604.33
2660    1.4659 2.603.3
2661    1.4660 2.605.33
2662    1.4661 2.605.33
2663    1.4662 2.606.33
2664    1.4663 2.606.33
2665    1.4664 2.606.33
2666    1.4665 2.608.33
2667    1.4666 2.612.34
2668    1.4667 2.612.34
2669    1.4668 2.613.34
2670    1.4669 2.616.34
2671    1.4670 2.616.34
2672    1.4671 2.616.34
2673    1.4672 2.616.34
2674    1.4673 2.616.34
2675    1.4674 2.616.34
2676    1.4675 2.624.34
2677    1.4676 2.624.34
2678    1.4677 2.629.35
2679    1.4678 2.629.35
2680    1.4679 2.630.35
2681    1.4680 2.630.35
2682    1.4681 2.630.35
2683    1.4682 2.630.35
2684    1.4683 2.630.35
2685    1.4684 2.631.35
2686    1.4685 2.638.35
2687    1.4686 2.638.35
2688    1.4687 2.640.35
2689    1.4688 2.640.35
2690    46892.
2691    1.4690 2.640.35
2692    1.4691 2.652.36
2693    1.4692 2.484.3
2694    1.4693 2.554.3
2695    1.4694 2.548.3
2696    1.4695 2.590.32

[0887]

TABLE 47
        1. Ex.
Product 2. m/z
2697    1.4701 2.498.27
2698    1.4702 2.512.28
2699    1.4703 2.518.28
2700    1.4704 2.524.29
2701    1.4705 2.528.29
2702    1.4706 2.528.29
2703    1.4707 2.528.29
2704    1.4708 2.535.29
2705    1.4709 2.540.3
2706    1.4710 2.541.3
2707    1.4711 2.544.3
2708    1.4712 2.546.3
2709    1.4713 2.548.3
2710    1.4714 2.550.3
2711    1.4715 2.553.3
2712    1.4716 2.554.3
2713    1.4717 2.554.3
2714    1.4718 2.554.3
2715    1.4719 2.559.31
2716    1.4720 2.559.31
2717    1.4721 2.562.31
2718    1.4722 2.562.31
2719    1.4723 2.564.31
2720    1.4724 2.564.31
2721    1.4725 2.566.31
2722    1.4726 2.568.31
2723    1.4727 2.568.31
2724    1.4728 2.568.31
2725    1.4729 2.573.32
2726    1.4730 2.574.32
2727    1.4731 2.574.32
2728    1.4732 2.576.32
2729    1.4733 2.578.32
2730    1.4734 2.578.32
2731    1.4735 2.580.32
2732    1.4736 2.580.32
2733    1.4737 2.582.32
2734    1.4738 2.584.32
2735    1.4739 2.585.32
2736    1.4740 2.588.32
2737    1.4741 2.588.32
2738    1.4742 2.590.32
2739    1.4743 2.591.33
2740    1.4744 2.592.33
2741    1.4745 2.592.33
2742    1.4746 2.592.33
2743    1.4747 2.598.33
2744    1.4748 2.598.33
2745    1.4749 2.602.33
2746    1.4750 2.602.33
2747    1.4751 2.602.33
2748    1.4752 2.615.34
2749    1.4753 2.615.34
2750    1.4754 2.616.34
2751    1.4755 2.616.34
2752    1.4756 2.624.34
2753    1.4757 2.624.34
2754    1.4758 2.626.24
2755    1.4759 2.624.34
2756    1.4760 2.626.34
2757    1.4761 2.638.35
2758    1.4762 2.472.26
2759    1.4763 2.534.29

[0888]

TABLE 48
        1. Ex.
Product 2. m/z
2760    1. 4801 2. 498.27
2761    1. 4806 2. 528.29
2762    1. 4802 2. 512.28
2763    1.. 4807 2. 528.29
2764    1. 4803 2. 524.29
2765    1. 4808 2. 528.29
2766    1. 4804 2. 524.29
2767    1. 4809 2. 540.3
2768    1. 4805 2. 526.29
2769    1. 4810 2. 540.3
2770    1. 4811 2. 544.3
2771    1. 4816 2. 562.31
2772    1. 4812 2. 548.3
2773    1. 4817 2. 562.31
2774    1. 4813 2. 553.3
2775    1. 4818 2. 564.31
2776    1. 4814 2. 554.3
2777    1. 4819 2. 564.31
2778    1. 4815 2. 560.31
2779    1. 4820 2. 568.31
2780    1. 4821 2. 568.31
2781    1. 4826 2. 574.32
2782    1. 4822 2. 573.32
2783    1. 4828 2. 576.32
2784    1. 4821 2. 574.32
2785    1. 4829 2. 578.32
2786    1. 4824 2. 574.32
2787    1. 4829 2. 580.32
2788    1. 4825 2. 574.32
2789    1. 4830 2. 584.32
2790    1. 4831 2. 588.32
2791    1. 4836 2. 616.34
2792    1. 4832 2. 602.33
2793    1. 4837 2. 624.34
2794    1. 4833 2. 602.33
2795    1. 4838 2. 626.34
2796    1. 4834 2. 602.33
2797    1. 4839 2. 626.34
2798    1. 4835 2. 610.34
2799    1. 4840 2. 564.31
2800    1. 4841 2. 535.29
2801    1. 4846 2. 568.31
2802    1. 4842 2. 541.3
2803    1. 4847 2. 578.32
2804    1. 4843 2. 559.31
2805    1. 4848 2. 580.32
2806    1. 4844 2. 559.31
2807    1. 4849 2. 580.32
2808    1. 4845 2. 564.31
2809    1. 4850 2. 584.32
2810    1. 4851 2. 590.32
2811    1. 4856 2. 616.34
2812    1. 4852 2. 591.33
2813    1. 4857 2. 624.34
2814    1. 4853 2. 610.34
2815    1. 4858 2. 626.34
2816    1. 4854 2. 615.34
2817    1. 4859 2. 537.3
2818    1. 4855 2. 615.34
2819    1. 4860 2. 550.3
2820    1. 4861 2. 554.3
2821    1. 4866 2. 587.32
2822    1. 4862 2. 566.31
2823    1. 4867 2. 588.32
2824    1. 4863 2. 566.31
2825    1. 4868 2. 592.33
2826    1. 4864 2. 578.32
2827    1. 4869 2. 592.33
2828    1. 4865 2. 582.32
2829    1. 4870 2. 573.32
2830    1. 4871 2. 616.34
2831    1. 4876 2. 594.33
2832    1. 4872 2. 616.34
2833    1. 4877 2. 598.33
2834    1. 4873 2. 624.34
2835    1. 4878 2. 592.33
2836    1. 4874 2. 638.35
2837    1. 4879 2. 569.31
2838    1. 4875 2. 546.3
2839    1. 4880 2. 583.32

[0889]

TABLE 49
        1. Ex.
Product 2. m/z
2840    1. 4901 2. 490.27
2841    1. 4906 2. 518.28
2842    1. 4911 2. 529.29
2843    1. 4902 2. 504.28
2844    1. 4907 2. 520.29
2845    1. 4912 2. 532.29
2846    1. 4903 2. 510.28
2847    1. 4908 2. 520.29
2848    1. 4913 2. 532.29
2849    1. 4904 2. 516.28
2850    1. 4909 2. 520.29
2851    1. 4914 2. 533.29
2852    1. 4905 2. 516.28
2853    1. 4910 2. 527.29
2854    1. 4915 2. 536.29
2855    1. 4916 2. 538.3
2856    1. 4921 2. 546.3
2857    1. 4926 2. 552.3
2858    1. 4917 2. 540.3
2859    1. 4922 2. 546.3
2860    1. 4927 2. 554.3
2861    1. 4918 2. 542.3
2862    1. 4923 2. 546.3
2863    1. 4928 2. 554.3
2864    1. 4919 2. 545.3
2865    1. 4924 2. 551.3
2866    1. 4929 2. 556.31
2867    1. 4920 2. 546.3
2868    1. 4925 2. 551.3
2869    1. 4930 2. 556.31
2870    1. 4931 2. 556.31
2871    1. 4936 2. 560.31
2872    1. 4941 2. 566.31
2873    1. 4932 2. 556.31
2874    1. 4937 2. 560.31
2875    1. 4942 2. 566.31
2876    1. 4933 2. 558.31
2877    1. 4938 2. 565.31
2878    1. 4943 2. 566.31
2879    1. 4934 3. 558.31
2880    1. 4939 2. 565.3
2881    1. 4944 2. 566.31
2882    1. 4935 2. 560.31
2883    1. 4940 2. 565.31
2884    1. 4945 2. 568.31
2885    1. 4946 2. 570.31
2886    1. 4951 2. 571.31
2887    1. 4956 2. 580.32
2888    1. 4947 2. 570.31
2889    1. 4952 2. 574.32
2890    1. 4957 2. 580.32
2891    1. 4948 2. 570.31
2892    1. 4953 2. 576.32
2893    1. 4958 2. 582.32
2894    1. 4949 2. 572.31
2895    1. 4954 2. 576.32
2896    1. 4959 2. 583.32
2897    1. 4950 2. 572.31
2898    1. 4955 2. 579.32
2899    1. 4960 2. 583.32
2900    1. 4961 2. 583.32
2901    1. 4966 2. 590.32
2902    1. 4971 2. 594.33
2903    1. 4962 2. 584.32
2904    1. 4967 2. 590.32
2905    1. 4972 2. 594.33
2906    1. 4963 2. 584.32
2907    1. 4968 2. 591.3
2908    1. 4973 2. 594.33
2909    1. 4964 2. 584.32
2910    1. 4969 2. 594.33
2911    1. 4974 2. 594.33
2912    1. 4965 2. 586.32
2913    1. 4970 2. 594.33
2914    1. 4975 2. 602.33
2915    1. 4976 2. 602.33
2916    1. 4981 2. 608.33
2917    1. 4986 2. 616.34
2918    1. 4977 2. 607.33
2919    1. 4982 2. 608.33
2920    1. 4987 2. 618.34
2921    1. 4978 2. 607.33
2922    1. 4983 2. 608.33
2923    1. 4988 2. 618.34
2924    1. 4979 2. 605.33
2925    1. 4984 2. 609.33
2926    1. 4089 2. 618.34
2927    1. 4980 2. 608.33
2928    1. 4985 2. 616.34
2929    1. 4990 2. 618.34
2930    1. 4991 2. 630.35
2931    1. 4992 2. 464.26
2932    1. 4993 2. 532.29
2933    1. 4994 2. 526.29
2934    1. 4995 2. 568.31

[0890]

TABLE 50
        1. Ex.
Product 2. m/z
2935    1. 5001 2. 476.26
2936    1. 5006 2. 504.28
2937    1. 5002 2. 490.27
2938    1. 5007 2. 506.28
2939    1. 5003 2. 496.27
2940    1. 5008 2. 506.28
2941    1. 5004 2. 502.28
2942    1. 5009 2. 506.28
2943    1. 5005 2. 502.28
2944    1. 5010 2. 513.28
2945    1. 5011 2. 515.28
2946    1. 5016 2. 524.29
2947    1. 5012 2. 518.28
2948    1. 5017 2. 526.29
2949    1. 5013 2. 518.28
2950    1. 5018 2. 528.29
2951    1. 5014 2. 519.29
2952    1. 5019 2. 531.29
2953    1. 5015 2. 522.29
2954    1. 5020 2. 532.29
2955    1. 5021 2. 532.29
2956    1. 5026 2. 538.3
2957    1. 5022 2. 532.29
2958    1. 5027 2. 540.3
2959    1. 5023 2. 532.29
2960    1. 5028 2. 540.3
2961    1. 5024 2. 537.3
2962    1. 5029 2. 542.3
2963    1. 5025 2. 537.3
2964    1. 5030 2. 542.3
2965    1. 5031 2. 542.3
2966    1. 5036 2. 546.3
2967    1. 5032 2. 542.3
2968    1. 5037 2. 546.3
2969    1. 5033 2. 544.3
2970    1. 5038 2. 551.3
2971    1. 5034 2. 544.3
2972    1. 5039 2. 551.3
2973    1. 5035 2. 546.3
2974    1. 5040
2975    1. 5041 2. 552.3
2976    1. 5046 2. 556.31
2977    1. 5042 2. 552.3
2978    1. 5047 2. 556.31
2979    1. 5043 2. 552.3
2980    1. 5048 2. 556.31
2981    1. 5044 2. 552.3
2982    1. 5049 2. 558.31
2983    1. 5045 2. 554.3
2984    1. 5050 2. 558.31
2985    1. 5051 2. 558.31
2986    1. 5056 2. 566.31
2987    1. 5052 2. 560.31
2988    1. 5057 2. 566.31
2989    1. 5053 2. 562.31
2990    1. 5058 2. 568.31
2991    1. 5054 2. 562.31
2992    1. 5059 2. 569.31
2993    1. 5055 2. 565.31
2994    1. 5060 2. 569.31
2995    1. 5061
2996    1. 5066 2. 576.32
2997    1. 5062 2. 570.31
2998    1. 5067 2. 576.32
2999    1. 5063 2. 570.31
3000    1. 5068 2. 577.32
3001    1. 5064 2. 570.31
3002    1. 5069 2. 580.32
3003    1. 5065 572.31
3004    1. 5070 2. 580.32
3005    1. 5071 2. 580.32
3006    1. 5076 2. 588.32
3007    1. 5072 2. 580.32
3008    1. 5077 2. 593.33
3009    1. 5073 2. 580.32
3010    1. 5078 2. 593.33
3011    1. 5074 2. 580.32
3012    1. 5079 2. 594.33
3013    1. 5075 2. 588.32
3014    1. 5080 2. 594.33
3015    1. 5081 2. 594.33
3016    1. 5086 2. 602.33
3017    1. 5082 2. 594.33
3018    1. 5087 2. 604.33
3019    1. 5083 2. 594.33
3020    1. 5088 2. 604.33
3021    1. 5084 2. 595.33
3022    1. 5089 2. 604.33
3023    1. 5085 2. 602.33
3024    1. 5090 2. 604.33
3025    1. 5091 2. 616.34
3026    1. 5092 2. 450.25
3027    1. 5093 2. 518.28
3028    1. 5094 2. 512.28
3029    1. 5095 2. 554.3

[0891]

TABLE 51
        1. Ex.
Product 2. m/z
3030    1. 5101 2. 448.8
3031    1. 5106 2. 476.8
3032    1. 5111 2. 490.8
3033    1. 5102 2. 462.8
3034    1. 5107 2. 478.8
3035    1. 5112 2. 494.8
3036    1. 5103 2. 468.8
3037    1. 5108 2. 478.8
3038    1. 5113 2. 498.8
3039    1. 5104 2. 474.7
3040    1. 5109 2. 478.8
3041    1. 5114 2. 503.8
3042    1. 5105 2. 474.7
3043    1. 5110 2. 490.8
3044    1. 5115 2. 504.8
3045    1. 5116 2. 504.8
3046    1. 5121 2. 514.8
3047    1. 5126 2. 524.8
3048    1. 5117 2. 504.9
3049    1. 5122 2. 514.8
3050    1. 5127 2. 524.9
3051    1. 5118 2. 510.8
3052    1. 5123 2. 519.2
3053    1. 5128 2. 524.9
3054    1. 5119 2. 512.8
3055    1. 5124 2. 519.2
3056    1. 5129 2. 524.9
3057    1. 5120 2. 512.8
3058    1. 5125 2. 523.8
3059    1. 5130 2. 526.9
3060    1. 5131 2. 528.8
3061    1. 5136 2. 552.8
3062    1. 5141 2. 567.8
3063    1. 5132 2. 530.9
3064    1. 5137 2. 553.7
3065    1. 5142 2. 574.9
3066    1. 5133 2. 534.8
3067    1. 5138 2. 553.7
3068    1. 5143 2. 576.9
3069    1. 5134 2. 538.9
3070    1. 5139 2. 560.9
3071    1. 5144 2. 576.9
3072    1. 5135 2. 552.8
3073    1. 5140 2. 566.9
3074    1. 5145 2. 514.8
3075    1. 5146 2. 485.8
3076    1. 5151 2. 519.2
3077    1. 5156 2. 534.8
3078    1. 5147 2. 491.8
3079    1. 5152 2. 523.8
3080    1. 5157 2. 540.9
3081    1. 5148 2. 509.8
3082    1. 5153 2. 528.8
3083    1. 5158 2. 541.8
3084    1. 5149 2. 509.8
3085    1. 5154 2. 530.9
3086    1. 5159 2. 541.8
3087    1. 5150 2. 514.8
3088    1. 5155 2. 530.9
3089    1. 5160 2. 560.9

[0892]

TABLE 52
        1. Ex.
Product 2. m/z
3090    1. 5201 2. 462.8
3091    1. 5206 2. 490.8
3092    1. 5202 2. 476.8
3093    1. 5207 2. 492.8
3094    1. 5203 2. 482.8
3095    1. 5208 2. 492.8
3096    1. 5204 2. 488.8
3097    1. 52009 2. 492.9
3098    1. 5205 2. 488.8
3099    1. 5210 2. 504.8
3100    1. 5211 2. 504.8
3101    1. 5216 2. 518.9
3102    2. 5212 2. 508.8
3103    1. 5217 2. 518.9
3104    1. 5213 2. 512.8
3105    1. 5218 2. 524.9
3106    1. 5214 2. 517.8
3107    1. 5219 2. 526.9
3108    1. 5215 2. 518.9
3109    1. 5220 2. 526.9
3110    1. 5221 2. 528.8
3111    1. 5226 2. 538.8
3112    1. 5222 2. 528.8
3113    1. 5227 2. 538.9
3114    1. 5223 2. 533.3
3115    1. 5228 2. 538.9
3116    1. 5224 2. 533.3
3117    1. 5229 2. 538.9
3118    1. 5225 2. 537.9
3119    1. 5230 2. 540.9
3120    1. 5231 2. 542.9
3121    1. 5236 2. 566.8
3122    1. 5232 2. 544.9
3123    1. 5237 2. 567.7
3124    1. 5233 2. 548.9
3125    1. 5238 2. 567.7
3126    1. 5234 2. 552.9
3127    1. 5239 2. 574.9
3128    1. 5235 2. 566.8
3129    1. 5240 2. 581
3130    1. 5241 2. 533.3
3131    1. 5246 2. 548.9
3132    1. 5242 2. 537.9
3133    1. 5247 2. 554.9
3134    1. 5243 2. 542.8
3135    1. 5248 2. 555.9
3136    1. 5244 2. 544.9
3137    1. 5249 2. 555.9
3138    1. 5245 2. 544.9
3139    1. 5250 2. 574.9
3140    1. 5251 2. 579.9
3141    1. 5256 2. 501.8
3142    1. 5252 2. 579.9
3143    1. 5257 2. 514.8
3144    1. 5253 2. 581
3145    1. 5258 2. 518.9
3146    1. 5254 2. 588.9
3147    1. 5259 2. 530.9
3148    1. 5255 2. 590.9
3149    1. 5260 2. 530.9
3150    1. 5261 2. 538.9
3151    1. 5266 2. 556.9
3152    1. 5262 2. 542.9
3153    1. 5267 2. 556.9
3154    1. 5263 2. 547.3
3155    1. 5268 2. 537.9
3156    1. 5264 2. 551.9
3157    1. 5269 2. 566.9
3158    1. 5265 2. 552.9
3159    1. 5270 2. 581
3160    1. 5271 2. 581.7
3161    1. 5276 2. 559.3
3162    1. 5272 2. 581.7
3163    1. 5277 2. 562.9
3164    1. 5273 2. 588.9
3165    1. 5278 2. 556.9
3166    1. 5274 2. 602.9
3167    1. 5279 2. 499.8
3168    1. 5275 2. 510.8
3169    1. 5280 2. 499.8

[0893]

TABLE 53
        1. Ex.
Product 2. m/z
3170    1. 5301 2. 434.7
3171    1. 5306 2. 462.8
3172    1. 5311 2. 476.8
3173    1. 5302 2. 448.8
3174    1. 5307 2. 464.8
3175    1. 5312 2. 480.8
3176    1. 5303 2. 454.8
3177    1. 5308 2. 464.8
3178    1. 5313 2. 484.8
3179    1. 5304 2. 460.7
3180    1. 5309 2. 464.8
3181    1. 5314 2. 489.8
3182    1. 5305 2. 460.7
3183    1. 5310 2. 476.8
3184    1. 5315 2. 490.8
3185    1. 5316 2. 490.8
3186    1. 5321 2. 500.8
3187    1. 5326 2. 510.8
3188    1. 5317 2. 490.8
3189    1. 5322 2. 500.8
3190    1. 5327 2. 510.8
3191    1. 5318 2. 496.8
3192    1. 5323 2. 505.2
3193    1. 5328 2. 510.8
3194    1. 5319 2. 498.8
3195    1. 5324 2. 505.2
3196    1. 5329 2. 510.8
3197    1. 5320 2. 498.8
3198    1. 5325 2. 509.8
3199    1. 5330 2. 512.8
3200    1. 5331 2. 514.8
3201    1. 5336 2. 538.8
3202    1. 5341 2. 553.8
3203    1. 5332 2. 516.9
3204    1. 5337 2. 539.6
3205    1. 5342 2. 560.9
3206    1. 5333 2. 520.8
3207    1. 5338 2. 539.6
3208    1. 5343 2. 562.9
3209    1. 5334 2. 524.9
3210    1. 5339 2. 546.9
3211    1. 5344 2. 562.9
3212    1. 5335 2. 538.8
3213    1. 5340 2. 552.9
3214    1. 5345 2. 500.8
3215    1. 5346 2. 471.7
3216    1. 5351 2. 505.2
3217    1. 5356 2. 520.8
3218    1. 5347 2. 477.8
3219    1. 5352 2. 509.8
3220    1. 5357 2. 526.8
3221    1. 5348 2. 495.8
3222    1. 5353 2. 514.8
3223    1. 5358 2. 527.8
3224    1. 5349 2. 495.8
3225    1. 5355 2. 516.9
3226    1. 5359 2. 527.8
3227    1. 5350 2. 500.8
3228    1. 5356 2. 516.9
3229    1. 5360 2. 546.9
3230    1. 5361 2. 551.8
3231    1. 5366 2. 473.8
3232    1. 5371 2. 510.8
3233    1. 5362 2. 551.8
3234    1. 5367 2. 486.8
3235    1. 5372 2. 514.8
3236    1. 5363 2. 552.9
3237    1. 5368 2. 490.8
3238    1. 5373 2. 519.2
3239    1. 5364 2. 560.9
3240    1. 5369 2. 502.8
3241    1. 5374 2. 523.8
3242    1. 5365 2. 562.9
3243    1. 5370 2. 502.8
3244    1. 5375 2. 524.8
3245    1. 5376 2. 528.8
3246    1. 5381 2. 553.7
3247    1. 5386 2. 531.2
3248    1. 5377 2. 528.8
3249    1. 5382 2. 553.7
3250    1. 5387 2. 534.8
3251    1. 5378 2. 509.8
3252    1. 5383 2. 560.9
3253    1. 5388 2. 528.8
3254    1. 5379 2. 538.9
3255    1. 5384 2. 574.9
3256    1. 5389 2. 538.8
3257    1. 5380 2. 552.9
3258    1. 5385 2. 482.8
3259    1. 5390 2. 471.7

[0894]

TABLE 54
        1. Ex.
Product 2. m/z
3260    1. 5401 2. 463.3
3261    1. 5406 2. 491.3
3262    1. 5411 2. 505.3
3263    1. 5402 2. 477.3
3264    1. 5407 2. 493.3
3265    1. 5412 2. 509.3
3266    1. 5403 2. 483.3
3267    1. 5408 2. 493.3
3268    1. 5413 2. 513.3
3269    1. 5404 2. 489.3
3270    1. 5409 2. 493.3
3271    1. 5414 2. 518.3
3272    1. 5405 2. 489.3
3273    1. 5410 2. 505.3
3274    1. 5415 2. 519.3
3275    1. 5416 2. 519.3
3276    1. 5121 2. 529.3
3277    1. 5426 2. 539.3
3278    1. 5417 2. 519.3
3279    1. 5422 2. 529.3
3280    1. 5427 2. 539.3
3281    1. 5418 2. 525.3
3282    1. 5423 2. 533.3
3283    1. 5428 2. 539.3
3284    1. 5419 2. 527.3
3285    1. 5424 2. 533.3
3286    1. 5429 2. 539.3
3287    1. 5420 2. 527.3
3288    1. 5425 2. 538.3
3289    1. 5430 2. 541.3
3290    1. 5431 2. 543.3
3291    1. 5436 2. 567.3
3292    1. 5441 2. 582.3
3293    1. 5432 2. 545.3
3294    1. 5437 2. 567.3
3295    1. 5442 2. 589.3
3296    1. 5433 2. 549.3
3297    1. 5438 2. 567.3
3298    1. 5443 2. 591.3
3299    1. 5434 2. 553.3
3300    1. 5439 2. 575.3
3301    1. 5444 2. 591.3
3302    1. 5435 2. 567.3
3303    1. 5440 2. 581.3
3304    1. 5445 2. 529.3
3305    1. 5446 2. 500.3
3306    1. 5451 2. 533.3
3307    1. 5456 2. 549.3
3308    1. 5447 2. 830.5
3309    1. 54525 2. 719.4
3310    1. 5457 2. 555.3
3311    1. 5448 2. 524.3
3312    1. 5453 2. 543.3
3313    1. 5458 2. 556.3
3314    1. 5449 2. 524.3
3315    1. 5454 2. 545.3
3316    1. 5459 2. 556.3
3317    1. 5450 2. 529.3
3318    1. 5455 2. 545.3
3319    1. 5460 2. 575.3
3320    1. 5461 2. 580.3
3321    1. 5466 2. 502.3
3322    1. 5471 2. 539.3
3323    1. 5462 2. 580.3
3324    1. 5467 2. 515.3
3325    1. 5472 2. 543.3
3326    1. 5463 2. 581.3
3327    1. 5468 2. 519.3
3328    1. 5473 2. 547.3
3329    1. 5464 2. 589.3
3330    1. 5469 2. 531.3
3331    1. 5474 2. 552.3
3332    1. 5465 2. 591.3
3333    1. 5470 2. 531.3
3334    1. 5475 2. 553.3
3335    1. 5476 2. 557.3
3336    1. 5481 2. 581.3
3337    1. 5486 2.
3338    1. 5477 2. 557.3
3339    1. 5482 2. 589.3
3340    1. 5487 2. 891.5
3341    1. 5478 2. 538.3
3342    1. 5483 2. 511.3
3343    1. 5488 2. 500.3
3344    1. 5479 2. 567.3
3345    1. 5484 2. 559.3
3346    1. 5489 2. 500.3
3347    1. 5480 2. 581.3
3348    1. 5485 2. 563.3
3349    1. 5490 2. 501.3

[0895]

TABLE 55
        1. Ex.
Product 2. m/z
3350    1. 5501 2. 488.81
3351    1. 5506 2. 516.87
3352    1. 5511 2. 530.87
3353    1. 5502 2. 502.84
3354    1. 5507 2. 518.84
3355    1. 5512 2. 534.84
3356    1. 5503 2. 508.87
3357    1. 5508 2. 518.84
3358    1. 5513 2. 538.87
3359    1. 5504 2. 514.81
3360    1. 5509 2. 518.88
3361    1. 5514 2. 543.85
3362    1. 5505 2. 514.81
3363    1. 5510 2. 530.87
3364    1. 5515 2. 544.9
3365    1. 5516 2. 544.9
3366    1. 5521 2. 554.87
3367    1. 5526 2. 564.87
3368    1. 5517 2. 544.92
3369    1. 5522 2. 554.87
3370    1. 5527 2. 564.91
3371    1. 5518 2. 550.89
3372    1. 5523 2. 559.29
3373    1. 5528 2. 564.91
3374    1. 5519 2. 552.9
3375    1. 5524 2. 559.29
3376    1. 5529 2. 564.91
3377    1. 5520 2. 552.9
3378    1. 5525 2. 563.88
3379    1. 5530 2. 566.93
3380    1. 5531 2. 568.9
3381    1. 5536 2. 600.95
3382    1. 5541
3383    1. 5532 2. 574.91
3384    1. 5537 2. 606.99
3385    1. 5542 2. 525.83
3386    1. 5533 2. 578.94
3387    1. 5538 2. 614.97
3388    1. 5543 2. 581.9
3389    1. 5534 2. 592.85
3390    1. 5539 2. 616.95
3391    1. 5544 2. 581.9
3392    1. 5535 2. 592.85
3393    1. 5540 2. 616.95
3394    1. 5545 2. 605.92
3395    1. 5546 2. 573.32
3396    1. 5551 2. 525.83
3397    1. 5547 2. 582.88
3398    1. 5552 2. 526.82
3399    1. 5548 2. 607.76
3400    1. 5553 2. 573.92
3401    1. 5549 2. 607.76
3402    1. 5550 2. 536.86

[0896]

TABLE 56
        1. Ex.
Product 2. m/z
3403    1. 5601 2. 481.26
3404    1. 5606 2. 548.3
3405    1. 5602 2. 495.27
3406    1. 5607 2. 554.3
3407    1. 5603 2. 535.29
3408    1. 5608 2. 554.3
3409    1. 5604 2. 543.3
3410    1. 5609 2. 555.31
3411    1. 5605 2. 543.3
3412    1. 5610 2. 559.31
3413    1. 5611 2. 565.31
3414    1. 5616 2. 579.32
3415    1. 5612 2. 565.31
3416    1. 5617
3417    1. 5613 2. 565.31
3418    1. 5618
3419    1. 5614 2. 569.31
3420    1. 5619
3421    1. 5615 2. 571.31
3422    1. 5620
3423    1. 5621 2. 615.34
3424    1. 5626 2. 547.3
3425    2. 5622 2. 680.37
3426    1. 5627 2. 547.3
3427    1. 5623 2. 529.29
3428    1. 5628 2. 554.3
3429    1. 5624 2. 543.3
3430    1. 5629 2. 555.31
3431    1. 5625 2. 547.3
3432    1. 5630 2. 559.31
3433    1. 5631 2. 561.31
3434    1. 5636 2. 565.31
3435    1. 5632 2. 563.31
3436    1. 5637 2. 579.32
3437    1. 5633 2. 563.31
3438    1. 5638 2. 581.32
3439    1. 5634 2. 563.31
3440    1. 5639 2. 581.32
3441    1. 5635 2. 563.31
3442    1. 5640 2. 585.32
3443    1. 5641 2. 587.32
3444    1. 5646
3445    1. 5642 2. 589.32
3446    1. 5647 2. 597.33
3447    1. 5643 2. 589.32
3448    1. 5648 2. 597.33
3449    1. 5644 2. 593.33
3450    1. 5949 2. 597.33
3451    1. 5645 2. 597.33
3452    1. 5650 2. 597.33
3453    1. 5651 2. 597.33
3454    1. 5656 2. 607.33
3455    1. 5652 2. 599.33
3456    1. 5657 2. 607.33
3457    1. 5653 2. 603.33
3458    1. 5658 2. 607.33
3459    1. 5654 2. 605.33
3460    1. 5659 2. 621.34
3461    1. 5655 2. 607.33
3462    1. 5660 2. 631.35
3463    1. 5661 2. 631.35
3464    1. 5662 2. 631.35
3465    1. 5663 2. 642.35
3466    1. 5664 2. 665.37
3467    1. 5665 2. 571.31

[0897]

TABLE 57
        1. Ex.
Product 2. m/z
3468    1. 5701 2. 535.29
3469    1. 5706 2. 547.3
3470    1. 5702 2. 540.3
3471    1. 5707 2. 547.3
3472    1. 5703 2. 543.3
3473    1. 5708 2. 554.3
3474    1. 5704 2. 543.3
3475    1. 5709 2. 555.31
3476    1. 5705 2. 547.3
3477    1. 5710 2. 555.31
3478    1. 5711 2. 559.31
3479    1. 5716 2. 563.31
3480    1. 5712 2. 559.31
3481    1. 5717 2. 565.31
3482    1. 5713 2. 561.31
3483    1. 5718 2. 565.31
3484    1. 5714 2. 562.31
3485    1. 5719 2. 565.31
3486    1. 5715 2. 563.31
3487    1. 5720 2. 565.31
3488    1. 5721 2. 569.31
3489    1. 5726 2. 581.32
3490    1. 5722 2. 571.31
3491    1. 5727 2. 585.32
3492    1. 5723 2. 579.32
3493    1. 5728 2. 587.32
3494    1. 5724 2. 579.32
3495    1. 5729 2. 589.32
3496    1. 5725 2. 581.32
3497    1. 5730 2. 589.32
3498    1. 5731 2. 591.33
3499    1. 5736 2. 597.33
3500    1. 5732 2. 597.33
3501    1. 5737 2. 597.33
3502    1. 5733 2. 595.33
3503    1. 5738 2. 596.33
3504    1. 5734 2. 597.33
3505    1. 5739 2. 597.33
3506    1. 5735 2. 597.33
3507    1. 5740 2. 581.32
3508    1. 5741 2. 605.33
3509    1. 5746 2. 613.34
3510    1. 5742 2. 607.33
3511    1. 5747 2. 615.34
3512    1. 5743 2. 607.33
3513    1. 5748 2. 621.34
3514    1. 5744 2. 607.33
3515    1. 5749 2. 631.35
3516    1. 57454 2. 613.34
3517    1. 5750 2. 680.37

[0898]

TABLE 58
        1. Ex.
Product 2. m/z
3518    1. 5801 2. 550.3
3519    1. 5806 2. 598.33
3520    1. 5802 2. 590.32
3521    10 5807 2. 602.33
3522    1. 5803 2. 598.33
3523    1. 5808 2. 602.33
3524    1. 5804 2. 598.33
3525    1. 5809 2. 603.33
3526    1. 5805 2. 598.33
3527    1. 5810 2. 609.33
3528    1. 5811 2. 609.33
3529    1. 5816 2. 618.34
3530    1. 5812 2. 610.34
3531    1. 5817 2. 624.34
3532    1. 5813 2. 612.34
3533    1. 5818 2. 626.34
3534    1. 5814 2. 614.34
3535    1. 5819 2. 634.35
3536    1. 5815 2. 614.34
3537    1. 5820 2. 632.35
3538    1. 5821 2. 636.35
3539    1. 5826 2. 648.36
3540    1. 5822 2. 640.35
3541    1. 5827 2. 654.36
3542    1. 5823 2. 642.35
3543    1. 5828 2. 660.36
3544    1. 5824 2. 644.35
3545    1. 5829 2. 670.37
3546    1. 5825 2. 644.35
3547    1. 5830 2. 676.37
3548    1. 5831 2. 735.4
3549    1. 5832 2. 522.29
3550    1. 5833 2. 584.32

[0899]

TABLE 59
        1. Ex.
Product 2. m/z
3551    1. 5901 2. 536.29
3552    1. 5906 2. 598.33
3553    1. 5911 2. 603.33
3554    1. 5902 2. 550.3
3555    1. 5907 2. 598.33
3556    1. 5912 2. 609.33
3557    1. 5903 2. 590.32
3558    1. 5908 2. 602.33
3559    1. 5913 2. 609.33
3560    1. 5904 2. 598.33
3561    1. 5909 2. 602.33
3562    1. 5914 2. 610.34
3563    1. 5905 2. 598.33
3564    1. 5910 2. 602.33
3565    1. 5915 2. 612.34
3566    1. 5916 2. 614.34
3567    1. 5921 2. 618.34
3568    1. 5926 2. 620.34
3569    1. 5917 2. 614.34
3570    1. 5922 2. 620.34
3571    1. 5927 2. 624.34
3572    1. 5918 2. 616.34
3573    1. 5923 2. 620.34
3574    1. 5928 2. 626.34
3575    1. 5919 2. 618.34
3576    1. 5924 2. 620.34
3577    1. 5929 2. 626.34
3578    1. 5920 2. 618.34
3579    1. 5925 2. 620.34
3580    1. 5930 2. 632.35

[0900]

TABLE 60
        1. Ex.
Product 2. m/z
3581    1. 6001 2. 536.29
3582    1. 6006 2. 588.32
3583    1. 6011 2. 595.33
3584    1. 6002 2. 576.32
3585    1. 6007 2. 588.32
3586    1. 6012 2. 595.33
3587    1. 6003 2. 584.32
3588    1. 6008 2. 588.32
3589    1. 6013 2. 596.33
3590    1. 6004 2. 584.32
3591    1. 6009 2. 589.32
3592    1. 6014 2. 598.33
3593    1. 6005 2. 584.32
3594    1. 6010 2. 595.33
3595    1. 6015 2. 600.33
3596    1. 6016 2. 600.33
3597    1. 6021 2. 606.33
3598    1. 6026 2. 612.34
3599    1. 6017 2. 602.33
3600    1. 6022 2. 606.33
3601    1. 6027 2. 620.34
3602    1. 6018 2. 604.33
3603    1. 6023 2. 606.33
3604    1. 6028 2. 620.34
3605    1. 6019 2. 604.33
3606    1. 6024 2. 606.33
3607    1. 6029 2. 622.34
3608    1. 6020 2. 604.33
3609    1. 6025 2. 606.33
3610    1. 6030 2. 626.34
3611    1. 6031 2. 628.35
3612    1. 6036 2. 638.35
3613    1. 6041 2. 648.36
3614    1. 6032 2. 630.35
3615    1. 6037 2. 638.35
3616    1. 60425 2. 648.36
3617    1. 6033 2. 630.35
3618    1. 6038 2. 638.35
3619    1. 6043 2. 648.36
3620    1. 6034 2. 634.35
3621    1. 6039 2. 622.34
3622    1. 6044 2. 648.36
3623    1. 6035 2. 638.35
3624    1. 6040 2. 646.36
3625    1. 6045 2. 654.36
3626    1. 6046 2. 654.36
3627    1. 6047 2. 656.36
3628    1. 6048 2. 662.36
3629    1. 6049 2. 721.4
3630    1. 6050 2. 570.31

[0901]

TABLE 61
        1. Ex.
Product 2. m/z
3631    1. 6101 2. 584.32
3632    1. 6106 2. 588.32
3633    1. 6102 2. 584.32
3634    1. 6107 2. 595.33
3635    1. 6103 2. 584.32
3636    1. 6108 2. 600.33
3637    1. 6104 2. 588.32
3638    1. 6109 2. 602.33
3639    1. 6105 2. 588.32
3640    1. 6110 2. 604.33
3641    1. 6111 2. 604.33
3642    1. 6116 2. 606.33
3643    1. 6112 2. 604.33
3644    1. 6117 2. 606.33
3645    1. 6113 2. 606.33
3646    1. 6118 2. 648.36
3647    1. 6114 2. 606.33
3648    1. 6119 2. 721.4
3649    1. 6115 2. 606.33
3650    1. 6120 2. 570.31

[0902]

TABLE 62
        1. Ex.
Product 2. m/z
3651    1. 6201 2. 514.28
3652    1. 6206 2. 576.32
3653    1. 6211 2. 581.32
3654    1. 6202 2. 528.29
3655    1. 6207 2. 576.32
3656    1. 6212 2. 587.32
3657    1. 6203 2. 568.31
3658    1. 6208 2. 580.32
3659    1. 6213 2. 587.32
3660    1. 6204 2. 576.32
3661    1. 6209 2. 580.32
3662    1. 6214 2. 587.32
3663    1. 6205 2. 576.32
3664    1. 6210 2. 580.32
3665    1. 6215 2. 588.32
3666    1. 6216 2. 590.32
3667    1. 6221 2. 596.33
3668    1. 6226 2. 598.33
3669    1. 6217 2. 592.33
3670    1. 6222 2. 596.33
3671    1. 6227 2. 596.33
3672    1. 6218 2. 592.33
3673    1. 6223 2. 598.33
3674    1. 6228 2. 602.33
3675    1. 6219 2. 592.33
3676    1. 6224 2. 596.33
3677    1. 6229 2. 604.33
3678    1. 6220 2. 594.33
3679    1. 6225 2. 598.33
3680    1. 6230 2. 604.33
3681    1. 6231 2. 610.34
3682    1. 6236 2. 614.34
3683    1. 6241 2. 630.35
3684    1. 6232 2. 610.34
3685    1. 6237 2. 618.34
3686    1. 6242 2.
3687    1. 6233 2. 612.34
3688    1. 6238 2. 622.34
3689    1. 6243 2. 630.35
3690    1. 6234 2. 612.34
3691    1. 6239 2. 622.34
3692    1. 6244 2. 630.35
3693    1. 6235 2. 614.34
3694    1. 6240 2. 626.34
3695    1. 6245 2. 630.35
3696    1. 6246 2. 630.35
3697    1. 6251 2. 636.35
3698    1. 6256 2. 646.36
3699    1. 6247 2. 630.35
3700    1.0 6252 2. 638.35
3701    1. 6257 2. 646.36
3702    1. 6248 2. 630.35
3703    1. 6253 2. 640.35
3704    1. 6258 2. 648.36
3705    1. 6249 2. 630.35
3706    1. 6254 2. 640.35
3707    1. 6259 2. 654.36
3708    1. 6250 2. 632.35
3709    1. 6255 2. 638.35
3710    1. 6260 2. 713.39
3711    1. 6261 2. 500.27
3712    1. 6262 2. 562.31
3713    1. 6263 2. 604.33

[0903]

TABLE 63
        1. Ex.
Product 2. m/z
3714    1. 6301 2. 500.27
3715    1. 6306 2. 562.31
3716    1. 6311 2. 567.31
3717    1. 6302 2. 514.28
3718    1. 6307 2. 562.31
3719    1. 6312 2. 573.32
3720    1. 6303 2. 554.3
3721    1. 6308 2. 566.31
3722    1. 6313 2. 573.32
3723    1. 6304 2. 562.31
3724    1. 6309 2. 566.31
3725    1. 6314 2. 573.32
3726    1. 6305 2. 562.31
3727    1. 6310 2. 566.31
3728    1. 6315 2. 574.32
3729    1. 6316 2. 576.32
3730    1. 6321 2. 582.32
3731    1. 6326 2. 584.32
3732    1. 6317 2. 578.32
3733    1. 6322 2. 582.32
3734    1. 6327 2. 584.32
3735    1. 6318 2. 578.32
3736    1. 6323 2. 584.32
3737    1. 6328 2. 588.32
3738    1. 6319 2. 580.32
3739    1. 6324 2. 582.32
3740    1. 6329 2. 590.32
3741    1. 6320 2. 582.32
3742    1. 6325 2. 584.32
3743    1. 6330 2. 596.33
3744    1. 6331 2. 598.33
3745    1. 6336 2. 606.33
3746    1. 6341 2. 616.34
3747    1. 6332 2. 598.33
3748    1. 6337 2. 608.33
3749    1. 6342 2. 616.34
3750    1. 6333 2. 600.33
3751    1. 6338 2. 608.33
3752    1. 6343 2. 616.34
3753    1. 6334 2. 600.33
3754    1. 6339 2. 612.34
3755    1. 6344 2. 616.34
3756    1. 6335 2. 604.33
3757    1. 6340 2. 616.34
3758    1. 6345 2. 616.34
3759    1. 6346 2. 616.34
3760    1. 6351 2. 622.34
3761    1. 6356 2. 626.34
3762    1. 6347 2. 616.34
3763    1. 6352 2. 624.34
3764    1. 6357 2. 632.35
3765    1. 6348 2. 616.34
3766    1. 6353 2. 626.34
3767    1. 6358 2. 632.35
3768    1. 6349 2. 618.34
3769    1. 6354 2. 626.34
3770    1. 6359 2. 634.35
3771    1. 6350 2. 600.33
3772    1. 6355 2. 626.34
3773    1. 6360 2. 640.35
3774    1. 6361 2. 650.36
3775    1. 6366 2. 486.27
3776    1. 6362 2. 650.56
3777    1. 6367 2. 548.3
3778    1. 6363 2. 661.36
3779    1. 6368 2. 590.32
3780    1. 6364 2. 684.38
3781    1. 6365 2. 699.38

[0904]

TABLE 64
        1. Ex.
Product 2. m/z
3782    1. 6401 2. 474.26
3783    1. 6406 2. 536.29
3784    1. 6411 2. 541.3
3785    1. 6402 2. 488.27
3786    1. 6407 2. 536.29
3787    1. 6412 2. 547.3
3788    1. 6403 2. 528.29
3789    1. 6408 2. 540.3
3790    1. 6413 2. 547.3
3791    1. 6404 2. 536.29
3792    1. 6409 2. 540.3
3793    1. 6414 2. 548.3
3794    1. 6405 2. 536.29
3795    1. 6410 2. 540.3
3796    1. 6415 2. 550.3
3797    1. 6416 2. 552.3
3798    1. 6421 2. 556.31
3799    1. 6426 2. 558.31
3800    1. 6417 2. 552.3
3801    1. 6122 2. 558.31
3802    1. 6427 2. 564.31
3803    1. 6418 2. 554.3
3804    1. 6423 2. 558.31
3805    1. 6428 2. 572.31
3806    1. 6419 2. 556.31
3807    1. 6424 2. 558.31
3808    1. 6429 2. 572.31
3809    1. 6420 2. 556.31
3810    1. 6425 2. 558.31
3811    1. 6430 2. 574.32
3812    1. 6431 2. 574.32
3813    1. 6436 2. 586.32
3814    1. 6441 2. 590.32
3815    1. 6432 2. 578.32
3816    1. 6437 2. 590.32
3817    1. 6442 2. 590.32
3818    1. 6433 2. 580.32
3819    1. 6438 2. 590.32
3820    1. 6443 2. 590.32
3821    1. 6434 2. 582.32
3822    1. 6439 2. 590.32
3823    1. 6444 2. 590.32
3824    1. 6435 2. 582.32
3825    1. 6440 2. 589.32
3826    1. 6445 2. 590.32
3827    1. 6446 2. 592.33
3828    1. 6451 2. 600.33
3829    1. 6456 2. 614.34
3830    1. 6447 2. 574.32
3831    1. 6452 2. 600.33
3832    1. 6447 2. 673.37
3833    1. 6448 2. 598.33
3834    1. 6453 2. 606.33
3835    1. 6458 2. 460.25
3836    1. 6449 2. 600.33
3837    1. 6454 2. 606.33
3838    6459 2.
3839    1. 6450 2. 600.33
3840    1. 6455 2. 608.33
3841    1. 6460 2. 564.31

[0905]

TABLE 65
        1. Ex.
Product 2. m/z
3842    1. 6501 2. 488.27
3843    1. 6506 2. 550.3
3844    1. 6511 2. 561.31
3845    1. 6502 2. 502.28
3846    1. 6507 2. 554.3
3847    1. 6512 2. 561.31
3848    1. 6503 2. 542.3
3849    1. 6508 2. 554.3
3850    1. 6213 2. 561.31
3851    1. 6504 2. 550.3
3852    1. 6509 2. 554.3
3853    1. 6514 2. 562.31
3854    1. 6505 2. 550.3
3855    1. 6510 2. 555.31
3856    1. 6515 2. 564.31
3857    1. 6516 2. 566.31
3858    1. 6521 2. 570.31
3859    1. 6526 2. 576.32
3860    1. 6517 2. 566.31
3861    1. 6522 2. 572.31
3862    1. 6527 2. 578.32
3863    1. 6518 2. 568.31
3864    1. 6523 2. 572.31
3865    1. 6528 2. 586.32
3866    1. 6519 2. 570.31
3867    1. 6524 2. 572.31
3868    1. 6529 2. 586.32
3869    1. 6520 2. 570.31
3870    1. 6525 2. 572.31
3871    1. 6530 2. 588.32
3872    1. 6531 2. 588.32
3873    1. 6536 2. 600.33
3874    1. 6541 2. 604.33
3875    1. 6532 2. 592.33
3876    1. 6537 2. 604.33
3877    1. 6542 2. 604.33
3878    1. 6533 2. 594.33
3879    1. 6538 2. 604.33
3880    1. 6543 2. 604.33
3881    1. 6534 2. 596.33
3882    1. 6539 2. 604.33
3883    1. 6544 2. 606.33
3884    1. 6535 2. 596.33
3885    1. 6540 2. 604.33
3886    1. 6545 2. 588.32
3887    1. 6546 2. 612.34
3888    1. 6551 2. 620.34
3889    1. 6556 2. 474.26
3890    1. 6547 2. 614.34
3891    1. 6552 2. 620.34
3892    1. 6557 2. 536.29
3893    1. 6548 2. 614.34
3894    1. 6553 2. 622.34
3895    1. 6558 2. 578.32
3896    1. 6549 2. 614.34
3897    1. 6554 2. 628.35
3898    1. 6550 2. 614.34
3899    1. 6555 2. 687.38

[0906]

TABLE 67
        1. Ex.
Product 2. m/z
3900    1. 6701 2. 474.26
3901    1. 6706 2. 526.29
3902    1. 6711 2. 536.29
3903    1. 6702 2. 514.28
3904    1. 6707 2. 526.29
3905    1. 6712 2. 538.3
3906    1. 6703 2. 522.29
3907    1. 6708 2. 526.29
3908    1. 6713 2. 538.3
3909    1. 6704 2. 522.29
3910    1. 6709 2. 533.29
3911    1. 6714 2.
3912    . 6705 522.29
3913    1. 6710 2. 534.29
3914    1. 6715 2. 542.3
3915    1. 6716 2. 542.3
3916    1. 6721 2. 550.3
3917    1. 6726 2. 564.31
3918    1. 6717 2. 542.3
3919    1. 6722 2. 558.31
3920    1. 6727 2. 566.31
3921    1. 6718 2. 544.3
3922    1. 6723 2. 558.31
3923    1. 6728 2. 568.31
3924    1. 6719 2. 544.3
3925    1. 6724 2. 560.31
3926    1. 6729 2. 568.31
3927    1. 6720 2. 544.3
3928    1. 6725 2. 560.31
3929    1. 6730 2. 572.31
3930    1. 6731 2. 576.32
3931    1. 6736 2. 576.32
3932    1. 6741 2. 586.32
3933    1. 6732 2. 576.32
3934    1. 6737 2. 576.32
3935    1. 6742 2. 586.32
3936    1. 6733 2. 576.32
3937    1. 6738 2. 576.32
3938    1. 6743 2. 592.33
3939    1. 6734 2. 576.32
3940    1. 6739 2. 584.32
3941    1. 6744 2. 592.33
3942    1. 6735 2. 576.32
3943    1. 6740 2. 586.32
3944    1. 6745 2. 600.33

[0907]

TABLE 68
        1. Ex.
Product 2. m/z
3945    1. 6801 2. 488.27
3946    1. 6806 2. 550.3
3947    1. 6802 2. 502.28
3948    1. 6807 2. 554.3
3949    1. 6803 2. 542.3
3950    1. 6808 2. 554.3
3951    1. 6804 2. 550.3
3952    1. 6809 2. 554.3
3953    1. 68058 2. 550.3
3954    1. 6810 2. 555.31
3955    1. 6811 2. 561.31
3956    1. 6816 2. 566.31
3957    1. 6812 2. 561.31
3958    1. 6817 2. 568.31
3959    1. 6813 2. 562.31
3960    1. 6818 2. 570.31
3961    1. 6814 2. 564.31
3962    1. 6819 2. 570.31
3963    1. 6815 2. 566.31
3964    1. 6820 2. 570.31
3965    1. 6821 2. 571.31
3966    1. 6826 2. 576.32
3967    1. 6822 2. 572.31
3968    1. 6827 2. 578.32
3969    1. 6823 2. 572.31
3970    1. 6828 2. 586.32
3971    1. 6824 2. 572.31
3972    1. 6829 2. 586.32
3973    1. 6825 2. 572.31
3974    1. 6830 2. 588.32
3975    1. 6831 2. 588.32
3976    1. 6836 2. 600.33
3977    1. 6832 2. 592.33
3978    1. 6837 2. 602.33
3979    1. 6833 2. 614.34
3980    1. 6838 2. 604.33
3981    1. 6834 2. 596.33
3982    1. 6839 2. 604.33
3983    1. 6835 2. 596.33
3984    1. 6840 2. 604.33
3985    1. 6841 2. 604.33
3986    1. 6846 2. 606.33
3987    1. 6842 2. 604.33
3988    1. 6847 2. 588.32
3989    1. 6843 2. 605.33
3990    1. 6848 2. 610.34
3991    1. 6844 2. 604.33
3992    1. 6849 2. 612.34
3993    1. 6845 2. 604.33
3994    1. 6850 2. 594.33
3995    1. 6851 2. 614.34
3996    1. 6856 2. 620.34
3997    1. 6852 2. 614.34
3998    1. 6856 2. 628.35
3999    1. 6853 2. 614.34
4000    1. 6857 2. 687.38
4001    1. 6854 2. 620.34
4002    1. 6859 2. 474.26
4003    1. 6855 2. 620.34
4004    1. 6860 2. 536.29

[0908]

TABLE 69
        1. Ex.
Product 2. m/z
4005    1. 6901 2. 514.28
4006    1. 6906 2. 580.32
4007    1. 6902 2. 568.31
4008    1. 6907 2. 580.32
4009    1. 6903 2. 576.32
4010    1. 6908 2. 580.32
4011    1. 6904 2. 576.32
4012    1. 6909 2. 581.32
4013    1. 6905 2. 576.32
4014    1. 6910 2. 587.32
4015    1. 6911 2. 587.32
4016    1. 6916 2. 594.33
4017    1. 6912 2. 588.32
4018    1. 6917 2. 596.33
4019    1. 6913 2. 590.32
4020    1. 6918 2. 596.33
4021    1. 6914 2. 592.33
4022    1. 6919 2. 596.33
4023    1. 6915 2. 592.33
4024    1. 6920 2. 598.33
4025    1. 6921 2. 598.33
4026    1. 6926 2. 604.33
4027    1. 6922 2. 598.33
4028    1. 6927 2. 612.34
4029    1. 6923 2. 598.33
4030    1. 6928 2. 612.34
4031    1. 6924 2. 598.33
4032    1. 6929 2. 614.34
4033    1. 6925 2. 602.33
4034    1. 6930 2. 614.34
4035    1. 6931 2. 618.34
4036    1. 6936 2. 630.35
4037    1. 6932 2. 620.34
4038    1. 6937 2. 630.35
4039    1. 6933 2. 622.34
4040    1. 6938 2. 630.35
4041    1. 6934 2. 622.34
4042    1. 6939 2. 630.35
4043    1. 6935 2. 626.34
4044    1. 6940 2. 630.35
4045    1. 6941 2. 630.35
4046    1. 6946 2. 636.35
4047    1. 6942 2. 630.35
4048    1. 6947 2. 638.35
4049    1. 6943 2. 630.35
4050    1. 6948 2. 640.35
4051    1. 6944 2. 632.35
4052    1. 6949 2. 640.35
4053    1. 6945 2. 614.34
4054    1. 6950 2. 640.35
4055    1. 6951 2. 640.35
4056    1. 6956 2. 675.23
4057    1. 6952 2. 646.36
4058    1. 6957 2. 713.39
4059    1. 6953 2. 646.36
4060    1. 6958 2. 500.27
4061    1. 6954 2. 648.36
4062    1. 6959 2. 562.31
4063    1. 6955 2. 654.36
4064    1. 6960 2. 604.33

[0909]

TABLE 70
        1. Ex.
Product 2. m/z
4065    1. 7001 2. 472.26
4066    1. 7006 2. 522.29
4067    1. 7002 2. 488.27
4068    1. 7007 2. 520.29
4069    1. 7003 2. 488.27
4070    1. 7008 2. 520.29
4071    1. 7004 2. 500.27
4072    1. 7009 2. 526.29
4073    1. 7005 2. 520.29
4074    1. 7010 2. 533.29
4075    1. 7011 2. 536.29
4076    1. 7016 2. 538.3
4077    1. 7012 2. 536.29
4078    1. 7017 2. 540.3
4079    1. 7013 2. 536.29
4080    1. 7018 2. 542.3
4081    1. 7014 2. 536.29
4082    1. 7019 2. 544.3
4083    1. 7015 2. 536.29
4084    1. 7020 2. 544.3
4085    1. 7021 2. 548.3
4086    1. 7026 2. 566.31
4087    1. 7022 2. 552.3
4088    1. 7027 2. 568.31
4089    1. 7023 2. 552.3
4090    1. 7028 2. 572.31
4091    1. 7024 2. 556.31
4092    1. 7029 2. 576.32
4093    1. 7025 2. 558.31
4094    1. 7030 2. 576.32
4095    1. 7031 2. 576.32
4096    1. 7036 2. 598.33
4097    1. 7032 2. 576.32
4098    1. 7037 2. 598.33
4099    1. 7033 2. 590.32
4100    1. 7038 2. 610.34
4101    1. 7034 2. 486.27
4102    1. 7034 2. 594.33

[0910]

TABLE 71
        1. Ex.
Product 2. m/z
4103    1. 7101 2. 474.26
4104    1. 7106 2. 522.29
4105    1. 7102 2. 488.27
4106    1. 7107 2. 522.29
4107    1. 7103 2. 500.27
4108    1. 7108 2. 526.3
4109    1. 7104 2. 522.29
4110    1. 7109 2. 533.29
4111    1. 7105 2. 522.29
4112    1. 7110 2. 536.29
4113    1. 7111 2. 536.29
4114    1. 7116 2. 538.3
4115    1. 7112 2. 536.29
4116    1. 7117 2. 540.3
4117    1. 7113 2. 536.29
4118    1. 7118 2. 542.3
4119    1. 7114 2. 536.29
4120    1. 7119 2. 542.3
4121    1. 7115 2. 536.3
4122    1. 7120 2. 542.3
4123    1. 7121 2. 546.3
4124    1. 7126 2. 558.31
4125    1. 7122 2. 550.3
4126    1. 7127 2. 440.3
4127    1. 7123 2. 552.3
4128    1. 7128 2. 566.31
4129    1. 7124 2. 552.3
4130    1. 7129 2. 565.31
4131    1. 7125 2. 556.31
4132    1. 7130 2. 572.31
4133    1. 7131 2. 576.32
4134    1. 7136 2. 590.32
4135    1. 7132 2. 576.32
4136    1. 7137 2. 590.32
4137    1. 7133 2. 576.32
4138    1. 7138 2. 598.33
4139    1. 7134 2. 584.32
4140    1. 7139 2. 598.33
4141    1. 7135 2. 585.3

[0911]

TABLE 72
        1. Ex.
Product 2. m/z
4142    1. 7201 2. 529.29
4143    1. 7206 2. 577.32
4144    1. 7202 2. 543.3
4145    1. 7207 2. 577.32
4146    1. 7203 2. 543.3
4147    1. 7208 2. 577.32
4148    1. 7204 2. 555.31
4149    1. 7209 2. 581.32
4150    1. 7205 2. 577.32
4151    1. 7210 2. 581.32
4152    1. 7211 2. 588.32
4153    1. 7216 2. 591.33
4154    1. 7212 2. 588.32
4155    1. 7217 2. 593.33
4156    1. 7213 2. 591.33
4157    1. 7218 2. 593.33
4158    1. 7214 2. 591.33
4159    1. 7219 2. 593.33
4160    1. 7215 2. 591.33
4161    1. 7220 2. 595.33
4162    1. 7221 2. 597.33
4163    1. 7226 2. 603.33
4164    1. 7222 2. 597.33
4165    1. 7227 2. 603.33
4166    1. 7223 2. 597.33
4167    1. 7228 2. 607.33
4168    1. 7224 2. 599.33
4169    1. 7229 2. 607.14
4170    1. 7225 2. 599.33
4171    1. 7230 2. 611.34
4172    1. 7231 2. 613.34
4173    1. 7236 2. 631.35
4174    1. 7232 2. 605.33
4175    1. 7237 2. 631.35
4176    1. 7233 2. 621.34
4177    1. 7238 2. 631.35
4178    1. 7234 2. 623.34
4179    1. 7239 2. 631.35
4180    1. 7235 2. 627.34
4181    1. 7240 2. 631.35
4182    1. 7241 2. 639.35
4183    1. 7246 2. 653.36
4184    1. 7242 2. 641.35
4185    1. 7247 2. 665.37
4186    1. 7243 2. 645.35
4187    1. 7244 2. 541.3
4188    1. 7245 2. 649.36

[0912]

TABLE 73
        1. Ex.
Product 2. m/z
4189    1. 7301 2. 529.29
4190    1. 7306 2. 567.31
4191    1. 7311 2. 577.32
4192    1. 7302 2. 541.3
4193    1. 7307 2. 567.31
4194    1. 7312 2. 577.32
4195    1. 7303 2. 563.13
4196    1. 7308 2. 574.32
4197    1. 7313 2. 579.32
4198    1. 7304 2. 563.31
4199    1. 7309 2. 574.32
4200    1. 7314 2. 579.32
4201    1. 7305 2. 563.31
4202    1. 7310 2. 577.32
4203    1. 7315 2. 579.32
4204    1. 7316 2. 581.32
4205    1. 7321 2. 585.32
4206    1. 7326 2. 599.33
4207    1. 7317 2. 583.32
4208    1. 7322 2. 589.32
4209    1. 7327 2. 591.33
4210    1. 7318 2. 583.32
4211    1. 7323 2. 591.33
4212    1. 7328
4213    1. 7319 2. 583.32
4214    1. 7324 2. 593.33
4215    1. 7329 2. 613.34
4216    1. 7320 2. 585.32
4217    1. 7325 2. 597.33
4218    1. 7330 2. 617.34
4219    1. 7331 2. 599.33
4220    1. 7336 2. 617.34
4221    1. 7341 2. 635.35
4222    1. 7332 2. 591.33
4223    1. 7337 2. 617.34
4224    1. 7342 2. 639.35
4225    1. 7333 2. 609.33
4226    1. 7338 2. 617.34
4227    1. 7343 2. 639.35
4228    1. 7334 2. 613.34
4229    1. 7339 2. 625.34
4230    1. 7335 2. 617.34
4231    1. 7340 2. 631.35

[0913]

TABLE 74
        1. Ex.
Product 2. m/z
4232    1. 7401 2. 515.28
4233    1. 7406 2. 563.31
4234    1. 7402 2. 529.29
4235    1. 7407 2. 563.31
4236    1. 7403 2. 541.3
4237    1. 7408 2. 567.31
4238    1. 7404 2. 563.13
4239    1. 7409 2. 567.31
4240    1. 7405 2. 563.31
4241    1. 7410 2. 574.32
4242    1. 7411 2. 574.32
4243    1. 7416 2. 579.32
4244    1. 7412 2. 577.14
4245    1. 7417 2. 579.32
4246    1. 7413 2. 577.32
4247    1. 7418 2. 579.32
4248    1. 7414 2. 577.32
4249    1. 7419 2. 581.32
4250    1. 7415 2. 577.32
4251    1. 7420 2. 583.32
4252    1. 7421 2. 583.32
4253    1. 7426 2. 593.33
4254    1. 7422 2. 585.32
4255    1. 7427 2. 597.33
4256    1. 7423 2. 585.32
4257    1. 7428 2. 591.33
4258    1. 7424 2. 589.32
4259    1. 7429 2. 609.33
4260    1. 7425 2. 591.33
4261    1. 7430 2. 613.34
4262    1. 7431 2. 617.34
4263    1. 7436 2. 639.35
4264    1. 7432 2. 617.34
4265    1. 7437 2. 639.35
4266    1. 7433 2. 617.34
4267    1. 7438 2. 651.36
4268    1. 7434 2. 627.34
4269    1. 7435 2. 631.35

[0914]

TABLE 75
        1. Ex.
Product 2. m/z
4270    1. 7501 2. 481.26
4271    1. 7506 2. 529.29
4272    1. 7511 2. 540.3
4273    1. 7502 2. 495.27
4274    1. 7507 2. 529.29
4275    1. 7512 2. 540.3
4276    1. 7503 2. 495.27
4277    1. 7508 2. 529.29
4278    1. 7513 2. 543.3
4279    1. 7504 2. 507.28
4280    1. 7509 2. 533.29
4281    1. 7514 2. 543.3
4282    1. 7505 2. 529.29
4283    1. 7510 2. 533.29
4284    1. 7515 2. 543.3
4285    1. 7516 2. 543.3
4286    1. 7521 2. 549.3
4287    1. 7526 2. 555.31
4288    1. 7517 2. 545.3
4289    1. 7522 2. 549.3
4290    1. 7527 2. 557.31
4291    1. 7518 2. 545.3
4292    1. 7523 2. 549.3
4293    1. 7528 2. 559.31
4294    1. 7519 2. 545.3
4295    1. 7524 2. 551.3
4296    1. 7529 2. 560.31
4297    1. 7520 2. 547.3
4298    1. 7525 2. 551.3
4299    1. 7530 2. 573.32
4300    1. 7531 2. 579.32
4301    1. 7536 2. 583.32
4302    1. 7541 2. 605.33
4303    1. 7532 2. 583.32
4304    1. 7537 2. 591.33
4305    1. 7542 2. 605.33
4306    1. 7533 2. 583.32
4307    1. 7538 2. 593.33
4308    1. 7543 2. 614.34
4309    1. 7534 2. 583.32
4310    1. 7539 2. 597.33
4311    1. 7535 2. 583.32
4312    1. 7540 2. 601.33

[0915]

TABLE 76
        1. Ex.
Product 2. m/z
4313    1. 7601 2. 453.25
4314    1. 7606 2. 501.28
4315    1. 7611 2. 512.28
4316    1. 7602 2. 467.26
4317    1. 7607 2. 501.28
4318    1. 7612 2. 512.28
4319    1. 7603 2. 467.26
4320    1. 7608 2. 501.28
4321    1. 7613 2. 515.28
4322    1. 7604 2. 479.26
4323    1. 7609 2. 505.28
4324    1. 7614 2. 515.28
4325    1. 7605 2. 501.28
4326    1. 7610 2. 505.28
4327    1. 7615 2. 515.28
4328    1. 7616 2. 515.28
4329    1. 7621 2. 521.29
4330    1. 7626 2. 527.29
4331    1. 7617 2. 517.28
4332    1. 7622 2. 521.29
4333    1. 7627 2. 529.29
4334    1. 7618 2. 517.28
4335    1. 7623 2. 521.29
4336    1. 7628 2. 541.3
4337    1. 7619 2. 517.28
4338    1. 7624 2. 523.29
4339    1. 7629 2. 545.3
4340    1. 7620 2. 519.29
4341    1. 7625 2. 523.29
4342    1. 7630 2. 547.3
4343    1. 7631 2. 551.3
4344    1. 7636 2. 555.31
4345    1. 7641 2. 577.32
4346    1. 7632 2. 555.31
4347    1. 7637 2. 563.31
4348    1. 7642 2. 577.32
4349    1. 7633 2. 555.31
4350    1. 7638 2. 565.31
4351    1. 7634 2. 555.31
4352    1. 7639 2. 569.31
4353    1. 7635 2. 555.31
4354    1. 7640 2. 573.32

[0916]

TABLE 77
        1. Ex.
Product 2. m/z
4355    1. 7701 2. 481.26
4356    1. 7706 2. 529.29
4357    1. 7702 2. 495.27
4358    1. 7707 2. 529.29
4359    1. 7703 2. 495.27
4360    1. 7708 2. 529.29
4361    1. 7704 2. 507.28
4362    1. 7709 2. 533.29
4363    1. 7705 2. 529.29
4364    1. 7710 2. 533.29

[0917]

TABLE 78
        1. Ex.
Product 2. m/z
4365    1. 7801 2. 507.28
4366    1. 7806 2. 555.31
4367    1. 7802 2. 521.29
4368    1. 7807 2. 555.31
4369    1. 7803 2. 521.29
4370    1. 7808 2. 555.31
4371    1. 7804 2. 533.29
4372    1. 7809 2. 559.31
4373    1. 7805 2. 555.31
4374    1. 7810 2. 559.31
4375    1. 7811 2. 566.31
4376    1. 7816 2. 569.31
4377    1. 7812 2. 566.31
4378    1. 7817 2. 571.31
4379    1. 7813 2. 569.31
4380    1. 7818 2. 571.31
4381    1. 7814 2. 569.31
4382    1. 7819 2. 571.31
4383    1. 7815 2. 569.31
4384    1. 7820 2. 573.32
4385    1. 7821 2. 575.32
4386    1. 7826 2. 581.32
4387    1. 7822 2. 575.32
4388    1. 7827 2. 583.32
4389    1. 7823 2. 575.32
4390    1. 7828 2. 585.32
4391    1. 7824 2. 577.32
4392    1. 7829 2. 585.32
4393    1. 7825 2. 577.32
4394    1. 7830 2. 589.32
4395    1. 7831 2. 591.33
4396    1. 7836 2. 609.33
4397    1. 7832 2. 599.33
4398    1. 7837 2. 609.33
4399    1. 7833 2. 601.33
4400    1. 7838 2. 609.33
4401    1. 7834 2. 605.33
4402    1. 7839 2. 609.33
4403    1. 7835 2. 609.33
4404    1. 7840 2. 617.34
4405    1. 7841 2. 619.34
4406    1. 7846 2. 631.35
4407    1. 7842 2. 623.34
4408    1. 7847 2. 643.35
4409    1. 7843 2. 519.29
4410    1. 7844 2. 627.34
4411    1. 7845 2. 631.35

[0918]

TABLE 79
        1. Ex.
Product 2. m/z
4412    1. 7901 2. 477.26
4413    1. 7906 2. 504.28
4414    1. 7902 2. 485.27
4415    1. 7907 2. 505.28
4416    1. 7903 2. 485.27
4417    1. 7908 2. 507.28
4418    1. 7904 2. 486.27
4419    1. 7909 2. 509.28
4420    1. 7905 2. 495.27
4421    1. 7910 2. 509.28
4422    1. 7911 2. 509.28
4423    1. 7916 2. 523.29
4424    1. 7912 2. 513.28
4425    1. 7917 2. 525.29
4426    1. 7913 2. 515.28
4427    1. 7918 2. 529.29
4428    1. 7914 2. 519.29
4429    1. 7919 2. 529.29
4430    1. 7915 2. 523.29
4431    1. 7920 2. 530.29
4432    1. 7921 2. 530.29
4433    1. 7926 2. 547.3
4434    1. 7922 2. 535.29
4435    1. 7927 2. 547.3
4436    1. 7923 2. 537.3
4437    1. 7928 2. 547.3
4438    1. 7924 2. 547.3
4439    1. 7929 2. 547.3
4440    1. 7925 2. 547.3
4441    1. 7930 2. 549.3
4442    1. 7931 2. 555.31
4443    1. 7936 2. 567.31
4444    1. 7932 2. 555.31
4445    1. 7937 2. 567.31
4446    1. 7933 2. 557.31
4447    1. 7938 2. 569.31
4448    1. 7934 2. 557.31
4449    1. 7939 2. 571.31
4450    1. 7935 2. 557.31
4451    1. 7940 2. 571.31
4452    1. 7941 2. 608.33
4453    1. 7946 2. 471.26
4454    1. 7942 2. 621.34
4455    1. 7947 2. 473.26
4456    1. 7943 2. 443.24
4457    1. 7948 2. 483.27
4458    1. 7944 2. 457.25
4459    1. 7949 2. 485.27
4460    1. 7945 2. 471.26
4461    1. 7950 2. 489.27
4462    1. 7951 2. 499.27
4463    1. 7956 2. 536.29
4464    1. 7952 2. 513.28
4465    1. 7957 2. 539.3
4466    1. 7953 2. 514.28
4467    1. 7958 2. 541.3
4468    1. 7954 2. 525.29
4469    1. 7959 2. 547.3
4470    1. 7955 2. 525.29
4471    1. 7960 2. 572.31

[0919]

TABLE 80
        1. Ex.
Product 2. m/z
4472    1. 8001 2. 459.25
4473    1. 8006 2. 477.26
4474    1. 8002 2. 459.25
4475    1. 8007 2. 485.27
4476    1. 8003 2. 469.26
4477    1. 8008 2. 485.27
4478    1. 8004 2. 469.26
4479    1. 8009 2. 485.27
4480    1. 8005 2. 473.26
4481    1. 8010 2. 486.27
4482    1. 8011 2. 493.27
4483    1. 8016 2. 495.27
4484    1. 8012 2. 495.27
4485    1. 8017 2. 495.27
4486    1. 8013 2. 495.27
4487    1. 8018 2. 502.28
4488    1. 8014 2. 495.27
4489    1. 8019 2. 502.28
4490    1. 8015 2. 495.27
4491    1. 8020 2. 502.28
4492    1. 8021 2. 505.28
4493    1. 8026 2. 509.28
4494    1. 8022 2. 505.28
4495    1. 8027 2. 509.28
4496    1. 8023 2. 507.28
4497    1. 8028 2. 513.28
4498    1. 8024 2. 507.28
4499    1. 8029 2. 513.28
4500    1. 8025 2. 507.28
4501    1. 8030 2. 513.28
4502    1. 8031 2. 515.28
4503    1. 8036 2. 523.29
4504    1. 8032 2. 519.29
4505    1. 8037 2. 525.29
4506    1. 8033 2. 521.29
4507    1. 8038 2. 529.29
4508    1. 8034 2. 523.29
4509    1. 8039 2. 529.29
4510    1. 8035 2. 523.29
4511    1. 8040 2. 530.29
4512    1. 8041 2. 530.29
4513    1. 8046 2. 547.3
4514    1. 8042 2. 535.29
4515    1. 8047 2. 544.3
4516    1. 8043 2. 537.3
4517    1. 8048 2. 547.3
4518    1. 8044 2. 547.3
4519    1. 8049 2. 547.3
4520    1. 8045 2. 547.3
4521    1. 8050 2. 547.3
4522    1. 8051 2. 548.3
4523    1. 8056 2. 569.31
4524    1. 8052 2. 548.3
4525    1. 8057 2. 569.31
4526    1. 8053 2. 547.3
4527    1. 8058 2. 571.31
4528    1. 8054 2. 555.31
4529    1. 8059 2. 608.33
4530    1. 8055 2. 553.3
4531    1. 8060 2. 621.34
4532    1. 8061 2. 443.24
4533    1. 8066 2. 473.26
4534    1. 8062 2. 457.25
4535    1. 8067 2. 483.27
4536    1. 8063 2. 471.26
4537    1. 8068 2. 485.27
4538    1. 8064 2. 471.26
4539    1. 8069 2. 483.27
4540    1. 8065 2. 469.26
4541    1. 8070 2. 499.27
4542    1. 8071 2. 505.28
4543    1. 8072 2. 537.3
4544    1. 8073 2. 537.3
4545    1. 8074 2. 547.3

[0920]

TABLE 81
	1. Ex.		1. Ex.
Product	2. m/zz	Product	2. m/z
4546	1. 8101 2. 510.28	4547	1. 8106 2. 528.29
4548	1. 8102 2. 518.28	4549	1. 8107 2. 537.3
4550	1. 8103 2. 518.28	4551	1. 8108 2. 538.3
4552	1. 8104 2. 519.29	4553	1. 8109 2. 540.3
4554	1. 8105 2. 526.29	4555	1. 8110 2. 540.3
4556	1. 8116 2. 556.31	4557	1. 8111 2. 542.3
4558	1. 8117 2. 558.31	4559	1. 8112 2. 542.3
4560	1. 8118 2. 562.31	4561	1. 8113 2. 548.3
4562	1. 8119 2. 580.32	4563	1. 8114 2. 552.3
4564	1. 8120 2. 580.32	4565	1. 8115 2. 554.3
		4566	1. 8121 2. 580.32
		4567	1. 8122 2. 580.32
		4568	1. 8123 2. 580.32
		4569	1. 8125 2. 580.32
		4570	1. 8126 2. 588.32
		4571	1. 8126 2. 588.32
		4572	1. 8127 2. 590.32
		4573	1. 8128 2. 590.32
		4574	1. 8129 2. 604.33
		4575	1. 8130 2. 612.34
		4576	1. 8131 2. 654.36
		4577	1. 8132 2. 476.26
		4578	1. 8133 2. 580.32
		4579	1. 8134 2. 580.32

[0921]

TABLE 82
	1. Ex.		1. Ex.
Product	2. m/z	Product	2. m/z
4580	1. 8201 2. 488.27	4581	1. 8206 2. 512.28
4582	1. 8202 2. 496.27	4583	1. 8207 2. 514.28
4584	1. 8203 2. 504.28	4585	1. 8208 2. 523.29
4586	1. 8204 2. 504.28	4587	1. 8209 2. 524.29
4588	1. 8205 2. 505.28	4589	1. 8210 2. 526.29
4590	1. 8211 2. 526.29	4591	1. 8216 2. 534.29
4592	1. 8212 2. 528.29	4593	1. 8217 2. 537.3
4594	1. 8213 2. 528.29	4595	1. 8218 2. 538.3
4596	1. 8214 2. 528.29	4597	1. 8219 2. 542.3
4598	1. 8215 2. 532.29	4599	1. 8220 2. 542.3
4600	1. 8221 2. 544.3	4601	1. 8226 2. 551.3
4602	1. 8222 2. 544.3	4603	1. 8227 2. 554.3
4604	1. 8223 2. 548.3	4605	1. 8228 2. 556.31
4606	1. 8224 2. 548.3	4607	1. 8229 2. 566.31
4608	1. 8225 2. 551.3	4609	1. 8230 2. 566.31
4610	1. 8231 2. 566.31	4611	1. 8236 2. 568.31
4612	1. 8232 2. 566.31	4613	1. 8237 2. 574.32
4614	1. 8233 2. 566.31	4615	1. 8238 2. 574.32
4616	1. 8243 2. 566.31	4617	1. 8238 2. 576.32
4618	1. 8235 2. 566.31	4619	1. 8240 2. 576.32
4620	1. 8241 2. 576.32	4621	1. 8246 2. 590.32
4622	1. 8242 2. 586.32	4623	1. 8247 2. 598.33
4624	1. 8243 2. 586.32	4625	1. 8248 2. 627.34
4626	1. 8244 2. 588.32	4627	1. 8249 2. 640.35
4628	1. 8245 2. 590.32	4629	1. 8250 2. 462.25
4630	1. 8251 2. 476.26	4631	1. 8256 2. 504.28
4632	1. 8252 2. 490.27	4633	1. 8257 2. 504.28
4634	1. 8253 2. 492.27	4635	1. 8258 2. 508.28
4636	1. 8254 2. 492.27	4637	1. 8259 2. 530.29
4638	1. 8255 2. 502.28	4639	1. 8260 2. 533.29
4640	1. 8261 2. 544.3	4641	1. 8266 2. 560.31
4642	1. 8262 2. 546.3	4643	1. 8267 2. 566.31
4644	1. 8263 2. 546.3	4645	1. 8268 2. 591.33
4646	1. 8264 2. 558.31	4647	1. 8269 2. 595.33
4648	1. 8265 2. 558.31	4649	1. 8270 2. 555.31

[0922]

TABLE 83
        1. Ex.
Product 2. m/z
4650    1. 8301 2. 465.882
4651    1. 8302 2. 465.885
4652    1. 8303 2. 475.827
4653    1. 8304 2. 479.89
4654    1. 8305 2. 483.829
4655    1. 8306 2. 491.79
4656    1. 8307 2. 491.792
4657    1. 8308 2. 492.787
4658    1. 8309 2. 499.846
4659    1. 8310 2. 501.826
4660    1. 8311 2. 501.825
4661    1. 8312 2. 501.833
4662    1. 8313 2. 510.822
4663    1. 8314 2. 510.821
4664    1. 8315 2. 511.841
4665    1. 8316 2. 513.855
4666    1. 8317 2. 515.832
4667    1. 8318 2. 515.832
4668    1. 8319 2. 515.837
4669    1. 8320 2. 519.782
4670    1. 8321 2. 519.783
4671    1. 8322 2. 519.781
4672    1. 8323 2. 525.813
4673    1. 8324 2. 529.806
4674    1. 8325 2. 529.81
4675    1. 8326 2. 531.804
4676    1. 8327 2. 531.812
4677    1. 8328 2. 535.83
4678    1. 8329 2. 535.831
4679    1. 8330 2. 541.788
4680    1. 8331 2. 543.821
4681    1. 8332 2. 553.797
4682    1. 8333 2. 553.796
4683    1. 8334 2. 553.795
4684    1. 8335 2. 554.73
4685    1. 8336 2. 554.727
4686    1. 8337 2. 554.738
4687    1. 8338 2. 554.738
4688    1. 8339 2. 554.727
4689    1. 8340 2. 561.836
4690    1. 8341 2. 561.838
4691    1. 8342 2. 564.714
4692    1. 8343 2. 564.704
4693    1. 8344 2. 564.72
4694    1. 8345 2. 573.823
4695    1. 8346 2. 573.735
4696    1. 8347 2. 575.839
4697    1. 8348 2. 577.818
4698    1. 8349 2. 577.814
4699    1. 9350 2. 585.818
4700    1. 8351 2. 529.808
4701    1. 8352 2. 614.763
4702    1. 8353 2. 628.727
4703    1. 8354 2. 449.857
4704    1. 8355 2. 463.867
4705    1. 8356 2. 479.856
4706    1. 8357 2. 511.842
4707    1. 8358 2. 520.859
4708    1. 8359 2. 533.903
4709    1. 8360 2. 545.823
4710    1. 8361 2. 547.909
4711    1. 8362 2. 510.817
4712    1. 8363 2. 542.833
4713    1. 8364 2. 573.815
4714    1. 8365 2. 547.798

[0923]

TABLE 84
        1. Ex.
Product 2. m/z
4715    1. 8401 2. 491.883
4716    1. 8402 2. 491.883
4717    1. 8403 2. 501.827
4718    1. 8404 2. 501.827
4719    1. 8405 2. 505.89
4720    1. 8406 2. 509.829
4721    1. 8407 2. 517.795
4722    1. 8408 2. 517.799
4723    1. 8409 2. 518.796
4724    1. 8410 2. 525.851
4725    1. 8411 2. 527.831
4726    1. 8412 2. 527.833
4727    1. 8413 2. 536.833
4728    1. 8414 2. 536.829
4729    1. 8415 2. 537.845
4730    1. 8416 2. 539.859
4731    1. 8417 2. 541.84
4732    1. 8418 2. 541.843
4733    1. 8419 2. 541.843
4734    1. 8420 2. 546.786
4735    1. 8421 2. 546.792
4736    1. 8422 2. 546.79
4737    1. 8423 2. 547.854
4738    1. 8424 2. 551.826
4739    1. 8425 2. 555.819
4740    1. 8426 2. 555.817
4741    1. 8427 2. 557.81
4742    1. 8428 2. 557.813
4743    1. 8429 2. 561.839
4744    1. 8430 2. 561.833
4745    1. 8431 2. 564.841
4746    1. 8432 2. 567.795
4747    1. 8433 2. 569.823
4748    1. 8434 2. 579.797
4749    1. 8435 2. 579.796
4750    1. 8436 2. 579.794
4751    1. 8437 2. 580.738
4752    1. 8438 2. 580.732
4753    1. 8439 2. 580.733
4754    1. 8440 2. 580.734
4755    1. 8441 2. 580.726
4756    1. 8442 2. 581.805
4757    1. 8443 2. 587.844
4758    1. 8444 2. 587.835
4759    1. 8445 2. 590.723
4760    1. 8446 2. 590.726
4761    1. 8447 2. 590.724
4762    2. 8448 2. 599.834
4763    1. 8449 2. 599.749
4764    1. 8450 2. 601.854
4765    1. 8451 2. 603.831
4766    1. 8452 2. 603.83
4767    1. 8453 2. 611.83
4768    1. 8454 2. 555.824
4769    1. 8455 2. 585.817
4770    1. 8456 2. 640.779
4771    1. 8457 2. 654.746
4772    1. 8458 2. 475.871
4773    1. 8459 2. 489.879
4774    1. 8460 2. 503.885
4775    1. 8461 2. 505.866
4776    1. 8462 2. 507.828
4777    1. 8463 2. 537.859
4778    1. 8464 2. 546.877
4779    1. 8465 2. 559.921
4780    1. 8466 2. 559.919
4781    1. 8467 2. 573.925
4782    1. 8468 2. 579.876
4783    1. 8469 2. 536.831
4784    1. 8470 2. 568.843

[0924]

TABLE 85
        1. Ex.
Product 2. m/z
4785    1. 8501 2. 367.2
4786    1. 8502 2. 381.2
4787    1. 8503 2. 443.2
4788    1. 8504 2. 457.3
4789    1. 8506 2. 443.1
4790    1. 8507 2. 323.1
4791    1. 8508 2. 365.2
4792    1. 8509 2. 379.21
4793    1. 8510 2. 381.21
4794    1. 8511 2. 381.21
4795    1. 8512 2. 393.22
4796    1. 8513 2. 395.22
4797    1. 8514 2. 397.22
4798    1. 8515 2. 407.22
4799    1. 8516 2. 409.22
4800    1. 8517 2. 411.23
4801    1. 8518 2. 421.23
4802    1. 8519 2. 421.23
4803    1. 8520 2. 425.23
4804    1. 8521 2. 429.24
4805    1. 8522 2. 439.24
4806    1. 8523 2. 443.24
4807    1. 8524 2. 443.24
4808    1. 8525 2. 445.24
4809    1. 8526 2. 445.24
4810    1. 8527 2. 444.24
4811    1. 8528 2. 444.24
4812    1. 8529 2. 446.25
4813    1. 8530 2. 457.25
4814    1. 8531 2. 480.26
4815    1. 8532 2. 483.27
4816    1. 8533 2. 483.27
4817    1. 8536 2. 431.24
4818    1. 8537 2. 429.24
4819    1. 8538 2. 397.22
4820    1. 8539 2. 411.23
4821    1. 8540 2. 411.23
4822    1. 8541 2. 432.24
4823    1. 8542 2. 433.24
4824    1. 8543 2. 438.24
4825    1. 8545 2. 464.26
4826    1. 8546 2. 466.26
4827    1. 8547 2. 478.26
4828    1. 8548 2. 498.27
4829    1. 8549 2. 365.1
4830    1. 8549 2. 337.1
4831    1. 8550 2. 351.1

[0925]

TABLE 86
        1. Ex.
Product 2. m/z
4832    1. 8601 2. 403.22
4833    1. 8602 2. 407.22
4834    1. 8603 2. 421.23
4835    1. 8604 2. 434.24
4836    1. 8605 2. 391.22
4837    1. 8606 2. 434.24
4838    1. 8607 2. 375.21
4839    1. 8608 2. 375.21
4840    1. 8609 2. 391.22
4841    1. 8610 2. 399.22
4842    1. 8611 2. 417.23
4843    1. 8612 2. 415.23
4844    1. 8613 2. 428.24
4845    1. 8614 2. 430.24
4846    1. 8615 2. 434.24
4847    1. 8616 2. 434.24
4848    1. 8617 2. 446.25
4849    1. 8618 2. 460.25
4850    1. 8619 2. 459.25
4851    1. 8620 2. 474.26
4852    1. 8621 2. 377.21
4853    1. 8622 2. 406.22
4854    1. 8623 2. 412.23
4855    1. 8624 2. 420.23
4856    1. 8625 2. 426.23
4857    1. 8626 2. 427.23
4858    1. 8627 2. 431.24
4859    1. 8628 2. 446.25
4860    1. 8629 2. 446.25
4861    1. 8630 2. 407.2
4862    1. 8631 2. 407.2
4863    1. 8632 2. 409.2
4864    1. 8633 2. 421.2
4865    1. 8634 2. 439.2
4866    1. 8635 2. 455.3
4867    1. 8636 2. 475.3
4868    1. 8637 2. 419.2
4869    1. 8638 2. 448.2
4870    1. 8639 2. 379.2
4871    1. 8640 2. 437.2
4872    1. 8641 2. 415.23
4873    1. 8642 2. 443.24
4874    1. 8643 2. 416.23
4875    1. 8644 2. 417.23
4876    1. 8645 2. 423.23
4877    1. 8646 2. 423.23
4878    1. 8647 2. 430.24
4879    1. 8648 2. 437.24
4880    1. 8649 2. 439.24
4881    1. 8650 2. 466.26
4882    1. 8651 2. 423.23
4883    1. 8652 2. 425.23
4884    1. 8653 2. 437.24
4885    1. 8654 2. 437.24
4886    1. 8655 2. 437.24
4887    1. 8656 2. 445.24
4888    1. 8657 2. 445.24
4889    1. 8658 2. 451.25
4890    1. 8659 2. 476.26
4891    1. 8660 2. 479.26
4892    1. 8661 2. 477.26
4893    1. 8662 2. 479.26

Claims

1. A compound represented by the structural formula:

2. The compound of claim 1, wherein R is —(CHR5)n-aryl, —(CHR5)n-heteroaryl, alkyl, cycloalkyl, heterocyclyl, or heteroarylalkyl (including N-oxide of said heteroaryl), wherein each of said alkyl, aryl, cycloalkyl, heterocyclyl and heteroaryl can be unsubstituted or optionally substituted with one or more moieties as stated in claim 1;R2 is halogen, alkyl, haloalkyl, CN, cycloalkyl, heterocyclyl or alkynyl; R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl, —NR5R6, 4899wherein said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures shown immediately above for R3 are optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF3, OCF3, lower alkyl, CN, —C(O)R5, —S(O2)R5, —C(═NH)—NH2, —C(═CN)—N H2, hydroxyalkyl, alkoxycarbonyl, —SR5, and OR5, with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR5 moiety; R4 is H or lower alkyl; R5 is H, lower alkyl or cycloalkyl; n is 1 to 2; and p is 1 or 2.

3. The compound of claim 2, wherein R is hydroxyalkyl, —(CHR5)n-aryl, or —(CHR5)n-heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or substituted with one or more groups which can be the same or different, each group being independently selected from the group consisting of heteroaryl, amine, heterocyclyl, —C(O)N(R5R6), —S(O2)R5, —S(O2)N(R5R6), alkoxy and halo.

4. The compound of claim 2, wherein R2 is Br, Cl, CF3, CN, lower alkyl, cyclopropyl, alkynyl, alkyl substituted with —OR6 or tetrahydrofuranyl.

5. The compound of claim 2, wherein R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl,

6. The compound of claim 2, wherein R4 is H or lower alkyl.

7. The compound of claim 2, wherein R5 is H.

8. The compound of claim 2, wherein n is 1.

9. The compound of claim 1, wherein p is 1.

10. The compound of claim 2, wherein R is benzyl or hydroxyalkyl.

11. The compound of claim 2, wherein R is pyrid-3-ylmethyl, wherein said pyridyl may be unsubstituted or optionally independently substituted with one or more moieties as stated in claim 1.

12. The compound of claim 2, wherein R is pyrid-4-ylmethyl, wherein said pyridyl may be unsubstituted or optionally independently substituted with one or more moieties as stated in claim 1.

13. The compound 2, wherein R is the N-oxide of pyrid-2-ylmethyl, pyrid-3-ylmethyl, or pyrid4-ylmethyl, wherein each of said pyridyl may be unsubstituted or optionally independently substituted with one or more moieties as stated in claim 1.

14. The compound of claim 4, wherein said R2 is Br.

15. The compound of claim 4, wherein said R2 is Cl.

16. The compound of claim 4, wherein R2 is ethyl.

17. The compound of claim 4, wherein R2 is cyclopropyl.

18. The compound of claim 4, wherein R2 is ethynyl.

19. The compound of claim 2, wherein R3 is lower alkyl, cycloalkyl, heterocyclyl, aryl or —N(R5R6).

20. The compound of claim 19, wherein R3 is isopropyl.

21. The compound of claim 19, wherein R3 is cyclohexyl or norbornyl wherein each of said cyclohexyl or norbornyl can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of alkyl and hydroxyalkyl.

22. The compound of claim 19, wherein R3 is unsubstituted phenyl.

23. The compound of claim 19, wherein R3 is a phenyl substituted with one or moieties which can be the same or different, each moiety being independently selected from the group consisting of F, Br, Cl and CF3.

24. The compound of claim 19, wherein R5 of said —N(R5R6) is H or hydroxyalkyl, and R6 of said —N(R5R6) is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl and methylenedioxy, wherein each of said alkyl and cycloalkyl can be unsubstituted or substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of amine, ethoxycarbonyl, amide, hydroxyalkyl, hydroxy,

25. The compound of claim 19, wherein R5 and R6 of said —N(R5R6) are joined together to form a heterocyclyl moiety, wherein said heterocyclyl moiety can be unsubstituted or optionally independently substituted with one or more groups which can be the same or different, each group being selected from the group consisting of hydroxyalkyl, amide, —C(O)R5, >C(CH3)2, —S(O2)R5, —S(O2)N(R5R6), —C(═NH)N(R5R6) and —C(═N—CN)N(R5R6).

26. The compound of claim 25, wherein said heterocyclyl moiety formed by R5 and R6 is a pyrrolidine or piperidine ring.

27. A compound of the formula:

28. A compound of the formula:

29. A compound of the formula:

30. A compound of the formula:

31. A compound of the formula:

32. A method of inhibiting one or more cyclin dependent kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 to a patient in need of such inhibition.

33. A method of treating one or more diseases associated with cyclin dependent kinase, comprising administering a therapeutically effective amount of at least one compound of claim 1 to a patient in need of such treatment.

34. The method of claim 33, wherein said cyclin dependent kinase is CDK2.

35. The method of claim 33, wherein said cyclin dependent kinase is mitogen activated protein kinase (MAPK/ERK).

36. The method of claim 33, wherein said cyclin dependent kinase is glycogen synthase kinase 3 (GSK3beta).

37. The method of claim 33, wherein said disease is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

38. A method of treating one or more diseases associated with cyclin dependent kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect.

39. The method of claim 38, further comprising radiation therapy.

40. The method of claim 38, wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.

41. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in combination with at least one pharmaceutically acceptable carrier.

42. The pharmaceutical composition of claim 39, additionally comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-1 1, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epinubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.

43. A compound of claim 1 in purified form.

44. A compound of the formula:

45. A compound of the formula:

46. A compound of the formula:

47. A compound of the formula:

48. A compound of the formula:

49. A compound of the formula:

50. A compound of the formula:

51. A compound of the formula:

52. A compound of the formula:

53. A compound of the formula: