AU2011202888B2 - Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith - Google Patents

Abstract

Provided herein are Aminopurine Compounds having the following structure: (I) wherein R', R2 and R3 are as defined herein, compositions comprising an effective amount of an Aminopurine Compound and methods for treating or preventing Type I diabetes, Type II diabetes, esophagitis, hepatitis, pancreatitis or nephritis, cancer, a cardiovascular disease, a renal disease, an autoimmune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related wasting, an asbestos relate condition, pulmonary hypertension or a condition treatable or preventable by inhibition of the JNK pathway comprising administering an effective amount of an Aminopurine Compound to a patient in need thereof.

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Pharmacopeia, LLC and Signal Pharmaceuticals, LLC Actual Inventor(s): Adam Kois, Yoshitaka Satoh, Elise Sudbeck, Ian Henderson, John Sapienza, Jonathan Wright, Kevin Hughes, Kiran Sahasrabudhe, Leticia Ayala, Lisa Nadolny, Maria M. Delgado Mederos, Marian Sloss, Meg McCarrick, Moorthy Palanki, Robert Hilgraf, Ronald Albers, Sayee Hedge, Steven S. Clareen, Veronique Plantevin-Krenitsky, Andrew G. Cole Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: HALOARYL SUBSTITUTED AMINOPURINES, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH Our Ref: 917163 POF Code: 125692/474699, 506836 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): - 1- HALOARYL SUBSTITUTED AMINOPURINES, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH [00011 The present application is a divisional application from Australian Patent 5 Application No. 2006204792, which claims the benefit of U.S. provisional application no. 60/643,796, filed January 13, 2005, and U.S. provisional application no. 60/709,980, filed August 19, 2005, the contents of each is incorporated by reference herein in their entirety. 1. FIELD [00021 Provided herein are certain amino-substituted purine compounds, compositions 10 comprising an effective amount of such compounds and methods for treating or preventing cancer, a cardiovascular disease, a renal disease, an autoimmune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related wasting, an asbestos-related condition, pulmonary hypertension, central nervous system (CNS) injury/damage or a condition treatable or preventable by inhibition of a kinase pathway comprising 15 administering an effective amount of such aminopurine compounds to a patient in need thereof. 2. BACKGROUND [0003] The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. See Cohen, Nature, 1:309-315 (2002). Various 20 protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including diabetes and stroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001). [00041 The protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a critical role in cellular signaling. Protein kinases may exert positive or 25 negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation -laof signal transduction by cytokines and the association of signal molecules with protooncogenes and tumor suppressor genes have been well documented. Similarly, the connection bet ween diabetes and related conditions, and eregulated levels of protein kinases, has been demonstrated. See e.g., Sridh"r et al. Phahmaceutical Research, 5 17(11):1345-1353 (2000). Viral infections and the conditions related thereto have also been associated with the regulation of protein kinases. Park et al. Cell 101 (7), 777-787 (2000). 100051 roteiri kinases can be divided into broad groups based upon the identity of the amino acid(s that they target (serine/threonine tyrosiie, lysine, and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs), such as growth factors 10 and non-receptor tyrosine kinases, such as the src kinase family. There are also dual specific protein kinases that target both tyrosine and serine/threonine; such as cyclin dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs). Any particular cell contains many protein kinases, some of which phosphorylate other protein kinases. Some protein kinases phosphorylate many different proteins, others phosphorylate only a 15 single protein. Not surprisingly, there are numerous classes of protein kinases. Upon receiving a signal, some proteins may also undergo auto-phosphorylation. [00061 The protein tyrosine kinases (PTKs) compose a large family of kinases that regulate cell to cell signals involved in growth, differentiation, adhesion, motility, and death. Robinson et al., Oncogene 19:5548-5557 (2000). Members of the tyrosine kinase include, 20 but are not limited to, Yes, BMX, Syk, EphAl, FGFR3, RYK, MUSK, JAKI and EGFR. Tyrosine kinases are distinguished into two classes, i.e., the receptor type and non-receptor type tyrosine kinases. Interestingly, the entire of family of tyrosine kinases is quite large consisting of at least 90 characterized kinases with at least 58 receptor type and at least 32 nonreceptor type kinases comprising at least 30 total subfamilies. Robinson et al., 25 Oncogene 19:5548-5557 (2000). Tyrosine kinases have been implicated in a number of diseases in humans, including diabetes and cancer. Robinson et al. at page 5548. Tyrosine kinases are often involved in most forms of human malignancies and have been linked to a wide variety of congenital syndromes. Robertson et al., Trends Genet. 16:265-271 (2000). [00071 The non-receptor tyrosine kinases represent a group of intracellular enzymes 30 that lack extracellular and transmembrane sequences. Currently, over 32 families of non receptor tyrosine kinases have been identified. Robinson et al., Oncogene 19:5548-5557 (2000). Examples are Src, Btk, Csk, ZAP70, Kak families. In particular, the Src family of -2non-receptor tyrosine kinase family is the largest, consisting of Src, Yes, Fyn, Lyn, Lck, Bik, Hck, Fgr and Yrk protein tyrosine kinases. The Srt family of kinases have been linked to oncogenesis, cell proliferation and turnor progression. A detailed disewssion of non receptor protein tyrosine'kinases is Ovailable in Oncogene 8:2025-2031 (199). Many of 5 these protein tyrosine kinases have been found to be involved in cellular signaling pathways involved in various pathological conditions including but not limited to cancer and hyperproliferative disorders and immune disorders. [0008] The dyclin'dependent kinases(CDKs represent a group of intracellular enzymes that control progression through the cell cycle and have essential roles in cell 10 proliferation. See Cohen, Nature, 1:309-315 (2002). Examples of CDKs include, but are not limited to, cyclin dependent kinase 2 (CDK2), cyclin dependent kinase 7 (CDK7), cyclin dependent kinase 6 (CDK6) and cell division control 2 protein (CDC2). CDKs have been implicated in the regulation of transitions between different phases of the cell cycle, such as the progression from a quiescent stage in Gi (the gap between mitosis and the onset of DNA 15 replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from 02 to M phase, in which active mitosis and cell division occur. See e.g., the articles compiled i Science, vol. 274 (1996), pp. 1643-1677; andAnn. Rev Cell Dev Biol., vol. 13 (1997), pp. 261-291. CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B 1, B2, D1, D2, D3, and E) and a catalytic kinase 20 subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As the name implies, CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific portions of the cell cycle. CDKs have been implicated in various disease states, including but not limited to, those displaying the cancer phenotype, various neoplastic 25 disorders and in neurological disorders. Hunter, Cell 100:113-127 (2000). [0009] The mitogen activated protein (MAP) kinases participate in the transduction of signals to the nucleus of the cell in response to extracellular stimuli. Examples of MAP kinases include, but are not limited to, ruitogen activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (ERK2), mitogen-activated protein kinase 7 (MAPK'), 30 mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase 14 (p38 alpha), mitogen-activated protein kinase 10 (MAPk1O), JNK3 alpha protein kinase, stress-activated protein kinase jNK2 and nmitogen-activated protein lnase 14 (MAPK14). MAP kinases are -3a family of prolbiedirected seine/treonieknases that sidiat6 signal transduction from extacelular receptors or heath shick.or UV radiation. See Sridharetal.;Phanaceutical .Reseach, 17l:11 1345-1353 (2000). MAP kinases activate through the phosphoiylation of theonine and tyrosine by dual-specificity protein kinases,- including tyrosine kinases suchas 5 grovth factors ell prOliferation and differentiation have been shown to be under the reguatory control of multiple'MAP kinabe cascades. See Sridharet al. Pharmceutical Research,1:11 1345-1353 (2000). As such, the.MAP kinase pathWa plays critical roles ingmnber f disesse W states For example, defetts in Activities bf MAP kinases have been shown to lead to aberrant cell proliferation and carcinogenesis. See Hu et al.) Cell Growth 10 DIffer. 11:191-200 (2000); and Das et,aL Breast Cancer Res. Treat. 40:141 (1996). Moreover, MAP kinase activity has also been implicated in insulin resistancde associated with type-2 diabetes. See Virkamaki et al., J. Clin. Invest. 103:931-943 (1999). [0010] Thelp9O ribosomal S6,kkases (Rsk) are serine/threonine kinases. The Rsk fatnily, members function in mitogen-activated cell growth and proliferation, differentiation, 15 and cell survival. Examples of members of the Rsk family of Idnases include, but are not limited to, ribosomal protein S6 kinase, 90kDa,polypeptide 2 (Rsk3), ribosomal protein S6 kinase,: 90kDagpolypeptide 6 (Rsk4), ribosomal protein S6 kinase, 90kDa, polypeptide 3 (Rsk2),and ribosomal protein S6 kinase, 90kDa, polypeptide 1 (Rskl/p90Rsk). The Rsk family members are activated by extracellular signal-related kinases 1/2 and 20 phosphoinositide-dependent protein kinase 1. Frodin and Ganmeltoft, Mol. Cell. Endocrinol. 151:65-77 (1999). Under basal conditions, RSK kinases are localized in the cytoplasm of cells:and uponstimulation by mitogens, the activated (phosphorylated by extracellular-related kinase) RSK transiently translocates to the plasma membrane where they become fully activated. The fully activated RSK phosphorylates substrates that are 25 involved in cell growth, proliferation, differentiation, and cell survival. Richards et al., Cur?. Biol: 9:810-820 (1999); Richards et al., Mol. Cell.. Biol. 21:7470-7480 (2001). RSK signaling pathways have also been associated with the modulation of the cell cycle. Gross et al., J. Riol. Chem. 276(49): 46099-46103 (2001). Current data suggests that small molecules that inhibit Rsk may be useful therapeutic agents for the prevention and treatment 30 of cancer and inflenunatory diseases. [0011] Members ofthescheckpointprotein kinase family are serine/threonine kinases that play an important role in cell cycle progression. Examples of members of the -4cells, and a ROCK inhibitor has been used to reduce tumor-c6ll dissemination In vivo. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states. See Nature Reviews Mol. Cell Biol. 4, 446-456 (2003). The ROCK 5 family members are attractive intervention targets for a variety of pathologies, including cancer and cardiovascular disease. For example, Rho inase inhibitors can be useful therapeutic agents for hypertension, angina pectoris, and.asthma. urthermoe, Ris exected to plaY a ro in pariyneral ion disoides, ar eoscle si iAnlaniao and autoimmune disease and as such, is a useful target for therapy. 10 [00141 The 70 kna ribosomal S6 kinase (p7OS6K) is activated by numerous mitogens, growth factors and hormones. Activation of p7086K occurs through phosphorylation at a number of sites and the primary target of the activated kinase is the 40S ribosomal protein S6, a major component of the machinery involved in protein synthesis in mammalian cells. In addition to its involvement in regulating translation, p70S6K activation 15 has been implicated in cell cycle control, neuronal cell differentiation, regulation of cell motility and a cellular response that is important in tumor metastases, immunity and tissue repair. Modulation of p70S6 kinase activity may have therapeutic implications in disorders such as cancer, inflammation, and various neuropathies. A detailed discussion of p7OS6K kinases can be found in Prog. Cell Cycle Res. 1:21-32 (1995), and Immunol Cell Biol. 20 78(4):447-51 (2000). [00151 Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed constitutively active serine/threonine kinase that phosphorylates cellular substrates and thereby regulates a wide variety of cellular functions, including development, metabolism, gene transcription, protein translation, cytoskeletal organization, cell cycle regulation, and 25 apoptosis. GSK-3 was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. Two forms of the enzyme, GSK-3a and GSK-3p, have been previously identified. The activity of GSK-3p is negatively regulated by protein kinase B/Akt and by the Wnt signaling pathway. Small molecules inhibitors of GSK-3 may, therefore, have several therapeutic uses, including the treatment of 30 neurodegenerative diseases, diabetes type II, bipolar disorders, stroke, cancer, and chronic inflammatory disease. Reviewed in Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways (Adv Cancer Res.;84:203-29, 2002); Glycogen -6synthase kinase,3 (GSKe-3) inhibitors s iew promising drugs for diabetes, neurodegeneration cancer, and inflammation (Med Res Rev.; 22(4):373-84, 2002); Role of glycogen synthase kinase-3 in the phosphatidylinositol -Kinase/Akt cell survival pathway. (J. Riol Chem., 273(32):19929-32,1998). 5 [00161 Because protein kinases regulate nearly every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell-cycle control and angiogenesis, irMhich protein kinases play aivot role arcellular poesses associated with numerous disease conditions such as but not limited to cancer, inflammatory 10 diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain. [0017] Protein kinases have become attractive targets for the treatment of cancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). It has been proposed that the involvement of protein kinases in the development of human malignancies may occur by: 15 (1) genomic rearrangements (e g., BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to constitutively active kinase activity, such as acute myelogenous leukemia and gastrointestinal tumors, (3) deregulation of kinase activity by activation of oncogenes or loss of tumor suppressor functions, such as in cancers with oncogenic RAS, (4) deregulation of kinase activity by over-expression, as in the case of BGFR and (5) 20 ectopic expression of growth factors that can contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). [0018] Certain cancers are associated with angiogenesis. Angiogenesis is the growth of new capillary blood vessels from pre-existing vasculature. Risau, W., Nature 25 386:671-674 (1997). It has been shown that protein kinases can contribute to the development and maintenance of the neoplastic phenotype. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). For example, VEGF A-D and their four receptors have been implicated in phenotypes that involve neovascualrization and enhanced vascular permeability, such as tumor angiogenesis and lymphangiogenesis. Matter, A., Drug Discov. 30 Today 6:1005-1023 (2001). [0019] Cardiovascular disease ("CVD") accounts for nearly one quarter of total annual deaths worldwide. Vascular disorders such as atherosclerosis and restenosis result -7from dysregulated growth of the vessel walls and the restriction of blood flow to vital organs. Various kinase pathways, e.g. JNK, are activated by atherogenic stimuli and regulated through local cytokine and growth factor production in vascular cells. Yang et al., Immunity 9:575 (1998). Ischemia and ischemia coupled with reperfusion in the heart, kidney or brain result in cell death and scar formation, 5 which can ultimately lead to congestive heart failure, renal failure or cerebral dysfunction. In organ transplantation, reperfusion of previously ischemic donor organs results in acute leukocyte-mediated tissue injury and delay of graft function. Ischernia and reperfusion pathways are mediated by various kinases. For example, the JNK pathway has been linked to leukocyte-mediated tissue damage. Li et al., Mal. Cell. Biol. 16:5947-5954 (1996). Finally, enhanced apoptosis in cardiac tissues has also been 10 linked to kinase activity. Pombo et al., J. Biol. Chem. 269:26546-26551 (1994). 100201 The elucidation of the intricacy of protein kinase pathways and the complexity of the relationship and interaction among and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase 15 pathways. 100211 It has therefore been suggested that due to the complexity of intracellular signaling cascades of protein kinase pathways, agents that affect multiple pathways simultaneously may be required for meaningful clinical activity. Indeed, it is known that some kinase drugs, such as Gleevec*, do target several kinases at once. Gleevec* primarily targets a mutant fusion protein containing the abl kinase, 20 which is created by a 9:22 chromosomal translocation event; Gleevec* also targets c-kit, a tyrosine kinase implicated in gastrointestinal stromal tumors (GIST). However, in recent clinical trials, patients have developed resistance to GleevecOor have shown incomplete response to treatment. [00221 Accordingly, there remains a need for new kinase modulators. [00231 Citation or identification of any reference in Section 2 of this application is not to be 25 construed as an admission that the reference is prior art to the present application. [0023a] Throughout the description and claims of the specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps. [0023b] A reference herein to a patent document or other matter which is given as prior art is not to 30 be taken as an admission or a suggestion that that document or matter was, known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims. 3. SUMMARY 100241 Provided herein are compounds having the following formula (1): -8- 2 HH a pharn tically accetae salts, polyn orphs, clathrates, sdl ates, hydrates, stereoisomers and prodrugs thereof, wherein R1, R 2 and Ra are as defined herein. 5 [00261 A compound of formula (1) or a pharmaceutically acceptable salt, clathrate, solvate, hydrate, stereoisomer or prodrug thereof (each being referred to herein as an "AIIIopurine Compound") is useful for treating or preventing dancer, a cardiovascular disease, a renal disease, an Wutoinmnune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related 10 wasting, an asbestos-related condition, pulmonary.hypertension, central nervous system (CNS) injury/damage or a condition treatable or preventable by inhibition of a kinase pathway, in one embodiment, the JNK pathway. [0027]. Further provided herein are compositions comprising an effective amount of an Aminopurine Compound and compositions comprising an effective amount of an 15 Aminopurine Compound and a pharmaceutically acceptable carrier or vehicle. The compositions are useful for treating or preventing cancer, a cardiovascular disease, a renal disease, an autoimmune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related wasting, an asbestos-related condition, pulmonary hypertension, central nervous system (CNS) 20 injury/damage or a condition treatable or preventable by inhibition of a kinase pathway, in one embodiment, the JNK pathway. [0028] Further provided herein are methods for treating or preventing cancer, a cardiovascular disease, a renal disease, an inflammatory condition, a metabolic condition, an autoimmune condition, macular degeneration, ischemia-reperfusion injury, pain and related 25 syndromes, disease-related wasting, an asbestos-related condition, pulmonary hypertension, central nervous system (CNS) injury/damage or a condition treatable or preventable by inhibition of a Idnase pathway, in one embodiment, the JNK pathway, comprising -9administering an effective amount of an Aminopurine Compound to a patient in need of the treating or preventing. [0029] In one embodiment, the Aminopurine Compound targets two or more of the following: Idnases from the kinase family, kinases from the Rsk kinase family, kinases 5 from the CDK family, kinases from the MAPK Idnase family, and tyrosine kinases such as Fes, Lyn, and $yk kinases. The agent may target two or more kinases of the same family, or may target kinases representing two or more kinase families or classes. [0030] Further provided herein are stents (e.g., stent graft) containing or coated with an amount of an Aminopurine Compound effective for treating or preventing a 10 cardiovascular disease or renal disease. [00311 The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. 4. DETAILED DESCRIPTION 15 4.1 DEFINITIONS [0032] A "C .

6 alkyl" group is a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative -(C- 1 alkyls) include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, - isopentyl, 2-methylpentyl, 3 20 methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. A -(Cl4alkyl) group can be substituted or unsubstituted. [00331 An "alkoxy" group is an -O-(CI..alkyl) group, wherein C1.sallcyl is defined above, including -OCH 3 , -OCH 2

CH

3 , -O(CH 2

)

2

CH

3 , -O(CH 2

)

3

CH

3

,-O(CH

2

)

4

CH

3 ,

-O(CH

2 )sCH 3 , and the like. 25 [00341 An "alkoxyalkyl" group is a -(Cj.6alkylene)-O-(C.6alkyl) group, wherein each Ci -alkyl is independently a C 1 alkyl group defined above, including -CH 2 0CH 3 ,

-CH

2

OCH

2

CH

3 , -(CH 2

)

2 0CH 2

CH

3 , -(CH 2

)

2 0(CH 2

)

2

CH

3 , and the like. [0035] An "alkylamino" group is a mono-alkylamino or di-alkylamino group, such as -NH(C 1

.

6 alkyl), -N(C 1 .- alkyl)(C 1 -6alkyl), -NH(C 3 -Iocycloalkyl), -N(C 3 .iocycloalkyl)( C 3 . 30 tocycloalkyl) or -N(CI6alkyl)(C3-ocycloallkyl) wherein each C 1 .aikyl and C 3 .Icycloalkyl is -10independently as defined herein, including, but not limited to NH, -NHCH 2 CH,

NH(C%)

2

,H

3 , -NH CHC 3

HH

3 , -NH( -NH(CH 2

)C

3

-N(CN

3 2, -N(dl CH) -N((CHj) 2

CH

3 )i, and N(CH 3

)(CH

2

CH

3 ). [0036] An "mnocarboyl" group is a -C(O)NR group, wherein each R is 5 independently hydrogen or a Calkyl group defined above, wherein each C 1 .ealkyl group can be optionally ubstituted. [037] An minoalkyl" group is aC(O)Ni4R2 group, whe ei eachi is iidependentl. hydrogea or a C 4 akyl group defied above whrein eah Calky grop can be optionally substituted 10 [0038] An "acylanino" group is a CI.6alkyl group substituted with one or more NR 2 groups, wherein R is hydrogen or a CI-6alkyl group defined above, wherein each C 1 .6alkyl group can be optionally further substituted. [0039] An "alkanesulfonylamino" group is a -NR-SO-C j.6alky group, wherein R is hydrogen or a CI.6allkyl group defined above, wherein each Ci.6alkyl group can be 15 optionally substituted. [00401 A "C3.iocy cloalkyl" group is a cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, 20 cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2 methylcyclooctyl, and the like, or multiple or bridged ring structures such as adamantanyl and the like. A -(C 3 .iocycloalkyl) group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanone and the like. [00411 A "carboxyl" or "carboxy" is a -COOH group. 25 [0042] A "halogen" is- fluorine, chlorine, bromine or iodine. [0043] An "aryl" group is an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. 30 [00441 A "C3.oheteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In -1certain embodiments, the heterocyclic ring system is monocyclic or bicyclic. 1on-limiting examples include the following: 1)( N N % a N NN' N N - - N [0045] wherein Q is CH 2 , C=CH 2 , 0, S or NH. A -(C 3 .oheteroaryl) group can be 5 substituted or unsubstituted. [00461 A "C 3 -loheterocycle" is an aromatic or non-aromatic cycloalkyl having from 3 to 10 ring atoms in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of 0, S and N. Representative examples of a heterocycle include, but are not limited to, azetidine, benzofuranyl, benzothiophene, indolyl, 10 benzopyrazolyl, coumarinyl, isoquinolinyl, morpholinyl, pyrrolyl, pyrrolidinyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridoiyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, (1,4)-dioxane, (1,3)-dioxolane, 4,5-dihydro-lH-imidazolyl, tetrahydropyran, tetrahydrofuran and tetrazolyl. Additional non-limiting examples include the following: X=X R4H 15 0R H 000 0 00 0 "i 0 -12- N N NH HN - [00471 including stereoisomers and enantiomers thereof, [00481 wherein each occurrence of X is independently CH 2 , 0, S or N and R! is H, substituted or unsubstituted Ci 4 alkyl, substituted or unsubstituted aryl, substituted or 5 unsubstituted C 3

.

1 ocycloalkyl, substituted or unsubstituted C 3 .ioheterocycle or substituted or unsubstituted C3-.oheteroaryl. A -(C 3 .iohateroary1) group can be substituted or unsubstituted. A -(C3.zoheterocycle) group can be substituted or untsubstituted. [0049] A "heterocyclocarbonyl" group is a -C(O)-C 3 .oheterocycle group, wherein

C

3 .1oheterocycle is as described herein, wherein the Cs.1oheterocycle group can be optionally 10 substituted. [0050] A "hydroxyalkyl" group is an alkyl group as desribed above substituted with one or more hydroxy groups. [0051] In one embodiment, when the groups described herein are said to be "substituted," they may be substituted with any substituent or substituents that do not 15 adversely affect the activity of the Aminopurine Compound. Examples of substituents are those found in the exemplary compounds and embodiments disclosed herein; as well as halogen (chloro, iodo, bromo, or fluoro); C14 alkyl; C 2 .6 alkenyl; C 2

.

6 alkynyl; hydroxyl; C 1 . 6 alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (=0); 20 haloalkyl (e.g., trifluoromethyl); B(OH) 2 , carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, 25 pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); O-lower alkyl; O-aryl, aryl; aryl-lower alkyl; CO 2

CH

3 ; CONH 2 ;

OCH

2

CONH

2 ; NH 2 ; SO 2

NH

2 ; OCHF 2 ; CF 3 ; OCF 3 . - 13 - [0OS2] "JNK" means a protein or an isoforni thereof expressed by a JNK 1, JNK 2, or JNK 3 gene (Gupta, S., Bartett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard, B. and Davis, RJ. The EMBO J. 15:2760-2770 (1996)). 10053] As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt 5 prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base additionsalts ofthe Aminopurine Compounds include, but are not limited to metallic salts made from aluminuncalcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzyiethylenediamine, chloroprocaine, choline, 10 diethanolamine, ethylenediamine, meglumnine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, 15 mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well known in the art, see for example, Remington's Pharmaceutical Sciences, 18 eds., Mack 20 Publishing, Easton PA (1990) or Remington: The Science and Practice ofPharmacy, 19th eds., Mack Publishing, Easton PA (1995). [0054] As used herein, the term "polymorph(s)" and related terms herein refer to solid forms of the Aminopurine Compounds having different physical properties as a result of the order of the molecules. in the crystal lattice. The differences in physical properties 25 exhibited by solid forms affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one solid form than when 30 comprised of another solid form) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable solid form) or both (e.g., tablets of one solid form are more susceptible to breakdown at high humidity). -14- As a result of solubility/dissolutioti differences, in the extreme case, some solid form transitions may result in lack 6f potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing, for example, one solid form might be more likely to form solvates or might be difficult to filter and wash free of 5 impurities (I.e., particle shape and size distribution might be different between one solid form relative to the other). [0055) As used herein and unless otherwise indicted, the term "clatirate" means an Aminopurine Compound, or a salt thereof, in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within or 10 a crystal lattice wherein an Aminopurine Compound is a guest molecule. [0056] As used herein and unless otherwise indicated, the term "hydrate" means an Aminopurine Compound, or a salt thereof; that further includes a stoichiornetric or non stoichiometric amount of water bound by non-covalent interiolecular forces. 10057] As used herein and unless otherwise indicated, the term "solvate" means an 15 Aminopurine Compound, or a salt thereof, that further includes a stoichiometric or non stoichiometric amount of a solvent bound by non-covalent intermolecular forces. [00581 As used herein and unless otherwise indicated, the term "prodrug" means an Aminopurine Compound derivative that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivoi)to provide an active compound, particularly an 20 Aminopurine Compound. Examples of prodrugs include, but are not limited to, derivatives and metabolites of an Aminopurine Compound that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In certain embodiments, prodrugs of compounds with carboxyl functional 25 groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application ofProdrugs (H. Bundgaard ed., 1985, 30 Harwood Academic Publishers Gmfh). [00591 As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of an Aminopurine Compound that is - 15 substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center vill be substantially free of the opposite enantiome f theaorhpound. A stere-iricaily purdompound having t6 chiral centers will be substantially fiee.of other diastereoners of the compound. A typical steomerically 5 pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by:weight of one steoisqoier of the compound and less thain about 10/o by weight of the other stereoisomers of the compound, greater han about95% by Weight of one stereoisomer of the compound and less than about 5% by weight of the other 10 stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The Aminopurine Comnpounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof. 15 [0060] Various Aminopurine' Compounds contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. The use of stereomerically pure forms of such Aminopurine Compounds, as well as the use of mixtures of those forms are encompassed by the enbodiments disclosed herein. For example, mixtures comprising equal or unequal 20 amounts of the enantiomers of a particular Aminopurine Compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantlomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); 25 Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). 10061] It should also be noted the Aminopurine Compounds include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain 30 embodiments, the Aminopurine Compounds are isolated as either the E or Z isomer. In other embodiments, the Aminopurine Compounds are a mixture of the E and Z isomers. -16- [0062] The term "effective amount" in connection with an Aminopurine Comipound can mean an amount capable of treating or preveliting a disease disclosed herein, such as cancer, a cardiovascular disease, a renal disease, an autoimmune coilition, an inflammatory condition, macular degeneration, ischemfia-reperfusion injury, pain and related syndromes, 5 disease-related waiting, an asbestos-related condition, pulmonary hypertension, central nervous system (CNS) injury/damage or a condition treatable or preventable by inhibition of a kinase pathway; in one embodiiiant, the JNK pathway. [0063] As used herein, the ter "macular degeneration" eno passes all forms of macular degenerative diseases regardless of a patient's age, although some rmacular 10 degenerative diseases are more common in certain age groups. These include, but are not limited to, Best's disease or vitelliform (most common in patients under about seven years of age); Stargardt's disease, juvenile macular dystrophy or fundus flavimaculatus (most common in patients between about five and about 20 years of age); Behr's disease, Sorsby's disease, Doyne's disease or honeycomb dystrophy (most common in patients between about 15 30 and about 50 years of age); and age-related macular degeneration (most common in patients of about 60 years of age or older). In one embodiment, the cause of the macular degenerative disease is genetic. In another embodiment, the cause of the macular degenerative disease is physical trauma. In another embodiment, the cause of the macular degeiierative disease is diabetes. In another embodiment, the cause of the macular 20 degenerative disease is malnutrition. In another embodiment, the cause of the macular degenerative disease is infection. [0064] As used herein, the phrase "ischemia-reperfusion injury" includes injury that occurs during or as a result of surgery, including, but not limited to, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, orthopedic surgery, 25 organ/vessel surgery, plaque/tumor removal surgery or organ/tissue transplant surgery (donor or recipient). The phrase "ischemia-reperfusion injury" also includes injury that occurs to an organ or tissue ex vivo prior to transplant. [0065] As used herein, the phrase "pain and related syndromes" includes nociceptive pain, such as that resulting from physical trauma (e.g., a cut or contusion of the skin; or a 30 chemical or thermal burn), osteoarthritis, rheumatoid arthritis or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced - 17 iatrogenically by drugs such as vinristine, velcade or thalido ide; or mixed pain (i.e., pain with both nocideptive and neuropathic components). Further types of pain that can be treated or prevented by administering an effective amount of aa Aminopurine Compound to patient in need thereof include, but are not limited to, visceral pain; headache pain (e.g. 5 migraine headache pain); CRPS; CRPS type I; CRPS type I; RSD; reflex neurovascular dystrophy; reflex dystrophy; sympathetically maintained pain syndrome; causalgia Sudeck atrophy of bone; algoneuodystrohy; shoulder hand syndrome; dst trdnaticO dystrophy; autonoinic dysf action; cancer-related pain; phanton linb a hronic fatgu sydrome post-operative pain; spinal cord injury pain; central post-stroke pain; radiculopathy; 10 sensitivity to temperature, light touch or color change to the skin (allodynia); pain from hyperthermic or hypothermic conditions; and other painful conditions (e.g., diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia). [0066] The term "disease-related wasting" means wasting (e.g, a loss of physical bulk through the breakdown of bodily tissue) associated with a disease such as HIV, AIDS, 15 cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, a chronic inflammatory disease (e.g., scleroderma or mixed connective tissue disease) or a chronic infectious disease (e.g., osteoarthritis or bacterial endocarditis). [0067] Tle term "asbestos-related disease" includes diseases and disorders such as 20 malignant mesothelioma, asbestosis, malignant pleural effusion, benign pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis, and bronchogenic carcinoma, as well as symptoms of asbestos-related diseases and disorders such as dyspnea, obliteration of the diaphragm, radiolucent sheet-like encasement of the pleura, pleural effusion, pleural thickening, decreased size of the chest, chest discomfort, 25 chest pain, easy fatigability, fever, sweats and weight loss. [00681 The term "pulmonary hypertension" includes diseases characterized by sustained elevations of pulmonary artery pressure as well as symptoms associated with pulmonary hypertension such as dyspnea, fatigue, weakness, chest pain, recurrent syncope, seizures, light-headedness, neurologic deficits, leg edema and palpitations. 30 [00691 The term "central nervous system (CNS) injury/damage" includes, but is not limited to, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, head injury, concussion, post-concussion syndrome, cerebral -18contusion and laceration subdural heinatoma, epideial hermata post-tralumatic epilepsy, chronic yegtativ tate, complete , incomplete SI acue SC, subacute SCI, chronic Sm central cd syndname, Bron-Sequard syndrome, anterio cord syndrome, conus medullaris syndrome, oada e uina syndrome, neurogenic shock, spinal shock 5 altered level of onsciousnesa, headaches nausea, enesis,-iemory loss, dizziness, dpopia, blurred visidu, emotional ability sleep disturbances, irritability, inability to concentrate nervoiusness, behavioral irpainmen, cognitive deficit, and seizte. 10070] The term "ptient" includes an ani al including but ot limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quil, cat, dog, mouse, rat, 10 rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. 42 AMINOPURINE COMPOUNDS [0071] Provided herein are Aminopurine Compounds having the following formula (I): HN 15 (1) [0072] and pharmaceutically acceptable salts, polymorphs, clathrates, solvates, hydrates, stereoisomers, enantiomers and prodrugs thereof, [0073] wherein: [00741 R' is substituted or unsubstituted Cj.alkyl, substituted or unsubstituted aryl, 20 substituted or unsubstituted C3.jocyclealkyl, substituted or unsubstituted C3-ioheterocycle or substituted or unsubstituted C3.1oheteroaryl; [0075] R 2 is H4, substituted or unsubstituted C 1 .calkyl, substituted or unsubstituted aryl, substituted or unsubstituted C3.Iocycloalkyl, substituted or unsubstituted C 3 . ioheterocycle or substituted or unsubstituted C3.1oheteroaryl; and 25 [0076] R3 is aryl substituted with one or more halogens or C3.1oheteroaryl substituted with one or more halogens, wherein the aryl or C3-ioheteroaryl group is optionally further -19substituted with one or more Cialkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylanino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl group [0077] In one embodiment, the Aminopurine Compounds of formula (I) are those 5 wherein R' is phenyl. 10078] In another embodiment, the Aminopurine Compounds of formula (1) are those wherein R' is substituted phenyl, in one embodiment alkoxy substituted phenyl, in one embodimentp-alkoxy substituted phenyl, and in one embodimentp-methoxy substituted ph6nyl. 10 [0079] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R' is m-alkoxy substituted phenyl, in one embodiment m-methoxy substituted phenyl. [0080] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R' is trifluoromethyl substituted phenyl, in one embodiment p-trifluoromethyl 15 substituted phenyl. [00811 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein RI is Ci6alkyl, in one embodiment isopropyl. [0082] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R' is p-halo substituted phenyl, in one embodimentp-fluoro substituted 20 phenyl. [0083] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 1 is p-CI.6alkyl substituted phenyl, in one embodiment p-methyl substituted phenyl. [0084] In another embodiment, the Aminopurine Compounds of formula (1) are 25 those wherein R 1 is o-halo substituted phenyl, in one embodiment o-fluoro substituted phenyl. [0085] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 1 is mp-dihalo substituted phenyl, in one embodiment mp-dichloro substituted phenyl. 30 [0086] In another embodiment, the Aminopurine Compounds of formula (I).are those wherein R 1 is m-cyano substituted phenyl. -20 - [0087] In another embodiment, the Amiiopurine Compounds of formuna (I) are those wherein R is p-Cf. oheterocycle substituted phenyl, in one embodimnentp miorpholino substituted phenyl. [00881 In another embodiment, the Aminopurine Compounds of formula (1) are 5 those wherein R' isp-sulfonyl substituted phenyl. [00891 In another embodiment, the Aininopurine Compounds of formula (I) are those wherein R' is C..oheteroayl, in one embodiment pyridine or pyridinone. [0090] In another embodiment, i Aminopuriie Compounds of formula (I) are those wherein R 1 is C 3 .icheterocycle, in one embodiment piperidine, piperidin-2-one, 10 pyrrolidinone or tetrahydropyran. [00911 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R. is N-substituted piperidine, in one embodiment N-sulfonyl substituted piperidine. [00921 In another embodiment, the Aminopurine Compounds of formula (I) are 15 those wherein R1 is C3.iocycloalkyl, in one embodiment cyclohexyl, cyclopentyl or cyclopropyl. [00931 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R1 is substituted C 3

.

1 ocycloalkyl, in one embodiment C 3 .iocycloalkyl substituted with one or more C1.6aikyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, 20 alkylamino, carboxy, heterocyclocarbonyl, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. [00941 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R' is substituted C 3 .Iocycloalkyl, in one embodiment C 3 .iocycloalkyl substituted with one or more alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, 25 aminoalkyl, amido, amidoalkyl, carboxy, heterocyclocarbonyl, sulfonamide or sulfonaminoalkyl groups. Cyclohexyl and cyclopentyl are particular C 3

.

1 cycloalkyl groups. [00951 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R1 is cyclohexyl substituted with one or more alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, amido, amidoalkyl, carboxy, heterocyclocarbonyl, 30 sulfonamide or sulfonaminoalkyl groups. -21- [0096] In another embodiment, the Aminopurine Coipounds of fornla () are those wherein R' is Ci-alkyl, in one embodiment methyl, ethyl, pfopyl (e.g. ne-ropyl or isopropyl) or butyl (e.g., isobutyl) [0097] In another embodiment the Aminopurine Compounds of forniula (1) are 5 those wherein R' is substituted-Ct.

6 alkyl, in one embodiment phenyl, hydroxy, C 3 . tocycloalkyl, or oxirane substituted Cj.6alkyl. [00981 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R' is benzyl. [00991 In another embodiment, the Aminhopurine Compounds of formula (I) are 10 those wherein R' is substituted Ci.alkyl, in one embodiment C 3 .ioheterocycle (e.g., piperidine or pyrrolidine substituted C 1 .alkyl. [001001 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is substituted or unsubstituted Ci 4 alkyl, substituted or unsubstituted aryl, substituted or unsubstittited C3.1oheterocycle or substituted or unsubstituted C 3 ..ioheteroaryl. 15 [00101] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is substituted or unsubstituted C3.1ocycloalkyl, in one embodiment cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. Cyclohexyl and cyclopentyl are specific C3.jocycloalkyl groups. In one embodiment, C3.iocycloalkyl substitutuents include

C

14 alky, hydroxy, hydlroxyaikyl, alkoxy, alkoxyaikyl, amino, aminoalkyl, amido, 20 amidoalkyl, carboxy, heterocyclocarbonyl, sulfonamide and sulfonaminoalkyl groups. [00102] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is cyclohexyl or cyclopentyl substituted with one or more Ci-6alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, amid, amidoalkyl, carboxy, heterocyclocarbonyl, sulfonamide or sulfonaminoalkyl groups. 25 [00103] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is cyclohexyl or cyclopentyl substituted with one or more Ci.

6 alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, heterocyclocarbonyl, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 30 [00104] In another embodiment, the Aminopurine Compounds of formula (1) are those wherein R 2 is CI.6alkyl, in one embodiment butyl (e.g., n-butyl, isobutyl or t-butyl), propyl (e.g., isopropyl), ethyl or methyl. -22.

[00105] In another embodiment, the Aminopurine CompnOads of formula (1) are those wherein R 2 is substituted CI.alcl, in one embodiment cyano, O 3 -tocycloalkyl or hydroxy substituted Cja4akyl. [00106] In another emNbodiient, the Aminopurine Compounds of formula (1) are 5 those wherein R 2 is substituted C1. alkylin one embodiment Cji-oheterocycle (e.g. piperidine or pyrrolidine) hydroxy or amido substituted C 1 .6alkyl. [00107] In another -mbodimnt, te Aminopurine Compounds of formula (I)are those wherein R 2 is aryl, in one embodiment phenyl. [00108i In another embodiment, the Ahiihopurine Compounds of fonula (I are 10 those wherein R is C3..1oheterocycle, in one embodiment piperidinepiperidin-2-one, tetrahydropyran, tetrahydrofuran or azetidine. [00109] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R2 is C3.woheterocycle, in one embodiment a sulfur containing C 3 . Ioheterocycle, including but not limited to 4-(l ,1 -dioxo)thiopyrianyl and 3-(1,1 15 dioxo)thiofuranyl. In a particularly embodiment, R2 is a sulfur, sulfonyl or sulfonamido containing C 3 .oheterocycle. [00110] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is substituted C3.ioheterocycle, in one embodiment acetyl substituted piperidine. 20 [00111] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R2 is substituted or unsubstituted 3-oxetanyl, 3-tetrahydrofuranyl, 4 tetrahydropyranyl, 4-piperidinyl, 4-(1-acy)-piperidinyl, 4-(l-alkanesulfonyl)piperidinyl, 3 pyrrolidinyl, 3-(1-acyl)pyrrolidinyl or 3-(l-alkanesulfonyl)pyrrolidinyl. [00112] In another embodiment, the Aminopurine Compounds of formula (I) are 25 those wherein R is o-halo substituted phenyl, in one embodiment o-fluoro or chloro substituted phenyl. [00113] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 3 is m-halo substituted phenyl, in one embodiment mn-fluoro or chloro substituted phenyl. 30 [00114.] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein RW is p-halo substituted phenyl, in one embodiment p-fluoro or chloro substituted phenyl. -23- [00115] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 3 is mp-dihalo substituted phenyl, in one embodiment mnp-difluoro or dichloro substituted phenyl. [00116] In another embodiment, the Aminopurine Compounds of formula (1) are 5 those wherein R is o,m-dilialo substituted phenyl, in one embodiment o,in-difluoro substituted phenyl. [00117] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R3 is op-dihalo substituted phenyl, in one embodiment op-difluoro substituted phenyl, o-fluoro-p-bromo substituted phenyl or o-fluoro-p-chloro substituted 10 phenyl. [00118] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 3 is o,o-dihalo substituted phenyl, in one embodiment o,o-difluoro substituted phenyl or o-chloro-o-fluoro substituted phenyl. [00119] In another embodiment, the Aminopurine Compounds of formula (I) are 15 those wherein R is 2,4,6-trihalo substituted phenyl, in one embodiment trifluoro substituted phenyl. [00120] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 3 is o-halo substituted, in one embodiment o-fluoro or chloro substituted, and m-trifluoromethyl substituted phenyl. 20 [00121] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 3 is halo substituted C 3 .ioheteroaryl, in one embodiment halo substituted pyridine. [00122] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is not aminoethyl. 25 [00123] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is not a five-membered heterocyclic ring. [00124] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is not a five-membered N-containing heterocyclic ring. [00125] In another embodiment, the Aminopurine Compounds of formula (I) are 30 those wherein R 2 is not a five-membered O-containing heterocyclic ring. [00126] In another embodiment, the Aminopurine Compounds of formula (I) are those wherein R 2 is not 2-tetrahydrofuranyl. -24- [00127] In another embodiment, the Aminopurine onpounds of formula (I) arc those wherein R is not 2-pyrrolidinyl. [00128] In a further embodinient, provided herein are Aiiiopurine Compounds of formula (I), and pharmacenticeily acceptable salts, polyrnorphs, clatrates, solvates, 5 hydrates, stereoisomers and prodnigs thereof, wherein: [00129] R' is substituted or unsubstituted C 1

.

6 alkyl, substituted or unsubstituted aryl, substituted or uisubstituted C3oCycloalkyl Substituted or unsubstituted d3 oheterocycle or substituted or unsubstituted C3.oheteroaryl; 100130] R2 Is: OH NR4Rs OH H HNH XNXX NH O NR4 OH 10 or K-2 10 [001311 R 3 is aryl or C 3 . oheteroaryl, each being substituted with one or more halogens; (00132] X is at each occurrence independently CH 2 , 0, S or N; [00133] RI and R are at each occurrence independently H, substituted or 15 unsubstituted CI-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3 . iocycloalkyl, substituted or unsubstituted C3.ioheterocycle or substituted or unsubstituted C 3 . -25- ,oheteroaryl; or R 4 and taken together with the N atom to which they are attached form a substituted or unsubstituted 5.7 membered heterocycle; and 00134 n is at each occurrence independently an integer ranging fom 0 to [00,135] In a another embodiment, the Aminopurine Compounds of formula (1) are 5 those wherein R 3 is: [00136) wherein: [00137] X is at each occurrence independently F, Cl, Br or I; [001381 R 6 is Ci6alky, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, 10 alkylamino, carboxy, anintocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl; 100139] m is an integer ranging from 1 to 5; and [00140] p is an integer ranging from 0 to 4. [001411 In a further embodiment, p is an integer ranging from 1 to 4. 15 [00142] In a further embodiment, provided herein are Aminopurine Compounds having the following formula (II): R2 NrN N H -(X)m (II) [00143] and pharmaceutically acceptable salts, polymorphs, clathrates, solvates, 20 hydrates, stereoisomers, enantiomers and prodrugs thereof, [00144] wherein: [00145] X is at each occurrence independently F, Cl, Br or I; [001461 R 2 is: -26- H2N' NH H N - R R 0 H 0 Hor 'rVv (00147] R 4 and R are at each occurrence independently H, substituted or unsubstituted CI.

6 alkl, substituted or unsubstituted aryl, substituted or unsubstituted C 3 locycloalkyl, substituted or unsubstituted C3.lcheterocycle or substituted or unsubstituted C 3 5 ioheteroaryl; or R 4 and 19 taken together with the N atom to which they are attached form a substituted or unsubstituted 5-7 membered heterocycle; [001481 R 6 is CI-alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl; 10 [001491 m is an integer ranging from I to 5; [00150] n is at each occurrence independently an integer ranging from 0 to 3; and [00151] p is an integer rangin from 0-4. [00152] In one embodiment, the Aminopurine Compounds of formula (II) are those wherein X is fluoro. 15 [001531 In another embodiment, the Aminopurine Compounds of formula (I) are those wherein X is fluoro and m is 3. [00154] In another embodiment, p is 0. [00155] In another emobidment, p is an integer ranging from 1 to 4. [00156] In a further embodiment, provided herein are Aminopurine Compounds 20 having the following formula (III): - 27 - NH - (X)m [00157] and pharmaceutically acceptable salts, polymorphs, clathrates, solvates, hydrates, stereoisomers, enantiomers and prodrugs thereof, 5 [00158] wherein: [00159] X is at each occurrence independently F, Cl, Br or I; (001601 m is an integer ranging from 1 to 5; [00161] p is an integer ranging from 0-4; [00162] R1 is: H4 3 HO O H 2 N 10 0H2 HO 0 ; and [00163] R 6 is C1.6alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl. [00164] In one embodiment, the Aminopurine Compounds of formula (III) are those 15 wherein X is fluoro. [00165] In another embodiment, the Aminopurine Compounds of formula (III) are those wherein X is fluoro and m is 3. [00166] In another embodiment, p is 0. -28- [00167] In another embodiment, p is an integer ranging from 1 to 4. [00168] In one embodiment, provided herein are Aminopurine Compounds having the following formula (IV): H HN N HO)7a1>-NH 5 (IV) [00169] and pharmaceutically acceptable salts, polymorphs, clathrates, solvates, hydrates, stereoisomers, enantiomers and prodrugs thereof, [00170] wherein: [00171] R 3 is: F F F Cl

CF

F F F 10 FF o F [00172] The following HPLC methods were used to characterized the compounds of Table 1, below. [00173] Method A= 5-+70% acetonitrile/water (0.1% TFA) over 20 minutes. [00174] Method B=20-+100% acetonitrile/water (0.1% TFA) over 20 minutes. 15 [00175] Method C=5-+50% acetonitrile/water (0.1% TFA) over 20 minutes. [00176] Method D=O-+75% acetonitrile/water (0.1% TFA) over 20 minutes. [00177] Method E: 0-75% Acetonitrile/Water (0.1% Formic Acid) over 5 minutes then hold at 75% Acetonitrile/Water (0.1% Formic Acid) for 2 minutes. - 29 - [00178] Miod F:0%A A nitileW e (0.1%7o Formic Acid) fo first t minutes, 10-100% Acetonitrile/Water (0.1% Forimic Acid) from 2 minutes to 25 minutes. [001791 Representative Aminopure Compounds are st forth iTable 1, blo,. Table 1 5 Compound. M+1 (mm/method) li'ehd 9 F6 /419.1 4 19.6 Ny10.32/B) (9.40/ B) 1 2 396.2 353.41 (2.51/ E) (3.49/ E) 3 4 403.7 419.1 NH N N (15.8 D) Nt H (10.57/B) 5 6 -30- Compound M+1 Compound M+1 HPLC HPLC (min/metbod) (min/method) 419.4 427.2 (9.517 B) (9.3 /B) 7 8 433.5 393.3 (9.817/ B) H (8.950 /B) 910 NH I 365.4 379.5 * NH>(8.083 B) N (8517 B) 12 PH 351.1 449.5 (8.98 /B) (7.967 /B) 2H N O 13 % 0 ,J 14 - 31 - Compound M+1 Compound M+1 HPLC HPLC (min/metod) (mm/mthod) 434.4 327.3 (6.283/ B) NH (8,433 /B) NHZH 15 16 341.2 355..3 (8.883 / B) N (9.267 B) 17 18 395.4.383 NH (10.183/B) 389.3 H FN(9.533 / B) 19 20 437.2 435.2 NH (9.37 / B) N (10.89 /B) F 22 21 -32- Compound M+1 Compound M+1 HPLC HRPLC (min/method) (nin/ethod) ?p cI 435.2 435.2 (10.89 B) (10.89 B) 23 24 390.42 393.1 (8.717 /B) (8.917 /B) F 25 26 407.5 .407.5 (9.317/ B) (9.467 /B) F 27 28 409.4 437.2 H (10.583 /A) (13.94/ A) NN rzNH X F \ 29 30 -33- Compound M+1 Compound M+1 HPLC HPLC (min/nmethod) (min/rethod) cI 469.2 411.35 )> (15.06 /A) (3.27 E) NH H N H H 32 31 404.45 407.5 N(13.388 / A) NI(10.315 /B) 33 34 H H 395.2 423.4 ,N (12.1 / A) (11.68 IA) H H.N 35 36 - 34 - Compound M+1 Compound M+1 RPLC HIPLC (mnin/method) (min/metbad) OH OH 385.4 425.4 (11. 164 /A) (8.25 /B) HF N N N 37 38 497.2 6 4. IH~ N)-~F (18.04/B1) N -(13.557 /B) 39 HO 40 409.2 H 423.4 N N (9.216 / B) N(8.633 / B) 41 42 OH 398.49 423.4 [ N N N (9.067 /B) NN (8.633 B) 43 44 -35- Compound M+1 Compou d M+1 HPLC HPLC (min/mthod) (mi/metod) 398.49 437 N (9.067 / B) (8.82 / B) F N 45 46 HNH 4517.3 448.3 N l (11.82 /B) N(8.867 /A) 47 48 424.5 407.4 (9.083 /B) (10.37 / B) NN 50 49 c? H H 409.3 385 N (9.269 / B) N 2 NH N, (9.643 / B) 51 52 -36- Compound, M+I compound M+1 FIPLC HPLC (minm/ethod) (min/ethod) HO 449.4 OH47. (10.717 / A) (11.63 /A) NN6 NF R- /\- -H F 0 54 53 OH 401.1 417.4 HO NH F (8.757/B) F (9.65 / B) 55 56 383.4 397.2 OH" NHN (11.5 / C) N (12.286 / C) 57 58 H P9H H 385.1 - 437.1 NH N (10.496 /B) F (7.58 /B) NN F N 59 6 60 -37- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) PH 45322 OH 487 (8.28 /B) (8.87 /B) C Q N F3C N 61 62 435.4 PH 453.2 F (8.133 B) (8.22 /B) H N H C /-NF 64 63 PH OH 487.1 -' 433.2 (8.92 /B) (7.93 /B) />NH F N /-NH F 65 66 -38- ComiiPound M+1 Copn ound PlklC. HPL4C S(inthod) (mn method)

NJH

2 448.3 410.6 (8.85 /A) r (9.517 / A) 0H2 67 68 bjH 490.5 452.3 (7.617/B) F (11.072 B) '-H1' NH/ §NH -6 70 69 397.4 476.4 (5.15 /E) (8.983/ A) 72 -39- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 438.6 9H 419.4 K NH (9.25 IA) Q p (7.53 /B) ! crn 73 74 HN- 526.5 488.4 (9.056 / B) (10.741 /B) NH F Oa N N4 F 76 75 OH 477 3 OH 463.5 (9.141 /B) (8.992 /B) O~ NBFs /> ~-N H F c 77 78 77 -40- Compound M+1 Conpound M+1 HPLC HPLC (niin/method) (mimthod) 453.3 491.5 (8.767 /B) F (8.767 /B) NH/ 79 80 F 414NH 2 448.4 N (9.1/ A) N (8.8 A) NH4% :N X._ H2o 82 81 H HN 476.7 398.4 00 (7.55/B) \/ (8.72/A) N N ~-Q ~J/-N H F 83 -41 - Compo ud M+1 Compound +1 RPLC HPLC _n_ (method) (nm/ethod) 384.2 463 (11.75 /A) (9.941 B) 85 86 329.15 355.25 H (3.41 /E) H (3.72 /E) 87 88 335.15 315.4 N (3.25 /E) - (3.24 / E) NH NNNHN ".N NH PH H 89 90 -42 - Compound M1 Compound M+1 HPLC HPLC (mmmetod)(mi/method) 329.4 343.25 F NH K J~7 i~(3.25 / E) (3.62/) N NNH 91 92 414.4 3614 N (9.27 /B) N (3.37 E) 93 d N 94 HN 504.5 427.1 (10.98 /A) (9.183 /B) SN NH O'cr X-N96 95 -43- Compound M+1 Campot.nd M+1 HPLC HIPLC (mi/method) (ininlmethod) N D 540.6 369.45 (13.3 IC) (3.9 /E) (9.02/A) (11.02 / F) 403.4 411.4 FIIN% H (12.16 / F) (12.84/ F) N N 101 102 -44- Conpound M+1 Compound M+ HPLC HPLC (min/method) (min/metthod) 391.4 405.4 (1 (12.39/ F) NH- (13.54 F) H 4 E 418.4 432.5 IIIuLNH (6.12 / F) H(.8/F H HH 107 108 -145 ..

Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) I N 331.4 34MNX F NH-< H 73F) Q(8.63 /F) 109 H 110 426.2 HN 518.6 (8.550 / A) (8.48 /B)

H

2 N OH F 112 HN 532.6 HN( N 533.5 (8.82 / B) (6.53 /B) o r N N )N 113 114 - 46 - Compound M+t Comtpounid M+1 HPLC IIPLC ____________________(mWMethod) (wnin/method) 0 504.6 397.4 (8.00 /B) (8.12 /B) N NH 116 115

H

2 / 432.1 437.4 H (7.60 / B) (11.040 /B) 117 118 381.05 357.4 (4.55 1E) (8.84 /F) QN NH 120 119 -47 - Compound M+1 Compound M+1 HIPLC HPLC (mInmaethod) (min/m method) 371.4 371.15 N: N(9.09 /F) N:CvN (3.17/t E) & NH OH 121 122 405.4 448.1 (10.3 /F) N (3.72 /B) N N NH 6N6 123 124 -48- Compo0un d M1CompotundM+ jPLc HPLC (mp/ od) minhod) 462.55 474.5 N (1 .69 /F) (11.97 / ) 125 126 482.5 476.6 F H (13.31 /F) NH2 (11.019 / B) N Y)lXN'r-NH F 128 127 -49 - Compound M+1 Compound M+1 H1PLC HPLC (min/method) (min/method) 481.3 343,4 (8.67/ A) N (6.25 /B) y N H FH

H

2 N N 130 129 0 448.6 HN 508.3 (10.733 / A) (8.517 /B) 131 132 HN 489.56 342.4 N (8.05 / A) Y, NFH 2 ., c r /-NH ,,O N134 133 -50- Compound M+1 Compound M+1 HPLC inL (mi/method) (win/metod) 396

HN-

4 426.1 H(6.33 IB) (9.707/ B) F

-

NH F 135 136 488.5 415.3 cN(9.045 / B) N (8.22 / B) 00H 137 138 367.4 399.5 (3.76 /E) N N (3.23/ E) NHNHH<H 139 OH 140 Compound M+1 Coinpound M+1 I~PLC HPLC (min/ethod) (min m ethod) 419.45 363.35 I (3.31 /E) H(4.39 / E) H 142 141 355.4 385.4 (3,67 / E) N N (3.05 /E) F NHNN N: NH N H 143 H 144 413.5 385.1 (8.62 B) NH 145 H 146 -52- Compound M+1 Compound M+1 HPLC IIPLC (min/method) (mii/method) 384.2 452.5

H

2 N (9.58 / A) (7.717/ B) 147 381.5 369.5 N(3.97 / E)N (3.84 /E) 55 6 6 149 150 385.4 403.3 H NN (7.15 /B) Hdr~ N " (7.28 / B) 151 152 402.1 382.4 H2N,,,. (6.18 / B) (2.23/ B) N HN N 153 154 - 53 - Compound M+1 Compound M+1 HPL.C IIPLC (min/method) (min/method) HJN 496.1 506.5 (7.87/B) 0--- (8.40 /) F~N F F H>NH F F 156 155 0 OH 495.4 0 482.5 (11.467 /B) (9.48 / A) 157 F 158 0 HN 500.4 384.5 (10.52 /B) \N. (8.65 IA) HO'0 $ % H2N 160 F 159 - 54 - Compound M+ Compound M+1 HPLC HPLC (mi/method) (min/method) 0 444.3 476.5

NH

2 N(10.837113) (7,417/B) /> NN NHF ~r I NO N 162 F 161 F 401.1 419.2 (9.97 A) H (10.13 /A) H 163 164 423.3 441.3 F (8.37 / A)

-

(8.82 /B) 165 166 - 55 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (minmethod) 445.4 HN< 499.5 /H H (6.800 / B) (8.83 A ) HO NHNH2N 167 F 168 437.4 HN 468.4 (12.757 / B) (9.50 /A) NH N >-!N FaNH F 169 170 0 HN 486.5 413.2 (9.67 /A) (11.061 /B) N N F Y-H N NH 172 F 171 -56- Compound M+1 Compound M+1 HAPC HPLC (min/method) (mi/method) 427.2 429 S(11.072/B) (10.67 A) HO 173 174 HN 559.2 HN 577.5 (9.85 /A) (10.02 /A) N H 175 176 429.4 447.4 AN H (10.80 /A) HQ.,'OXK% (10.5 F 177 178 OH 425.4 455.1 (8.067 / B) (7.100 /B) H O NH F _ N N 179 180 - 57 - Compound M+1 Compound M+1 HPLC HIPLC (mmh/method) (min/method) 425.3 467.4 H (11.78 /A) (11.45 /A) 181 182 OH441.5 HN- 518.5 (7.563 / B) (6.967 / B) JN? HONFHO%< F 183 184 540.3 474.3 Vr N \ N H (15.381 / B) 185 186 4)45.4 48.4 HO N (10.944.B) N17A) F 187 188 -58- Compound M+1 Compound +1 HPLC RPLC (Cniethod) (min/method) T, 529 473.4 (16.256 (14.624 B) HO NHFF HO OH F6j 0 189 190 F 192 191 428.4 46.4

H

2 N (9.05/ A) (.30 /A) 193 - 59 - Compound M41 Compound M+1 HPLC IIPLC (min/method) (min/method) 426.4 455.4 (5.600/ B) (9.617 /A) HO!tQ N..NN O Ha N HU"O 195 196 0 468.5 486 (6.567 / B) (9.467 A) H ,,NH aH2N )a..O' T9-c HO1 198 197 OH 483.5 O 441.3 (7.58 /B) OH(9.483 /A) N N O (7N/B-NH F H'', >-NH H0r'' N 200 199 -60- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) OH 441.5 469.3 N (9.43 /A) (8.533 /B) H NH 201 0 202 O 487.5 505.5 (10.66 /A) (8.017 /B) H-NH F HN 203 204 44 457 .'NH (8.000/B) HN(8.156 /B) y N F (8,000/B 205 206 -61- Compound M+1 Compound M+1 HPLC HPLC (min/method) (m/metnhod) 0 551.6 390.2 (9.95 /C) (7.10/B) O N 207 208 R408.4 534.4 NH / (8.52 /B) N (7.52 B) N 209 210 OH4 516.3 (7.983/B) NH ~ (7.48 IB) ON H F N />NH N 211 212 - 62 - Compound M+1 Compound M+1 RPLC HIPLC (min/method) (min/method 429 579.5 HO ::: NH F (9.233 / B) (1O.37 / 213 214 0 OH 542.4 H 4775 (10.57/C) N (8.233 / B) HOJIIIIY 'J/-NH F H-j HO NB HF 215 216

NH

2 472.5 OH 542.3 (8.467 / A) (10.57 /C) H O %yc I x N, 217 - 63 - Compound M+1 Compound M+1 IIPLC HPLC (mmi/method) mintqethod) 489.2 341.45 (2.6 /B) (3.44 / E) NH NH~ N NH 220 219 395.15 H391.1 $III~ <N ~(4.87/B)) N~'H (3.87/B ) N~N N/ N N 221 222 392.4 396.5 H (8.12 /F) NHH (2.32 / B) ~Nc§ 223 224 - 64 - Compound M+l Compound M+l HPLC HPLC (min/method) (mm/method) 404.45 / 391.4 H NH (2.71 /E) N4NH (11.67 F) N NH'N 225 226 405.2 404.4 (4.02 / E) (8.42 / F) N. 2292 -230 43. 422.1 Compound M+1 Compound M+1 HOLC HPLC (min/mthod) (mn/methd) 431.5 412.1 (4.27 / E) (3.08/B) N 232 231 446.15 365.4 N (2.68 /B) NN (8.85/F) N NH NH_ N NH 234 233 410.15 375.35 H (2.53 /B) (3.76 /B) NHH N NH 236 235 -66- Compound M+1 Compound M+1 HPLC HIPLC (min/m ethod) (mi/method) 359.15 397.1 F H (3.00 / E) (3.82 /B) NH NH 237 H 238 431.5 373.1 F (12.84 /F) N NHN(3.21 / E) N H 240 239 345.4 418.1 F NH N N (8.05 /F) FH (2.64/ E) NH N NH NH6 OH N 241 242 -- 67.- Compound M+1 Compound M+1 HIPLC HPLC (minimthod) (min/ethod) 411.4 ( 370.1 (10.52 A) N (2.30 E) 1 /-kN H F NH 243 244 359.4 ~i ~417.2 (8.83 /F) (4.14/ E) FN NH N OH 245 246 384.2 405.2 S (2.51 E) H (4.07 E) \NA ZNH 50N 247 248 - 68 - Compound M+1 Conipound M+1 HPLC HPJ.J (min/method) (minmethod) 379.4 .357 N (9.03 /F) N (11.41 /F) 6 NH OH 250 249 (Y 1400.1 /425.15 N(2.33 IB) _<N I.J (4.25/1E) N NH C NH 252 251 369.5 432.2 (3.86 / E) NH(2.54 / B) N N NH 253 254 - 69 - Cont ound M+1 Compound M+1 HPLC HPLC (min/mthod) (mi/method) 414.2 385.4 (2.55 / E) (9.83 IF) 2 HY(~~ ~Q NH 0 256 255 389.45 419.15 N (3.97 / E) H(4.19 / E) F NH-</ Y'NH NN NHI 257 258 423.05 426.9 F NH-K1N (4.09 /E) NH NH (6.84 /F) NN 259 260 - 70 - Compound M+1 Corn pound 1+1 H!PLC HL (win/method) (nlhod) 403.4 384.2 N N (4.18 /E) (2.32 E) F NH N N NH 261 262 438.05 434.1s (2.49 E) F N H -K ' (2 .6 7 / E ) H.N H 6NN 264 263 404.15 378.4 (2.61 /E) (7.18 IF) F NXANH N N NH N 266 265 -71- Compound M+1 Compound M+1 HPLC HPLC (mim/method) (mmmethod) N OH 599.6 393.5 (10.05 C) (3.25 E) F H 267 268 508 j508 NH (9.467 I A) a (9.433 /A) NQN N 'Ji />-NH F 269 270 00 526/NH 2 511.6 cy (.70 A (9.77 IC) HO N,: N F Ha- 271 F 272 -72- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) OH OH 454.5 472.5 (8.883 A) (10.150 /C)

H

2 N%! f'D3* N F H 2 N 273 274 565.8 537.7 (9.783 IA) (8.417 /A) N HO Y, >-NH F19 HO 276 275 0 N N 565.6 679 0N d (10.10/ C) (9.367 IA) HO Y /-NH F FD 278 277 -73- Compound M+1 Compound M+1 HPLC HPLC (mi/method) (min/ifthod) OH 442.5 581.6 jNH (7.650 / A) (10.95 IC) HaH F 280 279 OH 58. H 612.4 OH 583.5H (9.133 /A) (10.0 /A) N , -N H F N F 281 282 612 H 584.3 N (9.417 / A) (9,6 / A) Cf ~~~Q .-NH N O % N H (6A 283 284 697 458 (11.528 /A) H (9.933 /A) N ,. N OHH 2 N F 0 F 285 286F -74- Compound M+1 Compound M+1 HPLC HPLC (minlethod) (min/rMethod) 569 N 623.5 N (10.167/A) (8.97 /A) NN N ONH 28 F 287 288 569.7 OH 570.5 H (8.68 / A) (10.50 / A) J ~Y -NH F H Nl$; N HO' 290 289 N O 583.8 587 (9.92 /A) (10.217/A)

H

2 N YNH F F F 292 291 -75.

Compound M+1 Conpound M+1 HPLC HPLC (mnimethod) (min/ thod) 0 N N 569.8 679 (8.593 /C) (9.600 /A) HON FN1 N 294 293 O ' 601.8 540.3 (10.032 /A) (10.1 IA) YNs N HR Ho ,,-0 N NH \Q 296 F 295 N 626.7 OH 613.5 (10.167 /A) (10.83 /C) />-OH H N NH N N 298 F 297 - 76 - Compound M+1 Conpbiznd M+1 KfPLC HIPLC (min/method) (nin/inethod) OH 611.8 0 568.5 (11.28 /C) (9.32 A) N N H A NN 299 300 F N 646.3 680.7 N N(10.42C) ON(8.75 A) R? f.: Y, iH FQ F 302 301 HO ) 598.7 rN 611.5 (9.184 / A) (10.360 /A) NNN H2N '':: NH F HO ,F 303 F 304 -77- Compound M+1 Compound V+1 HPL HPLC (min/method) (mini/tethod) OH 583.5 661.5 (10.92 /C) (11.65 /C) N 305 306 N 622.7 568.5 (9.484 /A) NH (9256 /A)

H

2 N r N

H

2 NQ cr 307 308 F OH 500.4 583.5 (10.436 /A) (C) 2NN NH \F F 310 309 - 78 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 623.8 556.4 (C) (C) /H ~~~/ H He' 311 312 583.7 554.6 (C) (C) HO\H 313 314 NH 555.5 598:5 (C) (A) HO NH H H NH 316 315 -79- Compound M+1 Compound M+1 (m/nm e ) dnmethod) OH 560.5 NH 500.4 H (B) () F 318 317 514.5 NH 526.6 (B) (B) H >NH N NH N,, 320 319 H 0 487.148. (A) (A) HNH NN HO 322 321 -80- Compou nd M+1 Compound M+1 UPLC HPLC (min/m ethod) (miln/method) O N2 0 485.6 429.4 (A) OH (B) NH N 324 323 OH 421.4 OH . 429.1 (B)(B NH N F NH N F F -. 326 325 458.9 459.5 N (B) (B) HO HNH NH, 328 327 -81- Compound M+1 Compound M+1 HPLC BLC (inrn/mth6od) (m Inidethod) OH 431.3 OH 417.6 (B) -5(B) NH 330 329 OH 435.3 OH 417.3 (B3) (B) >~NH NN § NH I NH F NH YF F 332 331 OH 401 445 (B) (A) NH N F: 334 333 -82- Compound M+1 Compound M+1 HryIC HPLC (min/thod) (min/method) OH OH 414 463 (A) (A) HHF NH

F

335 336 OH H 445 414 (A) (A) jrYN NH N NH NH F H F 337 338 473 N 500.5 (A) (A) ON H y 7~H NH<Y N F H NHH NH 339 340 -83- CopounM+ Compund 1 HLPLC HPLC methodo) etod) 0 473 491 NH N- (A NAH N (A) NH H 341 342 491 473 NH (A) (A) H (NH%<N~ H H 344 343 473 H 487 NHH (A) (A) 345 346 -84- Compound M+1 Compound M+l HPLC HPLC (mn/method) (min/method) OH 487 487 (A) (A) Hd NH \H 348 347 7H 505 (A) (A) H NH HN 349 350 oQOH 505 463 (A) O rOH (A) HO NH H' NH N Ft F He 352 351 - 85 - Comou d M1 Compound M+ HP.LC HPLC J(m m thod) (A) N~ F~tHrN.N /( ~h9H 463 354 353 530 H 547 (A) (A) OHF5 358 F 357 -863 Compound M+1 Compound M+1 HPLC HPLC - (mn/method) (M.nnmethod) 560 520 OANYH (A)(A N HN N 359 360 546 448 (A) Q. H y/H (A) A 2 NN 361 362 OH 448 403.5 KY (A) (B) H2N NHNHH FF 363 F 364 -87- Compound. M+1 Compound M+1 RPLC HIPLC (mm/method) (Timthod) OH O 459.6 403.5 (A) (A) NH N 367F H )fJ/> NH F. 365 366 OH 501.6 471.6 (A) (A) N HO / H 368 367 479.4 479.5 C (A)(A F 370 369 - 88 - Compound M+1 Compound M+l ERPLC HPLC (win/method) (nin/method) O 493.5 493.5 (A) (A) HOQ N H N _ F F 372 371 437.4 405.5 (A) (A) NNNH N >NH -yH F/ 373 374 0 O O 437.4 463.5 (A) (A) NH F N NH, ___ 376_ 375 -89- Compound M+1 Compound M+1 HPLC HPI 4 C (miu/method) (min/method) 0 479.4 0 455.3 (A) (A) N FH NF N F 377 378F 479.4 463.5 §9( A ) 9() H N NH N 380 379 048.3 ,476.3 (A) (A) F0O~cK H F F 381 382 -90- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/ethod) 476.4 448.3 H 383 384 411.3 429.3 (A) NHO JK, (A) 385 386 467.5 467.5 HO, NH F A H ?H F 388 387 388 -91- Compound M+1 Compound M+1 HPLC RPLC (mi/method) (min/method)

H

2 445.5 422.3 (A) (A) SNHN N 389 F 390 NH2 422.3 412.4 N (11.33 /A) (A) NH H 392 F 391 NH 406.5 H 406.5 NH (A) (A) NH NH F NH N F F 393 F 394 -92- Compound M+1 Compound M+1 HPLC HPLC (min/meuthod) (min/method) HO - 546.3 Hq 546.3 N (A) (A) H NH F / H H F F 395 396 H 560.5 H 560.5 (A) (A) RH N NH F 398 397 -93- Compound M+1 Compound M+1 HLPLC HPLC (min/method) (min/method) 544.4 560.4 QN

HO

(A) N (A) NH NN / H F H F 400 399 HO 550.5 HO 550.5 HO (A) HO'. (A) NH NH 0 NH NAl F 402 401 - 94 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 477.3 (3 544.4 _(A) Q (A) 403 404 560.5 O 560.5 (A) (A) H H 405 406 377.1 377 HO N N+ F (A) NHF (A) N N 407 408 - 95 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (minmethod) 5194 0 488.5 H (B) (A) N HC /H F 409 F 410 OHQ N 492.5 418.5 (A) F (A N F N N N HN- 'NHN 411 412 -96- Compound M+1 Compound M+1 EPLC HPLC (min/metbod) (min/mthod) N HO NH 531.4 HF 504.5 O) H F (A) (AA) H N 0 NH FL ' 41351 F N. -3 416 H9

N

Compound M+1 Compound M+1 HPLC HPLC (minmet hod) (min/me6d 490.1 H0 518.3 F .(A) (A) F N KN N H N 418 417 HOJ 518.3 "476.5 F (A) (A) F 5H F NY 'J HAN 419 420 -98 - Compound M+1 Compound M+1 HPLC HPLC (mi/method) (min/method) HO HO 500.4 F526.5 H(A) NH \/ F (A) N N H H o NHN 421 422 HO 540.5 449.5 FF H _ F ( ) H O

-

$ NF N HN N 424 423 -99- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 449.3 449.3 HOH(A) HO(A) 425 426 367.3 473 p (A) H- r (A) 427 428 473 491 NH HN ( (A) c~rN~C~r/ H 429 430 487 487 (A) (A) NH N (ANH 431 432 -100- Compound M+I1 Compound M+1 HPLC HPLC (min/method) (min/ethod) 505 403 (A) (A) H NH F 433 F 434 431 431 (A) (A) %NH,,NN~rN _NH F 436 435 -lol1- Compound M+1 Compound M+1 HPLC HPLC (min/method) (minm/ethod H H 43518 (A) H (B) HNN Y N F F 437 438 OH (A) "OH (A) >NH N NNH NH F H F F 439 440 -102- Compound M+l Compound M+1 HIPLC HPLC (min/method) (min/method) NH 504 NH 478 OH (A) 11OH (A) NHA N6: NHA F F 441 442 532 490 0(A) (A) NH NH N N N F J~-NHF F444 443 516 490 NFTH (A) (%NH (A) HN N A)N 445 446 -103- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) H 516 451 (A) (A) NN NNN F F F9Z 447 448 OH 548 477 N (A) (B) HH NH N 4 F 450 F 449 F522.5 540.5 Hel(A) H A 451 452 - 104- Compound M+1 Compound M+1 HPlCo HPLIC (min/method) (m/method) F 522.5 419.5 F H F A) HH 453 454 H F 431.5 H431.5 -qN- (A) -q (A) KLNN~~H Q%1'F~" H (:)'N N N N 455 456 Hg NH F 431.5 NF 431.5 457 458 - 105 - Compound M+1 Compound M+1 HPLC HPLC (mm/method) (mnin/method) 449.4 449.4 F Hq~ $C\ (A). H (A) NH F 459 460 472.5 472.5 F F HO - (A) (A) 462 N H NH ON N 461 462 F 419.5 437.4 HNHH F (A) HQ (A) aNH NeH H 463 . 464 -106- Compound M+1 Corphotnd M+1 HPLC HPLC n (mm/method) (n net od 472.5 472.6 Hq () Hq SA O NH(A) 465 466 490.5 490.3 F Hq NH(A) HO (A) H 467 468 375.3 375.3 F (A) F (A) NHJI Z H 469 470 -.107- Compound M+1 Compound M+1 HPLC HPLC (min/method) (na/iethod 417.5 417.5 F- (A) F (A) NH N H 471 472 F 375.3 NH 375.2 IU )NH (A) ~4F (A) NH W> ANH N NH N 0 475 476 - 108 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 491.5 491.5 F (A) (B) 477 478

H

2 N N \ H 1 N N F (A 479 480 503.3 526.3 F (A) (A) HN H F N F tNi H a~i Hf H: F N )482 481 -109- Compound M+1 Coinpound M+1 HPLC HPLC (minm/ethod) (m/method) F 434.1 569.7 F (A) )H ( H N H F H 'N~flN HeO N/ 483 484 OH 375 OH 375.3 (B) (A) NH NH l N 485 F 486 OH OH H 457.1 (A) (A) NH~Nr N 39. NN N H NH F 488 487 -110- Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/metod) OH H 501.5 501.4 (A) (A) NH F 489 490 H 476.5 445.5 (A) (A) S N N NH N F F 491 492 463.4 445 (A) ) NH F NH N F 493 F 494 - 111 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 466.1 OH 445.3 (A) (A) NF N 495 496 NH (~NH r~cN448.4 1 Ij448.4 H NHF(A) H . Ny (A) F F -N 2 FFF 497 498 516.3 516.3 (A) NH (A) N NC .N N F F 499 500 - 112 - Compound M+i Compound M+I IIPLC HPLC (min/method) (min/method) H 560.5 546.5 (A) - (A) N 4 FNH NH F- F 502 501 461.5

NH

2 375.8 HO NHN (A) HN N(A) S// H 503 F 504 376 NH 2 376.1 (A)~ (A) N NHC N NN F 505 506 -113- Compound M+1 Compound M+1 HILC H1'LC (mnn/method) (mmn/method) NH2 O37.8 479.3 HN N 0 (A)(A H _NH FHO F 507 508 445.3

NH

2 408.1 (A) (A) H F H F F 509 F 510

NH

2 408.4 497 (A) (A) HN HO NH F 512 511 -114- Compound M+1 Comnpound M+1 HPLC HPLC (mlin/ethod) (min/method) 497 461.4 NH(A) H (A) HO HO N H F F 514 H 461.4 417.6 (A)(A) H >NH > N 515 516 HO 417.6

NH

2 486.6 (A) (A) FN60< H N 4 Z> N H F Hd N 517 518 - 115 - Compound M+1 Compound M+1 HPLC HPLC n(mt/method) (min/method) NH448.4 488.4 NH 0 (A) F(A) > NH NH F HNII N F 519 520 456.4 442.4 r (A) (A) NNH F 522 521 0 NH Nr'-.O 506 H O 506 (A) OH (A) Y RC N H N> NNH F F F F 523 524 -116- Compound M+1 Compound M+1 JJFLC HPLC (min/method) (min/method) OH 532.3 OH 532.3 (A) (A) >NH<N>N F N 55F 526 525 N 476.5 434.4 (A) (A) Fi F 528 527 H 518.6 H 544.4 (A) (A) 0 F' FH F H F 529 530 -117- Compound M+1 Compound M+1 HPLC HIPLC (min/method) min/tod) OH 558 O 514.6 OH (A) (A) NHN 531 532 505.3 g ~ 514.7 H(A) (A) NH NH F H F 534 533 -- 118 - Compound M+1 Compound M+1 HPLC HPLC (min/method) (min/method) 0 500.5 N4/. $NDA)Nk 470.6 (A) (A) N N HIN F 535 536 [00180] The compounds of Table 1 were purified by HPLC using one of the conditions A-F described above. The mass spectrometry data (M+1 ion) for each compound is also set forth. 5 100181] Aminopurine Compounds set forth in Table 1 were tested in the JNK inhibitor assays described herein and were found to have activity as JNK inhibitors. 4.3 METHODS FOR MAKING AMINOPURINE COMPOUNDS [001821 The Aminopurine Compounds can be made using conventional organic 10 syntheses. By way of example and not limitation, an Aminopurine Compound can be prepared as outlined in Schemes 1 and 2 shown below as well as in Examples 5.1 to 5.53. 15 20 - 119 - [00183] Scheme 1: C1 2 FtIH RNH NO g-NH2 N0N2 RI-NHi2 RNHO2 M n RNN ~ N0 I N02 Reducton C1 N Base, solvent Cl N Bsc, solvn HN R'NH5 R

DNH'

2 N2, NH2 R)-NCS R2 NH RR D2 R N N2 NI HN N DMPorTHF HN N N Nk3 RI RI 5 [00184] Scheme 2:

R

2 '-NH ,kN2 R 2

R

2 NINO2 RNH RNH

R'NH

2 Pol NH Cl N N NO 2 SnCI 2 N NH 2 POl 0R Pol"NN PoK N N R R1

NR

2

R

3 -NCS DIC TFA WorkUp PlN NPurification R' HT RI P., IO Pa" N [00185] Solid-phase reactions can be performed in, for example, 250 mL polypropylene bottles for large reactions (>50 mL) or in 20 mL fitted polypropylene syringes (<20 mL). All solvents used for washings are HPLC grade unless otherwise stated. - 120 - Each wash cycle is carried out with 100 mL of solvent for the large vessels or 10 mL of solvent for small vessels over 3-5 minutes unless otherwise stated. The reactions are shaken using a Lab-Line Instruments Titer Plate Shaker. [00186] Synthesis of( 2 -Chloro-5-nitropyrimidin-4-yl)R 2 anines R NH -N 0N2 R2NH2 N,, NO2 5 CAN DIEA, THF, -78 *C C KIL N [00187] N,N-diisopropylethylamine is slowly added to a solution of 2,4-dichlot-5 nitropyrimidine in THF at -78 *C. The desired R 2 amine is dissolved in THF and added dropwise to the reaction mixture at -78 *C. The reaction is stirred for about I hour at -78 *C and then allowed to slowly warm to room temperature overnight. Dichloromethane is added 10 and the organics are washed with water (500 mL) followed by NaHCO 3 (sat. aq., 2 x 500 mL). The organics are dried (MgSO4), filtered, and the solvent is removed in vacuo to provide the crude ( 2 -chloro-5-nitropyriidin-4-yl)-R 2 ine. The crude products are used without further purification. [00188] Reductive Amination with R' Amines H 1)HCI/DMF + RINH, Pol NH 15 Pl 0 2) NaH B(Ac) 3 RI [001891 A solution of R' amine and HCI (a 4 M solution in dioxane) in 5% AcOH/DMF is added to 4

-(

4 -formyl-3-methoxypenoxy)butyryl AM resin in, for example, a 250 mL polypropylene tube. The resin suspension is agitated on a shaker for about 3 h and sodium triacetoxyborohydride is added. Following shaking for about 1 h with periodic 20 venting, the resin is washed twice with 5% AcQH/DMF using, for example, a polypropylene gas-dispersion tube under vacuum to aspirate off the solvent. A second solution of R1 amine is added followed by agitation for 1 h. Sodium triacetoxyborohydride is added and the suspension is shaken overnight at room temperature with venting of the reaction vessel for about the first 1 h. The reaction vessel is drained and the resin is washed with DMF (2X), 25 50% MeOH/DMF (2), DMF (3X) and CH 2

C

2 (4X). The resin is then split into five, for example, 20 mL fritted polypropylene syringes using a suspension in DMF. [001901 -Arylation with ( 2 -Chmoro--nioprnidin-4-ylbR 2 amine - 121 - R NH l~r~ 2 N NO2 RNH YR..NH Po'- NH Cl N N NO 2 R~1

CH

2 Cl 2 , DIEA Pol N N

R

1 [00191] A solution of crude (2-chloro-5-ntropyrimidin-4-yl)-Ramine and NN diisopropylethylamine in CH 2 C1 2 is added to each syringe containing a different resin-bound secondary R' amine. After shaking the mixture overnight, the reaction solution is drained 5 and the resin is washed with DMF (5X) and CH 2

CI

2 (7X). [00192] Nitro Reduction R2NH R?.NH N NO 2 SnC 2 N NH 2 Pol N N DMF, DIEA l NN (00193] A solution of SnC 2 dihydrate in nitrogen-purged DMF is prepared in, for example, a graduated 1 L glass bottle. NN-Diisopropylethylamine is added, the volume is 10 adjusted to 1 L with nitrogen saturated DMF, and the solution is purged for about 30 min. with a gentle stream of nitrogen. The SnCl 2 solution is added to each resin-bound 5 nitropyrimidine in, for example, a 20 mL fitted polypropylene syringe. The reactions are capped and shaken overnight. The reaction solutions are expelled, the resin is washed with nitrogen-purged DMF (3X) and freshly prepared SnCl 2 solution is added. After shaking 15 overnight, the reaction solutions are expelled and the resin is washed with nitrogen-purged DMF (3X). Following a third treatment with SnCl 2 solution overnight, the reaction solutions are expelled, the resin is washed with DMF (3X) followed by alternating washes with 50% DMF/H 2 0 and DMF (3X each). This is followed by washing the resin with MeOH (2X), DMF (2X) and CH 2 C1 2 (7X). Each resin is split into four, for example, 20 mL 20 fitted polypropylene syringes using a suspension in DMF. [00194] Aminopurine Formation -122- R2

R

2

HN-R

3 NH N N NH 2

R

3 -NcS DIC N Pal N N 25% MFICHIC1 2

CH

2

C

2 N PO RN 1 Po N N

RR

1 [001951 The desired isothiocyanate is added to a suspension of each resin-bound 5 aminopyriidine in DMF and CH4 2 C1 2 . The 20 mL fitted polypropylene syringes containing the resin suspension are capped and allowed to shake overnight. The reaction 5 solutions a-e expelled followed by the addition of a solution of DIC in CN 2 Ol 2 . The reactions are allowed to shake for about 4 days, the reaction solutions are expelled and the resin is washed with DMF (5X) and CH 2 Cl 2 (7X). The resulting resin-bound anminopurines are dried in vacuo. 10 [00196] Cleavage from Resin

R

2

HN-R

3 N 50% TFA/CH 2

C

2 WorkUp N Pol N N Purification R R1 [001971 A 50% v/v TFA/CH 2 Cl 2 solution is added to the resin-bound aminopurines in, for example, 20 mL fitted polypropylene syringes. The resulting resin suspensions are allowed to shake overnight, the reaction solutions are collected and dried in vacuo. The 15 residues are partitioned between EtOAc and saturated aq. Na 2

CO

3 . After further extracting with EtOAc (2 x 4 mL) the organic layers are collected, passed through polyethylene fits and dried in vacuo. The residues are dissolved in DMSO, passed through a silica plug and purified using preparative HPLC to provide the desired aminopurine. (001981 Illustrative examples of Schemes I and 2 are set forth in Examples 5.1 to 20 5.14, below. [00199] Pharmaceutically acceptable salts of the Aminopurine Compounds can be formed by conventional and known techniques, such as by reacting a Aminopurine Compound with a suitable acid as disclosed above. Such salts are typically formed in high yields at moderate temperatures, and often are prepared by merely isolating the compound 25 from a suitable acidic wash in the final step of the synthesis. The salt-forming acid may - 123 dissolved in an appropriate organic solvent, or aqueous organic solvent, suth as an alIkanol, ketone or ester. On the other hand, if the Aminopurine Compound is desired in the free base form, it may be isolated from a basic final wash step, according to known techniques. For example, a typical technique for preparing hydrochloride salt is to dissolve the free base in a 5 suitable solvent, and dry the solution thoroughly, as over molecular sieves, before bubbling hydrogen chloride gas through it. 4.4 METHODS OF USE [00200] The Amfinopurine Compounds have utility as pharmaceuticals to heal or prevent disease in animals or humans. Further, the Aminopurine Compounds are active 10 against protein kinases including those involved in cancer, cardiovascular disease, inflammatory diseases, autoimmune diseases and metabolic disorders. Accordingly, provided herein are many uses of the Aminopurine Compounds, including the treatment or prevention of those diseases set forth below. [00201] Representative autoinmmune conditions that the Aminopurine Compounds are 15 useful for treating or preventing include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease and diabetes (e.g. 'Type I diabetes). [00202] Representative inflammatory conditions that the Aminopurine Compounds 20 are useful for treating or preventing include, but are not limited to, asthma and allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, (e.g., Type I diabetes and Type II diabetes) and obesity. [00203] Representative metabolic conditions that the Aminopurine Compounds are 25 useful for treating or preventing include, but are not limited to, obesity and diabetes (e.g., Type II diabetes). [00204] Representative cardiovascular diseases that the Aminopurine Compounds are useful for treating or preventing include, but are not limited to, stroke, myocardial infarction or iscehmic damage to the heart, lung, gut, kidney, liver, pancreas, spleen or brain. 30 [00205] Representative cardiovascular and renal diseases that an Aminopurine Compound containing or coated stent or stent graft is useful for treating or preventing -124include atherosclerosis and the treatment or prevention of restenosis after vascular intervention such as angioplasty. [00206] An Aminopurine Compound containing or coated stent or stent graft can further comprise an effective amount of another active agent useful for treating or 5 preventing a cardiovascular or renal disease, including, but are not limited to, an anticoagulant agent, an antimetabolite agent, an anti-inflammatory agent, an antiplatelet agent, an antithrombin agent, an antimitotic agent, a cytostatic agent or an antiproliferative agent. [002071 The Aminopurine Compounds are also useful for treating or preventing 10 ischemia /reperfusion injury in general. Accordingly, the Aminopurine Compounds are useful for treating or preventing acute or chronic organ transplant rejection and for the preservation of tissue and organs. [00208] Representative cancers that the Aminopurine Compounds are useful for treating or preventing include, but are not limited to, cancers of the head, neck, eye, mouth, 15 throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system. [00209] Cancers within the scope of the methods provided herein include those 20 associated with BCR-ABL, and mutants or isoforms thereof, as well as kinases from the src kinase family, kinases from the Rsk kinase family, kinases from the CDK family, kinases from the MAPK kinase family, and tyrosine kinases such as Fes, Lyn, and Syk kinases, and mutants or isoforms thereof. [00210] In a particular embodiment, provided herein are methods for the treatment or 25 prevention of a disease or disorder associated with the modulation, for example inhibition, of a dnase, including, but are not limited to, tyrosine-protein kinase (SYK), tyrosine-protein kinase (ZAP-70), protein tyrosine kinase 2 beta (PYK2), focal adhesion kinase 1 (FAK), B lymphocyte kinase (BLK), hemopoietic cell kinase (HCK), v-yes-I Yamaguchi sarcoma viral related oncogene homolog (LYN), T cell-specific protein-tyrosine kinase (LCK), 30 proto-oncogene tyrosine-protein kinase (YES), proto-oncogene tyrosine-protein kinase (SRC), proto-oncogene tyrosine-protein kinase (FYN), proto-oncogene tyrosine-protein kinase (FGR), proto-oncogene tyrosine-protein kinase (FER), proto-oncogene tyrosine -125protein kinase (FES), C-SRC kinase, protein-tyrosine kinase (CYL), tjrosine protein kinase (CSK), megakaryocyte-associated tyrosine-protein kinase (CTk), tyrosineprotein kinase receptor (EPH), Ephxin type-A receptor 1, Ephrin type-A receptor 4 (EPHA4), Ephrin type B receptor 3 (EPHB3), Ephrin type-A receptor 8 (EPHA8), neurotrophic tyrosine kinase 5 receptor, type I (NTRK1), protein-tyrosine kinase (PTK2), syk-related tyrosine kinase (SRK), protein tyrosine kinase (CTK), tyro3 protein tyrosine kinase (TYRO3), bruton agammaglobulinenia tyrosine kinase (BTK), leukocyfe tyrosine kinase (LII), protein tyrosine kinase (SYK), protein-tyrosine kinase (STY), tek tyrosine kinase (IEK), elk-related tyrosine kinase (ERX), tyrosine kinase with immunoglobulin and egf factor homology 10 domains (TIE), protein tyrosine kinase (TKF), neurotrophic tyrosine kinase, receptor, type 3 (NTRK3), mixed-lineage protein kinase-3 (MLK3), protein kinase, mitogen-activated 4 (PRKM4), protein kinase, mitogen-activated I (PRKM1), pri-otein tyrosine kinase (PTK7), protein tyrosine kinase (EEK), minibrain (drosophila) homolog (MNBH), bonemartow kinase, x-linked (BMX), eph-like tyrosine kinase 1 (ETKI), macrophage stimulating 1 15 receptor (MSTl R), btk-associated protein, 135 kd, lymphocyte-specific protein tyrosine kinase (LCK), fibroblast growth factor receptor-2 (FGFR2), protein tyrosine kinase-3 (TYK3), protein tyrosine kinase (TXK), tec protein tyrosine kinase (TEC), protein tyrosine kinase-2 (TYK2), eph-related receptor tyrosine kinase ligand 1 (EPLG1), t-cell tyrosine kinase (EMT), eph tyrosine kinase 1 (EPHTI), zona pellucida receptor tyrosine kinase, 95 20 kd (ZRK), protein kinase, mitogen-activated, kinase 1 (PRKMK1), eph tyrosine kinase 3 (EPHT3), growth arrest-specific gene-6 (GAS6), kinase insert domain receptor (KDR), ax receptor tyrosine kinase (AXL), fibroblast growth factor receptor-i (FGFR1), v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2), fms-like tyrosine kinase 3 (FLT3), neuroepithelial tyrosine kinase (NEP), neurotrophic tyrosine kinase receptor 25 related 3 (NTRKR3), eph-related receptor tyrosine kinase ligand 5 (EPLG5), neurotrophic tyrosine kinase, receptor, type 2 (NTRK2), receptor-like tyrosine kinase (RYK), tyrosine kinase, b-lymphocyte specific (BLK), eph tyrosine kinase 2 (EPHT2), eph-related receptor tyrosine kinase ligand 2 (EPLG2), glycogen storage disease VIII, eph-related receptor tyrosine kinase ligand 7 (EPLG7), janus kinase I (JAK1), fis-related tyrosine kinase-l 30 (FLTI), protein kinase, camp-dependent, regulatory, type I, alpha (PRKAR1A), wee-I tyrosine kinase (WEEl), eph-like tyrosine kinase 2 (ETK2), receptor tyrosine kinase musk, insulin receptor (INSR), janus kinase 3 (JAK3), fins-related tyrosine kinase-3 ligand protein -126kinase c, beta 1 (PRKCB,1), tyrosine kinase-type cell surface receptor (H513), janus kinase 2 (JAK2), lim domain kinase 1 (LIMK1), dual specificity phosphatase 1 (DUSP1), hemopoietic cell kinase (HCK), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide (YWHAH), ret proto-oncogene (RET), tyrosine 3 5 monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (YWHAZ), tyrosine 3 -monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide (YWHAB), hepatoma transmembrane kinase (HTK), map kinase kinase 6, phosphatidylinositol 3-kinase, catalytic, alpha polypeptide (PIK3 CA), cyclin-dependent kinase inhibitor 3 (CDKN3), diacylglycerol kinase, delta, 130 kd, protein-tyrosine 10 phosphatase, nonreceptor type, 13 (PTPN13), abelson murine leukemia viral oncogene homolog I (ABL1), diacylglycerol kinase, alpha (DAGK1), focal adhesion kinase 2, epithelial discoidin domain receptor 1 (EDDRI), anaplastic lymphoma kinase (ALK), phosphatidylinositol 3-kinase, catalytic, garmma polypeptide (PIK3CG); phosphatidylinositol 3-kinase regulatory subunit, (PI1t3R1), eph homology kinase-1 15 (EHK 1), v-kit hardy-zuckerman 4 feline sarcoma viral oncogene homolog (KIT), fibroblast growth factor receptor-3 (FGFR3), vascular endothelial growth factor c (VEGFC), epidermal growth factor receptor (EGFR), oncogene (TRK), growth factor receptor-bound protein-7 (GRB7), ras p21 protein activator (RASA2), met proto-oncogene (MET), src-like adapter (SLA), vascular endothelial growth factor (VEGF), vascular endothelial growth 20 factor receptor (VEGFR), nerve growth factor receptor (NGFR), platelet derived growth factor receptor (PDGFR), platelet derived growth factor receptor beta (PDGFRB), dual specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2), dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 3 (DYRK3), dual-specificity tyrosine-(Y) phosphorylation regulated kinase 4 (DYRK4), dual-specificity tyrosine-(Y)-phosphorylation 25 regulated kinase IA (DYRK1A), dual-specificity tyrosine-(Y)-phosphorylation regulated kinase IB (DYRKIB), CDC-like kinase 1 (CLK1), protein tyrosine kinase STY, CDC-like kinase 4 (CLK4), CDC-like kinase 2 (CLK2) or CDC-like kinase 3 (CLK3). [00211] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder associated with the modulation, for example inhibition, 30 of serine/threonine kinases or related molecules, including, but not limited to, cyclin dependent kinase 7 (CDK7), rac serine/threonine protein kinase, serine-threonine protein kinase n (PKN), serine/threonine protein kinase 2 (STK2), zipper protein kinase (ZPK), -127protein-tyrosine kinase (STY), bruton agammaglobulinemia tyrosine kinase (BTK), mkn28 kinase, protein kinase, x-linked (PRKX), elk-related tyrosine kinase (ERk), ribosoial protein s6 kinase, 90 kd, polypeptide 3 (RPS6KA3), glycogen storage diseaseNIII, death associated protein kinase 1 (DAPKl), pctaire protein kinase 1 (CTK1), protein kiee, 5 interferon-inducible double-stranded ma (PRKR), activin a receptor, type II-like kinase 1 (ACVRLK1), protein kinase, camp-dependent, catalytic, alpha (PRKACA), protein kinase, y-linked RKY), 0 protein- coupled receptor kinas 2(OPRK2l), protein kinase c, theta form (PRKCQ), lim domain kinase I (LIMK1), phosphoglyceigte kinase 1 GKI ,m domain kinase 2 (LIMK2), c-jun kinase, activin a receptor, type II-like kinase 2 10 (ACVRLK2), janus kinase 1 (JAKI), elkl motif kinase (EMK1), male germ cell-associated kinase (MAK), casein kinase 2, alpha-prime subunit (CSNK2A2), casein kinase 2, beta polypeptide (CSNK2B), casein kinase 2, alpha 1 polypeptide (CSNK2A), ret proto oncogene (RET), hematopoietic progenitor kinase 1, conserved helix-loop-helix ubiquitous kinase (CHUK), casein kinase 1, delta (CSNK1 D), casein kinase 1, epsilon (CSNK1E), v 15 akt murine thymoma viral oncogene homolog 1 (AKT1), tumor protein p53 (TP53), protein phosphatase 1, regulatory (inhibitor) subunit 2 (PPP1R2), oncogene pim-1 (PIM1), transforming growth factor-beta receptor, type II (TGFBR2), transformirig growth factor beta receptor, type I (TOFBR1), v-raf murine sarcoma viral oncogene homolog bi (BRAF), bone morphogenetic receptor type II (BMPR2), v-raf murine sarcoma 3611 viral oncogene 20 homolog I (ARAFi), v-raf murine sarcoma 3611 viral oncogene homolog 2 (AkAF2), protein kinase C (PItC), v-kit hardy-zuckerman 4 feline sarcoma vital oncogene homolog (KIT) or c-KIT receptor (KITR). 1002121 In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder associated with the modulation, for example inhibition, 25 of a MAP kinase, including, but not limited to, mitogen-activated protein kinase 3 (MAPK3), p44erkl, p44mapk, mitogen-activated protein kinase 3 (MAP kinase 3; p44), ERK1, PRKM3, P44ERK1, P44MAPK, mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase kinase 1 (MEKI), MAP2Klprotein tyrosine kinase ERK2, mitogen-activated protein kinase 2, extracellular signal-regulated kinase 2, protein tyrosine 30 kinase ERK2, mitogen-activated protein kinase 2, extracellular sigrial-regulated kinase 2, ERK, p38, p40, p41, ERK2, ERTI, MAPK2, PRKMI, PRKM2, P42MAPK, p4lmapk, mitogen-activated protein kinase 7 (MAPK7), BMKi kinase, extracellular-signal-regulated -128kinase 5, BMK1, ERK4, ERK5, PRKM7, nemo-like kinase (NLK) likely ortholog of mouse nemo like kinase, mitogen-activated protein kinase 8 (MAPK8), protein kinase JNK1, JNK1 beta protein kinase, JNKI alpha protein kinase, c-Jun N-terminal kinase 1, stress-Iactivated protein kinase JNK1; JNK, JNKI, PRKM8, SAPK1, JNKIA2, JNI21B1/2, mitogen 5 activated protein kinase 10 (MAPKI0), c-Jun kinase 3, JNK3 alpha protein kinase, c-Jun N terminal kinase 3, stress activated protein kinase JNK3, stress activated protein kinase beta, mitogeft-activated protein kigiase 9 (MAP ), MAP kinae , c-Jun kinase$ 2 -Jun N terminal kinase 2, stress-aOtivated protein kinase JNK2, J 1N2, JNKA, JNK2B, PIXM9, JNK-55, .NK2BETA, p54aSAPK, JNK2ALPHA, mitogen-activated protein kinase 14 10 (MAPK14), p38 MAP kinase, MAP kinase Mxi2, Csaids binding protein, MAX-interacting protein 2, stress-activated protein kinase 2A, p38 mitogen activated protein kinase, cytokine suppressive anti-inflammatory drug binding protein, RK, p38, EXIP, Mxi2, CSBP1, CSBP2, CSPB1, PRKM14, PRKM15, SAPK2A, p38ALPHA, mitogen-activated protein kinase I1 (MAPK1 1), stress-activated protein kinase-2, stress-activated protein kinase-2b, mitogen 15 activated protein kinase p38-2, iltogen-activated protein kinase p38beta, P38B, SAPK2, p38-2, PRKM1 1, SAPK2B, p38Beta, P38BETA2, mitogen-activated protein kinase 13 (MAPK13), stress-activated protein kinase 4, mitogen-activated protein kinase p38 delta, SAPK4, PRKMI 3, p38delta, mitogen-activated protein kinase 12 (MAPK12), p38gamma, stress-activated protein kinase 3, mitogen-activated protein kinase 3, ERK3, ERK6, SAPK3, 20 PRKM12, SAPK-3, P38GAMMA, nitogen-activated protein kinase 6 (MAPK6), MAP kinase isoform p97, mitogen-activated 5 protein kinase, mitogen-activated 6 protein kinase, extracellular signal-regulated kinase 3, extracellular signal-regulated kinase, p97, ERK3, PRKM6, p97MAPK, mitogen-activated protein kinase 4 (MAPK4), Erk3-related protein kinase, mitogen-activated 4 protein kinase (MAP kinase 4; p63), PRKM4, p63MAPK, 25 ERK3-RELATED or Extracellular signal-regulated kinase 8 (ERK7). [002131 More particularly, cancers and related disorders that can be treated or prevented by methods and compositions provided herein include but are not limited to the following: Leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, 30 myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome (or a symptom thereof such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia and chronic myelomonocytic leukemia (CMML), chronic leukemias such as but not limited to, chronic myelocytic granulocyticc) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas suclias but not limited to Hodgkin's disease, non-Hodgkin's 5 disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmadytoma and extamedullary plasmacytoma; Waldenstra5m's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as but not limited to bone 10 sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma. of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, 15 ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast 20 cancer; adrenal cancer such as but not limited to pheochromocytoma and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer, pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor, pituitary cancers such as but limited to Cushing's disease, 25 prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical 30 cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell -130tumor, and stromal tumor; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (sniall cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating 5 (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, squamous cell 10 carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer, testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such 15 as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant 20 melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypemephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/ or uterer); Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, 25 lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer 30 Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America). - 131 - [00214] Accordingly, the methods and compositions provided herein are als useful in the treatinent or prevention of a variety of cancers Or other abnormal proliferiative diseases, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and 5 skin; including squamous cell carcinoma; henatopoletic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lynphoblastic leukemia, B-cell lymiphorna, T-cell lymphoma, Berkiets lymphoma, heratopoletic tumors of myelbid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of uesenehymal orignin, including fibrosarcoma and thabdomyoscarcoma; other 10 tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma; tumors of the central and peripheral nervous system, including astrocytoma, glioblastoma multiforme, neuroblastoma, glioma, and schwannomas; solid and blood born tumors; tumors of mesenchymal origin, including fibrosafcoma, rhabdomyoscarama, and osteosarcoma; and other tumors, including melanoma, xenoderma pegmentosum, keratoactanthoma, seminoma, 15 thyroid follicular cancer and teratocarcinoma. It is also contemplated that cancers caused by aberrations in apoptosis would also be treated by the methods and compositions disclosed herein. Such cancers may include but not be limited to'follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis, and myelodysplastic 20 syndromes. In specific embodiments, malignancy or dysproliferative changes (such as metaplasias and dysplasias), or hyperproliferative disorders, are treated or prevented in the ovary, bladder, breast, colon, lung, skin, pancreas, or uterus. In other specific embodiments, sarcoma, melanoma, or leukemia is treated or prevented. [00215] In another embodiment, the methods and compositions provided herein are 25 also useful for administration to patients in need of a bone marrow transplant to treat a malignant disease (e.g., patients suffering from acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome ("preleukemia"), monosomy 7 syndrome, non-Hodgkin's lymphoma, neuroblastoma, brain tumors, multiple myeloma, testicular germ cell tumors, 30 breast cancer, lung cancer, ovarian cancer, melanoma, glioma, sarcoma or other solid tumors), those in need of a bone marrow transplant to treat a non-malignant disease (e.g., patients suffering from hematologic disorders, congenital immunodeficiences, -132mucopolysaccharidoses lipidoses, osteoporosis, Langeian's cel histibcytosis, Lech Nyhan syndrome or glycogen storage diseases), those undergoing chemotherapy or radiation therapy, those preparing to undergo chemotherapy o radiation therapy and thos who have previously undergone chemotherapy or radiation therapy. 5 [00216] In another embodiment, provided herein are methods for the treatment of myeloproliferative disorders or myelodysplastic sydriomes, comprising administering to a patient in needthereof an effective amount of an Aminopurine CoMpound or a composition thereof. In certain embodiments, the myelopiolife ve dirder is polycythemia rubra vera; primary thrombocythemia; chronic myelogenous leukemia; acute or chronic 10 granulocytic leukemia; acute or chronic myelomnonocytic leukemia; myelofibro erythroleukemia; or agnogenic mycloid metaplasia. [002171 In another embodiment, provided herein are methods for the treatment of cancer or tumors resistant to other kinase inhibitors such as imatinib mesylate (STI-571 or Gleevecm) treatment, comprising administering to a patient in need thereof an effective 15 amount of an Aminopurine Compound or a composition thereof. In a particular embodiment, provided herein are methods for the treatment of leukemias, including, but not limited to, gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia or chronic myelocytic leukemia resistant to imatinib mesylate (STI-571 or Gleevec'N treatment, comprising administering to a patient in need thereof an effective amount of an 20 Aminopurine Compound or a composition thereof. [002181 In one embodiment, provided herein are methods for treating or preventing a disease or disorder treatable or preventable by modulating a kinase pathway, in one embodiment, the JNK pathway, comprising administering an effective amount of an Aminopurine Compound to a patient in need of the treating or preventing. Particular 25 diseases which are treatable or preventable by modulating, for example, inhibiting, a kinase pathway, in one embodiment, the INK pathway, include, but are not limited to, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; 30 gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; Type II diabetes; obesity; atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic damages of heart, lung, 133 gut, kidney, liver, pancreas, spleen and brain; acute or chronic orgauntransplant rejection; preservation of the organ for transplantation; organ failure of loss of limb (e.g including, but not limited to, that resulting fron ischemia-reperfusion injury, traunia, gross bodily injury, car accident, crush injury or transplant failure); graft versus host disease; endotoxin 5 shock; multiple organ failure; psoriasis; burn from exposure to fire, chemicals or radiation; eczema; dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or traumatic injury (e.g., Vehicle accident, gunshot wound or limb crush); epilepsy; Alzheimer's disease; Parkinson's disease; immunological response to bacterial or viral infection; cachexia; angiogenic and proliferative dieseases; solid tumor; and cancers of a 10 variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine. 4.5 PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION 15 [00219] The Aminopurinie Compounds can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, 20 lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a 25 lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g., 30 hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the Aminopurine -134- Compounds in the pharmaceutical composition may be at alevel that will exercise the desired effect; for example, about 0.005~ rg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration. [002201 The dose of an Aminopurine Compound-to be administered to a patient is 5 rather widely variable and can be subject to the judgment of a health-care practitioner. In general, the Aminopurine Compounds can be administe-ed one to four times a day in a dose of about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration. In one 10 embodiment, the dose is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient's body weight, about 0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's body weight. In one embodiment, one dose is given per day. In any given case, 15 the amount of the Ainnopurine Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration. [00221] In another embodiment, provided herein are methods for the treatment or prevention of a disase or disorder comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 20 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of an Aminopurine Compound to a patient in need thereof. [0001] In another embodiment, provided herein are methods for the treatment or prevention of a disase or disorder comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about 1200 25 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of an Aminopurine Compound to a patient in need thereof. In a particular embodiment, the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of an Aminopurine Compound to a patient in need thereof. 30 [0002] In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg - 135 and about 1000 mg, about 250mg and about 1000 mg, or about 500 mg and about 1000 mg of an Aminopurine Compound. [00222] In a particular embodiment, provided herein are unit dosage formulation comprising about 100 mg or 400 mg of an Aminopurine compound. 5 [00223] In another embodiment, provided herein are unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140'mg, 175 mg, 200 mg, 250 ig, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 nig, 1000 mg or 1400 mg of an Arminopurine Compound. [00224] An Aminopurine Compound can be administered once, twice, three, fonr or 10 more times daily. In a particular embodiment, doses of 600 mg or less are administered as a a once.daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose. [00225] An Aminopurine Compound can be administered orally for reasons of convenience. In one embodiment, when administered orally, an Aminopurine Compound is 15 administered with a meal and water. In another embodiment, the Aminopurine Compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension. [002261 The Aminopurine Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, 20 intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition. [00227j In one embodiment, provided herein are capsules containing an Aminopurine 25 Compound without an additional carrier, excipient or vehicle. [002281 In another embodiment, provided herein are compositions comprising an effective amount of an Aminopurine Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a 30 pharmaceutical composition. [00229] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. -136- Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known 5 methods in pharmaceutical chemistry. Capsules can be prepared by mixing an Aminopurine Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual catriers and diluens include, but are noflimited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours 10 and similar edible powders. [0023.] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as 15 sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

20 [00231] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, 25 corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable 30 tablets, for example, by using substances such as mannitol in the formulation. [00232] When it is desired to administer an Aminopurine Compound as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which -137 can be modified by addition of waxes to raise its eltin point slightly. Water-misdible suppositofy bases com pricing, particularly polyethylene glycols of various molecular weights are in wide use. [00233] The effect of the Aminopurine Compound can be delayed or prolonged by 5 proper formulation.For example, a slowly soluble Pellet of the Aminopurine Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes makingpellts of several different dissolution rates and filling capsules with a mniture of the pellets. Tabletso sules can bencated with a film that resists dissolution for a predictable period of time. Even the-parenteral preparations can be 10 made long-acting, by dissolving or suspending the Aminopurine Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum. 5. EXAMPLES [002341 The following Examples are presented by way of illustration, not limitation. [00235] Example 5.1 Synthesis of 4-({8-[(2,6-Difluorophenyl)amino]-9 15 cyclopentylpurn-2-yl} amino) trans-cyclohexan-1-ol H HO' N, />NH F F [00236] 1. ( 2 -Chloro-5-nitropyrimidin4-yl)cyclopentylamine [00237] 2,4-Dichloro-5-nitropyrimidine (10.31 mmol, 2 g) and cyclopentylamine (10.31 mmol, 1.02 mL) were dissolved in THF (60 mL) and cooled to -78'C. NN 20 diisopropylethylamine (10.31 mmol, 1.8 mL) was added dropwise. The reaction mixture was stirred at -78'C for about 45 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for about 16 hours. After removal of the solvent the residue was redissolved in EtOAc and washed with water and brine. The organic phase was dried over MgSO 4 and the solvent evaporated. The residue was purified using column 25 chromatography (Si0 2 , 9:1 n-hexanes/ ethyl acetate) to give the desired product (2.11 g, 84% yield). ES-MS: 242 (M+l). When the hydrochloride salt of an amine is used in place of the cyclopentylamine described above, 2 to 3 equivalents of N,N-diisopropylethylamine and dichloromethane are used as solvent - 138 - {00238] 2. 4{ [ 4 -(Cyclopetylamino)-5-jiiropyrimidin-2 ylamino)ttans cyclohexan-1-ol [00239] ( 2 -Chloe-5nityriinidin-4yl)yelopenitylamine (6.18 mmo, 1.5 g.) and tran aminocyclohexan-176o (7.42 mniol, 854 ing mL)ere mixedin F (18 fl) and s N,N-diisoppeth ame (7.42 mio, 1.29 mL) was added. e creation mixture was stirred-overnight; Solvent was removed in vacuo andthe residue prified using column chromatography (SiCO 2 , 1: li-hexanes/ ethyl acetate -+ 7:3 n-hexanes/ ethyl acetate -+ ethyl adetate) to give the desired product (1.75 g, 88% yield). ES-MS: 322 (M+l). Whenthe hydrohlori selt ofaU amine i n pace otie tr 4 ocyclohean- 1-o 10 described above, 2 to 3 equivalents of NN-diisopropylethylamine or sodium bicarbonate and tetrahydrofuran or icetonitrile were used as solvent. [00240] 3. 4-{[5-Amino-4-(cyclopentylamino)pyrimidin.2-y]ino} trans cyclohexan-1-ol [00241] 4-{[4--(Cyclopentylamino)-5-nitropyrimidin-2-yl]aminotrans-cyclohexan-1 15 ol (2.18 mmol, 700 mg) was dissolved in 20 ml EtOH aid hydrogenated overnight at ibar with Pd/C (10%) as catalyst. The catalyst was filtered and the solvent evaporated to give the desired product (635 mng, 100% yield) which was carried on to the next step without further purification. ES-MS: 292 (M+1). This reduction can be also accomplished using the following procedure: Na 2

S

2 0 4 (140.0 mmol, 14 eq.) is dissolved in 150 mL water and 75 20 mL dioxane and 7.5 mL NH 4 0H solution are added. The corresponding nitro compound (10.0 mmol, 1 eq.) is added and the reaction mixture is stirred for 12 to 72 hours. Dioxane is evaporated and the product is extracted by using EtOAc or brineftHF. The organic phase is dried over MgSO 4 and evaporated to give the desired product. [00242] 4. 4

-({

8 -[(2,6-t)ifluoropheny)amino-9-cyclopentylpurin-2-yl} amino) 25 trans-cyclohexan-1-ol [00243] 4-{ [5-Amino-4-(cyclopentylamino)pyrimidin-2-y1]amino}trans-cyclohexan 1-ol (1.13 mmol, 330 mg) was dissolved in DMF (8.5 mL) and 2,6-difluorophenyl isothiocyanate (1.13 mmol, 0.146 mL) was added. The reaction mixture was stirred at room temperature for about 90 minutes. Ethanol (2.5 nL) was added and the reaction mixture 30 was stirred for about an additional 30 minutes. NN-Diisopropylcarbodiimide (3.40 mmol, 0.532 mL) was added and the reaction mixture was stirred overnight. Solvent was removed -139 and the residue was Purified using column chromatography (SiOz 1:1 n-hexanos/ ethyl acetate -+ ethyl acetate -+ 1% methanol/ ethyl acetate) to give the desired product (222.5 mg, 46%7o yield). ES-MS: 429 (M+1). Tetrahydrofuran canalso be used as solvent in this step. 5 [002441 Example 5.2 Synthesis of trans- (4-Aminocydlohexyl) {8-[,2,4 difluetoPhnlail-9-cyclopentlui-l} amine N N

H

2 NlI~~' ij/>-NH F F [00245] 1. trans- (4-Aminocyclohexyl) {8-[2,4-difluorophenyl)amino]-9 cYclopentYlpurin-2-yl} amine 10 [00246] N-[ 4

-({

8

-[(

2 ,4-difluorophenyl)amino]-9-cyclopntypurin-2.yl) amino) trans cyclohexyl](tert-butoxy)caboXarnide (0.71 mmol, 375 mg) was dissolved in ethanol (6 mL) and cooled to 0"C. Acetyl chloride (3 nL) was added dropwise and the reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off, washed with ethyl ether and dried under high vacuum to yield 372 mg.(98% yield) as a 15 trihydrochloride salt. ES-MS: 428 (M+1). [00247] Alternatively, N-[ 4

-({

8 -[(2,4-difluorophenyl)amino]-9-cyclopentylpurin-2 yl)amino) trans- cyclohexyl](tert-butoxy)carboxamide can be dissolved in 9 mL of methylene chloride followed by the addition of 2.25 mL of TFA. The reaction mixture is stirred for about 2 hours. Solvent is removed in vacuo, the resiudue is redissolved in 20 methylene chloride and neutralized with ammonium hydroxide. The solution is then washed with a saturated solution of sodium carbonate. The organic layer is separated and the aqueous layer is further extracted with methylene chloride. Combined organic layers are dried over sodium sulfate, filtered and the solvent removed in vacuo to yield the amine. [00248] Example 5.3 Synthesis of 8-(2-Fluorophenylamino)-2-(4 25 methoxvohenylamino)-94trans-44methylaminoicyclohexvl)-9H-ourine -140- NHMe MeNH F [00249] Boc-protected amine (481 mg, 0.88 mmol) was dissolved in THF (6 mL) and lithium aluminum hydride (1.0 M solution in THF, 2.64 mL, 2.64 mmol) added. The reaction mixture was heated at about 65"C overnight. The reaction mixture was cooled to 5 0"C and quenched dropwise with water until no further evolution of hydrogen was observed. The precipitate was filtered off and washed extensively with ethyl acetate. The solvent was removed in vacuo and the residue was purified using seni-preparative HPLC (20% acetonitrile/water (0.1% TFA) -+ 80% acetonitrile/water (0.1% TFA) over 30 min) to yield 191 mg of product 10 [00250] Example 5.4 Synthesis of 9-(trans-4-(Dimethylamino)cyclohexyl)-8-(2 fluorophenvl)- 2 -(4-methoxyphenyl)-9H-purine

N-

N ,1>-NH F 0~C NO [002511 Amine (200 mg, 0.359 mmol) was dissolved in a 1:1 mixture THF/ methylene chloride (4 mL) and a solution of formaldehyde (37% in water, 53 pL, 0.718 15 mmol) in THF (1 mL) was added dropwise, followed by sodium triacetoxyborohydride (761 mg, 3.59 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in DMS0/methanol (1:1 mixture) and purified by semipreparative HPLC (20-+70% acetonitrile/water (0.1% TFA) over 30min). Fractions containing product were quenched with ammonium hydroxide. After 20 standing overnight, a precipitate formed and it was filtered and dried under high vacuum, to yield 108 mg of the dimethylamino compound (63% yield). - 141 - [00252] Example 5.5 Synthesis of (4-{8-[(2-Fluorophenyl)amino]-2-[(4 methoxyphenv)amino purin-9-yl} transcyelohexyl)methan-1-ol HO. N H F [00253] Ethyl 4-{ 8

-[(

2 -flurophenyl)anino]-2-[(4-methoxyphenyl)amino] purin-9 5 yl}-trans-cyclohexanecarboxylate (0.28 g, 0.55 mmol) was dissolved in 9 mL of THF and cooled to 0*C (under nitrogen atmosphere). 1.38 mL of 1.OM LiAlH 4 in THF was added dropwise. The solution turned a dark orange as the LiAH 4 was added. The reaction mixture was stirred for about 5 h and quenched by the addition of 40 mL of water. The reaction was extracted three times with ethyl acetate. Organics were combined and dried with 10 magnesium sulfate, filtered and the solvent was removed in vacuo. The crude reaction mixture was then purified using reverse-phase preparative HPLC (20-80% acetonitrile/water (0.1% TFA) over 30min) to obtain 0.126 g of the desired product (50% yield) after neutralization of the TFA salt. ES-MS: 463 (M+1). [00254] Example 5.6 Synthesis of trans-4-{8-[(2-Fluorophenyl)amino]-9-[cis-4 15 (1-hydroxy-isopropyl~cyclohexyllpurin-2-ylamino)cyclohexan-1-ol HO H 'N N HO'~' '~3II/>-NH F [00255] Ethyl cis- 4

-{

8

-[(

2 -fluorophenyl)amino]-2-[trans-(4-hydroxycyclohexyl) amino]purin-9-yl}cyclohexane carboxylate (0.200g, 0.4 mmol) was dissolved in 4 mL of dry THF. Methyl magnesium bromide (0.6 mL, 3.OM solution in diethyl ether, 4.0 20 equivalents) was added dropwise at room temperature. The reaction mixture turned bright yellow and was stirred at rooin temperature for about 1 hour. The completion of the reaction -142was monitored by LC-MS. An additional 4 equivalents of methyl magnesium grignard solution were added and the reaction mixture was heated overnight at about 30 0 C. [00256] The reaction mixture was then cooled to room temperature and was quenched slowly with saturated aqueous ammonium chloride solution. The crude was-extracted in 5 ethyl acetate and the extracts were dried over Na 2

SO

4 ; The product Was purified using column chromatography on silica gel using 1-4% (ethanol/ammonium hydroxide: 8 1) in dichloromethane. The compoundwas isolated as a lightpink solid (57 mg, 29o yield). [OO257] Exenigl 5.7 Synthesis of cis--[[(2-Dfuophenyilami]2.-tau .

({

4

-[

4 -methylpiperazinyl)carbonyl]cycloheyl)aminopurin-9 10 vlcyclohexanecarboxylic acid N-(4-methylpiprazinyl)amide O N 0 . [00258] Diester (10.0 mmol, I eq.) was dissolved in 100 mL THF and LiOH (200.0 mmol, 20 eq.) (as a 1M aequous solution) was added. The reaction mixture was heated at about 60'C overnight. After cooling to room temperature, the pH was adjusted to 4 by 15 adding 6N HCL. Brine was added and phases were separated. The aequous phase was extracted with THF and the combined organic phases were dried over MgSO 4 . The solvent was evaporated to give the desired product [00259] Diacid (10.0 mmol, 1 eq.), HOBT (20.0 mmol, 2 eq.) and EDCI (24.0 mmol, 2.4 eq.) were mixed in 100 mL DMF and stirred for 15 minutes. Amine (24.0 mmol, 2.4 eq.) 20 was added and the reaction mixture was stirred overnight. The solvent was evaporated and the residue was purified using HPLC. [00260] Example 5.8 Synthesis of 4

-({

9 -[cis-4-(aminomethyl)cyclohexyl]-8 f( 2

,

6 -difluorophenyl)amino1purin-2-vlltras-amino)cyclohexan- I -ol - 143 -

H

2 N NN

HO"

0 ' >~C ,-NH F [00261] 1. cis- 4 -[(tert-Butokxy)arbonyilamjino Iohexe boxylic acid [ 2] eis-4-tcloil arboxyli acid (.g16 o dsissa i 40 mL of 1,4-dioxane. Two equivalents of di-tert-butyl-dicarbon te (6.094g, 27.92 nmol) 5 were added followed by 3 equivalent sodium bicarbonate (4.g,41.88 mmo1) dissolved in 40 mL of water. The reaction mixture was stirred at room temperature for about 12 hours. The completion of the reaction was monitored by LC-MS. Saturated aqueous

KHSO

4 was added dropwise, until gas evolution stopped. The solvent was then removed under reduced pressure and the crude product was extracted in ethyl acetate. The combined 10 organic extracts were washed with aqueous saturated KHS0 4 and dried over Na2SO4. The solvent was removed under reduced pressure, yielding 2.6 g of product. Based on IH NMR, the product was pure and used in subsequent steps without further purification. ES-MS (m/z) 244. [00263] 2. cis-(tert-Butox)-N-[4-(hydroxymethyl)cycloexyllcarboxamide 15 [00264] cis- 4 -[(tert-Butoxy)carbonylamino]cyclohexane carboxylic acid (2.6g, 10.68 nmol) was dissolved in THE (20r mL) and cooled to -10 0 C (MeOH-ice). N-Methyl morpholine was added followed by isobutyl chiloroformate (1.175mL, 10.68 mmol). After 10 min, NaBH 4 was added as a solid in one portion (1.213g, 32.06 mmol), The reaction mixture was warmed to 0O and methanol was added dropwise (13.35 mL). After 30 mi, 20 the reaction was quenched with 5% aqueous KHSO 4 . The reaction was monitored by LC MS until complete. The crude product was extracted with ethyl acetate and the combined extracts were dried over Na 2

SO

4 . A colorless oil was obtained and solidified slowly at room temperature. The product and purity were assessed by LC-MS and 'H NM R. No further purification was necessary. (quantitative yield) ES-MS (m/z) 230. 25 [00265] 3. cis-(tert-Butoxy)-N-{4-[(1,3-dioxobenzo[c]azolidin-2 Vllmethyllcvclohexvll carboxamide -144- [00266] cis -(tert-Butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.5g, 2.18 mmol) and resin-bound triphenyl phosphine (1.453g, 4.36 nmol, 3 mmol/g resin) were suspended in 15 mL of dry THF. Phthalimide was added in 5 mL of TIF followed by diisopropyl azodicarboxylate (DIAD) (0.858 mL, 4.36 mmol). The reaction was stirred at 5 room temperature and monitored by LC-MS. After overnight stirring at room temperature, the resin was removed by filtration and washed multiple times with 5 mL portions of THF. The filtrate combined with washings was concentrated under reduced pressure. The product was purified using column chromatography on silica gel using 10,/o ethyl acetate in hekanes as eluent. The product was isolated as a white solid (0.

4 86g, 1.35 mmol, 62% yield) ES-MS 10 (m/z) 359. [00267] 4. cis- 2 -r( 4 -Aminoccloheylmethyllbeocaolidi -1.3-dione [00268] cis-(tert-Butoxy)-N-{4-[(1,3-dioxobenzo[c]azolidin-2-yl) methyl]cyclohexyl} carboxamide (0.486g, 1.35 mmol) was suspended in ethanol (5 mL) and 15 reacted with acetyl chloride (1 mL). The reaction mixture was stirred at room temperature for about 4 hours. The completion of the deprotection was monitored by LC-MS. The solvent was removed under reduced pressure and the product Was isolated as its HCI salt as a white solid and used without further purification in the subsequent addition to 2,4 dichloro-5-nitropyrimidine: ES-MS (m/z) 259. 20 [00269] 5. 4-({9-[ cis- 4 -(Aminomethylcyclohexyl]-8-{(2,6 difluoroPhenvl)aminolpurin-2-yltrans-amino)cvclohexan-1-o [00270] 2

-[(

4

-{

8

-[(

2

,

6 -difluorophenyl)amino]-2-[trans-(4-hydroxycyclohexyl) amino]purin-9-yl}cyclohexylmethylbenzo[c]azolidine-1,3-dione (0.318g, 0.52 mmol) was dissolved in ethanol (4.5 mL) and reacted with hydrazine (42 gL, 2.4 eq) at reflux 25 temperature for about 5 hours. A white precipitate formed that was removed by filtration. The filtrate combined with washings of the precipitate, was concentrated under reduced pressure. The product was purified using column chromatography on silica gel using 5-10% (ethanol/NH4OH: 8/1) in dichloromethane as the eluent. The product was isolated as a white solid (198 mg, 80% yield). 30 100271] Example 5.9 Synthesis of 3 -((trans-4-(8-(2,6-Difluorophenylamino)-9

.

amino)cyclohexyloxycarboyl)propanoic acid - 145 - N HNH F o OH 0 [00272] trans- 4 -(8-( 2 ,6-Difluorophenylamino)-9-cyclopentyl-9H-purin-2 ylamino)cyclohexanol (1 mmol, 1 eq.) and succinic anhydride (10 mmol, 10 eq.) were mixed in 25 i pyidinf ahdstiied at rom tempeairfu o e days. m was 5 heated at 50'C for about 10 hours and the solvent was subsequently evaporated. The residue was recrystallized from acetone/MeOH to give the desired product. [00273] Example 5.10 Synthesis of trans-4-(8-(2,6-Difluorophenylamino)-9 clopentyl-9H-muin-2-yamino)cyclohexyi 2-aminoacetate --NH F No N 0-) NH F 10 [00274] trans-4-(8-(2,6-Difluorophenylamino)-9-cyclopentyl-91--purin-2 ylamino)cyclohexanol (1 mmol, 1 eq.) DCC (2 mmol, 2 eq.), BOC-glycine (1.12 mmol, 1.12 eq.) and DMAP (1.12 mmol, 1.12 eq.) were mixed in 20 mL DCM and stirred at room temperature for 2 days. Water and EtOAc were added, the phases were separated and the organic phase was dried over MgSO 4 . Solvent was evaporated and the residue was purified 15 using column chromatography to give the desired Boo protected product. [00275] The Boc protected product (-1 mmol, 1 eq.) was dissolved in 15 mL DCM and 4 ml TFA were added. The reaction mixture was stirred for about one hour and the solvent was evaporated. EtOAc and sat. NaHCO 3 solution were added and the phases separated. The organic phase was dried over MgSO 4 and the solvent was evaporated. The residue was 20 purified using column chromatography/HPLC to give the desired product. [00276] Example 5.11 Synthesis of 3

-(

8 -(2-Fluorophenylamino)-9-cyclopentyl 9 H-purin-2-ylamino)benzamide -146- HNOC>-NH F [002771 To a cooled solution (0*C) of the cyano compound (100 mg, 0.24 mmol) in ethanol (1 mL), sodium hydroxide (18 mg, 0.46 nimol) and hydrogen peroxide (30%, 53 p.L, 0.48 mmol) were added. The reaction mixture was stirred for about 4 h at room 5 temperature. Only starting material was observed by LCMS. Another 18 mg of sodium hydroxide and 53 pL of hydrogen peroxide were added and the reaction mixture was stirred for about another 8 h. Still only starting material was observed. The reaction was heated to 60*C for about 4 h. Product formation was observed together with traces of carboxylic acid. The reaction was quenched to pH=7 with 6N HC1 . The crude reaction mixture was 10 purified using semi-preparative reverse-phase HPLC (15% acetonitrile/water (0.1% TFA) -+ 80% acetonitrile/water (0.1% TFA) over 30 min) to yield 35 mg of amide as a solid after neutralization of the TFA salt. LRMS (ES) m/e 432 [MH]*. [00278] Example 5.12 Synthesis of 2 -((3-(2-(Piperidin-1-yl)ethoxy)phenyl) amino)- 9 -cVcloentyl-8-((2-fluorophenvl)amino)-9H-purine NH F NN 15 [002791 In a round bottom flask, sodium hydroxide (0.585g, 14.6 mmol) was dissolved in 10 mL of water. THF (20 mL), 3- {[ 4 -(cyclopentylanino)-5-nitropyrimin-2 yl]amino)phenol (1.1 5g, 3.66 mmol), and piperidyl ethyl chloride hydrochloride (0.81 g, 4.39 mmol) were added. The reaction mixture was heated at about 55 0 C overnight. The 20 reaction was monitored by LC-MS. The reaction mixture was poured in aqueous sodium bicarbonate solution and the crude was extracted in ethyl acetate. The combined organic -147were dried over sodiuin sulfate and evaporated to dryness. The desired product was isolated as a solid (1.338g, 98% yield) E5-MS (nVz) 427.3. [00180] Example 5.13 Synthesis of 8-((2-Fluorophenyl)amino)- 2-((4 methoxiphenylemiino).9l-purie Y)NH F 5 [00281] The cyaioethyl substituted compound (0.17 mmol) was dissolved in a mixture of THF:H 2 0 (8:2, 10 mL) and lithium hydroxide (1.05 mmol) was added. The reaction mixture was stirred at about 50*C for about 72 h. The solvent was removed in vacuo and the residue was purified using column chromatography (SiO 2 ) or reverse-phase 10 HPLC. [00282] Example 5.14 Synthesis of 4-({9-(2H-3,4,5,6-tetrahydropyranA-yl)-8-[(2,4 difluorophenl)aminolpurin-2-yllamino)thiane-1.1 -dione NF F [00283] 2

H-

3

.

4 .5.

6 -Tetrahydropyran-4-yl[5-nitro-2-(thian-4-ylamino)rimidin-4 15 yllamine [002841 2H-3,4,5,6.Tetrahydropyran-4-yl(2-chloro-5-nitropyrimidin-4-yl)amine (3.14 mmol, 810.6 mg, obtained from 2,4-dichloro-5-nitropyrimidine and 4-aminotetrahydropyran following the method described in Example 5.1) and 4-aminotetrahydrothiopyran (3.77 mmol, 441 mg, obtained following the procedure described in PCT Int. Appl. WO 20 2002083642) were dissolved in DMF (20 mL). NN-Diisopropylethylamine (3.77 mmol, 0.67 mL) was added and the reaction was stirred at room temperature overnight. DMF was -148'removed in vacuo and the crude was sonicated with ethyl acetate. Th precipitate was filtered to yield the title compound (992 mg, 93% yield). ES-MS: 340 (M+l). [00285] 2H-3,5,6-tetrahydropYr- 4-ylf5-amino-2-(thian-4-ylaminolpyrimidin-4 yllamine 5 [00286] The title compound (760 mg 93% yield) was obtained from 2H-3,4,5,6 tetrahydropyran-4-yl[5-nitro-2-(thian-4-ylamino)pyrimidin-4-yl]amine (2.63 mmol, 892 mg) by catalytic hydrogenatiofi following the procedure described in Example 5.1, step 3. ES MS: 310 (M+1). [002871 1942H-345,6-Tetrahydropyran-4-yl)-2-(ian 4ylaminolpurin-8-yly2,4 10 difluorophenvl)anine [00288] The title compound (577.1 mg, 71/ yield) was obtained from 2H-3,4,5,6 tetahydropyran-4-yl[5-4-yla2(tan4ymino)pyrim-idin4-yl]amine (1.81 mmol, 560 mg) and 2

,

4 -difluorophenylisothiocyanate following the procedure described in Example 5.1 step 4. ES-MS: 447 (M+1). 15 [00289] 4-(f 9-2H-3.

4 .5.

6 -teraydrovan-4-yl-84(2,4-difluorophenyl)lminopurin 2-yllamino)thiane- 11-dione [00290] [9-(2H-3,4,5,6-tetrahydropyran-4-yl)-2-(thian-4-ylamino)purin-8-91](2,4 difluorophenyl)amine (1.2 mmol, 537 mg) was dissolved in methylene chloride (15 mL) and 3-chloroperoxybenzoic acid (2.64 mmol, 591 mg) were added. The reaction was stirred at 20 room temperature for 18 h. The reaction mixture was washed with saturated solution of sodium bicarbonate (10 mL) and extracted with chloroform (3 x 15 mL). The organic layer was dried over magnesium sulfate and filtered. Solvent was removed In vacuo and the residue was purified by column chromatography (SiO 2 , 10% Methanol/ ethyl acetate) and reverse-phase HPLC (20% acetonitrile/ water (0.1% TFA) to 100% acetonitrile/ water 25 (0.1% TFA) over 30 min) to yield the title compound (146 mg, 25% yield). ES-MS: 479 (M+1). [002911 Example 5.15 Synthesis of 4-{ 8

-[(

2 ,4-difluorophenyl)amino]-2-[(4-trans hvdroxycyclohexyl)aminolurin-9-yllthiane-11-dione - 149- 0 N N F [00292J 4

-({

8

-[(

2 ,4-Difluorophenyl)amino)-9-thian-4-ylpu.rin-2-yl)amino)-trans cyclohexan-1-ol (0.49 mmol, 225 mg), obtained from 4 -aininotetrahydrothiopyran (PCT Int. Apple. WO 2002083642), trans-4-arhinocyclohexanol and 2,4-difluorophenyl isothiocyanate 5 following the general procedure described in Example 5.1, were dissolved in methylene chloride (5 mL), and 3 -chloroperoxybenzoic acid (1.08 mmol, 241mg) was added. The reaction was stirred at room temperature for 18 h. The reaction mixture was washed with saturated solution of sodium bicarbonate (5 mL) and extracted with chlorofdrm (3 x 10 mL). The organic layer was dried over magnesium sulfate and filtered. Solvent was removed in 10 vacuo and the residue was purified by column chromatography (SiO 2 , ethyl acetate to 2% methanol/ ethyl acetate) and reverse-phase HPLC (20% acetonitrile/ water (0.1% TFA) to 100% acetonitrile/ water (0.1% TFA) over 30 min) to yield the title compound (88.4 mg, 36% yield). ES-MS: 493 (M+1). [00293] Example 5.16 Building block involved in the synthesis of: H HH F 15 [00294] (SS)-5-aminopiperidin-2-one, hydrochloride O NH

NH

2 HCI [00295] (2S)-2-[(tert-Butoxy)carbonylaminol-4-(methoxycarbonylibutanoic acid - 150 - [00296] L-Glutamic acid 5-methyl ester (91.3 mmol, 14.7 g) was added to a solution of triethylamine (274 muol, 8 mL) in DMF (350 rnL). Di-t-butyl dicarbonate (183 mmol, 40g) was added and the reaction was stirred at 50 6C for 1 hour and then at roin temperature overnight Solvent was removed In vacuo and the crude material was purified 5 by column chromatography (SiO 2 , 1:1 n-hexanes/ ethyl acetate to ethyl acetate) to yield the title compound (20.36 g, 85% yield). ES-MS: 262 (M+!). [00297] Methyl ( 4

S-

4 -r(tert-buto)carbonylamino}-5-hvdrotypentanoate [00298] In a round-bottoni flask, ( 2 S)-2-[(tert-butoxy)carbonflaino]74 (methoxycarbonyl)butanoi6 acid (78 mmol, 20.36 g) was dissolved in THF (300 mL). The 10 solution was cooled to -100C and N-rmethylmorpholine (78 mmol, 8.58 mL) and ethyl chloroformate (78 mmol, 7.48 rnL) were added, followed by sodium borohydride (234 mmol, 8.85 g). The reaction was stirred for 30 min at this temperature and then quenched by slow addition of saturated solution of ammonium chloride until no further evolution of hydrogen was observed. The reaction mixture was then extracted with ethyl acetate and 15 dried over magnesium sulfate. After filtration, solvent was evaporated and the crude material was purified by column chromatography (SiO 2 , 1:1 n-hexanes/ ethyl acetate) to yield the title compound (l1.68g, 61% yield). ES-MS: 248 (M+1). [002991 Methyl ( 4

S)-

4 -[(tert-butox)carboylaminol-5-((4-methylphenyl) sulfonyloxyl pentandate 20 [00300] Methyl ( 4

S)-

4 -[(tert-butoxy)carbonylamino]-5-hydroxypentanoate (9.11 mmol, 2.25 g) was dissolved in 30 mL of methylene chloride. p-Toluenesulfonyl chloride (9.1 mmol, 1.7 g) and triethylamine (27.33 mmol, 3.8 mL) were added and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and crude was purified by column chromatography (SiO 2 , 4:1 n-hexanes/ ethyl acetate to 7:3 n-hexanes/ 25 ethyl acetate) to yield the title compound (1.98 g, 54% yield). ES-MS: 402 (M+l). [003011 Methyl ( 4 S)-5-azido- 4 -(tert-butoxy)carbonylaminolpentanomtb [00302] Methyl ( 4

S)-

4 -[(tert-butoxy)carbonylamino]-5-[(4-methylphenyl) sulfonyloxy] pentanoate (4.93 mmol, 1.98 g) was dissolved in DMF (15 mL) and sodium azide (14.8 mM'ol, 0.961 g) were added. The reaction was heated at 500C for 3 hours. The 30 reaction mixture was filtered and the solvent was removed in vacuo. The crude was purified by flash chromatography (SiO 2 , ethyl acetate) to yield the title compound (1.07 g, 80% yield). ES-MS: 273 (M+l). -151 - [00303} N-((3S -6-oxo3-piperidyl))(tert-butoxy)carboxamide [00304] Methyl (4')-5-azido-4-[(tert-butoxy)carbonylainno]pentanoate (3.9 mmol, 1.07 g)-was dissolved in methanol (10 mi.), and 10% palladium on carbon (0.1 g) was added. The reaction was stirred ovemight under 1 atm of hydrogen. The reaction was 5 filtered and the solvent was removed in vacuo to yield the title compound (0.83 g, 99% yield). ES-MS: 215 (M+1). [00305] (5 )-5-amiinoiperidin-2-onet.hydrochloride [00306] N.((3S)-6-Oxo(3-piperidyl))(tert-butoxy)carboxamide (3.9 mmol, 0.83 g) were dissolved in ethanol (10 mL) and cooled to 0 0 C. Acetyl chloride (2 mL) was added 10 and the reaction was allowed to reach room temperature. The reaction was stirred for 1 hour after which the solvent was removed in vacuo to yield the title compound (725 mg, 99% yield) as the dihydrochloride salt. ES-MS: 115 (M+1). [00307] Example 5.17 Building block used for the synthesis of: Ha N NH11 N F F l and 15 [00308] (5R)-5-aminopiperidin-2-one, hydrochloride 0 NH

NH

2 HCI [00309] The title compound was prepared as described in Example 5.15, starting from D-glutamic acid 5-methyl ester. [00310] Example 5.18 Building block used for the synthesis of: 20 NH N -152- [003111 Synthesis of 6 -chloro-2-fluorobenzeneisothiocyanate CI IN; S [00312] A solution of 2 -chloro-6-fluoroaniline (767 mg, 5.29 mmol) in tetrahydrofuran (5 ml) was added drop wise with stirring to a solution of di-2-pyridyl 5 thionocarbonate (2.46 g, 10.58 mmol) in tetrahydrofuran (7 ml) at room temperature. The reaction mixture was stirred for 60 hours at room temperature and then the solvent was evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with pentane. Fractions containing clean product were combined and the solvent evaporated to give the title compound (167 mg, 17%): 'H NMR (400 MHz, CDCl 3 ) 87.19 10 7.23 (m, 1H), 7.12-7.19 (m, 1H), 7.04-7.10 (m, 111). [003131 Example 5.19 Building block used for the synthesis of: HOO NH [00314] Synthesis of 3 -fluoropyridin-2-isothiocyanate CF S 15 [003151 A solution of 3 -fluoro-pyridin-2-ylamine (928 mg, 8.28 mmol) in dichloromethane (3 mL) was added dropwise with stirring to a solution of thiophosgene (1.9 mL, 24.83 mmol) in dichloromethane (6 mL) at 0 "C. The reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution 20 extracted 3 times with dichloromethane. The organic layers were combined and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 10% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (479 mg, 3 7%): 'H NMR (400 MHz, CDCl 3 ) 8 8.22-8.23 (h-, 1H), 7.48-7.52 (m, 1H), 7.21-7.26 (m, 1H). - 153 - [00316] ExaIple 5.20 Building block used for the synthesis of;

H

2 F F H [00317] Synthesis of methyl (2E)(4S)-4-aminopent-2-enoate hydrochloride

H

2 N O 5 H-Cl O [00318] ( 2

S)-

2 -r(tert-Butoxylcarbonylaminol-N-methoxy-N-methylpropanamide [00319] To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane (170 ml) was added HOBT (14.28 g, 105.7 mmol) and N, 0-dinethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then 10 triethylamine (30 ml, 211.4 mnol) and 1,3-dicyclohexylcarbodiimide (21.81g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with 1N aqueous sodium hydroxide (50 mL), twice with 10 % aqueous citric acid (50 mL), and 15 once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81%): ES-MS (m/z) 233.2 [M+1]*. 20 [00320] Methyl ( 2

Y

4 S)-4-[(tert-butoxy)carb6nylainolpent-2-enoate [00321] A solution of ( 2 S)-2-[(tert-butoxy)carbonylamino]-N-methoxy-N methylpropananide (13.05 g, 56.18 mmol) in ethyl ether (560 mL) was chilled with an ice water bath and then 95 % lithium aluminum hydride (2.80 g, 70.23 mmol) was added. The reaction was stirred at room temperature for 20 minutes and then a solution of aqueous 25 potassium hydrogen sulfate (300 mL, 0.33M) was added. The resulting mixture was -154extracted three times with ethyl ether. The combined organic layers were washed three times with IN hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate, and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting solid was dissolved in anhydrous tetrahydrofuran 5 (430 mL) then added to a cold solution of trimethyl phosphonoacetate (27.3 mL, 168.5 mmol) and sodium hydride (112 mmol) in anhydrous tetrahydrofiran (130 mL) that had been previously stirred at room temperature for 30 minutes. The reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes, and then Water (500 mL) was added. The reaction mixture was diluted with brine and ethyl acetate, stirred, and the 10 layers separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 0-30 % ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (8.85 g, 69%): ES-MS (m/z) 230.4 [M+1]*. 15 [00322] Methyl ( 2 E)4S)-4-aminpent-2-enoate hydrochloride [003231 A solution of methyl ( 2

E)(

4 5)-4-[(tert-butoxy)carbonylamino]pent-2-enoate (3.083 g, 13.45 mmol) in 4N hydrogen chloride in dioxane was stirred at room temperature for 1 hour. The volatiles were evaporated to give the title compound (2.2 g, 98 %): ES-MS (m/z) 130.3 [M+1] 4 *. 20 [003241 Methyl ( 4

)-

4 -(5-amino-2-f(methylethy)aminolvrimidin-4 yl)amino)pentanoate [00325] A solution of methyl ( 2

E)(

4 S)-4-aminopent-2-enoate hydrochloride (1.7 g, 10.31 mmol) in tetrahydrofuran (7 mL) was added drop wise to a solution of 2,4-dichloro-5 nitropyrimidine (2.0 g, 10.31 mmol) and diisopropylethylamine (3.6 mL, 20.6 mmol) in 25 tetrahydrofuran (17 mL) chilled at -78 "C. The reaction was stirred at -78 *C for 1 hour and then at room temperature overnight. The was solvent was evaporated and the resulting residue was purified by chromatography on a normal phase silica gel column with 0-20 % ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give 2.35 g white solid. To the solid were added anhydrous NN 30 dimethylformamide (40 mL), diisopropylethylamine (1.44 mL, 8.25 mmol), and isopropylamine (0.70 mL, 8.25 mmol). The mixture was stirred at room temperature for 70 hours, diluted with water, and extracted three times with dichloromethane. The organic - 155 layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. To the resulting oil was added anhydrous ethanol (50 n) and 100 % palladium on carbon (200 mg). The solution was treated with hydrogen gas from a balloon and stirred at room temperature overnight. The relation mixture was filtered and the solvent evaporated 5 to provide the title compound (2.24 g, 77 */): ES-MS (mlz) 282 [M+1]*. [00326] (4S)-4-[2-r(methylethylaminol-8-r(2,4,6-trifluoropheniylaminoprin-9 Yllpentanamide [003271 A solution of methyl ( 4 S)-4-{2-[(methylethyl)t8ino]-8-[(2,4;6 trifluorophenyl)amino]purin- 9yl)pentnoate (500 mg, 1.15 mmol) in anhydrous methanol 10 (25 mL) at -78 *C was saturated with ammonia gas. The solution was sealed in a reaction tube and allowed to warm to room temperature followed by heating at 40 0 C for 2 days. The solvent was evaporated and the resulting residue was purified by chromatography on a normal phase silica gel column with 70-100 % ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (223 15 mg, 46 %): ES-MS (m/z) 422.3 [M+1]*. [00328] Example 5.21 Building block used for the synthesis of:

NH

2 Q NN F F [00329] Synthesis of methyl ( 2

E)(

4 R)-4-amnopent-2-enoate hydrochloride H2N 10 01 H-Cl 0 20 (00330] (2R)-2-[(tert-Butoxy)carbonlaminol-N-methoxy-N-methylranamide [00331] The title compound was prepared as ( 2

S)-

2 -[(tert-butoxy)carbonylamino]-N methoxy-N-methylpropanamide with boc-D-alanine (20 grams, 105.7 mmol) to give the title compound (21.7 g, 88%): ES-MS (m/z) 233.2 [M+1]*. [00332] Methyl (2E)(4R)4-(tert-butoxy)carbonylaminolpent-2-enoate - 156 - [00333] The title compound was prepared as Methyl (2E)(4S)-4-[(tert butoxy)carbonylamino]pent-2-enoate with (2R)-2-[(tert-butoxy)carbonylamino]-N methoxy-N-methylpAnamide (13.05grams,.18 mmol) to give the title compound (10.2 g, 79 %): ES-MS (m/) 230 [M+1] 5 [003341 Methyl ()(4)-4,aniinopent-2-enoate hydrochiide [00335] A solution of methyl ( 2 E)(4R)-4.[(tert-butoxy)carbonylamino]pent-2-enoate (3.61 g, 15.75 mniol) in 4N hydrogen chloride in dioxane was stirred at room temperature for I hour. Thevolatiles were evaporated to give the title compound (2.6 g, 98 o): ES-MS (m/z) 130.3 [M+1]+. 10 [0O3361 Methyl ( 4

R)-

4 -({ 5-amino-2-[(methylethylaminolpvrimidin-4 yllamino)pentanoate [00337] The title compound was prepared as methyl (4S)-4-({5-amino-2 [(methylethyl)amino]pyrimidin-4-yl)amino)pentanoate with methyl (2E)(4R)-4-aminopent 2-enoate hydrochloride (1.7 g, 10.31 mmol) to give the title compound (2.17 g, 75 %): ES 15 MS (m/z) 282 [M+1]*. [003381 (4R)-4-f2-I(Mthlethyllaminol-8-f(2.4,6-trifluropherivIlainojurin-9 vli pentanamide [00339] The title compound was prepared as (4S)-4-{2-[(methylethyl)amino]-8

[(

2

,

4

,

6 -trifluorophenyl)amino]purin-9-yl)pentanamide with methyl (4R)-4-{2 20 [(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}pentanoate (500 mg, 1.15 mmol) to give the title compound (273 mg, 57%): ES-MS (m/z) 422.3 [M+1] . [00340] Example 5.22 Building block used for the synthesis of: F F )-NH H -157 - [00341] Synthesis of 4-Aminopiperidyl vrrolidinyl ketone

NH

2 N (00342] (tert-Butoxy)-N-fl-(vrrolidinvlcarbonyl)(4-ieridvlfcarboxanide [00343) 1-Pyrrolidine carbonylchloride (1.10 g, 9.99 mmol) was dissolved in 400 ml 5 if dichloromethane under N 2 . (Tert-butoky)-N-(4-piperidy)carboxniide (2.0 g, 9.99 mmol) and triethyl amine (1.40 mL, 9,99 mmol) were added and the reaction mixture was stirred for three days. The reaction was quenched with sat. NaHCO 3 solution and extracted with dichlorormethane. The combined organic phases were dried over MgSO 4 and the solvent evaporated to give the product as a white solid. (2.63 g, 8.84 mmol, 89 %). 10 [003441 4-Aminopiperidyl pyrrolidinyl ketone [003451 (tert-Butoxy)-N-[1-(pyrrolidinylcarbonyl)(4-piperidyl)]carboxamide (2.0 g, 6.73 mmol) was dissolved in 40 mL dichloromethane and trifluoroacetic acid (15 mL, 201.94 mmol) were added. The reaction mixture was stirred for 4 hours. The solvent was evaporated to give the product as a light brown semi-solid, which was used directly for the 15 next step. (2.09 g, 6.73 mmol, 100 %). [00346] Example 5.23 Synthesis of 4-[(R)-8-(2,4-difluoro-phenylamino)-9-(4 hydroxy-cyclohexvl)-7H-purin-2-vlamino}-cyclohexanone H H F 4 -[(R)-8-(2,4-Difluoro-phenylamino)-2-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-7H 20 purin-9-yl]-cyclohexanol (0.62 g, 1.7 mmol) was dissolved in 25 mL of methylene chloride under an N2 atmosphere. Trifluoroacetic acid (5 mL) was then added dropwise via addition funnel. After stirring for 24 h the resulting reaction mixture was concentrated under reduced pressure. Saturated sodioum bicarbonate was added to the resulting residue until pH 12. The basic aqueous layer was then extracted using chloroform (2 x 75 mL). The - 158 combined organic layers weredried with MgSO4 The rude Product was then purified on the preparatory HPLC using a 5-70% CH3NH20 over 39 minutes method. Fractions of greater then 98% purity via analytical HPLC were combined and concentrated. Excess trifluoroacetic acid was removed by washing the product with 1.75 Mptassium carbonate 5 (3 x 100 mL). The organic layers were then concentrated to dryness under vacuum to give the ketone (0.015g 0.033 mmol, 12%) as fine white powder: LC-MS (m/z) 457.1 [M+1]+. [00347] Example 5.24 buildingg block used for the synthesis of: HN (00348] Synthesis of (S)-(-)-4-amino-2-pyrrolidinone tJHg 10 [00349] (S)-(- 4 -azido-2-pyrrolidinone (00350] To an ice cooled solution of (R)-(+)-4-hydroxy-2-pyrrolidinone (25.0 g., 247 mmol) in dichloromethane (300 mL) was added triethylamine (17.0 g., 168.7 imol) and methane sulfonyl chloride (21 mL, 272 mmol) dropwise. The solution was stirred at 15 ambient temperature for one hour. The-reaction was monitored via TLC (100% ethyl acetate using permanganate stain). The solution was then condensed under reduced pressure to give a solid. The solid was diluted with DMF (300 mL) followed by the addition of sodium azide (48.24 g., 742 mmol). The solution was heated to 60 0 C for 3 hours. The reaction was monitored via TLC (100% ethyl acetate using permanganate stain). The 20 solution was then condensed under reduced pressure and the resultant oil purified via silica gel chromatography (50-80% acetate/hexanes followed by 12% methanol/dichloromethane) to afford the title-compound (10.2 g., 32%). 'H-NMR (CD 3 OD) 8 4.43 (m, 1H), 3.71 (dd, IH), 3.34 (m, IH), 2.75 (dd, 1H), 2.29 (dd, 1I). [00351] (S-(-)-4-amino-2-pyrrolidinone: 25 [00352] To a solution of (S-(-)-4-azido-2-pyrrolidinone (10.2 g., 80.8 mmol) in THF (450 mL) was added triphenylphosphine resin bound (40.5 g., 3minol comp/1.Og resin). -159- The solution was heated to 60*C for two hours. The evolution of nitrogen gasfrom the solution is an indicator of the reaction proceeding. The reaction is monitored via TLC and permanganate stain for completion. The solution was filtered through a glass frit and the resin bound product is then added to another reaction vessel and diluted with water 5 (500mL). The solution was heated to 70 0 C for sixteen hours. The solution filtered through a glass frit and the aqueous filtrate was condensed under reduced pressure and chased with toluene (3X) to afford the title compound upon vAcuum (5.62 g., 62%). 1 H- NMR (CD 3 0D) 8 3.68 (m, IH), 3.56 (m, IH), 3.04 (m, 1,H), 2.54 (m, EH), 2.05 (m, IH). [00353] Example 5.25 Synthesis of 5-[9-Cyclopentyl-8-(2,4,6 10 trifluorophenylamino)-9H-purin2-vlaminolnyridine-2-ol HO & [003541 9-Cyclopentyl-N2-(6-methoxypyridin-3-yl)-N8-(2,4,6-trifluorophenyl)-9H purine-2,8-diamine (0.350 g., 0.769 mmol) was dissolved in 30% HBr/acetic acid in a sealed tube and heated to 80 oC for 16 hours. Product confirmed by LC-MS. The solution was 15 partitioned between 1.75 M potassium carbonate and ethyl acetate (3X). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The resultant solid was purified via preparative HPLC (5-55% acetonitrile/water, 20mL/min.) to afford the title compound (0.212 g, 34%). ES-MS (m/z) 442 [M+l]+. Melting point 257-260*C. 20 100355] Example 5.26 Building block used for the synthesis of (S)-3-[8-(2,4 trifloro-phenvlamino)-2-isop~repylamino-purin-9-yll-butyamide 0 NH2 HN N N ),"->-NH F F [00356] (S)-(-)-3-Aminobutyramide hydrochloride [003571 To a solution of ( 3 S)-3-[tert-butoxycarbonyl)anino]butanoic acid (2 g, 9.8 25 minol) in acetonitrile (10 mL) was added HBTJ (4.8 g, 12.7 mmol), ammonium chloride -160 - (2.6 g, 49 rinmole) at room 'temperature. The reaction mixture was cooled to OCand diisopropylethyl amine (10.0 g, 78 mmole), Th ice-water bath was removed and the brown mixture was stirred under nitrogen for 12 hours. The solvent was removed In vacud and the residue was dissolved in dichloromethane (100 mL). The organic phase was washed with 5 sodium carbonate aqueous solution (saturated). The organic phase was dried with brine followed by sodium sulfate, which was subsequently filtered. The organic phase was concentrated and purified by normal phase silica gel chrormatography (50% ethyl acetate/hexane followed by 10 % methanol/dichlororethane)t afford partly unified fractions, which were combined and used in the next reaction. The crude aide was 10 dissolved in 10 mL dry dioxane and cooled to 0*C in an ice/water bath. 4N HCI in dioxane solution (12.2 mL, Aldrich) was added dropwise and the mixture was stirred for 3 houis at room temperature. The solvent was removed in-vacuo to afford oily solid which was not purified further but was suspended in THF (5 mL). Dilsopropylethyl amine (2.53 g, 19.6 mmole) was added to create a slurry. 15 [00358] (S)-3-(2-Chloro-5-nitro-pyrimidin-4-vlamino)-buamide [00359] - 2 ,4-dichloro-5-nitropyrimidine (1.9 g, 9.8 mmole) was added to a oven-dried 100 ml round-bottomed flask and THfF (27 mL) was added to afford a solution. The mixture was cooled to -78*C under nitrogen atmosphere and the slurry (Step A) was added dropwise. The reaction mixture was stirred at -78 0 C for 30 minutes and then warmed to room 20 temperature over 3 h. Water (10 mL) was added to the mixture and the organic solvent was removed in vacuo. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the resulting organic phase was dried with brine. The organic phase was concentrated to a residue. Normal phase silica gel chromatography (5-50% ethyl acetate/hexane) of the residue afforded the title compound (761 mg, 30% overall): ES-MS (m/z/) 260.0 [M+1f. 25 The intermediate was employed according to the standard procedure to provide (S)-3-[8 (2,4,6-trifluoro-phenylamino)-2-isopropylamino-purin-9-yl)-butyrade. [00360] Example 5.27 Building block used for the synthesis of (R)-3-[8-(2,4,6 trifluoro-phenylamino)-2-isopropylamino-purin-9-yll-butymide - 161 - _NH2 HNlN F (00361] (R)-3-(2-Chloro-5-nitro-pyrimidin-4-ylamino)-butyramide was similarly prepared (586 mg, 23% overall yield): ES-MS (m/z/) 260.0 [M+1] . The intermediate was employed according to the standard procedure to provide (R)-3-[8-(2,4,6-trifluoro 5 phenylamino)-2-isopropylamino-purin-9-yl]-butyramide. [00362] Example 5.28 Building block used for the synthesis of 4-[9-(R)-1,1-dioxo tetrahydro-ll 6 -thiophen-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-puin-2 ylaminol-cyclohexanol 0'O 'T'HIo> H F F 10 [00363] Preparation of (R)-tetrahydro-3-thiopheneamine hydrochloride [00364] Synthesis of title compound was performed according to Dehmlow, E.V et al. Synthesis 1992, 10, 947-9. Amine hydrochloride was employed in usual manner to afford 4-[(R)-9-tetrahydro-thiophen-3-yl-8-(2,4,6-trifluoro-phenflamino)-9H-purin-2 ylamino]cyclohexanol. 15 [00365] Synthesis of 4-r9-(R)-l i-dioxo-tetrahydro- 1X 6 -thiophen-3-yl)-8-(2,46 trifluoro-phenylamino)-9H-purin-2-vlamino]-cyclohexanol [00366] 4-[(R)-9-Tetrahydro-thiophen-3-yl-8-(2,4,6-trifluoro-phenylamino)-9H purin-2-ylamino]cyclohexanol (100 mg, 0.21 mmole) was dissolved in MeOH (1 mL) and the mixture was cooled to 0*C with ice/water bath. Oxone (338 mg, 0.52 mmole) was 20 dissolved in water (1 mL) and the solution was added dropwise to the former mixture at 00C with vigorous stirring. The bath was then removed and the cloudy mixture was stirred at room temperature for 10 minutes. The mixture was added to dichloromethane (100 mL) and the organic phase was washed with sodium carbonate (aqueous), brine and dried over -162sodium sulfate. After filtration, the solvent was removed and the residue was subjected to silica gel chromatography (5-10*/o methylene chloride/methanol) to afford sulfone (59 mg, 57%): ES-MS (re/z) 497.0 [M+1]*. [00367] Example 5.29 Building block used for the synthesis of 4-[9-(S)-1,1 -dioxo 5 tetrahydro- I X 6 -thiophen-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2 Vlaminol-cyclohexanol Q H N F F [003681 Preparation (S)-tetrahydro-3-thiopheneamine hydrochloride 10 [00369] Synthesis of title compound was performed according to Dehmlow, E.V.; Westerheide, R.;. Synthesis 1992, 10, 947-9. Amine hydrochloride was employed in usual manner to afford 4-[(S-9-Tetrahydro-thiophen-3-yl-8-(2,4,6-tfluoro-phenylamino)-9H purin-2-ylamino]cyclohexanol. [00370] Synthesis of 4-[9-(S)-1.1-dioxo-tetrahydro-1 'X-thiophen-3-yl)-8-(2,4,6 15 trifluoro-phenylamino)-9 H-purin-2-ylaminol-cyclohexanol [00371] Synthesis of sulfone was similarly performed to afford 4-[9-(S)- 1,1 -dioxo tetrahydro-1X6-thiophen-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-ylamino] cyclohexanol (51 mg, 49%): ES-MS (m/z/) 497.0 [M+I]*. [00372] Example 530 Building block used for the synthesis of: HO N H 20 [00373] Synthesis of 4

-[

9 -((1S, 2 R)-2-methyl-cyclopentvl)-8-(24,6-trifluoro phenylamino)-9H-purin-2-ylaminol-cyclohexanol [00374] Preparation of cyclopentanamine, 2-methyl. hydrochloride, (IS, 2R)- (9Cl) - 163 - [00375] Synthesis of title compound was performed according to Wiehl, W.; Frahn, A. W.;Chemische Berichte 1986 119(8), 2668-77. Amine hydrochloride was employed in usual manner. [00376] Example 5.31 Building block used for the synthesis of 4-[9-((IR,25)-2 5 Methyl-cyclpenty)-8-(2,4,6,-trifluoro-phenylamino)-9H-purin-2-ylamino] cyclohekanol HO~.QI '~( >- NH F HO, FF F 10 [00377J Preparation of cyclopentanamine, 2-methyl-, hydrochloride, (R2S- (9CIl [00378] Synthesis of title compound was performed according to Wiehl, W.; Frahm, A. W.;Chemische Berichte 1986 119(8), 2668-77. Amine hydrochloride was employed in usual manner. [003791 Example 5.32 Building block used for the synthesis of: 0 H OH N IyH F F F [00380] Synthesis of methl 4-amino-1 -hidroxvcyclohexanecarboxylate hydrochloride -164-

NH

2 H-CI 0 [00381] ((1S)-1 -Phenylethyl)(1.4dioxaspiror4.5ldec-8-yl)amhine [00382] 1, 4 -Dioxaspiro[4.5]decan-8-one (10g, 64.03 mmol) was dissolved in dry dichloroethane (300 mL) under an atmosphere ofnitroen. (1S)--phenylethylamine (8.96 5 mL, 70.43 ninol) was added ieat at romt erature f owed by sodium triacetexyborohydride (20.36 g, 96.04 mmol) neat in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of distilled water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. The 10 ffiltrate was concentrated under reduced pressure. A yellow oil was obtained of satisfactory purity based on (11.2g, 67% yield). M+l: 262. [00383] N-((1S)1-Phenvlethyl)-N-(I,4-dioxaspirof4.5ldec-8-yl)-2,22 trifluoroacetanide [00384] ((1S)-1-Phenylethyl)(1, 4 -dioxaspiro[4.5]dec-8-yl)amine (I l.2g, 42.85 mmol) 15 was dissolved in dichloromethane (135 mL) at room temperature. The solution was treated with pyridine (3.81 mL, 47. 14 mmol) and trifluoroacetic anhydride (7.15 mL, 51.42 mmol). The reaction was stirred over the week-end at room temperature. The completion of the reaction was ascertained by LC-MS. The reaction was washed with saturated ammonium chloride. After drying over sodium sulfate, the organic extracts were concentrated to a 20 yellow oil. The crude was used without further purification. [00385] N-((IS)-l-Phenvlethyl)-2,2,2-trifluoro-N-(4-oxocyclohexyl)acetamide [00386] N-((18)-l-Phenylethyl)-N-(1, 4 -dioxaspiro[4.5]dec-8-yl)-2,2,2 trifluoroacetamide (15.3 1g, 42.84 mmol) was dissolved in tetrahydrofuran (30 mL). The solution was treated with 30 mL of 3.0 N aqueous HCl, The reaction was heated to 50-60 *C 25 over 48h. The reaction was cooled to room temperature. THF was removed under reduced pressure. The crude product was extracted with dichloromethane and was purified by silica gel column fluentt 15-20% ethyl acetate in hexanes). The product was isolated as a yellow oil (5.49 g, 41% yield) M+l: 314. - 165 - [00387] N-((1 S)-1-Phenylethyl-N-[4-(. 1-dimethyl-1-silaethoxy)4 cyanocyclohexyll-2.2,2-triflioroacetamide [00388 N-((1 S)-1-Phenylethyl)-2,2,2-triflu6ro-N-(4-oxocyclohexy)acetamide (3.8g, 12.13 mmnol) was dissolved in 30 mL of dichloromethane. Znl2 (0.774g, 2.42 mol) was 5 added to the solution as a solid at room temperature followed by trimethylsilyl chloride (3.25 mL, 24.25 mmol). The reaction mixture was heated to reflux temperate. The conversion was monitored by LC-MS. After 4h, heating was stopped and the solvent was removed under reduced pressure. 50 mL of dry diethyl ether were added. The resulting cloudy suspension was evaporated to dryness. The resulting orange oil was re-suspended in 100 mL 10 of diethyl ether. A small amount of white solid was removed by filtration and was washed with a small volume of diethyl ether. The combined filtrates were evaporated to dryness and the residue was maintained under high vacuum overnight. The product was used without further purification (5.64g). M+1: 413. [00389] 4-[N-((1S)-1-Phenylethyl)-2.2.2-trifluoroacetylaminol-1 15 hydroxycyclohexanecarboxamide [00390] N-((1S)-1-Phenylethyl)-N-[4.(1 ,1-dimethyl-1-silaethoxy)-4 cyanocyclohexyl]-2,2,2-trifluoroacetamide (5.64 g, 13.67 mmol) was suspended in 15 mL of concentrated hydrochloric acid. The reaction was stirred at room temperature for 1.5 days resulting in the formation of a dark orange suspension..The solid was collected by filtration, 20 dissolved in 10 mL of methanol under mild temperature and slowly was precipitated out with water. (lightly colored solid separating from orange solution). The mother liquor was collected concentrated and the precipitation conditions were reproduced. This isolation step yielded overall 2.6 g of light yellow solid (5 %) clean by 'H and 1 9 F NMR. M+l: 359. [00391] Methyl -cis-4-amino- I-hydroxycyclohexanecarboxylate hydrochloride 25 [00392] 4-[N-((15)-1-Phenylethyl)-2,2,2-trifluoroacetylamino].-1 hydroxycyclohexanecarboxamide (2.6 g, 7.25 mmol) was suspended in 30 mL of concentrated hydrochloric acid and the reaction mixture was heated to 80"C for 6h (light yellow solution). The completion of the reaction was assessed by LC-MS. The reaction mixture was cooled to room temperature and 40 mL of methanol were added. The solution 30 was stirred at room temperature for 36 h. Methanol was removed under reduced pressure. Organic side products were removed by extraction in diethyl ether. The aqueous solution was concentrated under reduced pressure and the residue was dried overnight. Methyl-cis-4 -166amino-I -hydroxycyclohexanecarboxylate hydrochloride was isolated as a solid and was used without further purification. (quantitative yield). [00393] Example 5.33 Synthesis of 1-hydroxy-4-{2-[(inethylethyl)amino]-8-[(2,4,6 trifluorophenyl)aminolpurin-9-ylaciclohexanecrboxyccid HO ~-NH P 5 F [00394] Methyl 1-hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6 trifluorophenyl)amino]purin-9-yl)cyclohexanecarboxylate (1.858 g, 3.858 mmol) was dissolved in 27 mL of 4.0 N aqueous hydrochloric acid solution. The reaction mixture was heated to 60*C for 24 h. The mixture was then concentrated under reduced pressure to an oil 10 and purified by preparative HPLC (20-80 /o acetonitrile-water, 0.1 % TFA). The product was isolated is a white solid by filtration after evaporating acetonitrile from the combined fractions and neutralizing with concentrated ammonium hydroxide. (1.325 g, 73 % yield). [00395] Example 5.34 Building block used for the synthesis of N-cyclopentyl(1 hydroxy-4-{2- [(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)aminopurn 15 9-yllcyclohexyllcarboxamide -5;OH NNH > 1 /I;I>- NH F F [00396] 1-Hydroxy-4-{2-((methylethyl)amino]-8-[(2,4,6trifluorophenyl)amino]purin-9-yl)cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat 20 followed by di-isopropyl amine (0.105 mL, 0.6 mnnol). Benzotriazol-1 -167yloxytris(dimethylamino)phosphponium hexaflorophosphate (BOP) was ded last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confumed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid 5 was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66 % yield) M+1: 53 2. [00397_ Example 5.35 Buldingblock used for the synte of l-(hydro1ythyl)-4

{

2 -[(methylethy)amino]8-[(2,4,6-trifuorphrihylino]purin-9 10 Yllcyclohexan-1-ol HO O11H NH F F F [003981 Methyl 1-hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6 trifluorophenyl)aminolpuiin-9-yl}cyclohexanecarboxylate (0.300 g, 0.6 mmol) was dissolved in 3 mL of dry methanol. The solution was cooled to 0*C before addition of solid 15 sodium borohydride (0.300 g, 7.92 mmol). After lh at low temperature, the reaction was warmed to rt and stirred overnight. The reaction was quenched with 5 mL of a saturated solution of ammonium chloride. The crude product was extracted with dichloromethane (four times). The product was purified by column chromatography (75 % ethyl acetate in hexanes) followed by semi-preparative HPLC. The fractions were neutralized using a resin 20 exchange column. (0.101 g, 37 % yield). M+1: 451. [003991 Example 5.36 Building block used for the synthesis of: - 168 - F HO F HN N [00400] Synthesis of(3R M3-aninobutanol

NH

2 'R OH [00401] trLyl ( -34beazvff R)-1-phenylethvllaminolbutanoato 5 [00402] n-BuLi (29.5 mL, 47.3 mmol) was added via canula to a solution of (R)-(N benzyl)[N-(1-phenyl)ethyl]amine (10.0 g, 47.3 mmol) in THF (75 mL) at 0*C under N 2 . The reaction was stirred for 20 minutes, and subsequently cooled to -78 *C. tert-Butyl crotonate (3.5g, 24.6 mmol) dissolved in THF (30 mL) was added to the cooled reaction mixture over 20 minutes. After 75 minutes, the reaction was quenched with saturated 10 aqueous NH 4 CI and brine was then added. The layers were separated and the aqueous layer was further extracted with Et 2 0. The organics were combined, dried with MgSO 4 , filtered, and concentrated to a yellow crude oil. The crude product was dissolved in hexanes (100 mL) and washed with 10 % aqueous citric acid solution (3 x 25 mL). The organics were pooled, dried with MgSO 4 , filtered and condensed to yield 6.2 g (17.55 mmol, 37 %) of the 15 title compound. [00403] (3R-3-fbenzvlF(1R)-l -2henylethyllaminolbutanol [00404] tert-Butyl (3R)-3-{benzyl[(IR)-l-phenylethyl]amino}butanoate (6.2 g, 17.6 mmol) was dissolved in THF (100 mL). The IL-flask was purged with N 2 and cooled to 00C. Lithium aluminum hydride (2.7 g, 69.8 mmol) was slowly added over 5 minutes. The 20 reaction was allowed to stir at 00C for 1 hour, and then heated to 600C for 1 hour. The reaction was cooled to room temperature and diluted with Et 2 O (500 mL). This solution was quenched with a mixture of celite:Na 2

SO

4 10 H 2 0 (1:1) added over 15 minutes. The solution was then filtered and the mother liquor condensed to yield 3.9g (13.8 mmol, 78 %) of the title compound. 25 [004051

(

3 R)-3-Aminobutanol - 169 - [00406] (3R)-3.{benzyl[(1R)-1-phenylethyl]amino}butanol (3.9 g, 13.8 mmol), was dissolved in methanol (60 noL). Pearlman's catalyst was added to the reaction and subsequently pressurized to 30 psi with H2on a Parr shaker. After 24 hours, the reaction was filtered through celite and washed additionally with methanol (150 mL). This mixture 5 was condensed to yield 1.2 g (13.4 mmol) of the title product. [00407] Example 5.37 Building block used for the synthesis of: [004 081 Synthesis of trans-4-amino- 1-methylcyclohexanol

NH

2 SH-Cl 6H 10 [004091 trans-4-Dibenzlamininocyclohexanol [00410] To a solution of trans-4-aminocyclohexanol (7.90 g., 68.5 mmol) in acetonitrile (150 mL), was added cesium carbonate (51.4 g., 157.5 mmol) and benzyl bromide (18.2 g., 143.8 mmol). The solution was stirred at ambient temperature for 16 hours. The solution was complete by LC-MS and the mixture filtered through a frit, washed 15 with additional acetonitrile, and condensed under reduced pressure. The solid was partitioned between water and dichloromethane (500 mL) and dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (17.14 g, 85 %). ES-MS (m/z) 296.5 [M+1]*. [00411] trans- 4 -Dibenzvlaminocyclohexanone 20 [00412] Oxalyl chloride (12.89 g., 101.1 mmol) in dichloromethane (200 mL) was cooled to -78*C. DMSO (14.5mL) in dichloromethane (25 mL) was added by addition funnel slowly over 10 minutes until bubbling stopped. trans-4-Dibenzylaminocyclohexanol (17.14 g., 58.10 mmol) in dichloromethane (150 mL) as then dripped in slowly. After 30 minutes, triethylamine (56 mL) was then added dropwise and then the solution stirred at 25 ambient temperature. The reaction was monitored via TLC to assure starting material - 170 consumption. The solution was then condensed under reduced pressure and partitioned between water and ethyl acetate. The organic were dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The resultant oil waspurife via silica gel chromatography (30 % ethyl acetate/hexanes) to afford the title compound (13.71 g., 81 %). 5 ES-MS (m/z) 294 [M+1]*. [00413 franse4-Dibenzylamino- -methvlcyclohexanol: [00414] To i solution of trans- 4 -dibenzylaminocyclexanone (1,40 g, 4.77 nmnl) in THF at 00C (40 mL was added a .0 M methylmagnesium bromide souti on HF (6.36 mL, 19.1 mmol) dropwise. The solution was allowed to warm to ambient temperature and 10 allowed to stir for 16 hours. The solution was quenched with saturated ammonium chloride solution and partitioned between water and ethyl acetate (three times). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The resultant oil was purified via silica gel chromatography (15% ethyl acetate/hexanes) to afford the title compound (2.21 g, 17 %). ES-MS (m/z) 310.6 [M+1]+. 15 [00415] trans-4-Amino-1-methylcyclohexanol: [00416] To a solution of trans- 4 -dibenzylanino-1-methylcyclohexanol (2.21 g, 7.15 mmol) in ethanol (50 mL) was added palladium hydroxide (0.663 g, 30 % by wt.). The solution was flushed with fresh hydrogen gas and allowed to stir at ambient temperature for 16 hours. Starting material consumption was confirmed via LC-MS. The solution was 20 filtered through celite and washed with additional ethyl acetate. The filtrate was condensed under reduced pressure to afford the title compound (quantitative). ES-MS (m/z) 130.4 [M+l]*. [00417] Example 5.38 Amide Couplina OH N NN HONl i .)N FH .- NH F A F B F F 25 [00418] Amides coupling reactions as set forth above can be accomplished by Methods A-C described below. - 171 - [00419] Method A: HATU [00420] 0.164g (0.30 mmol) of A was dissolved in 5ml of DMF and 140g (1., eq.) of HATU was added in one lot The reaction was stirred at room temperature for about 0.5h under a nitrogen atmosphere, 0.040 g(1.2 eq.) of N-methylpiperazine was added and 5 stirring continued overnight. The reaction mixture was purified using preparative chromatography using a 15-40% gradient acetonitrile/water (0.1% TFA). After analyzing fractions by HI)LC, pure fractions were combined and concentrate to the TFA salt. TFA was exchanged using IN HOI and the TFA was extracted (1Oy I ml)ing eter pon neutralization of the aqueous layer, the freebase crashed out and was collected and dried to 10 give 0.020g of B in 10% yield. [00421] Method B: HATU/HBTU [00422] A solution of A (1 mmol) in 1Oml DMF (0.1 M) was treated with 1.2 eq. of HATU or HBTU (1.2 mmol) and stirred under a nitrogen atmosphere at room temperature for about 0.5 h and 1.2 eq of N-methylpiperazine (1.2 mmol) was added. The reaction 15 mixture was stirred at room temperature overnight. After concentrating the reaction mixture, it was purified using preparative chromatography. The clean fractions were combined and concentrated to the TFA salt. TFA was exchanged using IN HCl and the TFA was extracted with ether. Finally, the HCI salt was obtained upon concentration of the aqueous layer. 20 [00423] Method C: HOBT/EDCI [00424] A solution of A (1 minmol) in 1Oml DMF (0.1 M) was treated with 2.0 eq. of HOBT (2.0mmol), 2.4 eq of EDCI (2.4nmol), 2.4eq of the N-methylpiperazine (2.4mmol) and stirred under a nitrogen atmosphere at rom temperature overnight. After concentrating the reaction mixture, it was purified using preparative chromatography. The clean fractions 25 were combined and concentrated to the TFA salt. TFA was exchanged using IN HCl and the TFA was extracted with ether. Finally, the HCl salt was obtained upon concentration of the aqueous layer. [00425] Certain intermediates and reactants useful in the preparation of the aminopurine compounds can be prepared as described in Examples 5.15 to 5.29, below. 30 [00426] Example 5.39 Electron-poor Anilines -172- C N NiR RIHN N NHR

NH

2 NH 2 [004271 The chloropyrimidine compound is dissolved in acetic acid and the corresponding aniline is added. The reaction is stirred overnight at room temperature. Water is added to the reaction mixture until a precipitate forms. The precipitate is filtered out and 5 dried under high vacuum. [00428] Example 5.40 AcylationL/Mesylation/Chloroformylation of Amines [00429] An amine is suspended in methylene chloride and triethylamine is added. The mixture is stirred at room temperature until a clear solution is obtained. The corresponding acyl chloride, methanesulfonyl chloride or methyl chloroformate is added and the reaction 10 mixture is stirred for about 2 h. Typically, mono and diacylated compounds are obtained. The desired monoacylated product is obtained in a pure form after purification using semi preparative HPLC. [00430] Example 5.41 cis-Ethyl-4-aminoyclohexanecarboxylate Hydrochloride 0 OEt HCI

NH

2 15 [00431] 19.3 mL of concentrated hydrochloric acid (2.8 eq) was added to a solution of cis- 4 -aminocyclohexane carboxylic acid (10 g, 69.83 imol) in anhydrous ethyl alcohol (250 mL). Mixture was stirred overnight at about 60"C and then cooled to room temperature. Solvent was evaporated in vacuo. Crude material was then redissolved in acetonitrile, sonicated, and concentrated to a solid in vacuo. This acetonitrile wash was 20 repeated three times to obtain 11.5 g of while solid (96% yield). Tran.s-ethyl 4 aminocyclohexanecarboxylate hydrochloride can be prepared following the same procedure using trans-4-aminocyclohexane carboxylic acid. [00432] Example 5.42 Ester Hydrolysis (basic conditions) - 173 - [00433] The appropriate ester is added to a solution of 10 equivalent of LiOH in 1:1

THF/H

2 0. Gradually, the reaction mixture is heated to about 600C and stirred overnight. After about 12 h, the presence of the desired compound is verified via LC/MS. The reaction mixture is concentrated and IN HCl is added dropwise. The aqueou layers are extracted 5 with 2-butanone (3 x. 100 ml) and driqd With MgSO4. After filtering off the MgS04, the compound is concentrated under reduced pressure and purified using column chromatography or reverse-phase HPLC. [00434] Example 5.43 Ester Hydrolisis (acidic conditions) [00435] Carboxylic acid ethyl ester is dissolved in 2N hydrochloric acid. The 10 resulting solution is heated to about 750C and stirred for about three hours. After cooling to room temperature, excess aqueous ammonium hydroxide is added and the solvent is evaporated under reduced pressure. Trituration of the residue with ethanol, followed by filtration, gives the corresponding carboxylic acid. [00436] Example 5.44 Carboxamide Formation 15 [00437] Oxalyl chloride is added, under an N 2 W atmosphere, dropwise to a solution of the appropriate carboxylic acid in DCM. DMF is then added to the solution and bubbling is observed. After about 6h, the reaction mixture is concentrated under reduced pressure and DCM and NH40H (conc) are added. The reaction mixture is stirred for about an additional 4 h before being concentrated and purified via reverse-phase preparative HPLC (20-80% 20 acetonitrile/water (0.1% TFA)). [00438] Example 5.45 trans-(4-Aminocyclohexyl)methan-1-ol H aN H 2 [004391 Trans-4-aminooyclohexane carboxylic acid hydrochloride (2.00g, 14.3 mmol) was added in small portions to a stirred, hot (70-85 *C) solution of Red-Al (27.0 g) 25 for 2 h (a semisolid formed), and heating was continued overnight. After 24 h, the reaction mixture was cooled to room temperature and treated with a solution of NaOH (3.8 g) in H 2 0 (34 ml). Following the addition, the reaction was gradually heated to 800C, and cooled. The toluene layer was separated and the aqueous layer was extracted with CHC1 3 (3 x 100 ml). -174- The organic layers were dried with MgSO 4 and then concentrated under reduced pressure to provide the desired compound (1.81 g, 14.0 mmol) as a pure white solid in 50% yield. ES MS: 130 (M+1). [00440] Example 546_trans-2-(4-Aminocyclohexyl)proan-2-ol

NH

2 5 H 5 [00441] trans-Phenylmethyl 4-[N,N-dibenzylamino] cyclohexanecarboxylate [00442] To an 804C heated mixture of trans-4-Aminocyclohexanecarboxylic acid (8g, 55.97 mmol) and K 2 C0 3 (23.4g) in 112 mL of CH 3 CN, was added dropwise a solution of 10- BnBr (23.3 mL, 195.5 mmol) in 70 mL of CH 3 CN by addition funnel. Reaction stirred overnight at 80*C. The reaction was cooled to room temperature and filtered. Precipitate did not form in filtrate like it did with the cis-somer so the filtrate was concentrated to an oil and carried on to next step (23.01 g, 99% yield). [00443] trans- 2 -f4-.rNN-Dibisbezlaminolcyclohexvlnroan-2-ol 15 [00444] Phenylmethyl 4 -[bisbenzylamino]cyclohexanecarboxylate (6 g, 14.50 mmol) was combined with 460 mL of THF, flushed with N 2 and cooled to 0*C. Methylmagnesium bromide (48 ml, 145.08 mmol) was added to reaction and left to stir overnight. The reaction was quenched with 600 mL of saturated NH 4 C1. Layers were separated and organics were washed with saturated NaHCO 3 and brine (100 mL). Organics were dried with Na 2

SO

4 and 20 concentrated in vacuo. The mixture was dried overnight on high vacuum to afford 3.89g of solid product (80% yield). [00445] trans- 2 -(4-Aminocyclohexyl)propan-2-oI [00446] 3.85 g of trans-2-{ 4 -[N,N-dibenzylamino]cyclohexyl}propan-2-ol (11.40 mmol) was combined with 3.3 g of 20 wt% palladium hydroxide and dissolved with 100 mL 25 of anhydrous ethyl alcohol. The mixture was flushed with H2 (4X) before a H2 balloon was inserted into the reaction and allowed to stir overnight.

N

2 was bubbled through for about 20 minutes and the catalyst was filtered off. The reaction was washed with methanol. The filtrate was concentrated in vacuo and redissolved in acetonitrile and sonicated which -175 produced a white solid. The mixture was filtered and 0.67 g of white product was obtained (37% yield). [00447] Example 5.47 trans- 4 -(NN-Dibenzylamino)cyclohexanol [00448] To a 1 -L round bottom flask equipped with magnetic stirring, nitrogen inlet 5 and dropping funnel was charged trans-4-aminocylohexanol hydrochloride (50.0 g, 0.33 mol), sodium carbonate (139.9 g, 1.32 mol) and anhydrous DMF (400 mL). Stirring was initiated and benzyl bromide (82.3 mL, 0.69 mol) was added via dropping funnel over a period of about 15 minutes. A slight exotherm was observed following addition of benzyl bromide. The reaction was allowed to stir at ambient temperature for about 18 h, then a 10 sample was taken for LCMS analysis. LCMS indicated complete conversion of starting material at this time. [00449] The reaction mixture was filtered through a medium frit under vacuum to remove salts, and the filtrate was diluted with water (400 mL) and MTBE (400 mL).' The mixture was agitated in a separatory funnel, then the lower aqueous layer was drained off. 15 The organic layer was decanted, then the aqueous layer was extracted with MTBE (200 mL). The organic layers were combined and extracted twice with water (300 mL), then extracted with saturated brine (100 mL). The organic layer was dried (sodium sulfate), filtered and evaporated under reduce pressure to yield a white solid. The solid was further dried at 50*C under vacuum. To the dry solid was added cyclohexane (400 mL) and the 20 mixture was stirred in a water bath at 80"C until most solids were in solution. The solution was quickly filtered using celite and a fritted funnel under vacuum. The resulting slurry was heated to boiling to redissolve solids and stirred while cooling slowly. The fine white crystals were filtered on a frit, then washed with two portions of cyclohexane (50 mL). The crystals were then dried for about 18 h at 60 'C under vacuum to yield 5 8 .4g (60%) of pure 25 material. LRMS (ES) m/e 296.2 [MH]*; HPLC (5-+70% acetonitrile/water (0.1% TFA) over 20 minutes) RT = 9.55 min. [00450] Example 5.48 trans-NN-DibenzylA-(2-(piperidin-1 Yllethoxy)cyclohexanarnine [00451] Into a nitrogen flushed 250-mL round bottom flask was charged 35% 30 potassium hydride suspension in oil (16.27 g, 142 mmol) and hexanes (60 mL). The mixture was stirred briefly, then allowed to settle. The supernatant was drawn off via -176syringe, then trans-4-(dibenzylamino)cyclohexanol (10.0 g, 33.9 mmol), 1-(2 chloroethyl)piperidine hydrochloride (18.72 g, 101.7'mmol) and dioxane (120 mL) were added and the mixture stirred at ambient temperature. The reaction mixture tends to thicken. Once hydrogen evolution had ceased the mixture was brought to 90-100*C for 5 about 2 h, then cooled to ambient temperature. Methanol (20 mL) was added and the mixture was stirred until hydrogen evolution ceased. The solvents were evaporated under reduced pressure, and the residuepartitioned between 5% sodium carbonate solution (100 rL) and dichloromethane (200 niL). The layers were separated and the aqueos layer extracted with dichloromethane (100 mL). The organic extracts were combined and dried 10 (sodium sulfate), filtered and evaporated under reduced pressure. The residue was chromatographed (silica gel, 330 g, using a gradient of chloroform-ethanol-conc. ammonia soin. from (98:2:0) to (92:8:2)) to give 4.7 g of an oil (61%). LRMS (ES) m/e 407.3 [MH]+ HPLC (5-+70% acetonitrile/water (0.1% TFA) over 20 minutes) RT= 9.23 min. [00452] Example 5.49 trans-4(2-(Piperidin-1-yl)ethoxy)cyclohexanamine 15 [004531 Trans-NN-dibenzyl-4-(2-(piperidin- 1 -yl)ethoxy)cyclohexanamine (4.7 g, 11.6 mmol), 20% Pd(OH) 2 /C (0.94 g) and methanol (40 mL) were charged into a septum sealed flask. The reaction mixture was placed under balloon pressure of hydrogen for 18 h at ambient temperature, at which time LCMS indicated complete debenzylation to form the free amine. The catalyst was filtered off and the filtrate evaporated under reduced pressure 20 to give 2.42 g of a crystalline material (93%). In some cases an additional portion of catalyst (ca. 50% of the initial charge) was needed in order to attain complete reaction. LRMS (ES) mi/e 227.2 [MH]*; 'H NMR (300 MHz, CD 3 0D) 8 3.51(t,.2H), 3.12(m, 1H), 2.61(m, 1H), 2.42(t, 2H), 2.18(m, 4H), 1.93(m, 2H), 1.80(m, 2H), 1.50(m, 4H), 1.33(m, 2H), 1.12(m, 4H). 25 [00454] Example 5.50 L-Methylsulfonylpyrrolidin-3S-amine Hydrochloride

NSO

2 Me HCI

NH

2 [00455]

(

3

S)-

3 -(tert-Butylcarbonylamino)pyrrolidine (10.0 mmol, leq.) and N,N diisopropylethylamine (25.0 mmol, 2.5 eq.) were dissolved in 20 ml DCM. Methanesulfonylchloride (10.0 mmol, 1 eq.) was added dropwise and the reaction mixture -177was stirred overnight at rt Aftei adding wei the phases were separated and the organic phase was dried over MgSO 4 and evaporated to give the desired product. This compound was dissolved in 12 ml dioxan and 23 ml 4NHACl in dioxane was added, The reaction mixture was stirred overnight. Evaporation of the solvent and additional coevaporation with 5 toluene gave the desired product. This reaction can also be performed with the R enantioiuer. [00456] Examile 5.51 cIs- 4 r( 2 -nipeiidylethony)methylicclohdaylamine

NH

2 [00457] Benzvl cis- 4 -[NN-dibenzylaminocyclohdxane carboxylate 10 [00458] cis- 4 -Aminocyclohexanecrboxylic acid (10.0 g, 67.48 mmol) was dissolved in 140 mL of dry acetonitrile. Solid potassium carbonate (28.0g, 202.6 mmol) was added. The suspension was heated to about 80*C. To this solution, was added benzyl bromide (28.09 mL, 236.2 mmol) in 70 mL of acetonitrile, dropwise via addition finnel. The reaction mixture was stirred at about 80*C under nitrogen for about 2 hours then about 40 0 C 15 overnight. The reaction was cooled to room temperature and the suspension was filtered. The filtrate was concentrated under reduced pressure. The compound was purified using column chromatography on silica gel (100% hexanes to remove excess benzyl bromide, then 10% ethyl acetate in hexanes). The product was isolated as a white solid (14.35 g, 51% yield) : ES-MS (m/z) 414. 20 [004591 cis-f 4 -rN.N-DibenzylaminolcyclohexIlmethan-1 -ol [00460] A solution of benzyl cis- 4 -[N,N-dibenzylamino]cyclohexane carboxylate (14.35g, 34.70 mmol) in dry THF (180 mL) was prepared and then cooled down to -78*C. A solution of lithium aluminum hydride (104.0 mL, 1.0 M solution in diethyl ether) was added dropwise. At the end of the addition, the reaction temperature was raised to about 25 -50*C (acetonitrile/dry ice) and the temperature was maintained for about 3 hours. The completion of the reaction was monitored by LC-MS. The reaction was quenched by dropwise addition of saturated aqueous sodium sulfate. Saturated aqueous sodium bicarbonate (10 mL) and diethyl ether (50 mL) were then added. A white solid formed and -178 was removed by filtration and washed with THF. The organicphase was separated and concentrated under reduced pressure. The product was purified by slow precipitation. The residue was dissolved in 5 mL of diethyl ether and the solution was layered with 50 mL of hexanes. Clear large crystals were obtained after overnight diffusion. (7.219g, 67% yield) 5 ES-MS (m/z) 310. [00461] cis-N,N-Dibenzyl-N-{4-[(2-piperidylethoxy) methyllcyclohexyllamine [00462] cis-{ 4 -[NN-Dibenzylamino]cyclohexyl}methan-1-ol (2.851g, 9.21 nupol) and ( 2 -chidroethyl)piperidiie hydrhioride were suspended in 50 mL of dioxane. 10 Potassium hydride (3.16g, 35% by weight in mineral oil) was added dropwise in suspension in 20 mL of dioxane. The reaction mixture was stirred at room temperature for about I hour. The reaction mixture was then warmed to about 70*C and one equivalent of potassium hydride (1.05g, 35% by weight in mineral oil) was added dropwise. The temperature was maintained for about 2 hours, after which the conversion was complete. 15 The reaction was cooled to room temperature and quenched with methanol. Solvents were removed under reduced pressure. Acetonitrile was added (200 mL) and the gray brown solid was removed by filtration. The crude was purified by column chromatography on silica gel using 3% (ethanol/ammonium hydroxide =8:1) in dichloromethane. The product was isolated as an orange oil that solidified under vacuum. ( 2 .84g, 72% yield): ES-MS 20 (m/z) 421. [004631 cis- 4

-[(

2 -Piperidylethoxy)methyllcyclohylamine [004641 cis-N,N-Dibenzyl-N-(4-[(2-piperidylethoxy)methyl]cyclohexyl)amine

(

2 .84g, 6.65 mmol) was dissolved in 20 mL of ethanol. Palladium hydroxide (20% weight) was added (50 mg) and the reaction was stirred overnight under an atmosphere of hydrogen. 25 The catalyst was removed by filtration and washed with small portions of ethanol. The filtrate was concentrated and used without further purification. (quantitative yield) ES-MS (m/z) 241. [00465] Exaimnple 5.52 cis - 4 -(Methoxymethl)cyclohexyl amine H2N - 179-.

[00466] cis- 4 -I(tert-Butoxy)carbonylaminolcyclohexane carboxylic acid [004671 cis-4-Aminocyclohexyl carboxylic acid (2.0g, 13.96 rInmol) was dissolved in 40 mL of 1,4-dioxane. Two equivalents of di-tett-butyl-dicarbonate (6.094g, 27.92 mnimol) were added followed by 3 equivalents of sodium bicarbonate (4.06g, 41.88 mmol) dissolved 5 in 40 mL of water. The reaction mixture was stirred at room temperature for about 12 hours. The completion of the reaction was monitored by LC-MS. Saturated aqueous KHSO 4 was added dropwise, until gas evolution stopped. The solvent was then removed under reduced pressure and the crude product was extracted in ethyl acetate. The combined organic extracts were washed with aqueous saturated KHSO 4 and dried over Na 2

SO

4 . The solvent 10 was removed under reduced pressure, yielding 2.6 g of product. Based on 'H NMR, the product was pure and used in subsequent steps without further purification ES-MS (m/z) 244. [00468] cis-(tert-Butoxy)-N-r4-(hvdroxymethyl)cyclohexIcarboxamide [00469] cis- 4 -[(tert-Butoxy)carbonylamino]cyclohexane carboxylic acid (2.6g, 10.68 15 mmol) was dissolved in THF (20 mL) and cooled to -1 0*C (MeOH-ice). N-Methyl morpholine was added followed by isobutyl chloroformate (1.1 75mL, 10.68 mmol). After 10 min, NaBH 4 was added as a solid in one portion (1.213g, 32.06 mmol). The reaction mixture was warmed to 0*C and methanol was added dropwise (13.35 mL). After about 30 min, the reaction was quenched with 5% aqueous KHSO 4 . The reaction monitored by LC 20 MS was complete. The crude product was extracted with ethyl acetate and the combined extracts were dried over Na 2

SO

4 .A colorless oil was obtained and solidified slowly at room temperature. The product and purity were assessed by LC-MS and 'H NMR. No further purification was necessary. (quantitative yield) ES-MS (m/z) 230. [004701 cis- 4 -(Methoxymethvl)cvclohexyl amine 25 [004711 Sodium hydride (72 mg, 1.78 mmol, 60% by weight suspended in mineral oil) was washed three times with 10 mL portions of hexanes, and suspended in dry THF (12 mL). The suspension was cooled to 0*C. To this suspension, cis-(tert-butoxy)-N-[4 (hydroxymethyl)cyclohexyl]carboxamide (0.273g, 1.20 mmol) and 15-crown-5 (0.250 mL, 1.25 mmol) were added. The reaction mixture was then stirred at 0*C for about 30 min. 30 Methyl iodide was then added dropwise (75 pL, 1.20 mmol). Since the reaction was not complete after overnight stirring at room temperature, the mixture was cooled to 0*C and reacted with 100 mg of sodium hydride and 0.250 mL of 15-crown-5. After about 2 hours -180at room temperature, the reaction was complete. The reaction *as quenched by the slow addition of water and the crude product was extracted with ethyl acetate. Purification was effected by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent. ES-MS (m/z) 244. cis-(Tert-butoxy)-N-[4-(methoxyinethyl) cyclohexyl]carboxamide 5 was dissolved in ethanol (5 mL) and the solution was treated with 1 mL of acetyl chloride at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressureand the resulting solid was used without further purification. (79% yield) ES-MS (/z) 144. [004721 Example 553 trans-4-Methoxycyclohexylamine 10 RHI [004731 trans- (tert-Butoxy-N-(4-methoxycyclohexl)6arboxamide [004741 Sodium hydride (60% in mineral oil, 278 mg, 6.96 mmol) was suspended in THF (5 mL) and cooled to 0*C. trans- tert-B3utoxy-N-(4-hydroxycyclohexyl) carboxamide (1 g, 4.64 mmol) and 15-crown-5 (0.965 mL, 4.88 nmol) were added and the reaction 15 mixture was stirred at 00C for about 30 minutes. lodomethane (0.289 mL, 4.64 mmol) was added and the reaction stirred at 0*C for about 1 hour after which the LCMS showed it was complete. The reaction was quenched with methanol, the solvents removed in vacuo and the crude purified by column chromatography (SiO 2 , 8:2 n-hexanes/ ethyl acetate) to afford 642 mg of the mehyl ether. ES-MS: 230 (M+1). 20 [00475] trans-4-Methoxcyclohexylamine [00476] trans- (tert-Butoxy)-N-(4-methoxycyclohexyl)carboxamide (642 mg, 2.80 mmol) was dissolved in ethanol (5 mL) and cooled to 0*C. Acetyl chloride (1.5 mL) was added and the reaction was allowed to reach room temperature and stirred overnight. Solvent was removed in vacuo to give the desired product (458 mg, quantitative yield) as a 25 hydrochloride salt. ES-MS: 130 (M+1). [00477] The Aninopurine Compounds can be assayed for their activity according to the following procedures. [00478] JNK1 Assay - 181 - [00479] To 10 sL of an Aminopurine Oompound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES~(pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xlOO, 2 pg/mL leupeptin, 20 mM p-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 sL of 50 ng His6-JNK1 in the same dilution 5 buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 gg GST-c-Jun(l-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride 1 mM DTT,.25 mM PNPP, 0.05% Triton x100, 11 pM ATP, and 0.5 piCiy- 32 P AT? in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The c-Jun phosphorylation is terminated 10 by addition of 150 p.L of 12.5% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 pL of the scintillation fluid and quantified by a counter. The ICso values are calculated as the concentration of the Aminopurine Compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Certain compounds have an IC 5 0 value ranging from 0.01 - 10 pM in this assay. 15 [00480] JNK2 Assay [00481] To 10 jiL of an Aminopurine Compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton x100, 2 gg/mL leupeptin, 2O mM p-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 pL of 50 ng His6-JNK2 in the same dilution 20 buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 pg GST-c-Jun(1-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05% Triton xO0, 11 pM ATP, and 0.5 pCi y- 32 P ATP in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The c-Jun phosphorylation is terminated 25 by addition of 150 pL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 pL of the scintillation fluid and quantified by a counter. The IC50 values are calculated as the concentration of the Aminopurine Compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Certain compounds have an IC 50 value ranging from 0.01 - 10 pM in this assay. 30 [004821 JNK3 Assay [00483] To 10 pL of an Aminopurine Compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, -182- 0.004% Triton xO, 2 tg/mL leupoptin, 20 mM 0-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 L of 200 ng Hl6-JNK3 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 p±g GST-c-Jun(1-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50 mM 5 sodium chloride, 0.1 mM EDTA, 24 mlM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05% Triton x100, 11 pM ATP, and 0.5 gCi y- 32 P ATP in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The cJun phosphorylation is terminated by addition of 150 pL of 12.50% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 pL of the scintillation fluid and quantified by a 10 counter. The IC 5 o values are calculated as the concentration of the Aminopurine Compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Certain compounds have an ICso value ranging from 0.00 1 - 10 gM in this assay. [004841 p38a assay [004851 The p38a kinase assay is carried out in 96-well plate format at a final volume 15 of 100 1 . ATP is used at a final concentration of 340 pM, three fold the apparent Km. Kinase is diluted in Dilution Buffer (20 mM HEPES pH 7.6, 0.1 mM EDTA, 2.5 mM MgCl 2 ,0.004%(w/v) Triton XIOO, 2 pg/ml Leupeptin, 20 mM B-glycerol phosphate, 0.1 mM-Na 3

VO

4 , 2 ml dithiothreitol) and pre-mixed with MBP diluted in Substrate Solution Buffer (20 mM HEPES pH 7.6, 50 mM NaCL, 0.1 mM EDTA, 2.5 mM MgCL 2 , 0.05%(w/v) 20 Triton X100) to give final assay concentrations of 50 ng/well (7.8 nM) for p38a and 30 pg/well (16pM, 2X Km) for MBP. The p38a/MBP mix (85 pl) is added to an Aminopurine Compound (5 pl) diluted in 100% DMSO to give a final DMSO assay concentration of 5%(v/v). Enzyme, substrate and Aminopurine Compound are allowed to equilibrate at room temperature for about 15 minutes. The reaction is started by addition of 10 1lOX ATP in 25 kinase buffer (130 mM MgC12. 6 mM dithiothreitol, 150 mM para-nitrophenyl phosphate, 100 pCi/mi y-[ 33 P]-ATP). Reactions are allowed to proceed for 60 minutes before precipitation of protein via trichloroacetic acid (7.2% TCA final). After a 30 minute incubation with TCA, reaction products are collected onto glass microfilter 96-well plates (Millipore MAHF CIH60) using a Packard Filtermate. The precipitate is washed with 30 Phosphate Buffered Saline and the amount of phosphate incorporated into MBP is quantified by scintillation counting using a Packard Topcount-NXT. - 183 - [00486] Jurkat T-celf 11-2 Production Assay [00487] Jurkat T cells(clone E6- ) are purchased from the Ameican Tissue Culture Collection andmaintaned ingrowth media consisting of RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10% fetal bovine serum cyclonee) and 5 penicillin/streptomycin. All cells are cultured at 370C in 95% air and 5% C02. Cells are plated at a density of 0.2 x 106 cells per well in 200 d 1 of med Aminopurine Compound stock (20 mM) is diluted ingrowth media and added to each well as a IOx concentrated solution in a volume of 25 m ixed, and allowed to pre-inoubate With cells for 30 minutes. The compound vehicle (dimethylsulfoxide) is maintained at a final concentration of 0.5% in 10 all samples. After 30 minutes the cells are activated with PHA (phorbol myristate acetate; final concentration 50 pg/mL) and PHA (phytohemagglutinin; final concentration 2 g/mL). PMA and PHA are added as a 1Ox concentrated solution made up in growth media and added in a volume of 25 p.L per well. Cell plates are cultured for 10 hours. Cells are pelleted by centrifugation and the media removed and stored at -20 0 C. Media aliquots are analyzed 15 by sandwich ELISA for the presence of IL-2 as per the manufacturers instructions (Endogen). The ICso values are calculated as the concentration of the Aminopurine Compound at which the 11-2 production was reduced to 50% of the control value. Certain compounds have an ICso value ranging from 0.01 - 10 pM in this assay. 1004881 Rat in vivo LPSinduced TNF-a Production Assay 20 [00489] Male CD rats procured from Charles River Laboratories at 7 weeks of age are allowed to acclimate for one week prior to use. A lateral tail vein is cannulated percutaneously with a 22-gage over-the-needle catheter under brief isoflurane anesthesia. Rats are administered an Aminopurine Compound either by intravenous injection via the tail vein catheter or oral gavage 15 to 180 min prior to injection of 0.05 mg/kg LPS (E. Coli 25 055:BS). Catheters are flushed with 2.5 mUkg of normal injectable saline. Blood is collected via cardiac puncture 90 minutes after LPS challenge. Plasma is prepared using lithium heparin separation tubes and frozen at -800C until analyzed. TNF-a levels are determined using a rat specific TNF-a ELISA kit (Biosource). The EDso values are calculated as the dose of the Aminopurine Compound at which the TNF-a production is 30 reduced to 50% of the control value. Certain compounds have an EDso value ranging from 1-30 mg/kg in this assay. [00490] Abl LANCE HTRF Tyrosine Kinase Assay - 184- [00491] The day prior to performing the assay, the following are prep ared: [00492] (1) 2 mg/ml BSA/M% Triton X10/50 mM HEPES pH 7.6 (kept at 40C); [00493] (2) Streptavidin-APC (PerkinElmer Life Scin es CR130-100) diluted in 5 nH 2 0 according to instuctions (kept at 4"C, up to 2 weeks maximum); [00494] (3) Tyrosine K.inase Biotinylated Pept ide Substrate 2 (Pierce 29914) diluted in nH20 (kept at 40); [00495] (4) Ainnopurine Compound dilutions in DMSO. [004961 The following mixtures are prepared the day on which the assay is 10 performed: [004971 (5) 2 mM DTT/50 mM HEPES pH 7.6; [004981 (6) 2 mM Staurosporine for Background Control and 1:3 serial dilutions for Reference Control in DMSO; [00499] (7) LANCE Mixture in 2 mg/ml BSA/0.2% Triton X100/50 mM HEPES 15 pH-7.6 prepared as follows: 250 nM Streptavidin-APC (PerkinElmer Life Sciences CR130 100), 250 nM Tyrosine Kinase Biotinylated Peptide Substrate 2 (Pierce 29914), and 250 ng/ml Eu-anti-phosphoTyrosine (PerkinElmer Life Sciences AD0066); [00500] (8) Kinase/detection mixture prepared as follows: 18.7 ng/ml Abl (Calbiochem 102555), 5.9 mM MgC 2 , and 58.8% LANCE Mixture from (7), brought to 20 final volume with 2 mM DTT/50 mM HEPES pH 7.6; 100501] (9) 240 pM ATP in 2 mM DTT/25 mM HEPES pH 7.4. [00502] To a black 384 well microtiter plate (Corning 3710) is added 2.5 pl/well compound dilutions/DMSO and 42.5 .1/well kinase/detection mixture. The plate is incubated for 5 minutes on shaker followed by 10 minutes static incubation at room 25 temperature. [00503] 5 pl/well ATP is added to the plate and the plate is incubated for 5 minutes on shaker followed by 55 minutes static incubation at room temperature. 100504] 30 p.l/well 16.7 mM EDTA is added to the plate and the plate is incubated for at least 2 minutes on a shaker followed by 30 minutes static incubation at room temperature. 30 The plate is then read (TR-FRET) on Packard Fusion instrument. - 185 - [00505] Certain compounds have an IC 5 o value ranging from 0.01 - 10 pM in this assay. [00506] Alamar Blue Assay for K562 Cells [00507] Chronic myelogenous leukemia K562 is routinely maintained in RPMI 1640 5 with 10% heat inactivated FBS and 1% Penicillin-Streptomycin. For cell proliferation assay, K562 cells are plated in 96-well round bottom plates, Cells are treated with an Aminbpurine Compound the same day of plating. For dose response experiments, a 30 mM solution of an Aminopi rine Compound is diluted to give final concentrations of 30 , 3 pM, 0.3 pM, 0.03 pM, and 0.003 sM. The final DMSO concentration is 0.2% in each well. 10 Alamar Blue iss used to quantify cell number after a 72 hour incubation with an Amionpurine Compound. Certain compounds have an ICso value ranging from 0.1 - 10 pM in this assay. [00508] The embodiments disclosed herein are not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few 15 aspects of the disclosed embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. 20 [00509] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety. -186-

Claims (17)

1. A method for treating or preventing Type I diabetes, Type II diabetes, esophagitis, hepatitis, pancreatitis or nephritis, comprising administering to a patient having Type I diabetes, Type II diabetes, esophagitis, hepatitis, pancreatitis or nephritis an effective 5 amount of a compound having the formula (I): HNN N (I) or a pharmaceutically acceptable salt thereof, wherein: 10 R' is substituted or unsubstituted Ci. 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3 .iocycloalkyl, substituted or unsubstituted C 3 .ioheterocycle or substituted or unsubstituted C 3 .-oheteroaryl; R2 is H, substituted or unsubstituted CI-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C3.1ocycloalkyl, substituted or unsubstituted 15 C 3 .ioheterocycle or substituted or unsubstituted C 3 .ioheteroaryl; and R3 is aryl substituted with one or more halogens or C 3 .ioheteroaryl substituted with one or more halogens, wherein the aryl or C 3 .ioheteroaryl group is optionally further substituted with one or more Ci. 6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, 20 alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups for the preparation of a medicament for treating or preventing Type I diabetes, Type II diabetes, esophagitis, hepatitis, pancreatitis or nephritis.

2. The method of claim I wherein R' is substituted or unsubstituted aryl, substituted or unsubstituted CI- 6 alkyl, substituted or unsubstituted C 3 .iocycloalkyl, substituted or 25 unsubstituted C 3 .oheterocycle, substituted or unsubstituted C 3 .,oheteroaryl.

3. The method of claim 2 wherein the C 3 .iocycloalkyl is substituted with one or more C1. 6alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, - 187- aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups.

4. The method of any one of claims I to 3 wherein R2 is substituted or unsubstituted aryl, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C 3 .iocycloalkyl, 5 substituted or unsubstituted C 3 .ioheterocycle, or substituted or unsubstituted C 3 . ioheteroaryl.

5. The method of claim 4 wherein R 2 is cyclohexyl substituted with one or more CI- 6 alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or 10 imidazolyl groups.

6. The method of claim 4 wherein R2 is cyclopentyl substituted with one or more CI. 6 alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 15

7. The method of claim 6 wherein R2 is substituted or unsubstituted 3-oxetanyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, 4-piperidinyl, 4-(l -acyl)-piperidinyl, 4-(1 alkanesulfonyl)piperidinyl, 3-pyrrolidinyl, 3-(I-acyl)pyrrolidinyl, and 3-(1 -alkanesulfonyl)pyrrolidinyl.

8. The method of claim 6 wherein R2 is substituted or unsubstituted sulfur containing C 3 . 20 joheterocycle.

9. The method of claim 8, wherein the sulfur containing C 3 . 1 oheterocycle is 4-(1,1 dioxo)thiopyranyl or 3-(1,1 -dioxo)thiofuranyl.

10. The method of any one of claims 1 to 9 wherein R 3 is halogen substituted aryl, or halogen substituted C 3 . 1 oheteroaryl. 25

11. The method of claim 10 wherein R 3 is fluoro substituted aryl, or fluoro substituted C 3 . Ioheteroaryl.

12. The method of any one of claims I to 11 wherein R 3 is - 188- (X)m (R6), wherein: X is at each occurrence independently F, Cl, Br or I; R 6 is C1. 6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, 5 carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl; m is an integer ranging from I to 5; and p is an integer ranging from 1 to 4.

13. The method of claim 12 wherein X is F, Cl or Br. 10

14. The method of claim 12 wherein m is 1, 2 or 3 and X is F or Cl.

15. The method of claim 12 wherein m is 2 or 3 and at least one X is F and at least one X is Cl.

16. The method of claim 1 wherein the compound is selected from the group consisting of: N H -NH N NH N NN 2 H ~H F N NH F N N 3 4 - 189- NHN Q K~NHl NNF /NH-NH F N N 5 6 0, Nr N ~NH NN H. />N NH F I 1>-NH F N-. / r ): / N-. 78 0 NH N NH N INNH F ~-N- N H 10 9 1 NH N ) ~N>_N H~N NI />-NH F N N r N -0)-(X 13 0 14 - 190 - NH N 9 O" NH N N FN .< N OKN /NH F />NH F 16 rNH NH F NH N F 0 N O 17 18 DNHN NHF N N F N0 N 19 20 NH N N NH />-NH FNH N roN >-NH CI -N F 22 21 NNH N N NH N N />-NH I>NN N N 23 24 O NH N N ONH N I /-NH >-NN NH 25 26 O NH N NO o NH N N 27 HO N NN N>-NH F TO., -NNH K N N N 0'5 N F 29 0 30 27l H N NNHI N H N N H N 32 03 31 - 192 - N H NB F O NH> NNH F 33 34 OH NNH~ N N D N />- NH F O N H<N N F N 0FN 35 36 OH OH H H N N NH N N / HF />-NHF N N N 37 38 OH NH-N NF -- "I NH N N H HH NN N N 39 Br HO . LN N 40 -193- OH OH NHJN : NH NN H HNI 'f~ ~N N NH F N NH F 42 41 OH OH H H N N N N N N I /NH F I 0 "I *N >-NH F N: NN 43 44 HO H N< Y \ I , ) N H NN F NN N ciH N CI 47 48 -194- HN NH N N N H NNF >/N F i ,>N CrN-.." FO N N 50 49 OH 52 HO 53 OH F NHHH N NH N NH-~ /" N -- NH F N N 55 56 -0 54 53 OH H N N N N. NH N N ,I >-NH F />NH F 55 56 - 195 - NNH N N OH NH F HO/-NH F OH'K N 0 N 57 58 OH OH F H K ) NHN NF N F 60 OH OH NH H N FN N N SNH >-NH F ci~ :zN FC NXN 61 64 - H9 N N H N I '~>-NH F 63 -196- OH OH H H cI N N N N N N N />NH F N -NH F C N0 N N N 65 66 -NH 2 NH F N N HN FN N N Nb -l: Nf~ ,I >-NH FN :NHN 67 68 0 N N NH N~ NH-K' \-N NH _N -0 70 69 QN F NH-' / ) N N NNH NH NH F 71 C IN - 197 - OH N NH N N- NH 73 WS\ HN HH N-e NHb yN /-NH F H 75 76 OH OH H jH O ~N NF ON N />NH F N ~ ( ,>-NH F N NH 0 I 78 77 F N NHb NH N N N NH N NN 79 80 - 198- F NH 2 Ny NH H H N O N N N /NH H 2 N 82 81 H HNP H N H N N F No N NFN N84 83 HO K- NH < \>- NHH N N NH N 86 F NH NH F NH- NH 87 88 - 199 - F NH- N F HN H RH NHF NH-NH N N NH NK' IN 90 89 N:C N 5 N F NH-< jjN F NH-' j FNH F F HN N N N H N N N H 91 92 N N N N N~ N- N F H-K' - ~~I >-NH F NNN NH N N F NF 93 94 0P F s- Ny- >-NH 0 (::N />NH F- N 95 96 95 - 200 - N p H F NH-</ N<N N N N F N -NH iN' NNHK HO 98 F 97 HNH pNNN -N H F NH-<N "ir' />-NH F 991 100 F NH-K F H NH N N NH 103 102 F NH-F NH-20 N N H N N H 103 104 -201- Q N D:-~N p N -~N F NH- N F NH-KN N N- NH N N NH 105 106 N -;N P N " F NH-K' -V- K F NH-<' N NH N N NH NF H NH HN H6N 107 108 / N N F H-< N F NH-< I N NH N N NH OH 110 OH 109 0 HN HH N N H 2 N H O NH F 0 K<: N 3 NH N, 2 -' 112 - 202 - 00 HN HN A-N H H N N N,> -NH F s o N F O N 114 113 0 N-J NH N N N N 0 N NH , H 1 ,-NH F N N' N NX N N\-/ N(X N 116 115 H 2 N 0 H2N N N NH N NF O NH F F H NH F F 118 117 F NH< 2 N N N NHF NHK I N NH OH F 120 119 - 203 - N N F NH-KN F NH-< NC N NH N H OH 121 122 N N F NHI F NH-NN N N NH N N NH 0N 123 cO 124 N N N N F NH NH F NH NH o o 125 126 -204- F NH-K NHNH 2 N NONH HNH I ~N N H O >-NH F H2 N N F N 2128 127 0 HN{H H N XN N H~i />-NH F N N N FU' N H 2 N~~I I ' - / >-NH F13 H2"131 N): 132 129 0 N H P , N H N N N N 0 ~ jN ,>-NH F >-NN N NH 131 N - NF: 132 - 205 - 0 HN H H N N N N NHF/2Nl3>-NH F H N N N N N NHF Y1I~ />-NH F 13N5 N 134 133 O N-NH F NH N N H NN N N N-NH F 135 2 136 H 9 N ? N N N -NH F ( ~~NH F Nc NH H" N O NQ 137 F 138 Q 206 NCF NH-</ F NH-/ N Y N NH NN NH 139 OH 140 - 206 - F NH-K' Jj N N N NH F NH N N NH OH 142 141 _<~ NN NH< : N FF H FN NHK' N NHN 143 OH 144 O F H NH NN N NH N 145 OH 146 H-N r J\ ul-- N>NH H 2 N H -NH F HN N N F 147 148 - 207 - F NH-<' F NH-K' NH N NH N N NH b 6 -- J 6 149 150 NH NH F HO NH N F H0') N N F 151 152 F N N H2N,. N NH N'NH NH N N H F 155 153 NO 154 0 HN HNHNA H a N N H K5 , />-NH FN N ' I:' />-NH F F N N F 156 155 - 208 - OH 0 HNK H H N N N H Ii i>-NH F (~~NN N N N' N / H"K , >-NH F HON H 2N 60 N F 158 157 0 HNO N H NF N N F H N>FNF F N N N N ,-NH F H Hl />-NH F HO"'C N16 16 164 F 159 0 NH2 HH NI />-NH F Ny NN N :): />-NH F~ 0 162 F 161 F/\ F~_F HN NA ~NH xlO" N iN~ NH N N N H bo N N 163 164 - 209 - 0 0 F NH H FCF NH NHN N HN H INN N> . >NH F / II /-NH F Fo N N FN 165 166 0 o HNK ~NH N N HI S/>-NH F N N N F>NH F 167 F 168 0 HNH HH />-NH F NH N YJ- />-NH F 169 bF 0 N) 170 0 H NK HF YI~~~ />-N O NYr NHH* c NN )>N NH 0 172 F 171 -210- NH p N NH F/Q>NN N H F HO NH N F HO N 173 174 0 0 HN HN oH 9 N NF >-NH F Q~NN ,/>-NH H " HF 175 176 D~NH N NH H NH p F, ,r>-NH F HO"'' NF F- F 177 178 H OH ON N N H Cr ~[f >-NH F N N HO~K>N- N H<)Y />-NH F 179 HU 'N 0 180 N N ~NH N ~K >-NH F N ,>NH F 0 0 181 182 -211- OH 0 ,,0 HNS H H HON / F NO N F ,Y /-NH Fx~ HO~'K> T'- />-NH F 183 184 9N 9 rNH F % 2NH N NH F 185 186 H HO N N N HN F ON F H 2 N" NN N F 187 188 -2§-OH N N N U /-HF ~ N N N N ,,NH >_N F / OH FO~ / F 0 H 189 190 -212- OH 0 HP SN N N NH N NH FHON N F Ni I />-NH F HO"Cr Nr N HO NF F F N -0 F F 192 191 p F NH NH O ri"' /-H F N >N H 2 NO NN F H 2 N NF F FF 193 194 H 0 OOH O N N F2N N HO~IIIII ~ />-NH F HO"KX /-i " >-NH F N N ~ N 6195 196 N N N N 0 (~y~y >-NH F 0#O .,,F H 2 N,-)k . N HO N :198 197 -213 - OH H r OH H [ N N N N N N N N >-NH F HO NN N H F HO' N N HO "C N X N200 199 OH OH 0 NH rlN" N N N ,>-NH F HON N HO' N >-NH F 201 204 202 0 24 H H N '-N ~~ N N [ f~ Li /V- >-NH F HO"K 2 N N 203 204F H "O . ,NII N § 1FHON N -N F />-NH F. /N 205 206 -214- or Nj NH H HN~N HN NH N HN FNH N N,>-NH F "O N 207 2 208 OH F 6> - (7N)p' -\ N F~ NH F SNH~F N N HO N NH N 6N209 J. 210 OH 21o NH HN N N NN H"NZ N NH N 211 *' NO 212 -215 - OH p ON NO" N Oa NH /> NH F HON F HN N NF 215 214 H 2 OH OH OH NN ~y . ~ / >-NH F HO N -H F HO". N N F-O F 215 216 NH 2 H OH NN O 22H H " Nj F- HV' 218 217 F NH-26 N N N N H IN N NH (0 220 219 -216- F NH/ F NH-</ N N NH 2 NH N 2213 222 F NH-</' N~N F NH-<' NH 223 224 / N ~ N F NH NN F NH N NH N FNNH N NH NH 226 225 - Q F NH< N F N N N F"N N/ N I 228 227 -217- N N N F NH\~F NH-K j N NHNH N NH NHN F 229 230 F NN 4 F N .NH F NH-/ NH 232 231 / N F NH NH NHN N NNH OH 233 -218- NN F NH- NH N d N NH N N N N 236 235 F NH- F NH-C N NH NH 237 OH 238 p N F NH F NH NH N s OH 240 239 -219- P P:: N F NHNFNH N N N -\N NH NH OH N 241 242 PN H§ F NH-$ N N N N N HO~K)/>,-NH F NH 243 N H 244 F N F NH-N F NH 7 -- N N \ d NH NA NH NH OH 245 246 - 220 - P Q N F NH NF NH N N N NH NH NH 247 248 N F" FNH NH N NH OH 250 249 NQ F NH- NH F NH-(: NH 252 O21 2 -221- \H NH P N N N N F N H ( N F NH-NN NNNNH N N NH 253 254 N1 F NH-222 NN NH F H l NH-NH cC 256 255 N N N NF NH-< j F NH-</ NN C NH N N NH 258 257 - 222 - F NH-K' F NH-K' I N N H NH N NH s (N 259 260 N N HF N N H F NH-</' NIH-/\/~ F ~ N NH N IN N N 261 262 N NH N NH NH-</NH N 264 263 - 223 - N N N F NH NH F NH NNH NH 266 265 o NNN OH H F NH NH HO N -/-NH F 267 F 268 OH N H F NH-</ H ~N N NH NN NHF /> I-NHF HO,,- N NF 269 270 H0 H NH 2 Hj N N H HO />-NH F />-NH F N N HO'~ NN F F- F F 271 F 272 - 224 - OH OH H H 2N/N> NH H 2 N N N Y /NH F ,, >-NH F 273 274 OH N 0 N NN H~~ N>-H N N N N HNH F H O " K > > - N H F H O 2 7 6 275 oN., H N N H N N N NH F N ,..N F H "N 02 7 277 OH NH N N OH HH HO h N /-NH F HO N F 280 279 - 225 - OH O OH NCrNN N F ON Oi~ N NF 281 282 OHH N H -NH F H2-NNH F 0 F F 283 284 OHH HO H H N F N NN H N N N X, >-HF -HF 287 288 O 26 N 'NNN H >-H F ,N N N 0N HO..&N:: UL>-N 285 226 F OH N OH NH HN Cr >-NH F NN N N F92F O N N, HO" N H FNN F 290 289 NN HOH H ~~a 0N ~N~ H N N N >NH F H ,,NH F , N N 292 F F 291 O- 227 H N<N N N rN N NN A J A..>NH F N >-NH F I F , N:X 294 F 293 Nj9 H-j ONN N N HY N />-NNH F HO~.K N - N F0296 F F 295 -227 - CN OOH COH H H( N N l >-NH F K~rYN />-NHFN HO N FNNN-NN 0 298 F 297 OH 0 N 0N2 N N F O j ~N N F H2N N N F 299 300 F N N N V rN N NN O X 301 H O F F 302 301 HO o r-\ N j HH N N N Yi />-NH F H 2 N K)Nlz NH ON 0 F 33F 304 - 228 - OH N NH 07NH F N N N A NK /N-N 0 H F 305 F 30306 O H N N N H HF HO N N F H 2 N"' N N 0H 2 N"C 3F F32 F 2 308 307 HO N > NH N ~NJ H2N"&:: N / >-NH F N N 0O 0N FF 310 309 O NoQJ\_ >-N F NH F 311 F 312 - 229 - N No HO N -NH F HO NHNH F F F 313 314 NH N O N- NNH O NH. N ,NH F ~ NHyN N NH F H O, NN HO N F 316 315 OH NH OH NH HO NH N F HO />-NH F F F 318 317 - 230 - o N NH HO NH HO NH N >N H HON HNNH H H NH N N 0 F F 320 319 HO O NH N N <NH~N N\ LIf Y />-NH F N i //NH F N N 322 F 321 OH NH N N NH N /,>-NH F N I/-N H F Cr N- N 324 F F 323 -231 - OH OH NH N N , H N H /-NH F N I />-NH F N F F F 326 325 ONHH N />-NH F H-NH F NUfDl- F F 328 327 -OH OH NH N N >NHYN />N0 FH NN N N ~ F F 330 329 - 232 - OH OH NN s >NH F > NH YN />N H F 332 331 OH OH V7 NH N 61" NH F Nr N F F 334 333 OH OH NH N NH FNH N ,>NH F N N F N FF 335 336 - 233 - OH OH NH N H NH N N N NNH F6 N. Oa N-' 0. F N F F 337 338 0 o/[--"o N NH N N <N. r/>-NH F oNH N N F N N 339 F 340 00 NH N N F NHN N TI r>NHF \J1 ', >-NH F NlN N X OH OH F 0 F 341 F 342 NH ,>-NH F NH N N N N \1 ,>-NH F N, N) N /OH F F F 344 343 - 234 - OH NH NH F HdNNH NH F N H6*(N HO OHF 345 346 F kOH OH OKNH N FNH N N _? HO N NF F 348 347 OH OH NH N NH FHNH NH F H Y 1'iN F F N F F -235 F 349 350 OHN >NH N ( N N -NH F I N HU" N N FF0 FF F 352 351 - 235 - OH >-(:::N NH oHh iN HO NH NH FN NH N H F / F QN 03 ' NA F0 FF F 354 353 ,, OH ~QNH N NN HNF NH 'I >NH F Ho NH ,,,, I NH N NH F35 ON~ N /\:" 0 0 ,,N , F 0 F 355 356 F O O OYNH N FNH N />-NH F N F0 359 F 358 F 357 O-NH N ~NH N 1{ -NH F ;u- >-NH F O' , N F TF HN F0 F IOH 359 360 -236- 0 NH N NH N N F H2 N N N F /NH F N F F O F F 361 362 OH Q0 _, -N N H N N H 2 N N " NH F N N FNi~' />-NH F F F N FF 363 F 364 OH OH HO NNH N N NH N N >-NH F NF 365 366 OH H O N [ NH H H O ,,,-H N HF H N NN 0F 368 FF 367 - 237 - F07 0 ONH N F NH N N H F F />-NHF F 370 369 40 A/0 0 NH N NN H N N SF N >-NH F i, N -6 F 372 371 0 -3 NHNH N N NHI ri /-NH F N~ N FF 373 374 - 238 - 0 O0 s 1W::0o NH<N l N F />-NH F NH NH F F F 376 375 0 0 NH~ N N NH N N Ii />-NH F '11 ,->-NH F N X N F NF 377 F 378 0 NH N N NHN N. >-NH F <NH ~TN. N 0c N- XN a\-N ri/>N F F 380 379 - 239 - HT NNH N NH F NHN NH H F N F F 381 382 0 NH §1 NONNH 7 O NH<N /N HOJaNH N N F O N N N HO B NH NH F HO'B N HN F HN FH F FF 7F 384 383 KO., NHrN F N N /Ny >-NHF HoO<) -NH F --- N H N F| 385 386 N0 'ONH NN pI~ />-NNHFNN N HO, N ,>N-FNH r F B N HOB~ N 4 -A OH 6H F F 388 387 - 240 - NH 2 pHN H NHNNH F>-NH F >-N F HO K>' NN NF 389 F 390 NH 2 O', F Nr 0 NH F HNN HO N N 392 F 391 0 0 F FH NHI NH FHNH F F F 393 F 394 -241 - HN \ N F NH O N N N HNH F H > NH F N N F F F -0- F 395 F 396 HO d HO NH N N NH N NHN F F F F 398 397 CON 9 HO NH N NH NH F >$NH F N XN N) N F F0 FF NFN F400 F 399 - 242- HO HO HO HO" NH N NH N>NH N H NH F F F F F F 402 401 HO ir C N ~ N HO ,/>-NH F > NH F F 4 F 403 F 404 OH 0 NH OH H O /N H F 0 F HO .( NH N N H H ~N N F 405 406 - 243 - FF HO NHF HO NHF HN N N N N HN 1 N HN N 407 408 HO F HO>~ H~ F ~JN,-H F NN 0N N NH N 409 F F 410 OH 0 0 N FNH F NH F N N F N F HN HN p 411 412 -244- NH HO F NH N F NF N 'N N FHN N N N N F0 F 0 NH 2 413 414 N NH F NH F N- Nii NEF F HN N HN N 416 415 NH- FO 0 N _F NH\/ F N F N N I -N HN N HN N 418 417 - 245 - HO 0 0 FNH F N HF N N HN N HN N 419 420 HO HO NH F HO Q NH / F N Np N HN N bN b O NH 421 422 - 246 - HO NH F HO N b - F N NH -F HN<N N b HN O N 424 423 N />-NH F F FO' NA: O) :: NF F F 425 F 426 P NH N N 427z N >-NH *F 0 NJ, NF 427 428 -27N Nq ~NH N N ri1 TII,>-NHF TI ,r >-NH F ~ -~*K2 N. X..N F Nl 'N F - F 0 F 429 430 - 247 - 00 N F NH N N C NH<N N N r~ >-NH F 431 432 OH pp NHN N N 1>-NH F NH NH F 433 434 NH NNH NH F N>_NH F N:) />-N N -N F F 436 435 -248- HO OH "OH NHIN NH NH F NH N N N'~N' /I>-NH F F F 437 438 F 0 OH H "OH NHN N NH F NH N NH F II />-N F />NH F N F -0N N F -N FF F 440 439 NH 0 NH 'OH -"OH NH N N NH N N II />NH F "T >-N F NF F F-F 441 F 442 - 249 - 09 NH 'OH I NH N N\ >HNH F NH/ NH F HNFF F> F 444 F 443 NH N N NH N N N >-N H\F N xTC NF HN FN HN F-0 HN.~lF 445 F 446 HO HO,, NH N N NNH F NH N N HN N NF >-NH F > 7 N ) N 47F F0 447 F 448 -250- OH N NJ NHH N_ OH >_NNF F N NHIrN NH FHF NH N -NH FO N 450 F F F 449 NH F NH 0 2 F F F ONH F NNH HN FHQ NH ' NH H NH H N 0 0 451 452 - 2 OH HOK> 11,NN \>-NH N 1' :N> NH N N ~NH NN 453 454 H0 F F ~ \-NH F _ ~ NH F 455 045 -251 - F F HO N \>-NH F H \>-NH F N H"N N , C"N H N N 457 458 F F HO0 N NH F HO NH H0 F F Hp<> I~ \>-NH F 'Kh N -NHF K~>N H <N l N I~NH <N:" N 459 460 F F HO HO -~ \>-NH\>-NH a NH N N NH N 0 462 461 F HN N N-P FO NHN ,~INH <N N HOHO 463 HO4 - 252 - HOFP FP HO:: ' N N \>-NH F H N-NH F [ NH NN ~NH N N a 6 465 0 466 F F F F HOcl-K \>-NH F >' N F NNH N NH NH 467 468 F F N F-- N N -0 NH N N NH N 469 470 - 253 - F F F F >K-\-NH ~ >NH c NH N N NH N H F 471 472 F F' N N F NH N F SF \>-NH F ONH N N FNH N Fe 0< 0 473 474 F F -K--- \>-NH F c 1- >NHF NH N NNH N 475 0476 F F H 5 N F-- HO F _o [I J~~ -NH F"K- _K >NH F NN N ~NH NN 477 047 - 254 - F F 0 F0 F0 H 2 N N -NH F H 2 N NH NH N >, F NH N N N 40 479 480 F F F NH N F 0 Qo N F NHNN \>-NH F N -Io 482 481 F 0 ,:NH F NH H H NH N NH F HOlNHu NHN < F 4 484 483 - 255 - OH OH NH H FO H N N />-NH F />- NH F N N N F F 485 F 486 OH OH pNH NHF NH N F ~N N /-NH F />-NH F N /> N X F-0 F F 488 487 OH OH NH N N F <0N~NHN >-NH F N >N F 489 490 - 256 - OH NH.<N N UN NH F NH N N N N ojaNF- N s- N 491 492 NH N N NH N NNF NH-NH F />NH F N > NNF N F F0 F 493 496 OH N NH~ N N NH N N >-NH F NHN F -F 495 496 -257- N NHa N NH HO NHNNH FF F F- F F F 497 498 NH NH NH N N N FNH N N < r ,>-NH F ,>-NH F OH N:)H NN F F0 F 502 501 F - 258 - NH 2 YO HNH N HN N F F 503 504 F NH 2 NH 2 HN, N y~ -1 O_ H2N-,: /N>NH F HN N NH F F 506 F FF 507 508 505 NH 2 NH NH F H N N 509 CI F 510 - 259 - 0 NH 2 HN NN~~, HN-NH F HO N/>-NH F I ' N HO"'KN F F- F F F 512 511 0 , H NH H F N N HN F F F-0 F F 514 513 HO HON O />-NH F NH N N H"N Fri " >-NH F FF 515 F 516 - 260 - HO 0 NH 2 NHN N\ ~NHr~N. N , _NH FiNi ,,/>-NH F F H OJ : NH N F F 517 518 O NH NH 2 0 NH-F FH NHN FN- 0 N H N N N F F HN N 519 520 N 0 NH N N N~. 1 N >1N F ~ NH<rNN N-' N H >~N~ N F F F 522 521 OH NHyO N H N NH N F />-NH ~IN/>-NH N N N 523 F 524 -261 - OH OH N N N H N N F NH N N F 2i r >-NH N - N NF~ Fi F F F 526 525 0 NH O NHN F N H N F HN' II >-NH N N:) :N /N 2 F F F3F F 527 OH OH NH N N F ~ NH N N F / >-NH I>-,2NH IN NH Fl NH F F NH F F53 529 - 262 - OH OH 0 N ,NH N N F rN />-NHI 0 N N NH N N H F - N >-NH F NF NN 531 F 532 OH O ND OH OO ~NH N N F N~-NH NH NH 6 ,) 'rfjN ,>-NH -F N:-~ N 534 F 533 NH N N F NH~ N N F > N ) " />..N H N , 535 i53 or a pharmaceutically acceptable salt thereof. - 263 -

17. The method of any one of claims I to 16, substantially as hereinbefore described with reference to any of the Examples. -264-