OA11455A - 6,9-Disubstituted 2-Ätrans-(4-aminocyclohexy)aminoÜpurines. - Google Patents

Abstract

Compounds of Formula (I) wherein R is selected from the group consisting of R2, R2NH-, or R3R4N-R5-, and R1 is selected from the group consisting of cyclopentyl, cyclopentenyl and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof. A method of inhibiting cell cycle progression, a method of inhibiting cyclin dependent kinases, particularly cdk-2, a method of preventing apoptosis in neuronal cells and a method of inhibiting the development of neoplasms, a composition comprising an assayable amount of a compound of Formula (I) in admixture or otherwise in association with an inert carrier, and a pharmaceutical composition comprising an effective inhibitory amount of a compound of Formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

Description

-011455 l

5 6.9-DISUBSTITUTED 2-rTR.4NS-r4-AMINOCYCLOHEXYL)AMINO1PURINES

The présent invention relates to 6,9-disubstituted 2-[trans-(4-aminocyclohexyl)amino]-purines and methods of using the same for antineoplastic agents or for treatment for neuronalinjury and degeneration.

10 BACKGROUNDOF THE INVENTION

Cell division, in both normal and neoplasüc cells, is a tightly controlled event whichoccurs by defined stages. Quiescent cells which are not actively dividing, are in the Go phase, asare those terminally differentiated or in a State of temporary airest The first phase is the firstgap (G,) phase during which the cell préparés to synthesize DNA. In late G, phase at what is

I 15 termed a restriction point or R point, the cell commits to entering S phase during which DNAsynthesis occurs. Upon completion of S phase, the cell enters the second gap (G2) phase duringwhich the cell préparés to divide, which is followed by mitosis, or M phase.

Initial experiments in cell cycle régulation revealed the existence of a protein called"Maturation Promoting Factor" (MPF), a heterodimer with kinase activity. Later, comparison 20 of subsequently identified proteins and their underlying genes revealed a family of yeast genesknown as cell division control (cdc) genes. Further experiments demonstrated that some of thecdc genes encode kinases, and were later called cyclin-dependent kinases (cdks). As the resuitof this reclassification, some cell cycle proteins hâve dual désignations, such as cdkl which isalso known as cdc2. The kinase component of the MPF is now identified as p34cdc2 and the 25 regulatory subunit of MPF is now called cyclin B. Cyclins were first identified as proteins whose levels oscillated during the cell cycle and were specifically degraded at mitosis. To date, animal cyclins A-I and cdks 1-8 hâve been identified. To further complicate nomenclature, subtypes of cyclins and cdks hâve been identified, such as cyclins B1 and B2. z

Subséquent research on cell régulation has demonstrated that the stages of cellular 30 division are achieved in part by modulation cyclins and cyclin-dependent kinases (cdks).

Cyclins sequentially regulate cdks and are characterized by a 100 amino acid homology régiontermed the "cyclin box" which is involved in binding a protein kinase partner. Cdks are closelyrelated in sequence and size (35-40 kDa) and are defined as protein kinases activated by bound

U i H3D 2 cyclin regulatory subunits. Cdks contain a conserved active-site cleft of approximately 300 amino acids that is characteristic of ail eukaryotic protein kinases. Thus, both the cyclins and cdks appear to be highly conserved protein families.

Isolation of individual cyclins and cdks has enabled further identification of the rôles 5 and interactions of each component in cell cycle phase transitions. Excess levels of cdks persistthroughout the cell cycle. Activation of cdks occurs upon cyclin synthesis and binding to thecatalytic cdk subunit, the resuit of which is stimulation of the cdk serine/threonine kinaseactivity. Complété cdk activation requires phosphorylation on a conserved threonine residuelocated in the T-loop by a cyclin-dependent kinase activating kinase (CAK), which is itself a 10 cdk/cyclin complex composed of cyclin H and cdk7, and a third protein of about 32 kDa.

Inactivation of the cdk-cyclin complex can resuit ftom the phosphorylation of a threonine and/or tyrosine residue in the ATP-binding site of the cdk or ftom binding of one of anumber of endogenous inhibitor proteins.

In Gj phase, D-type cyclins bind to several different cdks, including cdk2, cdk4, cdk5 15 and cdk6, but are most commonly associated with cdk4 and cdk6. D-type cyclins are thought to act as growth factor sensors, which link cell cycle progression to extemal eues. Cyclin E-cdk2complexes appear in the mammalian cell cycle after the D-type cyclin-cdk complexes. CyclinE synthesis is tightly regulated and occurs in late G, and early S phase. The cyclin E-cdk2complex is essential for the cell to begin DNA réplication. 20 The G, cyclins, cyclin D and cyclin E, are transiently produced proteins, with a half-life of about 20 minutes. The short half-life is thought to resuit from a PEST sequence in the C-terminal régions of these proteins, the dégradation of which appears to be mediated by theubiquitination pathway.

The G2 cyclins, cyclin A and cyclin B, are stable throughout interphase and specifically 25 destroyed at mitosis through an ubiquitination pathway. Both cyclin A and cyclin B2 appear tobe degraded only when complexed with their cdk partner [cyclinA-cdk2 and cyclin A/B-cdkl(cdc2)]. However, cyclin B1 destruction is connected with the integrity of the mitoticapparatus at the end of metaphase. If the spindle is incorrectly assembled, or chromosomesincorrectly aligned, then cyclin B1 destruction is prevented. 30 Retinoblastoma protein (Rb), a 105 kDa nuclear phosphoprotein, is a substrate of cyclin- cdk complexes of cdks-2,4 and 6 in Gt phase and functions as one of the major checkpointControls in the cell cycle via carefully orchestrated phosphorylation and déphosphorylation. InGq/G,, Rb exists in a hypophosphoryiated State. As the cell progresses into late G,, Rb becomes 011455 3 hyperphosphorylated by D-cyclin complexes, which inactivâtes Rb and drives the cell into Sphase resulting in cell cycle progression and cell division. This State of hyperphosphorylation ofRb remains in G2. During late M phase, Rb is dephosphorylated, thus retuming to thehypophosphorylated State. Phosphorylation of the Rb protein alters its binding characteristics; 5 in the hypophosphorylated state, Rb binds to and sequesters spécifie transcription factors, suchas E2F, the binding of which prevents the exit from the Gj phase. Once cdkshyperphosphorylate Rb, the transcription factors are released which can then activatetranscription of genes necessary for S phase progression, for example, thymdine kinase, myc,myb, dihydrofolate reductase, and DNA polymerase-ot. 10 Localization of cyclin-CDK complexes is also very suggestive about the rôle each complex plays in the pathway. Nuclear cyclins A and E bind to pl07 and pl30, possiblybecause they are in the nucléus. Mammalian cyclin B1 accumulâtes in the cytoplasm in G2phase and translocates into the nucléus at the beginning of mitosis. Cyclin B associâtes withthe spihdle apparatus, in particular with the spindle caps, and it is thought that the cyclin B-cdc2 15 kinase riiay be involved in the formation of the spindle through phosphoiylating components ofthe mitoûc apparatus. In addition, cyclin B1 is part of a feedback mechanism ensuring correctassemblÿ'of the metaphase mitotic apparatus. Human cyclin B2 is almost exclusivelyassociated with the membrane compartment, and in particular the Golgi apparatus. Cyclin B2-cdc2 is involved in the disassembly of the Golgi apparatus when cells enter mitosis. 20 Cdc2-cyclin B kinase is a key mitotic factor which appears to be highly conserved and is thought to be involved in cell cycle transitions in ail eukaryotic cells. Histone H1 is a substratefor cdc2-cyclin B; histone H1 is selectively phosphorylated on spécifie sites in mitosis, which isthought to be important for chromatin condensation. The cdc2-cyclin B complex alsophosphorylâtes lamin, which is responsible for nuclear lamina breakdown. The nuclear lamina 25 is made up of a polymer of lamin subunits that are hyperphosphorylated at mitosis, and thisphosphorylation is responsible for their disassembly. Lamins are part of the intermediatefilament family of proteins, and cdc2-cyclin B phosphorylâtes a subset of the sitesphosphorylated at mitosis on the cytoplasmic intermediate filament subunits, vimentin anddesmin. Thus, the cdc2-cyclin B complex is involved in the reorganization of the cell 30 architecture at mitosis.

In addition, cdc2-cyclin B is involved in the reorganization of microfilaments, throughphosphorylation of non-muscle caldesmon, an 83 kDa protein that binds to actin andcalmodulin, and inhibits actomyosin ATPase activity. At mitosis, caldesmon is phosphorylated 4 - UU455 by cdc2-cyclin B, which weakens its affmity for aciin and causes it to dissociate frommicrofilaments.

Cdc2-cyclin B is implicated in actomyosin filament régulation, by phosphorylating themyosin in the contractile ring, which divides the cell into two (cytokinesis). In metaphase, the 5 myosin Π regulatory light chain (MLC) is phosphorylated on two main sites at the N-terminus.Once phosphorylated, the myosin is prevented from interacting with actin. At anaphase, thesetwo sites are dephosphoryiated.

Cdc2-cyclin B also plays a rôle in reorganization of the membrane compartment atmitosis. For example, cdc2-cyclin B phosphorylâtes rablAp and rab4p. Whenrab4pis 10 phophorylated by cdc2-cyclin B, it dissociâtes from the membrane compartment.

At mitosis, most forms of transcription are inhibited. Again, cdc2-cyclin B plays a rôle in inhibition of pol ΙΠ-mediated transcription by phosphorylating TFIHB. Given that pol L polΠ and pol ΠΙ-mediated transcription share several common factors, such as TATA-hindingprotein (TB A), it is likely that cdc2-cyciin B is involved in down-regulating ail forms of 15 transcription at mitosis.

Given the importance of cyclin/cdk complexes in triggering cell cycle division, they areunder tight regulatory mechanisms. Since their initial discovery, cyclins and cdks hâve beenshown to internet with other transcription factors and proteins involved in a broad range ofcellular pathways. Cdk7 has been identified as a component in transcription factor ΠΗ (’i'HïH),

20 which contains the RNA polymerase II C-tertninal domain (CTD) kinase activity. Morerecently, cdk8 which partners with cyclin C, has also been discovered to phosphorylate theCTD of RNA polymerase Π, but does not appear to possess CAK activity. Thus, it is clear thatcdks participate in a broad range of cellular functions in addition to cell cycle régulation. CDK-inhibitor proteins (CDIs) are small proteins that bind and inactivate spécifie cyclin-CDK 25 complexes, or monmeric CDKs. These inhibitors can be grouped into two families based onsequence and functional similarities. The INK4 family includes pl5INK4B, p 16^^, pl8 and pl9which specifically bind cdk4 and cdk6. p 16WK4 and pl51NK4B contain four ankyrin repeats and,in addition to sharing significant homology, are encoded by adjacent genes on the 9p 12 locus.

High cellular levels of p 16 results in inactivation of cdk4 because p 16 binds cyclinD- 30 cdk4 and cyclin D-cdk6 complexes. The gene for p 16tNK4 (MTS 1) is recognized as a potentialtumor suppressor gene, as it is rearranged, deleted or mutated in a large number of tumor cellIines, and in some primary tumors. In one study of hereditary melanoma, about half thefamilies hadgermline mutations in the pl6WK4 gene. Rb is a repressor of plô^4. Inactivation 5 011455 of cellular Rb, either by mutation or viral antigens, correlates with increased levels of plô^4. P16WK4, p 15INK4B, and p 18 inhibit binding of cyciin D with cdk4 and cdk6.

The second family of CDIs is the Kip/Cip family which includes p21c'pI'WAF‘l, p27KÎpland p57Kip2. p27KIP1 is présent in proliferating cells in a latent or masked fonn. Upon 5 stimulation, p27KIPl is unmasked and binds to and inhibits cyclin-CDK4/6 complexes. TheKip/Cip family proteins hâve strong homology in the N-terminus, the région that binds thecyciin-cdk complexes. The Kip/Cip family proteins preferentially bind to and inhibits cyclin-cdk complexes involved in the G, and S phase complexes over those involved in the M phase. P21 (also known as WAF1, Cipl and Sdil) is induced by p53 and forms a temary 10 complex with proliferating cell nuclear antigen (PCNA), a subunit of DNA polymerase δ inseveral cyclin-CDK2 complexes, including cyçlins A, DI and E. P21waf-‘ expression ingrowing, quiescent and senescent cells correlates with a rôle as a négative regulator of S phaspentry. P21WAF'! mRNA is upregulated as cells become senescent or quiescent, and after sérumstimulation of quiescent cells, and decreases as cells enter S phase. p21 inactivâtes cyciin E- 15 cdk2, cyciin A-cdk2, and cyclins Dl-, D2- and D3-cdk4 complexes.

Genetic analysis of numerous human tumors reveals a disproportionate numer of altered cell cycle proteins, and it is this aberration that is thought to cause abnormal cell cycle. Forexample, cyciin Dl is the bcl-1/PRADl proto-oncogene that is either overexpressed orderegulated in a variety of human tumors. The cyciin D1/CCND1 gene, located at chromosome 20 1 lql3, is amplified in a number of cancers, mainly breast and non-small cell lung carcinomas.

This correlates with the observation that overexpression of cyciin Dl is a common feature in thetumors with this spécifie 1 lql 3 amplicon. The gene for pl6 is rearranged, deleted or mutatedin a large number of tumour cell lines, and in some primary tumours. Mutations in cdk4,specifically an Arg24Cys mutation, has been identified in two unrelated hereditary melanoma 25 families. This mutation was found in 11/11 of the melanoma patients, 2/17 unaffecteds and 0/5spouses (Zuo, L., et al., Nature Genetics 12 1996:97-99). This mutation has a spécifie effect onthe pl6INK4a binding domain of cdk4, but has no affect on the ability to bind to cyciin D andform a functional kinase. As a resuit of this mutation, the cyciin D/cdk4 complex is résistant tonormal physiological inhibition by pl6INK4a. Other studies hâve demonstrated that about half 30 the familial melanoma kindreds show evidence of linkage to the région of chromosome 9p21that contains the pl61NK4i gene. The types of pl6INK4a mutations identified include a nonsensemutation, splice donor mutation, an unidentified mutation that prevents pl6INK4a transcription,and 3 missense mutants that are unable to bind to cdk4 or cdk6. Overexpression of cdk4 as a V I I *t ο Ο 6 resuit of gene amplification has been identified in a study of 32 glioma cell lines (He, J., et al.,Cancer Res. 54:5804-5807, 1994). This alteration was observed among the ten cases bavinginuct pl6 genes. Genetic analysis of glioma cell lines revealed that 24 of 32 glioma cell Uneshad one of two alternative genetic alterations, each of which indicates that increased cdk4 5 kinase activity is important to glial tumor development Cdk4 maps to the long arm of chromosome 12 and is found overexpressed in certain tumors because of its amplification as acomponent of an amplicon that includes other relevant genes, such as SAS and MDM2. AU ofthe above conditions lead to activation of cdk4. Overcxpression of cyclins B1 and E inleukemic and solid tumor cell lines, as well as altered patterns of cyclin E expression in breast 10 cancer has also been reported.

Cellular hyperproliferation occurs in a number of disease states. The most commonhyperproliferative diseases are neoplasms, which are typicaUy named according to the originalsource of the hyperproliferative tissue. Neoplasms are defined as new growths nf animal nrplant tissue that resemble more or less the tissue from which it arises, but serve no physiologie 15 function, and are benign, potentially malignant or malignant in character. Neoplasms arise asthe resuit of loss of normal Controls, leading to unregulated growth. Neoplastic cells may lackdifférentiation and acquire the ability to invade local tissues and metastasize. Neoplasms maydevelop in any type of tissue of any organ at any âge. The incidence, and mortality rate, ofneoplasms generaUy increases with âge, with certain neoplasms having peak incidence between 20 the âges of 60 and 80 (e.g. prostate, stomach and colon). However, other neoplasms hâve apeak incidence ffom birth to 10 years of âge (e.g. acute lymphoblastic leukemia). Diet,exposure to carcinogens, particularly use of tobacco, and familial prédispositions also affectincidence of particular neoplasms.

Neoplastic cells differ from normal cells in a number of important aspects, including 25 loss of différentiation, increased invasiveness and decreased drug sensitivity. Another important différence is the unchecked growth of cells, which is thought to resuit from loss ofnormal cellular control mechanisms of these cells are either deactivated, bypassed or otherwisedisregarded, leaving the neoplastic cells to proliferate without regard to the normal controllingmechanisms. 30 Neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinatedwith that of the normal tissue, and persists in the same excessive manner after cessation of thestimuli which evoked the change.

Neoplasms are classified as either benign or malignant. Benign neoplasms exhibit slow, 011455 7 locaiized growth that is usually circumscribed due to their encapsulation by a ftbrousconnective tissue capsule. Whereas benign neoplasms rarely cause the death of the organism,untreated malignant neoplasms hâve a high probability of killing the organism. Malignantneoplasms are generally nonencapsulated, and usually exhibit a more rapid growth rate. 5 Malignant neoplasms often invade surrounding tissues and vessel and spread to distant bodysites. Malignant neoplasms are generically described as "cancer" or as "tumors"; the latter termdénotés swelling.

Myeloproliferative disorders are a group of disorders characterized by abnormalprolifération by one or more hematopoietic cell lines or connective tissue éléments. Four 10 disorders are normally included as myeloproliferative disorders: polycythemia vera (primarypolycythemia; Vaquez’ Disease), myelofibrosis (agnogenic myeloid metaplasia), chronicmyelogenous leukemia and primary (essential) thrombocythemia. Acute leukemia, especiallyerythroleukemia, and paroxysmal noctemal hemoglobinuria are also classified asmyeloproliferative disorders. Each of these disorders is identi&ed according to its prédominant 15 feature or site of prolifération. Although each results from prolifération of different cells, eachhas been shown to be caused by a clonal prolifération arising at the level of a pluripotent stemcell. which causes varying degrees of abnormal prolifération of erythroid, myeloid, andmegakaryocytic precursors in the bone marrow. Ail myeloproliferative disorders hâve atendency to terminate in acute leukemia. 20 Leukemias are malignant neoplasms of the blood-forming tissues. At least two viruses are associated with causing leukemias in humans. The Epstein-Bair virus is associated withBurkitt’s lymphoma and the human T-cell lymphotropic virus, also called human acuteleukemia/lymphoma virus (HTLV-1) has been linked to some T cell leukemias and lymphomas.Exposure, especially prolonged exposure to Chemical agents, such as benzene and some 25 antineoplastics, or to ionizing radiation, genetic prédisposition (e.g. Down’s syndrome) andsome familial disorders (e.g. Fanconi’s anémia) resuit in prédispositions to leukemias.

Development of leukemias appears to occur through a single cell cycle through two ormore steps with subséquent prolifération and clonal expansion. Leukemias are currentlyclassified according to their cellular maturity; acute leukemias are predominantly 30 undifferentiated cell populations and chronic leukemias are more mature cell forms. Acute leukemias are further divided into lymphoblastic (ATJ., also known as acute lymphocytic leukemia) and myeloid (AML, also known as acute myelocytic, myelogenous, myeloblastic, myelomonoblastic) types. They may be further classified by morphologie and cytochemical U'I I S· Oô 8 appearance according to the French-American-British (FAB) classification or according to typeand degree of différentiation. Chronic leukemias are classified as either lymphocytic (CT T .) ormyelocytic (CML). CLL is characterized by the appearance of mature lymphocytes in theblood, bone marrow and lymphoid organs. CML is characterized by the prédominance of 5 granulocytic cells of ail stages of différentiation in blood, bone marrow, liver, spleen and otherorgans.

Myelodysplastic Syndrome (MDS) is characterized as a clonal proliférative disorder inwhich a normal or hypercellular bone marrow is associated with anémia and dysmyelopoiesis.Hemapoietic cells which may proliferate include erythroid, myeloid and megakaryocytic forms. 10 MDS is a relatively new désignation of group of disorders known as

Preleukemia, Refractory Anémias, Ph-Chromosome-Negative Chronic Myelocytic Leukemia,Chronic Myelomonocytic Leukemia and Agnogenic Myeloid Metaplasia. The FAB Systemprovides further classification of Myelofibrosis.

Lymphomas are a heterogeneous group of neoplasms arising in the réticuloendothélial 15 and lymphatic Systems. The major types of lymphomas are Hodgkin’ s disease and non-Hodgkin’s lymphoma, as well as the rarer Burkitt’s lymphoma and mycosis fungoides.Hodgkin’s disease is a chronic disease with lymphoreticular prolifération of unknown causethat may présent in localized or disseminated form, and is further classified according to fourhistopathologie profiles. Non-Hodgkin’s lymphomas are a heterogeneous group of 20 diseases consisting of neoplastic prolifération of lymphoid cells that usually disseminate throughout the body. The former terms, lymphosarcoma and réticulum cell sarcoma, are nowbeing replaced with terms that reflect that cell of origin and biology of the disease. TheRappaport classification is based on the histopathology; on the degree of the différentiation ofthe tumor; and on whether the growth pattern is diffuse or nodular. The Lukes and Collins 25 classification is based upon the cell of origin, specifically whether it is T cell or B cell derived,histiocytic (or monocytic) origin or unclassifiable. The International Panel WorkingFormulation of the National Cancer Institute categorizes non-Hodgkin’s lymphomas using theabove classifications.

Burkitt’s lymphoma is a highly undifferentiated B cell lymphoma that tends to in volve 30 sites other than the lymph nodes and reticulendoethlial System. Burkitt’s lymphoma, unlikeother lymphomas, has a spécifie géographie distribution, which suggests an unidentified insectvector and an infectious agent. Evidence points to the herpes like Epstein-Barr virus.

Mycosis fungoides is an uncommon chronic T cell lymphoma primarily affecting the 011455 skin and occasionally internai organs.

Plasma cell dyscrasias (PCDs), or monoclonal gammopathy, are disorders characterizedby the disproportionate prolifération of one clone of cells normally engaged in immunoglobulin(Ig) synthesis, and the presence of a structurally and electrophoretically homogeneous IG or 5 polypeptide subunit in sérum or urine. The disorders may be primarily asymptomatic toprogressive, overt neoplasms (e.g., multiple myeloma). The disorder results fromdisproportionate prolifération of one clone producing a spécifie Ig: IgG, IgM, IgA, IgD or IgE.

Multiple myeloma, also known as plasma cell myeloma or myelomarosis, is aprogressive neoplastic disease characterized by marrow plasma cell tumors and overproduction 10 of an intact monoclonal Ig (IgG, IgA, IgD or IgE) or Bence Jones protein, which is free monoclonal κ or λ light chains. Diffuse osteoporosis or discrète osteolytic lésions arise due toreplacement by expanding plasma cell tumors or a osteoclast-activating factor secreted bymalignant plasma cells. '·- Macroglobulinemia, or primary or Waldenstrom’s macroglobulinemia, is a plasma cell 15 dÿscrasia involving B cells that normally synthesize and secrete IgM. Macrogolbulinemia isdistinct from myeloma and other PCDs, and resémbles a lymphomatous disease. Many patientshâve symptoms of hyperviscosity, fatigue, weakness, skin and mucosal bleeding and so forth.

Heavy chain diseases are neoplastic plasma cell dyscrasias characterized by theoverproduction of homogenous γ, α, μ, and δ Ig heavy chains. These disorders resuit in 20 incomplète monoclonal Igs. The clinical picture is more Iike lymphoma than multiplemyeloma.

Hypersplenism is a syndrome in which circulating cytopenia is associated withsplenomegaly. Treatment of patients with hypersplenism requires therapy for the underlyingdisease, not splenectomy. Lymphoproliférative and myeloproliferative diseases are some, but 25 not the sole, causes of hypersplenism. Myeloproliferative disorders causing hypersplenisminclude polycythemia vera, myelofibrosis with myeloid metaplasia, chronic myelogenousleukemia and essential thrombocythemia. Chronic lymphocytic leukemia and the lymphomas(including Hodgkin’s disease) are spécifie lymphoproliférative disorders chat may causehypersplenism. 30 Lung tissue is the site for both benign and malignant primary tumors, as well as the site of metastasis from cancers of many other organs and tissues. Cigarette smoking causes anoverwhelming percentage of lung cancers, estimated at over ninety percent of the cases in menand about seventy percent of the cases in women. Exposure to occupational agents such as υ ι ι 455 10 asbestos, radiation, arsenic, chromâtes, nickel, chloromethyl ethers, poison gas, and coke ovenémissions is also associated with lung cancer. The most common types of lung cancer aresquamous cell, small and large cell and adenocarcinoma.

About ninety-five percent of the stomach cancers are carcinoma; less common arelymphomas and leiomyosarcomas. Gastric carcinomas are classified according to grossappearance; protruding, penetradng (the tumor has a sharp, well-circumscribed border and maybe ulcerated) and spreading or miscellaneous, which has characteristics of two of the othertypes.

Pancreatic cancers may be exocrine tumors, which are mostly adénocarcinomes arisingfrom duct cells rather than the acinar cells, or endocrine tumors, which include insulinoama.Gastrin-producing pancreatic tumors involving cells of the ηοη-β-type or in the duodenal wallcan cause Zollinger-Eliison Syndrome, a syndrome marked by hypergastrinemeia. Sometimesother endocrine abnormalities, particularly with the parathyroids, or pituitary and adrenal glandscause a polyglandular disorder known as multiple endocring neoplasia (ΜΕΝ). Νοη-β islet celltumors may cause a syndrome known as Vipoma Syndrome, which is characterized byprolonged massive watery dianhea.

Neoplasms of the bowel include tumors of the small intestine, tumors of the largeintestine, and cancer of the colon and rectum. Benign small intestine tumors may arise fromjejunal and ileal neoplasms, including leiomyomas, lipomas, neurofibromas, and fibromas.Malignant small intestine tumors, such as adenocarcinomas, are uncommon, and typically arisein the proximal jéjunum. Patients with Crohn’s disease of the small intestine are more prône tosuch adenocarcinomas rather than patients with Crohn’s disease of the colon. In patients withCrohn’s disease, the tumors tend to occur distally in the bypassed or inflamed loops of thebowel. Carcinoid tumors typically arise in the small bowel, especially the ileum, and in abouthalf the cases, multiple tumors exist Kaposi’s sarcoma, which occurs frequently in transplantrécipients and AIDS patients, hâve gastrointestinal involvement in about half the cases. Lésionsmay occur anywhere in the GI tract, but are usually found in the stomach, small intestine, ordistal colon.

Tumors of the large bowel include polyps of the colon and rectum. Polyps are a mass of tissue that arises from the bowel wall and protrudes into the lumen. Polyps are classified on the basis of their histology, as tubular adenomas, tubulovillous adenomas, villous adenomas, hyperplastic polyps, hamartomas, juvénile polyps, polypoid carcinomas, pseudopolyps, lipomas, leiomyomas and even rarer tumors. 011455 11

Malignant tumors may also anse in the anorectum. These are epidennoid (squamouscells) carcinoma of the anorectum which comprise about three to rive percent of rectal and analcancers.

In Western countries, cancer of the colon and rectum are second to lung cancer in5 accounting for more new cases each year. In the USA, aobut 75,000 people died of these cancers in 1989; about 70 % occurred in the rectum and sigmoid colon, and 95% wereadenocarcinomas.

Neoplasms of the liver include benign neoplasms, which are relatively common butoften undetected, and malignant neoplasms. Hepatocellular adenoma is the most important 10 benign liver neoplasm. Asymptomatic small hemangiomas occur in one to five percent ofadults. Bile duct adenomas and other mesenchymal neoplasms also occur, but are relativelyrare. Malignant neoplasms of the liver are the most common form of hepatic tumor, and theliver is a frequent site of bloodbome métastasés, usually. from lung, breast, colon, pancréas andstomach primary tumors. The incidence of hepatocellular carcinoma is linked with chronic 15 hepatitis B virus in certain parts of Africa and Southeast Asia. In North America, Europe andother areas of low prevelence, most of the patients hâve underlying ciiThosis. Fibrolamellarcarcinoma is a distant variant of hepatocellular carcinoma with characteristic morphology ofmalignant hépatocytes enmeshed in lamellar fibrous tissue. Fibrolamellar carcinoma usuallyaffects relatively young adults, and has no association with preexisting cirrhosis, chronic 20 hepatitis B virus infection or other known risk factors. Other primary malignancies of the liverinclude cholangiocarcinoma (a tumor arising from intrahepatic biliaiy epithelium),hepatoblastoma (which is one of the most common cancers in infants) and angiosarcoma (whichis associated with industrial exposure to vinyl chloride). Leukemia and related disorders mayinvolve hepatic tissues, thought to be the resuit of infiltration with abnormal cells. 25 Multiple Endocrine Neoplasia (MEN) Syndromes are a group of genetically distinct familial diseases involving adenomatous hyperplasia and malignant tumor formation in severalendocrine glands. Three distinct syndromes hâve been identified. Type I (MEN-I) ischaracterized by tumors of the parathyroid glands, pancreatic islets, and the pituitary. Type Π(MEN-Π) is characterized by medullary carcinoma of the thyroid, pheochromocytoma and 30 hperparthyroidism. Type IH (MEN-EH) is characterized by multiple mucosal neuromas,medullary carcinoma of the thyroid, and pheochromocytoma.

Carcinoid syndrome is usually caused by metastatic intestinal carcinoid tumors thatsecrete excessive amount of vasoactive substances, including serotonin, bradykinin, histamine, 12 prostaglandins and polypeptide hormones. Abnormal levels of these subtances cause a variety of symptoms, often episodic cutanteous flushing, cyanosis, abdominal cramps, diarrhea, and valvular heart disease.

Neoplasms of the bone and joints may be benign or malignant. Benign tumors of the 5 bone include osteochondromas (osteocartilaginous exostoses), which are the most common benign bone tumors in children between âges 10 to 20, benign chondromas (which are locatedwithin the bone), which occur most commonly in children and young adults between the âges10 to 30, chondroblastoma (which anses in an epiphysis), which is rare, but most common inchildren between the âges of 10 to 20, chondromyxofibromas, osteoid osteoma, giant cell 10 tumors and fibromatous lésions. Primary malignant tumors of the bone include ostéogéniesarcoma (osteosarcoma), which is the second most common primary bone tumor,fibrosarcomas, malignant fibrous histiocytoma, chondrosarcomas, mesenchymalchondrosarcoma, Ewing’s tumor (Ewing’s sarcoma), malignant lymphoma of bone, multiplemyeloma, and malignant giant cell tumor. 15 Primary cancers of other tissues may metastasize to bone tissue. The most common are carcinomas arising in the breast, lung, prostate, kidney, and thyroid.

Central nervous System (CNS) neoplasms are generally classified according to theorgan. Primary intracranial neoplasms are subdivided into six classes: tumors of (1) the skull;(2) the méningés; (3) the cranial nerves; (4) the neuroglia and ependyma; (5) pituitary orpineal 20 gland; and (6) those of congénital origin. Skull neoplasms include osteoma, hemangioma,granuloma, xanthoma, and osteitis deformans. The méningés neoplasms include meningioma,sarcoma, and glomatosis. The cranial nerve neoplasms include glioma of the optic nerve, andschwannoma of the 8th and Sth cranial nerves. The neuroglia neoplasms include gliomas andependymomas. The pituitary or pineal body neoplasms include pituitary adenoma and 25 pinealoma. The congénital origin neoplams include craniopharyngioma, chordoma, germinoma,teratoma, dermoid cyst, agioma and hemangioblastoma.

Spinal cord neoplasms are lésions that compress the spinal cord or its roots, arising fromthe cord parenchyma, roots, méningés, or vertebrae. Primary spinal cord neoplasms are muchless common than intracranial tumors. Metastatic lésions are common and may arise from 30 carcinomas of the lung, breast, prostate, kidney, thyroid or lymphoma.

Genitourinary neoplasms occur at any âge and in both sexes; however, they account forabout 30% of cancer in the male and 4% in the female. Adenocarcinoma of the prostateaccounts for a significant number of malignancies in men over 50. Prostate adenocarcinoma is 0114 55 13 thought to be hormone related and its pathology is typically glandular. Carcinoma of thekidney, adenocarcinoma, is only about one to two percent of adult cancers, but most solidkidney tumors are malignant. Wilms’ tumors, an embryonal adenomyosarcoma of the kidneys,occurs fetally and is often not diagnosed for several years. Rénal pelvis and ureter neoplasms 5 are histologically similar. Urinary bladder neoplasms may be induced by known urinarycarcinogens such as aniline dyes, and the most common is transitional cell carcinoma, lesscommon is squamous cell carcinoma. Rarer genitourinary neoplasms inciude carcinoma of theurethra, and pénis. Neoplasms of the testis account for the majority of solid malignancies inmales under 30. Most malignant testicular tumors arise from the primordial germ cell and are 10 classified according to the cell type involved.

Breast cancer is the most common cancer in women. In the USA, the cumulative risk for women of ail âges of developing breast cancer is about 10%, but that of dying from thedisease is only about 3.6%. However, the risk increases with âge, a family history of breastcancer, exposure to radiation, and even diet is implicated in higher risk. 15 i Breast cancers are routinely typed for estrogen- and progesterone-receptor analysis.About two thirds of the patients hâve estrogen-receptor positive (ER+) breast tumors. Tumorswhich are progestérone positive are thought to hâve functional estrogen receptor and thepresence of both receptors gives a greater likelihood of favorable response to endocrinetreatment than the presence of just one receptor. Endocrine therapy, usually tamoxifen, is 20 preferred in estrogen receptor-positive tumors. Estrogens and androgens are also effective, butless favored due to undesirable side effects induced by higher levels of these hormones thanother forms of endocrine treatment. Breast cancer may metastasize to almost any organ in thebody, but most common sites of metastatisis are the lung, liver, bone, lymph nodes and skin.

Lobular carcinoma in situ (LCIS) or lobular neoplasia, is most frequently found in 25 premenopausai women. Ductal carcinoma in situ (DCIS) occurs in both pre- and postmenopausal women. DCIS forms a palpable mass. LCIS and DCIS account for about 90%of ail breast cancers. The rarer forms, medullary and tubular lésions, hâve a somewhat betterprognosis.

The most common gynécologie neoplasms are endométrial carcinomas, which ranks 30 fourth in frequency after breast, colorectal and lung cancers in women. Endométrial carcinomasare characterized by their clinical staging, ranging from in situ at stage 0, to metastasis todistant organs at stage IVB. Endométrial carcinomas typically produce estrogen and the currenttreatment approaches are surgery and progestérone therapy. 14

Ovarian cancers account for about 18% of ail gynécologie neoplasms. About 80% ofmalignant ovarian cancers arise from the ovarian epithelium and are classified according totheir histology. Tumors may also arise from germ cells or stroma.

Vulvar carcinoma accounts for about 3-4% of ail gynécologie neoplasms. Vulvar5 carcinoma usually occurs after ménopausé, and about 90% are squamous cell carcinomas

About 4% are basal cell carcinomas and the rest include intraepithélial carcinomas,adnocarcinoma of Bartholin’ s gland, fibrosarcoma and melanoma.

Vaginal carinoma accounts for about 1% of gynécologie malignancies, with a peakincidence from about âges 45 to 65. About 95% of vaginal carcinomas are squamous cell 10 carcinoma. Primary carcinoma of the oviduct is rare, and typically spread directly or by thelymphatics.

Trophoblastic disease or neoplams of trophoblastic origin, can follow intra- orextrauterine pregnancy. A degenerating pregancy rcsults in a hydatidiform mole of which about80% are benign. 15 Neoplasms may arise in the ear canal and affect hearing. Ceruminomas also arise, are typically malignant despite appearing benign histologically and are treated by surgical removal.Basal cell and squamous cell carcinomas frequently develop on the extemal ear as the resuitfrom regular sun exposure, and are also typically treated by surgical removal. The middle earmay be the site of squamous cell carcinomas. Nonchromaffin paragangliomas may arise in the 20 temporal bone.

The most common malignant tumor in the nose and paranasal sinuses is squamous cellcarcinoma; less common are adenoid cystic and mucoepidermod carcinomas, malignapt mixedtumors, adenocarcinomas, lymphomas, fibrosarcomas, osteosarcomas, chondrosarenmas, andmelanomas. 25 Squamous cell carcinoma of the nasopharynx is more commonly observed in children and young adults.

The most common malignancies of the upper respiratory tract are squamous cellcarcinomas of the tonsil and of the larynx. Both are more common in males and are associatedwith tobacco smoking and éthanol ingestion; about 85 % of patients with cancer of the head or 30 neck hâve a history of éthanol and tobacco consumption.

In the head and neck, about 90% of the cancers are squamous cell (epidermoid)carcinoma. Melanomas, lymphomas and sarcomas are relatively rare forms of primary head andneck cancers. Cancers of the head and neck are classified according to the size and site of . 011455 15 involvement of the primary neoplasm; number and size of métastasés to the cervical lymphnodes; and evidence of distant métastasés.

Ophthalmologic cancers may arise in the skin of the eyelids and may be benign orneoplastic. Common benign growths are xanthelasmas, which form yellow-white fiat plaquesof lipid material subcutaneously. Basal cell carcinomas are more common; treatment istypically surgical removal or radiation therapy. Other less common malignant tumors aresquamous cell or meibomian gland carcinomas and other types of melanomas. The mostcommon primary ocular malignancy is malignant melanoma of the choroid.

Tumors also arise in the skin tissue, and include benign tumors such as moles, Iipomasand the like, as well as malignant tumors. About 40-50% of malignant melanomas arise frommélanocytes in moles. Malignant skin cancers are either basal cell or squamous cell carcinomasand frequently arise in sun-exposed areas of skin. They are the most common malignancies,and the incidence is rising. Less common malignancies include malignant melanoma, Paget’sdisease of the nipple or estramammary Patent’s, Kaposi’s sarcoma (KS), and cutaneous T celllymphoma (mycosis fongiodes). The incidence of KS is increasing as the resuit of theincréased incidence of AIDS. KS arises in about one third of patients with AIDS. .? Oral cancers account for about 5% of cancers in men and 2% of cancers in women. Themost common form of oral cancer is squamous cell carcinoma. Incidence increases with âgeand risk factors, particularly tobacco and alcohol consumption.

Surgery is the oldest effective form of treatment of neoplasms. Success is largelyachieved if the neoplasm is detected in its early stages and has not metastasized. Radiation isalso important therapy, and is the favored therapy of many neoplasms such as Hodgkin’sdisease, early stage non-Hodgkin’s lymphomas, and squamous cell carcinoma of the head andneck. Radiation has proven very successful as an adjunct to' surgery and antineoplastic drugs.

Antineoplastic drugs are also usefol in the treatment of neoplasms, and are classifiedaccording to their mechanism of action. Numerous combinations, typically of antineoplasticdrugs with differing mechanisms of action, hâve proven to be particularly effective therapy,permit lower doses and frequently minimize négative side effects. Antineoplastic drugsfrequently target fondamental biological processes necessary for cell réplication or growth.

Alkylating agents, such as mechlorethamin and cyclophosphamide, alkylate DNA, andrestrict DNA réplication.

Antimetabolites, which are directed to disruption of necessary cell division pathways,include: 16 011455

Folate antagoniste bind to dehydrofolate reductase and interfère with pyrimidinesynthesis. Folate antagoniste are S-phase spécifie. Methotrexate is a very commonly usedantineoplastic folate antagonist.

Purine antagoniste block de novo purine synthesis and are S-phase spécifie. 6-5 Mercaptopurine is an example of a purine antagonist.

Pyrimidine antagoniste interfère with thymidylate synthase to reduce thymidineproduction and are S-phase spécifie. A frequently used pyrimidine antagonist is 5-fluorouracil.

Cytarabine inhibits DNA polymerase and is S-phase spécifie.

Plant alkyloids include vincas, such as Vinblastine and vincristine, and10 podophyllotoxins, such as etoposide. Plant alkyloids are effective in the metaphase and inhibit mitosis by a variety of mechanisms including altering microtubular proteins.

Antibiotics include doxorubicin and daunomycin, which intercalate between DNAstrands to inhibit the uncoiling of DNA; bleomycin, which causes incisions in DNA strands;and mitomycin, which inhibits DNA synthesis by acting as a bifimctional alkylator. 15 Nitrosureas include carmustine and lomustine and alkylate DNA or cause carbamoylate amino acids in proteins.

Inorganic ions, such as cisplatin, cause inter- and intracalation of DNA strands to inhibitthe uncoiling of DNA.

Biologie Response Modifiers, such as the interferons, hâve antiproliférative effects, but20 their spécifie rôle is not known. Interferons include a (leukocyte) interferon, β (fibroblast) interferon and γ (lymphocyte) interferon.

Enzymes, such as asparaginase, are aiso used to alter metabolic pathways important incancerous cells. Asparaginase depletes the cell of asparagine, on which leukemic cells dépend.

Hormones and their analogs, such as tamoxifen, flutamide and progestérone, hâve non-25 spécifie effects but are useful to treat certain neoplams which are known to be hormone responsive, especially breast, ovarian and prostate neoplasms. Tamoxifen, frequently used inthe treatment of breast neoplasms, places cells at rest, and binds to the estrogen receptor.Flutamide, frequently used in the treatment of prostate neoplasms, binds the androgen receptor.

Cytokinins are naturally occurring and artificial plant growth regulators. Natural30 cytokinins tend to be non-specific inhibitors of various protein kinases. The molecular mechanisms by which cytokinins regulate cell growth and division are still being determined.Studies hâve indicated that cytokinins may increase accessibility of the DNA template, activateRNA polymerases, affect polyadenylation and secondary structure of mRNA and stimulate 011455 17 formation and activity of polyribosomes. Cytokinins are thought to affect cell division byinteracting with regulatory proteins of the cell cycle. Both cytokinins and cyclin-dependentkinases (cdks) act at multiple and similar control points of cell cycle, for example, at the G,/Sand Gz/M transitions and S and M phases.

Olomoucine, 6-(benzylamino)-2-[(2-hydroxyethyl)amino]-9-methylpurine, was firstdiscovered as an herbicide. More recently, it has been discovered that Olomoucine is anartificial cytokinin, which specifically inhibit some cdks, including p34cdc2/cyclin B kinases, atmicromolar concenuation, but has.no effect on other major protein kinases such as cAMP- andcGMP-dependent kinases, and protein kinase C. Olomoucine has recently been shown to hâvegood selectivity for the CDK-cyclin protein kinases, but only has moderate inhibitory activity,with an IC50 of about 7 μΜ. Vesely, J., el al.. Eur. J. Biochem.. 1994,224,771-786. A 2.4 Acrystal structure of olomucine co-crystallized with cdk2 revealed that the purine portion ofolomoucine binds in the conserved ATP binding pocket, while the benzylamino group entendsinto a région of the active site unique to the cdk2 kinases.

Roscovitine, 2-(l-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine, is arecently synthesized purine which has been shown to hâve selectivity towards some cyclin-dependent kinases and to be 10-fold more active on cdk2 and cdc2 than olomoucine (Meijer, L.,et al., Eur. J. Biochem.. 243:527-536,1997 and PCT/FR96/01905). Meijer et al report thatmost kinases are not significantly inhibited by roscovitine. However, cdc 2-cyclin B, cdk 2-cyclin A, cdk 2-cyclin E and cdk 5-p35 are substantially inhibited with ICÎO values of 0.65,0.7,0.7 and 0.2 μΜ, respectively. In contrast, roscovitine displayed IC50 values of greater than 100μΜ for cdk 4-cyclin DI and cdk 6-cyclin D2.

Havlicek, L., et al., J. Med. Chem. (1997)40:408-412 report that Roscovitine, andrelated analogs substituted in the 2,6 and/or 9 positions, inhibit p34aic2-cyclin B kinases. Noneof the analogs had superior IC50 values over the (R) enantiomer of Roscovitine, which had anIC50 value of 0.2 μΜ. The (S) enantiomer had an IC50 value of 0.8 μΜ; the racemic mixture(R/S) had an IC50 value of 0.65 μΜ. These authors conclude that the N6-benzyl substituent ofRoscovitine was superior over the isopentenyl or cyclohexylmethyl substituents.

The National Cancer Institute (NCI) is a US Govemment-run organization directed atthe discovery and development of novel therapeutic oncology products. In 1985, the NCIestablished a new cancer screening strategy involving human tumor cell lines in an in vitroassay as the primary cancer screen. A total of sixty human tumor cell lines, derived from seven 011455 18 cancer types (lung, colon, melanoma, rénal, ovarian, brain and leukemia) were selected forinclusion in the NCI panel (Grever, M.R., et al., Seminars in Oncology. 19:1992:622-638). Theprotocols used in the assays hâve also been reported in the literature. American Type TissueCollection (ATCC) acts as a depository for these and other tumor cell Unes. Useful human5 tumor cell Unes inciude the following: MCF7: human breast adenocarcinoma, hormone-dependent; MDA-MB-231: human breast adenocarcinoma, hormone-independent; HT-29: human colon adenocarcinoma, moderately well-differentiated grade Π; HCT-15: human colon adenocarcinoma; 10 A549: human non-small cell lung carcinoma; DMS-114: human small cell lung carcinoma; PC-3: human prostate adenocarcinoma, hormone-independent; andDU 145: human prostate carcinoma, hormone-independent

Skehan, P., et al., J. Natl. Cancer Inst. 82: 1107-1112,1990 sets forth useful protocols for using 15 such tumor cell Unes for screening antineoplastic drugs.

Meijer, et al„ supra, report that roscovitine inhibits the prolifération of the NCI disease-oriented m vitro screen, i.e., 60 human tumour cell lines comprising nine tumour types(leukemia, non-small cell lung cancer, colon cancer, central nervous System cancer, melanoma,ovarian cancer, rénal cancer, prostate cancer, breast cancer) with an average IC50 value of 16 20 μΜ. The results of individual tumour lines were not reported.

Two distinct cdk inhibitors, flavopiridol and olomoucine, suppress the death of neuronalPC 12 ceUs and sympathetic neurons in two model Systems of neuronal survival (Park et al., LBiol. Chem. 271(14):8161-8169,1996). The concentration of each required to promotesurvival correlated with the amount required to inhibit prolifération. Neuronal apoptosis is an 25 important aspect of both nervous System development and a component of neuronal injury anddisease.

The PC 12 cell line was initially derived from a rat adrenal medullarypheochromocytoma. When grown in serum-containing medium, PC 12 cells divide andresemble precursors of adrenal chromaffin cells and sympathetic neurons. Upon addition of30 nerve growth factor (NGF), PC 12 cells attain the phenotypic properties of sympathetic neurons.Upon removal of either sérum or sérum and NGF, both naive and neuronally differentiatedPC 12 cells undergo apoptosis, which is analogous to the response of sympathetic neurons.

The rôle of cell cycle régulation in apoptosis may be demonstrated by withdrawal of 011455 19 NGF or sérum which results in uncoordinated cell cycle progression and cell death from naïvePC-12 cells. Cdk inhibitors did not prevent the death of these prolifération competent naivePC-12 cells after removal of trophic support. Post-mitotic differentiated or sympathetic neuronsare hypothesized to attempt inappropriate re-entry of the cell cycle following withdrawal of 5 NGF which results in cell death. However, exposure to flavopiridol or olomoucine whichinhibit cdks prevented apoptosis in these cells.

Changes in the activity of cdks and cyclins are observed during apoptosis of manydifferent cell types. Camptothecin- or araC-induced apoptosis of HL60 cells is associated withelevated cdc2 activity and cyclin E-associated kinase activity. Camptothecin-induced apoptosis 10 of RKO cells is associated with an increase in expression of cyclin Dl.

Camptothecin causes apoptotic death of rat cérébral cortical neurons. Morris and Geller,J. Cell Biol. 134:757-770(1996). Camptothecin-treated nonproliferating neuronallydifferentiated PC 12 cells die within 6 days after treatment, and cultured rat sympatheticneurons die within 5 days after treatment, even in the presence of NGF. Park et al., J. Neurosci. 15 17(4):1256-1270(1997). However, administration of either both, or individual olomoucine or flavopiridol, in the presence or absence of camptothecin resulted in approximately 30% celldeath at day 6. Maximal protection of PC 12 cells, or rat sympathetic neurons, from death wasobserved with 1 μΜ flavopiridol and 200 μΜ olomoucine, which are the minimumconcentrations that fully inhibit DNA synthesis by proliferating PC12 cells. Administration of 20 iso-olomoucine, an inactive analog of olomoucine, failed to prevent the cell death ofcamptothecin-treated neuronal cells

Flavopiridol and olomoucine were also shown to protect against camptothecin-inducedcortical neuronal death. Park et al., J. Neurosci. 17(4):1256-1270(1997). The ICS0 values offlavopiridol and olomoucine were 0.1 μΜ and 100 μΜ, respectively. Administration of iso- 25 olomoucine failed to prevent the cell death of camptothecin-treated neuronal cells.

There are several implications of the above observations. It is well recognized thatpatients treated with radiation or antineoplastic agents expérience undesirable side effects,including developing new neoplasms or undesirable cellular apoptosis. For example, somepatients treated with high-dose araC for refractory leukemia develop a cerebellar toxicity 30 syndrome, characterized by loss of Purkinje neurons. Winkelman and Hinges, Ann Neurol.14:520-527(1983) and Vogel and Horouipian, Cancer 71:13Ο3-13Ο8Γ19931. Patients treatedwith cis-platinum hâve been reported to develop periperal neuropathies. Wallach, et al., J. Fia.Med. Assoc. 79:821-822(1992) and Mansfield and Castillo, AJNR Am. J. Neuroradiol. 011455 20 15:1178-1180(1994). In view of these observations, either co-administration or soleadministration of the présent compounds in the treatment of neoplasms would reduce orpreciude cellular apoptosis, in particular, neuronal damage caused by treatment withantineoplastic agents or radiation. 5 Cerebrovascular disease is the most common cause of neurologie disability in Western countries. The major spécifie types of cerebrovascular disease are cérébral insufficiency due totransient disturbances of blood flow, infarction, hemmorrhage, and arteriovenous malformation.Stroke generally dénotés ischémie lésions. Undesirable neuronal apoptosis occurs incerebrovascular disease. Treatment with inhibitors of cdks may be an approach to prevent 10 neuronal injury and degeneration in such cases. SUMMARY OF THE INVENTIONThe présent invention provides novel compounds of the formula (I) 15

wherein 20 R is selected from the group consisting of R2, R2NH-, or R3R4N-R5- whereinR2 is selected from the group consisting of C,-C,2 alkyl,

25 30 wherei n each R6 is independently selected from the group consisting ofhydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH^æ-phenyl, wherein mis an integer 0-8; x is an integer 1-8; n is an integer 0-8; Z is selectedfrom the group consisting of phenyl, heterocycle, cycloalkyl, andnaphthanlene; and M is selected from the group consisting of hydrogen,C,-C4 alkyl. FL' Γ —(γ)η-

Re' and 011455 21 R.' r -φχ—oqRe' 10 wherein each R6' is independentiy selected from the groupconsisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and(CH2)m.-phenyl, wherein m’is an integer 0-8; n’ is aninteger 0-8; x’ is an integer 1-8; Q is hydrogen or C,-C4alkyl; and Z’ is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and napthalene; and 15 20 wherein each C9-C12 alkyl or Z is optionally substituted with 1 to3 substituents, which may be the same or different, and which areselected from the group consisting of D, E, ?6" (O)b ! -(Ç)x“—S—Re"«6*· B ” R “ T6 i —(Ç)x“— N—R- R, -(Ç)x“—OM’ and —(Ç)n5—Z"Re" 25 30 wherein each D is independentiy selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 aikoxy;each E is independentiy selected from the group consisting ofHal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected fromthe group consisting of phenyl, heterocycle, cycloalkyl, andnaphthalene; each R6” is independentiy selected from the groupconsisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and(CH2)m--phenyl, wherein m” is an integer 0-8; n” is an integer 0-8;x” is an integer 1-8; and M’is selected from the group consistingof hydrogen, C,-C4 alkyl, 22 FL" Γ —(Clx^OQ·

V 10 15 20 25 30 and R."

I -φη=

V -Z“ 011455 wherein cach R6’” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m.—phenyl, wherein m’” is an integer 0-8;n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogenor C,-C4 alkyl; and 27” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, andnapthalene, wherein the groups M’ and Z” may be optionally substituted withthe groups D’, E’ or —(C)x“-OQ* wherein each R6”” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m--phenyl, wherein m’”’ is an integer 0-8;x’”’ is an integer 0-8; Q” is hydrogen, C,-C4 alkyl orphenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4alkoxy, each E’ is independently selected from the groupconsisting of Hal, OH, and C,-Cg alkyl; R3 and R4 are selected from the group consisting of hydrogen, C,-C4alkyl and (CH2)y-phenyl, wherein y is an integer 0-8, with the proviso thatR3 and R4 not both be hydrogen; R5 is C)-Cg alkylene; and 23 01Ί 455 RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl. and the pharmaceutically acceptable salts, optical isomère, and hydrates thereof,5 with the proviso that when R2 is the group R6

-Z R6 10 wherein n is 1 or greater; RI is isopropyl or cyclopentyl; R6 is hydrogen, C,-C4 alkyl, or(CH2)m-phenyl; and Z is phenyl, heterocycle, or cycloalkyl, that Z is substituted with 1 to 3substituents, which may be the same or different, and which are selected from the groupconsisting of 15

Rs· f)bD, —(C>x—S-Rs R/ f5' f6" V 9.' (^x—N-R6" —ίθχ°—OM' and — R/ ((ρ)χ“·—OM'R/

FV 20 wherein D, b, R6”, x”, η”, M’, and Z” are as previously defined.

In addition, the présent invention provides a method of inhibiting cell cycle progression.

More specifically, the présent invention provides a method of inhibiting cdk-2.

The présent invention also provides a method of preventing apoptosis in neuronal cells. A particularly preferred method of the présent invention is preventing apoptosis of neuronal 25 cells induced by antineoplastic agents or resulting from cerebrovascular disease. Anotherpreferred embodiment of the présent invention is the method of preventing apoptosis inducedby oxygen déplétion. A more preferred invention provides a method of preventing apoptosisinduced cerebrovascular disease. Another prefereed invention provides a method of preventingapoptosis induced by stroke or infarction. 30 The présent invention provides a method of inhibiting the development of neoplasms.

The présent invention provides a method for treating a patient afflicted with a neoplastic diseaseState comprising administering a compound of the formula provided. It is preferred that theamount administered is a therapeutically effective amount of a compound of the formula. A 011455 24- preferred method of the présent invention administers a single compound of the formulaprovided. Altematively, a preferred method of the présent invention administers an amount of acompound of the formula in conjunction with other antineoplastic agents.

In addition, the présent invention provides a composition comprising an assayable5 amount of a compound of Formula (I) in admixture or otherwise in association with an inertcarrier. The présent invention also provides a pharmaceutical composition comprising aneffective inhibitory amount of a compound of Formula (I) in admixture or otherwise inassociation with one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION OF THE INVENTION 10 The présent invention provides novel compounds of the formula (I)

I R1 15 wherein 20 R is selected from the group consisting of R2, R2NH-, or R3R4N-R5- whereinR2 is selected from the group consisting of Co-CI2 alkyl, R6

I —(Ç)x—OMR6

RB

I and ~ (Ç)n—z R6 wherein each R6 is independently selected from the groupconsisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and25 (CH2)m-phenyl, wherein m is an integer 0-8; x is an integer 1-8; n is an integer 0-8; Z is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and naphthanlene; and M is selected from the group consisting of hydrogen, C,-C4 alkyl, 30

RJ r

—(«px1—OQ

Rb’ and —φη-

Re' 10 15 20 25 .25 011455 wherein each R6’ is independently selected from the groupconsisting of hydrogen, C3-Cg cycloalkyl, Cj-C4 alkyl, and(CH2)m-phenyl, wherein m’is an integer 0-8; n’ is aninteger 0-8; x’ is an integer 1-8; Q is hydrogen or C,-C4alkyl; and Z’ is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and napthalene; and wherein each C9-Cn alkyl or Z is optionally substituted with 1 to3 substituents, which may be the same or different, and which areselected from the group consisting of D, E, (O)b 1 (Ç)x—s-R6" R6"

Be" —(Ç)x--N-R'' —(C)x“—OM’ and —(C)na—Z” wherein each D is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy;each E is independently selected from the group consisting ofHal, OH, and Ο,-Cg alkyl; b is an integer 0-2; Z” is selected fromthe group consisting of phenyl, heterocycle, cycloalkyl, andnaphthalene; each R6” is independently selected from the groupconsisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and(CH2)m--phenyl, wherein m” is an integer 0-8; n” is an integer 0-8;x” is an integer 1-8; and M’is selected from the group consistingof hydrogen, C,-C4 alkyl, and FL" r -(Ç)n^-2”· fy wherein each R6’” is independently selected from the 30 FL" Γ —(ÇJx^OQ1

V 26 U I 14bb group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4alkyl, and (CH2)m..-phenyl, wherein m’” is an integer 0-8;n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogenor C,-C4 alkyl; and Z’” is selected from the group 5 consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z" may be optionally substituted withthe groups D’, E’or 10 —(Ç)x“-OQ"

V wherein each R6’”’ is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m--phenyl, wherein m’”’ is an integer 0-8;x’”’ is an integer 0-8; Q” is hydrogen, C,-C4 alkyl orphenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4alkoxy; each E’ is independently selected from the groupconsisting of Hal, OH, and C.-C. alkyl; 15 20 R3 and R4 are selected from the group consisting of hydrogen, C,-C4alkyl and (CH2)y-phenyl, wherein y is an integer 0-8, with the proviso that 25 R3 and R4 not both be hydrogen; R5 is C,-Cg alkylene; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl and30 isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof, 011 455 27 with the proviso that when R2 is the group R6

R6

-Z wherein n is 1 or greater, RI is isopropyl or cyclopentyl; R6 is hydrogen, C,-C4 alkyl, or(CH^-phenyl; and Z is phenyl, heterocycle, or cycloalkyl, that Z is substituted with 1 to 3substituents, which may be the same or different, and which are selected ffom the groupconsistingof 10

R6" <°>b 1 t D " R “ r6 R." 1 R6“ 1 D, —(Ç)x“—S-R6" —(Ç)X—N-R6" —(C)x*·—OM' 1 and —(C)n“—Z" 1 Re" Rs- FV V 15 wherein D, b, R6”, x”, n”, M’,andZ”areaspreviouslydefined,

As used herein, the term “heterocycle” means any closed-ring moiety in which one ormore of the atoms of the ring are an element other than carbon and includes, but is not iimitedto the following: piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl,piperazinyl, benzimidazolyl, thiazolyl, thiophene, furanyl, indolyl, 1,3-benzodioxolyl, 20 tetrahydropyranyl, imidazolyl, tetrahydrothiophene, pyranyl, dioxanyl, pyrrolyl, pyrimidinyl,pyrazinyl, triazinyl, oxazolyl, purinyl, quinolinyl, and isoquinolinyl.

As used herein, the tenu “C,-C4 alkyl” rëfers to a saturated or unsaturated, straight ofbranched chain hydrocarbyl radical of ffom one to four carbon atoms and includes, but is notIimited to the following: methyl, ethyl, propyl, isopropyl, 1-propenyl, 2-propenyl, n-butyl, 25 isobutyl, tertiary butyl, sec-butyl, 1-butenyl, 2-butenyl, 3-butenyl, and the like.

As used herein, the term “CrC8 alkyl” refers to a saturated or unsaturated, straight orbranched chain hydrocarbyl radical of from one to eight carbon atoms and includes, but is notIimited to the following: methyl, ethyl, propyl, isopropyl, 1-propenyl, 2-propenyl, n-butyl,isobutyl, tertiary butyl, sec-butyl, 1-butenyl, 2-butenyl, 3-butenyl, pentyl, neopentyl, hexyl, 30 heptyl, octyl, and the like.

As used herein, the term “C9-C12 alkyl” refers to a saturated or unsaturated, straight orbranched chain hydrocarbyl radical of from nine to twelve carbon atoms and includes, but is notIimited to the following: nonyl, decyl, undecyl, and dodecyl, and the like. 011455 . 28

As used hercin, the term “C,-Cg alkylene” refers to a saturated or unsaturated, straight ofbranched chain hydrocarbylene radical of from one to eight carbon atoms and includes, but isnot limited to the following: methylene, ethylene, propylene, isopropylene, 1-propenylene, 2-propenylene, n-butylene, isobutylene, tertiary butylène, sec-butylene, 1-butenylene, 2- 5 butenylene, 3-butenylene, pentylene, neopentylene, hexylene, heptylene, octylene, and the like.

As used hercin, the term “cycloalkyl” refers to a saturated or unsaturated alicyclicmoiety containing thrce to eight carbon atoms and includes, but is not limited to, the following:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

As used hercin, the désignation10 (O)b t s refers to a sulfur atom which is optionally oxidized to a sulfoxide (b=l) or a sulfone (b=2).

As used hercin, the term “Hal” refers to a halogen moiety and includes fluoro, chloro, 15 bromo, and iodo moieties.

As used hercin, the term “optical isomer” or “optical isomers” refers to any of thevarious stéréo isomeric configurations which may exists for a given compounds of Formula (I).

As used hercin, the term “hydrate” or “hydrates” refers to the reaction product of one ormore molécules of water with a compound of formula (I) in which the H-OH bond is not split 20 and includes monohydrates as well as multihydrates.

As used hercin, the term “pharmaceutically acceptable salts” refers to the reactionproduct of one or more molécules of any non-toxic, organic or inorganic acid with thecompounds of Formula (I). Illustrative inorganic acids which fonn suitable salts includehydrochloric, hydrobromic, sulphuric and phosphoric acid and acid métal salts such as sodium 25 monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acidswhich form suitable salts include mono, di and tricarboxylic acids. Illustrative of such acidsare, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid,glutaric acid, fumaric acid, malic acid acid, tartane acid, citric acid, ascorbic acid, maleic acid,hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, 30 salacylic acid, 2-phenoxybenzoic acid and sulfonic acids such as methane sulfonic acid,trifluoromethane sulfonic acid and 2-hydroxyethane sulfonic acid.

The compounds of Formula (I) can be prepared by utilizing procedures and techniqueswell known and appreciated by one of ofdinary skill in the art. A general synthetic scheme for 0114 55 29 preparing these compounds is set forth in Scheme A wherein ail substituent, unless otherwiseindicated, are as previously defined.

Scheme A

In Scheme A, step a, 2,6-dichloropurine Q) is reacted with the appropriate alcohol ofstructure 2 to give the corresponding 9-substituted-2,6-dichloropurine compound of structure 3using techniques and procedures well known to one of ordinary skill in the art.

For example, 2,6-dichloropurine (_D can be reacted with the appropriate alcohol ofstructure 2 in the presence of triphenylphosphine and diethyl azodicarboxylate in a suitableanhydrous aprotic solvent, such as tetrahydrofuran. The reactants are typically stirred togetherat room température for a period of time ranging ffom 5 hours to 5 days. The resulting 9-substituted-2,6-dichloropurine of structure 3 may be recovered from the reaction zone by 011455 30 extractive methods as is known in the art or more typically, the resulting 9-substituted-2,6-dichloropurine of structure 3 is recovered by removal of solvent following by charging directlyonto a silica gel column and eluting with a sutiable solvent, such as methylene chloride ormixture of solvents, such as a mixture of hexane and ethyl acetate. The crude 9-substituted-2,6-5 dichloropurine of structure 3 may then be purified by chromatography or may be used in thenext step without purification.

In step b, the 6-chloro functionality of the 9-substituted-2,6-dichloropurine of structure 3is reacted with an appropriate amine of structure 4 to give the corresponding 9-substituted-6-amino-2-chloropurine compound of structure 5. 10 For example, the 9-substituted-2,6-dichloropurine of structure 3 can be reacted with the appropriate amine of structure 4 in a suitable anhydrous polar solvent such as éthanol. Thereactants are typically stirred together at reflux températures for a period of rime ranging from30 minutes to 3 days. The resulting 9-subsrituted-6-amino-2-chloropurine of structure 5 isrecovered from the reaction zone by extractive methods as are known in the art, or, if the 9- 15 substituted-6-amino-2-chloropurine of structure 5 précipitâtes out of solution, it may berecovered by filtration.

In step c, the 2-chloro functionality of the 9-substituted-6-amino-2-chloropurine ofstructure 5 is reacted with 1,4-çyclohexanediamine (6) to give the corresponding compound ofFormula I. 20 For example, the appropriate 9-substituted-6-amino-2-chloropurine of structure 5 can be reacted with a molar excess of 1,4-cyclohexanediamine (6). The reactants are typically placed ina pressure tube, sealed, and heated at a température of from about 80°C to about 150°C for aperiod of time ranging from 30 minutes to 3 days. The resulting compound of Formula I isrecovered from the reaction zone by extractive methods as‘are known in the art and may be 25 purified by chromatography.

Starting materials for use in the general synthetic procedures outlined in Scheme A arereadily available to one of ordinary skill in the art. For example, certain 4-aminopiperidines and3-aminopyrrolidines of structure 4 may be prepared as described in Schemes B and C below.

Starting amines of structure 4 for use in Scheme A which are 4-amino-l-piperidine and30 3-amino-l-pyrrolidine dérivatives (structure 4J may be prepared as shown in Scheme B,wherein ail substituents, unless otherwise indicated, are as previously defined. 011455 31

Scheme B

9 41 t = O, 1 * Sub = optional substitution a In Scheme B, step a, the free amino functionality of an appropriate 4-carboxamide-l-piperidine or 3-carboxamide-l-pynolidine dérivative of structure 7 is reacted with theappropriate alkyl halide of structuré 8 to give the corresponding 4-carboxamide-l-alkylated-piperidine or 3-carboxamide-1 -alkylated-pyrrolidine of structure 9.

For example, the 4-carboxamide-l-piperidine or 3-carboxamide-1-pyrrolidine ofstructure 7 can be reacted with the appropriate alkyl halide of structure § in a suitable aproticorganic solvent, such as 3-pentanone, in the presence of a suitable base, such as césiumcarbonate, and a catalytic amount of a suitable alkylation catalyst, such as potassium iodide.

The reactants are typically stirred together at reflux température for a period of time rangingfrom 30 minutes to 12 hours. The resulting 4-carboxamide-l-alkylated-piperidine or 3-carboxamide-l-alkylated pyrrolidine of structure 9 is recovered from the reaction zone byfiltration and évaporation of solvent.

In step b, the carboxamide functionality of the appropriate 4-carboxamide-l-alkylatedpiperidine or 3-carboxamide-1-alkylated pyrrolidine of structure 9 is dehydrogenated to give thecorresponding 4-amino-l-alkylated-piperidine or 3-amino-l-alkylated-pyrrolidine of structure4’.

For example, the appropriate 4-carboxamide-l-alkylated piperidine or 3-caiboxamide-l- 011455 32 alkylated pyrrolidine of structure 9 is reacted with a molar excess of bis(trifluoroacetoxy)-iodobenzene in a suitable aprotic polar solvent such as acetonitrile. The reactants are typicallystirred together at a température of about 50°C to about 95 °C for a period of time ranging from30 minutes to 5 hours. The resulting 4-amino-l-alkylated-piperidine or 3-amino-l-alkylated-5 pyirolidine of structure Ψ is recovered ffom the reaction zone by extractive methods as areknown in the art.

Altematively, starting amines of structure 4 for use in Scheme A which are 4-amino-l-piperidine and 3-amino-l -pyrrolidine dérivatives (structure £) may be prepared as shown inScheme C, wherein ail substituents, unless otherwise indicated, are as previously defined. 10

Scheme C 15 n sub (U>,

N

H R7-Hal 8 JLzSub HjN-OH HCI 12. step a 20 25 1Ώ. NHOH.Sub

lâ step c L (CH,),

N

I R7

II step b NH, Λ3 L JCH,),

N

I R7

Sub 4' t = 0, 1

Sub = optional substitution

In Scheme C, step a, the free amino functionality of an appropriate 4-piperidone or 3-30 pyrrolidone dérivative of structure 10 is reacted with the appropriate alkyl halide of structure 8to give the corresponding l-alkylated-4-pipéridone or l-alkylated-3-pyrrolidone of structure 11.

For example, the 4-piperidone or 3-pyrrolidone of structure 10 can be reacted with theappropriate alkyl halide of structure 8 in a suitable aprotic organic solvent, such as 3-pentanone, 011455 33 in the presence of a suitable base, such as césium carbonate, and a catalytic amount of a suitablealkylation catalyst, such as potassium iodide. The reactants are typically stirred together atreflux température for a period of time ranging from 30 minutes to 12 hours. The resulting 1-alkylated-4-piperidone or l-alkylated-3-pyrrolidone of structure H is recovered from the 5 reaction zone by filtration and évaporation of solvent.

In step b, the ketone functionality of the appropriate l-alkylated-4-piperidone of 1- alkylated-3-pyrrolidone of structure IL is reacted with hydroxyiamine hydrochloride (121 togive the corresponding l-alkylated-4-piperidone oxime or l-alkylated-3-pyrrolidone oxime ofstructure 13. 10 For example, the l-alkylated-4-piperidone or l-alkylated-3-pyrrolidone of structure 11 is reacted with hydroxyiamine hydrochloride (121 in the presence of a suitable base, such assodium acetate in a suitable protic solvent, such as aqueous éthanol. The reactants are typicallystirred together at reflux températures for a period of time ranging from 30 minutes to 5 hours.The resulting l-alkylated-4-piperidone oxime or l-alkylated-3-pyirolidone oxime of structure 15 13 is recovered from the reaction zone by extractive methods as are known in the art.

In step c, the oxime functionality of the appropriate l-alkylated-4-piperidone oxime or l-alkylated-3-pyrrolidone oxime of structure 13 is reduced to give the correponding 4-amino-l-piperidine and 3-amino-l-pyrrolidine dérivatives (structure £).

For example, the l-alkylated-4-piperidone oxime or l-alkylated-3-pyrrolidone oxime of 20 structure 13 is reacted with a suitable reducing agent, such as lithium aluminum hydride, in asuitable anhydrous solvent, such as tetrahydrofuran under an inert atmosphère. The reactantsare typically stirred together at reflux température for a period of time ranging from 30 minutesto 5 hours. The resulting 4-amino-l-piperidine and 3-amino-l-pyrrolidine dérivatives (structure£) is recovered from the reaction zone by extractive methods as are known in the art. 25 The following examples présent typical synthèses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of theprésent invention in any way. As used herein, the following tenns hâve the indicated meanings:“g” refers to grams; “mmol” refers to millimoles; “niL” refers to milliliters; “bp” refers toboiling point; “°C” refers to degrees Celsius; “mm Hg” refers to millimeters of mercury, “pL” 30 refers to microliters; “pg” refers to micrograms; “pM” refers to micromolar, and “APCI” refersto Atmospheric Pressure Chemical Ionization. Rf values are determined by an AQ 4x50column (YMC) with a linear gradient from 100% C to 100% D in four minutes with a twominute hold at 100% D, where C is 5:95 acetonitrile:water with 0.1% TFA, and D is 95:5 011455 34 acetonitrile:water with 0.085% TFA. Molecular ion déterminations were made using aFmnigan MAT SSQ-7-.10 mass spectrometer.

Example 1 2-rTrans-(4-aminocvclohexv0amino'l-6-lï4-trifluorobenzvl)amino1-9-cvclopentvlpurine 5 dihvdrochloride

Scheme A. step a: 2,6-Dichloro-9-cvclopentvlpurine

Dissolve cyclopentanol (260 mg, 3.02 mmoi), 2,6-dichloropurine (680 mg, 3.60 mmol) andtriphenyl phosphine (950 mg, 3.60 mmol) in dry THF (20 mL) and cool to 0°C. Add diethylazodicarboxylate (570 pL, 3.60 mmol) dropwise over a period of 15 minutes under a nitrogen10 atmosphère. Stir the resulting solution for 60 hours at room température. Evaporate the solventin vacuo, charge directly onto a silica gel column, and elute with methylene chloride to give thetitle compound as a crude mixture.

Scheme A, step b: 2-Chloro-6-ff4-trifluorobenzvl)amino1-9-cvclopentvlpurine

Dissolve 2,6-dichloro-9-cyclopentylpurine (3.00 mmol), 4-trifluorobenzyIamine (3.00 mmol) 15 and triethylamine (835 pL, 6.00 mmol) in dry éthanol (20 mL). Heat at reflux for 15 hours,cool, and filter the solid to give the title compound.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl)amino1-6-i(4-trifluorobenzyl)aminol-9- cvclopentvlpurine dihvdrochloride

Mix 2-chloro-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurine (0.287 mmol) and 1,4-20 cyclohexanediamine (2.00 g, excess) in a pressure tube, seal and heat to 140eC for 18 hours.

Cool the réaction mixture, add CH2C12 (40 mL) and wash with H2O (2x20 mL). Dry (MgSO4),evaporate the solvent in vacuo, and purify by silica gel chromatography (10:l:dropsCH2Cl2/MeOH/NH4OH) to give the title compound. Convert to the hydrochloride sait. CIMS (NH3) 474 (MH*); Rf (min.) = 0.58 25

Example 2 2-rTrans-f4-aminocvclohexvl)amino1-6-(2-chlorophenvlhvdrazino)-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-(2-chlorophenvlhvdrazino)-9-cvclopentvlpurine30 2-Chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9- cyclopentylpurine, 2-chlorophenylhydrazine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-(4-aminocvclohexvl)aminol-6-f2-chlorophenvlhvdrazino)-9- 011455 35 cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(2-chlorophenylhydrazino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 5 CIMS (NH3) 475 (MH*); Rf (min.) = 3.49

Example 3 2-ÎTrans-(4-aminocvclohexyl~)aminol-6-(3.4.5-trimethoxvbenzvlamino)-9-cvclopentylpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-(3.4.5-trimethoxvbenzvlamino)-9-cvclopentvlpurine 10 2-Chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4.5-trimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A. step c: 2-irrans-f4-aminocvclohexvI)arnino1-6-(3.4.5-trimethoxvbenzvlanrino)-9- cvclopentvlpurine dihvdrochloride 15 2-[T rans-(4-aminocyclohexyl)amino]-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyClopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NHj) 496 (MH*); Rf (min.) = 3.42

Example 4 20 2-FTrans-(4-aminocvclohexvl)amino1-6-i(2.6-dimethoxvbenzvI)aminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-r(2.6-dimethoxvbenzvl)amino1-9-cvclopentvlpurine2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dimethoxybenzylamine, and triethylamine essentially as described 25 above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexyl)aminol-6-f(2.6-dimethoxvbenzvl)aminol-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chioro-6-[(2,6-dimethoxybenzyl)amino]-9- 30 cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (ΝΗ3) 466 (MH*); Rf (min.) = 2.29

Example 5 2-rTrans-i4-aminocvclohexvbamino1-6-ii4-trifluoromethoxv)phenvlaminol-9- 011455 36 cvclopentylpurine dihvdrochloride

Scheme A. step b: 2-Chloro-6-i(4-trifluoromethoxv)phenylamino1-9-cvclopentvlpurine 2-Chloro-6-[(4-trifluoromethoxy)phenyiamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-trifluoromethoxyaniline, and triethylamine essentially as5 described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocyclohexvl)amino'l-6-f(4-trifluoromethoxv)phenvlaTninol- 9-cvciopentvipurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-[(4-10 trifluoromethoxy)phenylamino]-9-cyclopentylpurine essentially as described in Example 1,Scheme A, step c. CIMS (NH3) 476 (MH*); Rf (min.) = 4.00

Example 6 2-fTrans-(4-aminocvclohexvl)aminol-6-i2-fdiethvlamino)ethvlamino1-9-cvclopentvlpurine 15 trihvdrochloride

Scheme A. step b: 2-Chloro-6-i2-(diethvlamino)ethvlamino1-9-cvclopentvlpurine2-Chloro-6-[2-(diethyiamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-diethylaminoethylamine, and triethylamine essentially as described abovein Example 1, Scheme A, step b. 20 Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-r2-(diethvlamino)ethvlaminol-9- cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurinetrihydrochloride is prepared from 2-chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 25 CIMS (NH3) 415 (MH*); Rf (min.) = 3.15

Example 7 2-rTrans-(4-aminocvclohexvl)aminol-6-f(l-napthvl)methylaminol-9-cvclopentvlpurine dihvdrochloride

Scheme A. step b: 2-Chloro-6-r(l-napthyllmethvlamino1-9-cvclopentvlpurine 30 2-Chloro-6-[( 1 -napthyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9- cyclopentylpurine, l-(aminomethyl)naphthylene, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvbaminol-6-i(l-napthvnmethvlaminol-9- 011 455 37 cyclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(l-napthyl)methylamino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(l-napthyI)methylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 456 (MH*); Rf (min.) = 3.43

Example 8 2-rTrans-(4-aminocvclohexvBaminol-6-if4-methoxvbenzvl)amino'l-9-cvcIopentvlpurine dihydrochloride

Scheme A. step b: 2-Chloro-6-r(4-methoxvbenzyl)amino1-9-cvclopentvIpurine 2-Chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybenzylamine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvI)aminol-6-IT4-methoxvbenzvPamino1-9- cyclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)aniino]-6-[(4-methoxybenzyl)aniino}-9-cyclopentylpurine t dihydrochloride is prepared from 2-chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

QMS (NH3) 436 (MH*); Rf (min.) = 2.2S

Example 9 2-iTrans-(4-aminocvclohexvl)aminol-6-i(3-(5-methoxvindoIvl))-2-ethylamino1-9- cvclopentylpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-r(3-(5-methoxvindolvl))-2-ethvIaminol-9-cvclopentvlpurine 2-Chloro-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 5-methoxytryptamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocyclohexvl)aminol-6-i(3-f5-methoxyindolvI))-2- ethvlaminol-9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.CIMS (NH3) 489 (MH*); Rf (min.) = 3.44

Exampfe 10 2-fTrans-i4-aminocvciohexvl)aminol-6-i4-ihvdroxvmethvl')cvclohexanemethvlamino1-9- 011455 38 çvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-r4-fhvdroxvmethvl)cvclohexanemethviamino]-9- cvclopentvlpurine 2-Chloro-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurine is prepared from 5 2,6-dichloro-9-cyclopentylpurine, 4-(aminomethyl)cyclohexanemethanol, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-f4-('hvdroxvrnethvDcvclohexanemethvlaminol-9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9- 10 cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-[4- (hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. CIMS (NH3) 442 (MH*); Rf (min.) = 3.34

Example 11 15 2-ITrans-(4-aminocvclohexvl)aminol-6-r2-fluorophenvlhvdrazinol-9-cvclopentvlpurine dihvdrochloride

Scheme A. step b: 2-Chloro-6-f2-fluorophenylhvdrazinol-9-cvclopentvlpurine2-Chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorophenylhydrazine, and triethylamine essentially as described above in20 Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvDamino'l-6-i2-fluorophenvlhvdrazino'l-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[2-fiuorophenylhydrazino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine25 essentially as described in Example 1, Scheme A, step c. CIMS (NHj) 425 (MH*); Rf (min.) = 3.41

Example 12 2-rTrans-('4-aminocvclohexvDamino'l-6-rf2-methoxvbenzv0aminol-9-cvclopentvlpurine dihvdrochloride 30 Scheme A, step b: 2-Chloro-6-r(2-methoxvbenzvPamino'l-9-cvclopentvlpurine 2-Chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9- cyclopentylpurine, 2-methoxybenzylamine, and triethylamine essentially as described above in

Example 1, Scheme A, step b. 39 011455

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-i(2-methoxvbenzvl')amino'|-9- cyclopentylpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine 5 essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 436 (MH*); Rf (min.) = 2.30

Example 13 2-rTrans-(4-aminocvclohexvl)amino1-6-i(2.3-dimethoxvbenzvl)amino1-9-cvclopentvlpuripe dihvdrochloride 10 Scheme A, step b: 2-Chloro-6-ff2.3-dimethoxvbenzvl)amino1-9-cvclopentvlpurine 2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,3-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-(4-aminocvclohexvl)amino1-6-r(2.3-dimethoxvbenzvDaminol-9- 15 cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NHj) 466 (MH*); Rf (min.) = 2.29 20 Example 14 2-rTrans-(4-aminocvclohexvI)amino1-6-i2-(4-methoxyphenvl')ethvlaminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-r2-(4-methoxvphenyl)ethvlamino'l-9-cvclopentvlpurine 2-Chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6- 25 dichloro-9-cyclopentylpurine, 2-(4-methoxyphenyl)ethylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-i2-(4-methoxyphenvl)ethvlamino1- 9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(4-methoxyphenyI)ethylamino]-9-cyclopentylpurine 30 dihydrochloride is prepared from 2-chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 450 (MH*); Rf (min.) = 3.53

Example 15 011455 40 2-rTrans-(4-aminocvclohexvi)aminol-6-r3-f2-methoxvethoxv)propylamino1-9- cvclopentvlpurine dihvdrochloride

Schemê A. step b: 2-ChIoro-6-i3-f2-methoxvethoxv1propyÎaminol-9-cvclopentvÎpurine 2-Chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurine is prepared from 2,6- 5 dichloro-9-cyclopentylpurine, 3-(2-methoxyethoxy)propylamine, and triethylamine essentiallyas described above in Exampie 1, Scheme A, step b.

Scheme A, step c: 2-ITrans-(4-aminocvclohexvl)aminol-6-f3-(2-methoxvethoxv)propylaminol- 9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(2-methoxyethoxy)propylamino]-9- 10 cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-[3-(2- methoxyethoxy)propylamino]-9-cyclopentylpurine essentially as described in Example 1,

Scheme A, step c. CIMS (NHj) 432 (MH+); Rf (min.) = 3.31

Example 16 15 2-rTrans-(4-aminocvclohexvl)amino1-6-(,2-methoxvethylamino)-9-cyclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-(2-methoxvethvlamino)-9~cvcIopentvIpurine2-Chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine·, 2-methoxyethylamine, and triethylamine essentially as described above in 20 Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexvl')amino1-6-f2-methoxvethvIamino)-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(2-methoxyethylamino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine 25 essentially as described in Example 1, Scheme A, step c. CIMS (NHj) 374 (MH+); Rf (min.) = 3.23

Example 17 2-rTrans-(4-aminocvclohexvl)amino1-6-[f2.4-dimethoxvbenzvDamino1-9-cvclopentvlpurine dihvdrochloride 30 Scheme A. step b: 2-Chloro-6-i(2.4-dimethoxvbenzvl')aminol-9-cvclopentvlpurine 2-Chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro- 9-cyclopentylpurine, 2,4-dimethoxybenzyIamine, and triethylamine essentially as described above in Example 1, Scheme A, step b. 41 - 011455

Scheme A, step c; 2-ÎTrkhs-(4-aminocvciohexvl)amino1-6-f(2.4-dimethoxvbenzyl)amino1-9- cvclopentylpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 466 (MH*); Rf (min.) = 2.29

Example 18 2-fTrans-(4-aminocvclohexvl’>aminol-6-r(3-diethvlamino)propvlaminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-if3-diethvlamino)propylamino1-9-cvclopentvlpurine 2-Chloro-6-[(3-diethylamino)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-diethylaminopropylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-(4-aminocvclohexvl)amino1-6-f(3-diethvIamino)propvîamino1-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-diethyiamino)propylamino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(3-diethylamino)propylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 429 (MH*); Rf (min.) = 3.13

Example 19 2-ÏTrans-f4-aminocvclohexvI)amino'|-6-f(3.4-dimethoxvbenzvt)aminol-9-(2-propvl)purine dihvdrochloride

Scheme A. step a; 2.6-Dichloro-9-(2-propyI)purine 2,6-Dichloro-9-(2-propyl)purine is prepared from 2,6-dichlbropurine and isopropanolessentially as described in Example 1, Scheme A, step a, but substituting isopropanol forcyclopentanol.

Scheme A. step b: 2-Chloro-6-if3.4-dimethoxvbenzvl)amino1-9-(2-propvl)purine2-Chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine, 3,4-dimethoxybenzylamine, and triethylamine essentially as described abovein Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-î(3,4-dimethoxvbenzvl)amino1-9-(2- propvl)purine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine 42 u l 1455 dihydrochloride is prepared from 2-chloro-6-[(3,4'dimethoxybenzyj)amino]-9-(2-propyl)piuineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 440 (MH*); Rf (min.) = 3.33

Example 20 5 2-rTrans-(4-aminocyclohexvl)amino1-6-f2.6-dichlorophenvlhvdrazinol-9-cvclopentvipurine dihydrochloride

Scheme A, step b: 2-Chloro-6-r2,6-dichlorophenvlhvdrazino1-9-cvcIopentvlpurine2-Chloro-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dichlorophenylhydrazine, and triethylamine essentially as described 10 above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-r2.6-dichlorophenvlhvdrazinol-9- cvcîopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[2,6-dichlorophenylhydrazino]-9- 15 cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 475 (MH*); Rf (min.) = 3.43

Example 21 2-rrrans-(4-aminocvclohexvl)aminol-6-(3-fluorophenvlamino)-9-cvclopentvlpurine dihydrochloride 20 Scheme A, step b: 2-Chloro-6-(3-fluorophenylamino)-9-cvclopentvlpurine 2-Chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-fluoroaniline, and triethylamine essentially as described above in Example1, Scheme A, step b.

Scheme A. step c: 2-rTrans-f4-aminocvclohexvl)aminol-6-f3-fluorophenvlamino)-9- 25 cyclopentylpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(3-fluorophenylamino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(3-fluorophenyIamino)-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 44S (MH*); Rf (min.) = 3.44 30 Example 22 2-n'rans-{,4-aminocvclohexvl)amino'l-6-(,3-methoxvpropvlaminoV9-cvclopentvlpurine dihydrochloride

Scheme A, step b: 2-Chloro-6-(3-methoxvpropvlamino)-9-cvclopentvlpurine 43 - 011455 2-Chlôro-6-(3-methoxypropylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methoxypropy lamine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexyl’)amino]-6-(3-methoxvpropvlamino'|-9- cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(3-methoxypropylamino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(3-methoxypropylamino)-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. CIMS (NHj) 388 (MH*); Rf (min.) = 3.29

Example 23 2-rrrans-(4-aminocvclohexvl)aminol-6-r(4-pentvl)phenvlaminol-9-cvclopentvlpurine dihydrochloride

Scheme A, step b: 2-Chloro-6-r(4-pentvI)phenvlamino1-9-cvclopentylpurine 2-Çhloro-6-[(4~pentyl)phenylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-butylphenylamine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-n"rans-f4-aminocvclohexvl)aminol-6-r(4-pentvl)phenylamino1-9- cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyi)amino]-6-[(4-pentyl)phenylamino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 462 (MH*); Rf (min.) = 4.15

Example 24 f+M-2-f'Trans-(4-aminocvcIohexvl>)aminol-6-i(g-cvclopropvl-4-chlorobenzyl)aminol-9- cvclopentvlpurine dihydrochloride

Scheme A. step b: 2-Chloro-6-i(a-cyclopropyl-4-chlorobenzvl)amino]-9-cvclopentvlpurine 2-Chloro-6-[(a-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, a-cyclopropyl-4-chlorobenzylamine, and triethylamine essentiallyas described above in Exampie 1, Scheme A, step b.

Scheme A, step c: 2-FTrans-(4-aminocvclohexvl)aminol-6-r(a-cvclopropvl-4- chlorobenzvl)aminol-9-cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(a-cyciopropyl-4-chlorobenzyI)amino]-9- 44 011455 cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-((a-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine essentialiy as described in Example 1, Scheme A,stepc. CIMS (NH3) 480 (MH*); Rf (min.) = 2.35 5 Example 25 2-rrrans-(4-aminocvclohexvl)aminol-6-i(2-trifluorobenzvl)amino'l-9-cvclopentvIpurine dihydrochloride

Scheme A, step b: 2-Chloro-6-[Y2-trifiuorobenzvl')aminol-9-cvciopentvlpurine2-Chloro-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-10 cyclopentylpurine, 2-trifluorobenzylamine, and triethylamine essentialiy as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-n,rans-(4-aminocvclohexyl)amino1-6-if2-trifluorobenzvl)aminol-9- cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurine 15 dihydrochloride is prepared from 2-chloro-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurineessentialiy as described in Example 1, Scheme A, step c. CIMS (NH3) 474 (MH*); Rf (min.) = 2.31

Example 26 2-lTrans-(4-aminocvclohexvl)amino1-6-(2-hvdroxve;thoxvethvlamino)-9-cvclopentvlpurine 20 dihydrochloride

Scheme A. step b: 2-Chioro-6-f2-hvdroxvethoxvethvlamino)-9-cvclopentvlpurine2-Chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(2-aminoethoxy)ethanol, and triethylamine essentialiy as described abovein Example 1, Scheme A, step b. 25 Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-f2-hvdroxyethoxvethvIamino’>-9- cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurineessentialiy as described in Example 1, Scheme A, step c. 30 CIMS (NHj) 404 (MH*); Rf (min.) = 3.16

Example 27 2-ÎTrans-(4-aminocvclohexvl)amino1-6-r2-(3-methoxvphenvI)ethvlaminol-9-cvclopentvlpurine dihydrochloride 45 -Q11455

Scheme A, step b: 2-Chloro-6-f2-(3-methoxyphenvl)ethvlaminol-9-cvclopentylpurine 2-Chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(3-methoxyphenyl)ethylamine, and triethyiamine essentially asdescribed above in Example 1, Scheme A, step b. 5 Scheme A, step c: 2-rTrans-<,4-aminocvciohexvI)aminol-6-r2-f3-methoxvphenvilethvlanuno'!- 9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)ainino]-6-[2-(3-methoxyphenyl)ethylamino]-9-cyciopentylpurinedihydrochloride is prepared from 2-chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 10 QMS (NHj) 450 (MH*); Rf (min.) = 3.54

Example 28 2-rTrans-f4-aminocvcIohexvl)aminol-6-i(3.5-dimethoxvbenzvl)aminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-rf3.5-dimethoxvbenzvl)amjnol-9-cvclopentvlpurine 15 2-Çhloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,5-dimethoxybenzylamine, and triethyiamine essentially as describedabove in Exampie 1, Scheme A, step b.

Scheme A, step c: 2-tTrans-('4-aminocvciohexvl')amino1-6-rf3.5-dimethoxvbenzvI'iaminol-9- cvclopentvlpurine dihvdrochloride 20 2-[Trans-(4-aminocyclohexyI)amino]-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NHj) 466 (MH*); Rf (min.) = 2.27

Example 29 25 2-fTrans-f4-aminocvcIohexvI)aminol-6-(4-methoxvbutvlamino)-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-(4-methoxvbutvlamino)-9-cyclopentvlpurine2-Chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybutylamine, and triethyiamine essentially as described above in 30 Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvl)aminol-6-f4-methoxvbutvlamino)-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(4-methoxybutylaniino)-9-cyclopentylpurine 46 - 0114 55 dihydrochioride is prepared from 2-chioro-6-(4-methoxybutylamino)-9-cyclopentylpurineessentially as described in Exemple 1, Scheme A, step c. CIMS (NHj) 388 (MH*); Rf (min.) =3.29 5 Example 30 2-rrrans-(4-aminocvclohexvi)aminol-6-r(2.3-dimethoxvbenzvl)aminol-9-(2-propvl)purine dihydrochioride

Scheme A. step b: 2-Chloro-6-i(2.3-dimethoxybenzvI)amino)-9-(2-propvl)purine2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9- 10 (2-propyl)purine (see Example 19 for préparation), 2,3-dimethoxybenzylamine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexvl)aminol-6-i(2,3-dimethoxvbenzvl)amino1-9-(2- propvDpurine dihydrochioride 2-[Trans-(4-aminocyclohexyl)aniino]-6-[(2,3-dimethoxybenzyl)amino]-9--(2-propyl)purine 15 dihydrochioride is prepared from 2-chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 440 (MH*); Rf (min.) = 3.39

Example 31 2-fTrans-(4-aminocyclohexvl)amino1-6-f2-(phenvlamino)ethvlamino1-9-cvclopentvlpurine 20 trihvdrochloride

Scheme A, step b: 2-Chloro-6-i2-(phenvlamino)ethvlamino1-9-cvclopentvlpurine2-Chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, N-phenylethylenediamine, and triethylamine essentially as described abovein Example 1, Scheme A, step b. 25 Scheme A. step c: 2-rTrans-('4-aminocvclohexvl)amino'l-6-r2-(phenvlamino)ethvlaminol-9- cvclopcntvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)ainino]-6-[2-(phenylainino)ethylamino]-9-cyclopentylpurinetrihydrochloride is prepared from 2-chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 30 CIMS (NHj) 435 (MH*); Rf (min.) = 3.34

Example 32 2-ITrans-<'4-aminocvclohexvl)aminol-6-(phenvlamino)-9-cvclopentvlpurine dihydrochioride

Scheme A. step b: 2-Chloro-6-(phenvlamino)-9-cvclopentvlpurine .011455 47 2-Chloro-6-(phenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9- cyclopentylpurine, aniline^ and triethylamine essentially as described above in Example 1,Scheroe A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvI)aminol-6-(phenvlamino)-9-cycIopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(phenylamino)-9-cyclopentylpurinedihydrochloride isprepared from 2-chIoro-6-(phenylamino)-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. CIMS (NHj) 392 (MH*); Rf (min:) - 3.35

Example 33 2-rTrans-(4-aminocvclohexvl')aminol-6-i4-(l-benzvl)piperidinvlaminol-9-cvclopentvÏpurine trihvdrochloride

Scheme A, step b: 2-Chloro-6-i4-U-benzvl)piperidinvlamino1-9-cvclopentvlpurine 2-Chloro-6-[4-(l-benzyl)piperidinyIamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-benzylpiperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)aininol-6-r4-(l-bePZvl)ptperidinvlaminol-9- cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocycIohexyl)amino]-6-[4-(l-benzyl)piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from 2-chloro-6-[4-(l-benzyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 489 (MH*); Rf (min.) = 3.29

Example 34 2-rTrans-(4-aminocvcIohexvl)aminol-6-f3.4-dimethoxvbenzvl)aminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: 2-Chloro-6-i3.4-dimethoxvbenzvl)amino1-9-cvclopentvlpurine2-Chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-dimethoxybenzylamine, and triethylamine essentially as described abovein Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-i4-aminocvclohexvliamino'l-6-['3.4-dimethoxvbenzvhamino1-9- cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride is prepared from 2-chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyciopentylpurine 48 011455 essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 466 (MH*); Rf (min.) = 2.25

Example 35 2-rTrans-(4-aminocvclohexvl)aminol-6-f(3-iodobenzvl)amino1-9-(2-cvclopentenvl)purine 5 hvdrochloride

Scheme A, step a: 2.6-Dichloro-9-cvclopentenvlpurine 2,6-Dichloro-9-cyclopentenylpurine is prepared from 2,6-dichloropurine and cyclopentenolessentially as described in Example 1, Scheme A, step a, but substituting cyclopentenol forcyclopentanol. 10 Scheme A. step b: 2-Chloro-6-[(3-iodobenzvl)amino1-9-cvclopentenvlpurine 2-Chloro-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine is prepared from 2,6-dichloro-9-cyclopentenylpurine, 3-iodobenzylamine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-f(3-iodobenzvDamino'l-9- 15 cvclopentenvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurinehydrochloride is prepared from 2-chloro-6-[(3-iodobenzyl)amino]-9-cyciopentenylpurineessentially as described in Example 1, Scheme A, step c. CIMS (NHj) 530 (MH*) 20 Example 36 2-ΓΤ rans-( 4-aminocvclohexvl)aminol -6-( dodecvlamino)-9-cvclopcntvlpurine dihvdrochloride

Scheme A. step b: 2-Chloro-6-(dodecvlamino)-9-cvclopentvlpurine2-Chloro-6-(dodecylamino)-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-dodecylamine, and triethylamine essentially as described above in25 Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-(dodecvlamino)-9-cvclopentvlpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyI)amino]-6-(dodecylamino)-9-cyclopentylpurine dihydrochloride isprepared from 2-chloro-6-(dodecylamino)-9-cyclopentylpurine essentially as described in30 Example 1, Scheme A, step c. CIMS (NHj) 484 (MH*); Rf (min.) = 5.09

Example 37 2-rTrans-f4-aminocvclohexvl)amino1-6-i(4-methoxvbenzvBaminol-9-(2-propvl)purine 49 011455 dihvdrochloride

Scheme A. step b: 2-Chloro-6-i(4-methoxvbenzvbamino1-9-('2-propvl)purine 2-Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for préparation), 4-methoxybenzylamine , and triethyiamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-[Trans-i4-aminocvclohexvl)aminol-6-r('4-methoxvbenzvI')aminol-9-f2- propvDpurine dihvdrochloride 2-[Trans-(4-aminocyclohexyl)ainino]-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride is prepared from 2-chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purineessentially as described in Example 1, Scheme A, step c. CIMS (NH3) 410 (MH*); Rf (min.) = 3.37

Example 38 2-fTrans-(4-aminocvclohexvl)amino1-6-f4-(l-(4-chlorobenzvl))piperidinvlamino'|-9- cvclopentvlpurine

Préparation of 4-Amino-l-('4-chlorobenzvl)piperidine·. Méthod 1:

Schème B, step a: 4-Carboxamide-l-(4-chlorobenzvI)piperidine

Dissolve isonipecotamide (39 mmol) in 3-pentanone (25 mL) and heat to reflux. Add césiumcarbonate (24 mmol) and a catalytic amount of potassium iodide (2 spatula tips, cat) followedby 4-chiorobenzyl chloride (47 mmol). Stir and reflux for 5 hours. Filter the hot solutionthrough celite, wash the filter cake with hot acetone (4x20 mL), combine the filtrate andwashings, and evaporate the solvent in vacuo and residue was recrystallized from acetone togive the titie compound.

Scheme B, step b: 4-Amino-l-(4-chlorobenzvl)piperidine

Dissolve bis(trifluoroacetoxy)iodobenzene (84 mmol) in acetonitrile (20 mL) and dilute withwater (20 mL). Add 4-carboxamide-l-(4-chlorobenzyl)piperidine (7 mmol) and heat forovemight at 65 °C. Cool the mixture (ice bath), add water (60 mL), followed by concentratedHCl. Extract with ether (2X). The aqueous layer was concentrated in vacuo, and the residuewas dissolved in water in 40 mL of water. Basify with aqueous sodium carbonate, and extractinto methylene chloride, the organic layer was drived over Na2SO4, filtered and the solvent wasevaporated in vacuo to give the titie compound.

Method 2:

Scheme C, step a: l-f4-Chlorobenzvl)-4-piperidone 50 - 011455

Dissolve 4-piperidone (17 mmol) in 3-pentanone (25 mL) and heat to reflux. Add césiumcarbonate (19 mmol) and a catalytic amount of potassium iodide, followed by 4-chlorobenzylchloride (20 mmol). Stir and reflux for 4 hours. Filter the hot suspension, wash tbe residuewith hot acetone (4x20 mL), combine the filtrate and washings, and evaporate the solvent in 5 vacuo to give the title compound.

Scheme C, step b: l-(4-ChlorobenzvI)-4-piperidone oxime

Dissolve l-(4-chlorobenzyl)-4-piperidone (0.0456 mmol), hydroxylamine hydrochloride(0.0456 mmol) and sodium acetate (0.0456 mmol) in aqueous éthanol (450 mL). Stirapproximately 30 minutes to 2 hours while warming. Add methylene chloride (450 mL), 10 separate the organic phase, and extract the aqueous phase with methylene chloride ( 100 mï.)Combine the organic phases and dry (MgSOJ. Evaporate the solvent in vacuo to give the titlecompound.

Scheme C, step c: 4-Amino-l-(4-chIorobenzvl)piperidine

Add l-(4-chlorobenzyl)-4-piperidone oxime (1.87 mmol) to a solution of lithium aluminum 15 hydride (2.5 mL of a IM solution in tetrahydrofuran) and place under a nitrogen atmosphère.Heat at reflux for 2 hours, cool and pour into dilute aqueous sodium hydroxide. Extract with amixture of ethyl ether/ethyl acetate (2x), wash with aqueous sodium chloride and dry (MgSO4).Evaporate the solvent in vacuo to give the title compound.

Scheme A. step b: 2-Chloro-6-r4-(l-(4-chlorobenzvlDpiperidinvlaininol-9-cvclopentvlpurine 20 2-Chloro-6-[4-( l-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6- dichloro-9-cyclopentylpurine, 4-amino-l-(4-chlorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)amino1-6-î4-(l-(4- chlorobenzvl))piperidinvlamino1-9-cvclopentvlpurine 25 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-chlorobenzyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf: (min) = 2.29; purity 94%; MS (APCI): 523 M*1

Example 39 30 2-rTrans-(4-aminocvcIohexvl,)aminol-6-r4-( l-f4-methoxvbenzvl))piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-l-f4-methoxvbenzvl)piperidine

Method 1 51

Scheme B, step a: 4-Carboxamide-l-(4-methoxvbenzvQpiperidine 4-Carboxamide-1 -(4-methoxybenzyl)piperidine may be prepared from isonipecotamide and 4-methoxybenzyl chloride essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-f4-methoxvbenzvI)piperidine 5 4-Amino-1 -(4-methoxybenzyl)piperidine is prepared from 4-carboxamide-1 -(4- methoxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-Methoxvbenzvl)-4-piperidone l-(4-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 4-methoxybenzyl 10 chloride essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(4-Methoxvbenzvl>-4-piperidone oxime 1- (4-Methoxybenzyl)-4-piperidone oxime is prepared from l-(4-methoxybenzyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C,step b. 15 Scheme C, step c: 4-Amino-l-f4-methoxvbenzvl,)piperidine 4--Amino-l-(4-methoxybenzyl)piperidine is prepared from l-(4-methoxybenzyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-f4-methoxvbenzvlï)piperidinvlamino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 20 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-methoxybenzyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocyclohexyDaminol-6-f4-(l-(4- methoxvbenzyl))piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(4-methoxybenzyI))piperidinylamino]-9- 25 cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf; (min) = 2.26; purity 100%; MS (APCI): 519 M+1

Example 40 2-fTrans-('4-aminocvcIohexvi)amino'|-6-r4-('l-f4-methvIbenzvIÏ)piperidinvlamino1-9- 30 cyclopentylpurine

Préparation of 4-Amino-l-('4-methylbenzyl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-methvlbenzvl)piperidine .. - ü i i η 5 5 52 4-Carboxamide-1 -(4-methylbenzyl)piperidine may be prepared from isonipecotamide and a-chloro-p-xylene essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(4-methvlbenzvl)piperidine 4-Amino-l-(4-methylbenzyl)piperidine is prepared from 4-carboxamide-1-(4- 5 methylbenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(4-Methvlbenzvl)-4-piperidone l-(4-MethyIbenzyl)-4-piperidone is prepared from 4-piperidone and a-chloro-p-xyleneessentially as described above in Example 38, Scheme C, step a. 10 Scheme C. step b: l-(4-Methvlbenzvl)-4-piperidone oxime l-(4-Methylbenzyl)-4-piperidone oxime is prepared from l-(4-methylbenzyi)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C. step c: 4-Amino-l-(4-methvlbenzvI)piperidine 1- Amino-l-(4-methylbenzyI)piperidine is prepared from l-(4-methylbenzyl)-4-piperidone 1S oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-!4~{'l-('4-methvlbenzvlOpiperidinvlamino~l-9-cvcIopentvlpurine 2- Chloro-6-[4-(l-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichIoro-9-cyclopentylpurine, 4-amino-l-(4-methylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. 20 Scheme A, step c: 2-FTrans-(4-aminocvclohexvl)aniipo1-6-f4-(l-(4- methvlbenzvl ))pjperidinvl aminol -9-cvcIopentvlpurine 2-(Trans-(4-aminocyclohexyl)amino]-6-(4-(l-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 25 Rf: (min) = 2.26; purity 100%; MS (APCI): 503 M*1Example 41 2-rTrans-(4-aminocvcIohexvl)aminol-6-f4-(l-f3-methoxvbenzvl))piperidinvlamino1-9- cyclopentylpurine

Préparation of 4-Amino-l-(3-methoxvbenzvl)piperidine 30 Method 1

Scheme B, step a: 4-Carboxamide-1-f 3-methoxvbenzvl)piperidine 4-Carboxamide-i-(3-methoxybenzyl)piperidine may be prepared from. isonipecotamide and 3-methoxybenzyl chloride essentially as described above in Example 38, Scheme B, step a. 53 071455

Scheme B. step b: 4-Amino-l-fS-methoxvbenzvllpiperidine4-Amino- l-(3-methoxybenzyl)piperidine is prepared from 4-carboxamide-1-(3-methoxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 5 Scheme C. step a: l-(3-Methoxvbenzvll-4-piperidone l-(3-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 3-methoxybenzylchloride essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(3-Methoxvbenzvll-4-piperidone oxime 1- (3-Methoxybenzyl)-4-piperidone oxime is prepared from l-(3-methoxybenzyl)-4-piperidone 10 and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-methoxvbenzvl)pjperidine 4-Amino- l-(3-methoxybenzyl)piperidine is prepared from l-(3-methoxybenzyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 15 Scheme A. step b: 2-Chloro-6-i4-f l-f3-methoxybenzvl))piperidinylaminol-9-cvclopentylpurine 2- Chloro-6-[4-(l-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-methoxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvt)aminol-6-Î4-('l-(3- 20 methoxvbenzvl»piperidinvlaminol-9-cvclopentvlpurine 2- [T rans-(4-aminocyclohexyl)amino] -6- [4-( 1 -( 3-methoxybenzyl))piperidinylamino] -9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf: (min) = 2.27; purity 99%; MS (APCI): 519 M+l 25 Example 42 2-fTrans-f4-aminocvclohexvl')aminol-6-f4-fl-(3-chloroben2vlOpiperidinvlaminol-9- cyclopentvlpurine

Préparation of 4-Amino-l-fS-chlorobenzvQpiperidine

Method 1 30 Scheme B. step a: 4-Carboxamide-1-fS-chlorobenzvDpiperidine 4-Carboxamide-1 -(3-chlorobenzyl)piperidine may be prepared from isonipecotamide and 3- chlorobenzyl chloride essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(3-chlorobenzvl)piperidine UI1455 4-Amino-l-(3-chlorobenzyl)piperidine is prepared from 4-carboxamide-1-(3-chlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-(3-Chlorobenzvl)-4-piperidone 5 l-(3-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 3-chlorobenzyl chlorideessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(3-Chlorobenzvl>-4-piperidone oxime 1- (3-Chlorobenzyl)-4-piperidone oxime is prepared from l-(3-chlorobenzyl)~4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b. 10 Scheme C, step c: 4-Amino-l-(3-chlorobenzyl)piperidine 4-Amino-l-(3-chlorobenzyl)piperidine is prepared from l-(3-chlorobenzyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(3-chlorobepzvl))piperidinvlamino-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6- 15 dichloro-9-cyclopentyIpurine,4-amino-l-(3-chlorobenzyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-(l-(3- chlorobenzvl))piperidinvlaminol-9-cvclopentvlpürine 2-[Trans-(4-aminocyclohexyl)amino3-6-[4-(l-(3-chlorobenzyl))piperidinylamino]-9- 20 cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3-chiorobenzyl))piperidinylamino}-9- cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf: (min) = 2.25; purity 95%; MS (APCI): 523 M*1

Example 43 2-rrrans-(4-aminocvclohexvl)aminol-6-i4-(l-(2-chlorobenzvl))piperidinvlaminol-9- 25 cvclopentvlpurine

Préparation of 4-Amino-l-(2-chlorobenzvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-chlorobenzvl)piperidine 4-Carboxamide-l-(2-chlorobenzyl)piperidine may be prepared from isonipecotamide and 2- 30 chlorobenzyl chloride essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-chlorobenzvDpiperidine4-Aminoe-l-(2-chlorobenzyi)piperidine is prepared from 4-carboxamide-1-(2-chlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b. 55 011455

Method 2:

Scheme C, step a: H2-chIorobenzvI)-4-piperidone l-(2-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 2-chlorobenzyl chlorideessentially as described above in Example 38, Scheme C, step a. 5 Scheme C. step b: l-(2-Chlorobenzvl)-4-piperidone oxime 1- (2-Chlorobenzyl)-4-piperidone oxime is prepared from l-(2-chlorobenzyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C. step c: 4-Amino-l-f2-chîorobenzvDpiperidine 4-Amino-l-(2-chlorobenzyl)piperidine is prepared from l-(2-chlorobenzyl)-4-piperidone oxime 10 essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-f l-(2-chlorobenzvl))piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(2-chlorobenzyl))piperidinyiamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-chlorobenzyl)piperidine, and triethylamineessentially as described above in Exampie 1, Scheme A, step b. 15 Scheme A, step c: 2-fTrans-f4-aminocvclohexvl)aminol-6-i4-(l-(2- chlorobenzvl))piperidinylaminol-9-cvcIopentylpurine 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-( 1 -(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 20 Rf: (min) = 2.25; purity 92%; MS (APCI): 523 M+1

Example 44 2-ÎTrans-f4-aminocvclohexvl)amino1-6-f4-(l-(2-methylbenzvl))piperidinvIaminol-9- cvclopentylpurine

Préparation of 4-Amino-l-f2-methvlbenzvl)piperidine 25 Method 1

Scheme B, step a: 4-Carboxamide-l-(2-methylbenzyl)piperidine 4-Carboxamide-l-(2-methylbenzyl)piperidine may be prepared from isonipecotamide and a-chloro-o-xylene essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f2-methvlbenzvl)piperidine 30 4-Amino-1 -(2-methylbenzyl)piperidine is prepared from 4-carboxamide-1 -(2- methylbenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: .1 -(2-Methvlbenzvl)-4-piperidone 56 011455 1- (2-Methylbenzyl)-4-piperidone is prepared from 4-piperidone and a-chloro-o-xyleneessentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: 4-Amino-l-f2-methvlbenzvl)piperidine oxime4-Amino-l-(2-methylbenzyl)piperidine oxime is prepared from 4-amino-l-(2- 5 methylbenzyl)piperidine and hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-('2-methvibenzvlk)iperidine 4-Amino-l-(2-methyIbenzyi)piperidine is prepared from essentially as described above inExemple 38, Scheme C, step c. 10 Scheme A, step b: 2-ChIoro-6-f4-(l-(2-methvlbenzvl))piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-methylbenzyl)piperidine, and triethylamineessentially as described above in Example l, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvDamino1-6-r4-(l-(2- 15 methvlbenzvl)~)piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-methylbenzyl))piperidinylaniino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf: (min) = 2.26; purity 98%; MS (APCI): 503 M*‘ 20 Example 45 2-rTrans-(4-aminocvclohexvl)aminol-6-r4-(l-(2.6-dichlorobenzvl))piperidinvlamino1-9- cyclopentylpurine

Préparation of 4-Amino-l-(2,6-dichlorobenzvl)piperidine

Method 1 25 Scheme B, step a: 4-Carboxamide-l-(2,6-dichlorobenzvl)piperidine 4-Carboxamide-1-(2,6-dichlorobenzyI)piperidine may be prepared from isonipecotamide anda,2,6-trichlorotoluene essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b:4-Amino-l-(2,6-dichlorobenzvl)piperidine 4-Amino-l-(2,6-dichlorobenzyl)piperidine is prepared from 4-carboxamide-1-(2,6- 30 dichlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(2.6-Dichlorobenzvl)-4-piperidone l-(2,6-Dichlorobenzyl)-4-piperidone is prepared from 4-piperidone and a,2,6-trichlorotoluene 57 011455 essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(2.6-Dichlorobenzvl)-4-piperidone oxime 1- (2,6-Dichiorobenzyl)-4-piperidone oxime is prepared from l-(2,6-dichlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, 5 Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2.6-dichlorobenzyl,)piperidine 4-Amino-1 -(2,6-dichlorobenzyl)piperidine is prepared from 1 -(2,6-dichlorobenzyl)-4- piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-(l-(2,6-dichIorobenzyl))piperidinvlaminol-9- 10 cvclopentvlpurine 2- Chloro-6-[4-(l-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyciopentylpurine, 4-amino-l-(2,6-dichlorobenzyl)piperidine (made according tothe Method 1 of Example 45), and triethylamine essentially as described above in Example 1,

Scheme A, step b. 15 Scheme A. step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-F4-(l-(2,6- dichlorobenzvl))piperidinvlamino1-9-cvclopentylpurine 2-[rrans-(4-aminocyclohexyl)amino]-6-[4-(l-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 20 Rf: (min) = 2.28; purity 98%; MS (APCI):557M+I.

Example 46 2-n,rans-(4-aminocyclohexvl)amino'|-6-i4-(l-f4-trifluoromethvlbenzvl))piperidinvlaniino'l-9- cvclopentvlpurine

Préparation of 4-Amino-l-(4-trifluoromethvlbenzvl)piperidine 25 Method 1

Scheme B, step a: 4-Carboxamide-l-(4-trifluoromethyIbenzvl)piperidine4-Carboxamide-l-(4-trifluoromethylbenzyl)piperidine may be prepared from isonipecotamideand a’-chloro-a,a,a-trifluoro-p-xylene essentially as described above in Example 38, SchemeB, step a. 30 Scheme B, step b:4-Amino-l-(4-trifluoromethvIbenzvI')piperidine 4-Amino-l-(4-trifluoromethylbenzyl)piperidine is prepared from 4-carboxamide-l-(4-trifluoromethylbenzyl)piperidine essentially as described above in Example 38, Scheme B, stepb. 58 011455

Method 2:

Scheme C, step a: l-f4-TrifluoromethvlbenzvI)-4-piperidone l-(4-Trifluoromethylbenzyl)-4-piperidone is prepared from 4-piperidone and a’-chloro-a,a,a-trifluoro-p-xylene essentially as describcd above in Example 38, Scheme C, step a. 5 Scheme C, step b: l-(4-TrifluoromethvlbenzvI)-4-piperidone oxime 1- (4-Trifîuoromethylbenzyl)-4-piperidone oxime is prepared from H4-trifluoromethylbenzyI)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C, step c: 4-Amino-l-(4-trifIuoromethvlbenzvl)piperidine10 4-Amino-l-(4-trifluoromethylbenzyl)piperidine is prepared from l-(4-trifluoromethylbenzyl)-4- piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-f4-trifluoromethvIbenzvl))piperidinvlamino-9- cvclopentvlpurine 2- Chloro-6-{4-(l-(4-trifluoromethylbenzyl))piperidinylamino3-9-cyclopentylpurine is prepared15 from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-trifluoromethylbenzyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, stepc: 2-ÎTrans-(4-aminocvclohexvI')aminol-6-f4-fl-(4- trifluoromethvlbenzvl))piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-trifluoromethylbenzyl))piperidinylamino]-9-20 cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4- trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Rf: (min) = 2.38; purity 100%; MS (APCI): 557 M*1

Example 47 25 (+/-)-2-rTrans-(4-aminocvclohexvl)aminol-6-i4-fl-(a-methvlbenzvl))piperidinvlanünc>l-9- cvclopentvlpurine

Préparation of (R.S)-4-Amino-l-(tt-methvlbenzvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-I-(a-methvIbenzvl)piperidine30 4-Carboxamide-l-(a-methylbenzyl)piperidine may be prepared from isonipecotamide and a- methylbenzyl bromide essentially as described above in Example 38, Scheme B, step a.Scheme B. step b: (R.S)-4-Amino-1 -(g-methvlbenzvl)piperidine(R,S)-4-Amino-l-(a-methylbenzyl)piperidine is prepared from 4-carboxamide-l-(a- 59 011455 methylbenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-fa-MethvlbenzvlM-piperidone l-(a-Methylbenzyl)-4-piperidone is prepared from 4-piperidone and α-methylbenzyl bromide 5 essentially as described above in Example 38, Scheme C, step a,

Scheme C, step b: l-fg-MethvlbenzvD-4-piperidone oxime 1- (a-Methylbenzyl)-4-piperidone oxime is prepared from l-(cc-methylbenzyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: (R.S)-4-Amino-l-fa-methvlbenzvl)piperidine 10 (R,S)-4-Amino-l-(a-methylbenzyI)piperidine is prepared from l-(a-methylbenzyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(a-methvIbenzvn)piperidinvlamino1-9-cvclopePtvlpurine 2- Chloro-6-[4-(l-(a-methylbenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopcntylpurine, (R,S)-4-amino-l-(a-methylbenzyl)piperidine, and 15 triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvnaminol-6-r4-(l-(g- methvlbenzvD)piperidinvlamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(a-methylbenzyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(a-methylbenzyl))piperidinylamino]-9- 20 ' cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 48 2-rTrans-f4-aminocvclohexvbaminol-6-r4-(l-(3-phenoxvpropvlïlpiperidinvlamino'l-9- cyclopentylpurine

Préparation of 4-Amino-l-(3-phenoxvpropyl')piperidine 25 Method 1

Scheme B, step a: 4-Carboxamide-l-(3-phenoxvpropvl)piperidine 4-Carboxamide-l-(3-phenoxypropyI)piperidine may be prepared from isonipecotamide and 1-chloro-3-phenoxypropane essentially as described above in Example 38, Scheme B, step a.Scheme B. step b: 4-Amino-l-('3-phenoxvpropvl)piperidine 30 4-Amino-1 -(3-phenoxypropyl)piperidine is prepared from 4-carboxamide-l-(3- phenoxypropyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, steo a: l-f3-Phenoxvpropyl)-4-piperidone ου U. I I *+ 0 0 1 -(3-Phenoxypropyl)-4-piperidone is prepared from 4-piperidone and 1 -chloro-3-phenoxypropane essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3-Phenoxvpropvl)-4-piperidone oxime 1- (3-Phenoxypropyl)-4-piperidone oxime is prepared from l-(3-phenoxypropyl)-4-piperidone 5 and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-phenoxvpropvl)piperidine 4-Amino-l-(3-phenoxypropyl)piperidine is prepared from l-(3-phcnoxypropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 10 Scheme A, step b: 2-Chloro-6-r4-fl-(3-phenoxvpropvl))piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-phenoxypropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-f4-aminocvclohexvBaminol-6-r4-(l-f3- 15 phenoxypropvl)')piperidinylaminol-9-cvclopentvlpurine 2-(Trans-(4-aminocyciohexyl)amino]-6-[4-(l-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 49 20 2-rTrans-f4-aminocvclohexvbaminol-6-f4-( 1 -(2-phenoxvethvD)piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-l-f2-phenoxyethvDpiperidinc

Method 1

Scheme B. step a: 4-Carboxamide-l-(2-phenoxvethybpiperidine 25 4-Carboxamide-l-(2-phenoxyethyl)piperidine may be prepared from isonipecotamide and 1-chloro-2-phenoxyethane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-f2-phenoxyethvDpiperidine 4-Amino-l-(2-phenoxyethyl)piperidine is prepared from 4-carboxamide-l-(2-phenoxyethyl)piperidine essentially as described above in Example 38, Scheme B, step b. 30 Method 2:

Scheme C, step a: l-f2-Phenoxyethvl)-4-piperidon&amp; l-(2-Phenoxyethyl)-4-piperidone is prepared from 4-piperidone and l-chloro-2-phenoxyethaneessentially as described above in Example 38, Scheme C, step a. 61 011455

Scheme C. step b: l-(~2-Phenoxyethvl)-4-piperidone oxime 1- (2-Phenoxyethyl)-4-piperidone oxime is prepared from l-(2-phenoxyethyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C. step c: 4-Amino-l-f2-phenoxvethvI~)piperidine 5 4-Amino-l-(2-phenoxyethyl)piperidine is prepared from l-(2-phenoxyethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-r4-('l-('2-phenoxvethvl’))piperidinvlaminol-9-cvcIopentvlpurine 2- Chloro-6-[4-(l-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-phenoxyethyl)piperidine, and triethylamine 10 essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvI)amino1-6-f4-fl-f2- phenoxvethvl1~>piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-(l-(2-phenoxyethyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-phenoxyethyl))piperidinylamino]-9- « 15 cyclopentylpurine essentially as described in Example 1, Scheme A, step c.γ Example 50 2-fTrans-(4-aminocvcIohexvl’)aniinol-6-r4-( 1 -(2-phenvlethvl~))piperidinvlaminol-9- cyclopentvlpurine

Préparation of 4-Amino-l-(2-phenvlethyl')piperidine 20 Method 1

Scheme B, step a: 4-Cafboxamide-l-(2-phenvlethvl,)piperidine 4-Carboxamide-l-(2-phenylethyl)piperidine may be prepared from isonipecotamide and (2-chloroethyl)benzene essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b:4-Amino-l-f2-phenvlethvl')piperidine 25 4-Amino-l-(2-phenylethyl)piperidine is prepared from 4-carboxamide-l-(2- phenylethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-f2-Phenvlethyl)-4-piperidone l-(2-phenylethyl)-4-piperidone is prepared from 4-piperidone and (2-chloroethyl)benzene 30 essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-f2-Phenvlethvl)-4-piperidone oxime l-(2-Phenylethyl)-4-piperidone oxime is prepared from l-(2-phenylethyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b. 62 011455

Scheme C, step c: 4-Amino-1-f2-phenvlethvl)piperidine 4-Amino-1-(2-phenylethyl)piperidine is prepared from l-(2-phenylethyl)-4-piperidone oximeessentialiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-('l-f2-phenvlethvl))piperidinvlamino'l-9-cvclopentvlpurine 5 2-Chioro-6-[4-( 1 -(2-phenylethyl))piperidinylamino]-9-cyclopentyipurine is prepared from 2,6- dichloro-9-cyclopentylpurine, 4-amino-l-(2-phenylethyl)piperidine, and triethylamineessentialiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-!Trans-<4-aminocvclohexvBanùnol-6-i4-fl-(,2- phenvlethvI))piperidinvlamino1-9-cvclopentylpurine 10 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-phenylethyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurine essentialiy as described in Example 1, Scheme A, step c.

Example 51 2-rrrans-(4-aminocvclohexvbaminol-6-f 4-( 1 -propvbpiperidinvlaminol-9-cvclopentvIpurine 15 Préparation of 4-Amino-1-propvlpiperidineMethod 1

Scheme B. step a: 4-Carboxanude-l-propylpiperidine 4-Carboxamide-1-propylpiperidine may be prepared from isonipecotamide and 1-chioropropaneessentialiy as described above in Example 38, Scheme B, step a. 20 Scheme B, step b:4-Amino-l-propvlpiperidine 4-Amino-1-propylpiperidine is prepared from 4-caiboxamide-1-propylpiperidine essentialiy asdescribed above in Example 38, Scheme B, step b.

Method 2:

Scheme C. step a: l-Propvl-4-piperidone 25 l-Propyl-4-piperidone is prepared from 4-piperidone and 1-chloropropane essentialiy asdescribed above in Example 38, Scheme C, step a.

Scheme C, step b: l-Propvl-4-piperidone oxime l-Propyl-4-piperidone oxime is prepared from l-propyl-4-piperidone and hydroxylaminehydrochloride essentialiy as described above in Example 38, Scheme C, step b. 30 Scheme C, step c: 4-Amino-1-propylpiperidine 4-Amino-1-propylpiperidine is prepared from l-propyl-4-piperidone oxime essentialiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-propvl)piperidinvlamino1-9-cvclopentvlpurine 63 011455 2-Chloro-6-[4-(l-propyl)piperidinylamino]-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyciopentylpurine, 4-amino-1-propylpiperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-<'4-aininocvciohexvl1aminol-6-f4-('l-propvl)proeridinvlaminol-9- 5 cvclopentvlpurine 2-[T rans-(4-aminocyclohexyl)amino] -6-[4-( 1 -propyl)piperidinylamino] -9-cyclopentylpurine isprepared from 2-chloro-6-[4-( l-propyl)piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme À, step c.

Example 52 10 2-fTrans-(4-aminocvclohexvDaminol-6-f4-( 1 -cvclopropvlmethvl)piperidinvlaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-cvclopropylmethvlpiperidine

Method 1

Sctîeme B, step æ 4-Carboxamide-l-cvclopropvlmethvlpiperidine 15 4-Carboxamide- 1-cyclopropylmethylpiperidine may be prepared from isonipecotamide and (chloromethyl)cyclopropane essentially as described above in Example 38, Scheme B, step a.ScnemeB, step b: 4-Amino-l-cvclopropvlmethvlpiperidine 4-Amino-l-cyclopropylmethyIpiperidine is prepared from 4-carboxamide-1-cyclopropylmethylpiperidine essentially as described above in Example 38, Scheme B, step b. 20 Method 2:

Scheme C, step a: l-(Cvclopropylmethvl)-4-piperidone 1- (Cyclopropylmethyl)-4-piperidone 1s prepared from 4-piperidone and(chloromethyl)cyclopropane essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-(Cvclopropvlmethvl)-4-piperidone oxime 25 l-(Cyclopropylmethyl)-4-piperidone oxime is prepared from l-(cyclopropylmethyl)-4- piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C, step c: 4-Amino-l-cvclopropvlmethvlpiperidine 4-Amino-1-cyclopropylmethylpiperidine is prepared from l-(cyclopropylmethyI)-4-piperidone 30 oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-i4-f 1 -cvclopropvlmethvl')piperidinvlamino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-cyclopropylmethylpiperidine, and triethylamine 64 011455 essentially as described above in Exemple 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-f4-f 1- cyclopropvImethyI)piperidinvlamino1-9-cvclopentvIpurine 2-[Trans-(4-aminocycIohexyl)amino]-6-[4-( 1 -cyclopropylmethyl)piperidinylamino]-9- 5 cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -cyclopropylmethyl)piperi<ünylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Rf: (min) = 2.19; purity 100%; MS (APCI): 454 M*1

Example 53 2-rTrans-f4-aminocvclohexvl)aminol-6-i4-(l-(2-pyridinvlmethvl))piperidinvlaminol-9- 10 cyclopentylpurine

Préparation of 4-Amino-1 -(2-pvridinvlmethvI)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-pvridinylmethvl)piperidine 4-Carboxamide-l-(2-pyridinylmethyl)piperidine may be prepared from isonipecotamide and 2- 15 picolyl chloride hydrochloride essentially as described above in Example 38, Scheme B, step a.Scheme B, step b:4-Amino-l-(2-pvridinvlmethvl)piperidine4-amino-1 -(2-pyridinylmethyI)piperidine is prepared from 4-carboxamide-1-(2-pyridinylmethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 20 Scheme C. step a: l-(2-PyridinvlmethvI)-4-piperidone l-(2-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 2-picolyl chloridehydrochloride essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f2-Pvridinvlmethvl)-4-piperidone oxime 1- (2-Pyridinylmethyl)-4-piperidone oxime is prepared from l-(2-pyridinylmethyl)-4-piperidone 25 and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-pvridinvlmethvl)piperidine 4-Amino-l-(2-pyridinylmethyl)piperidine is prepared from l-(2-pyridinylmethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 30 Scheme A. step b: 2-Chloro-6-f4-(l-(2-pvridtnylmethvlï)piperidinvlaminol-9-cycIopentvlpurine 2- Chloro-6-[4-(l-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyciopentylpurine, 4-amino-l-(2-pyridinylmethyl)piperidine, and triethylamine 65

O1HSS essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl’)aminol-6-f4-fl-{2- pvridinvlmethvlOpiperidinvlaniinol-Ç-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-pyridinylmethyl))piperidinylamino]-9- 5 cyclopentylpurine is prcpared from 2-chloro-6-[4-(l-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme À, step c.

Example 54 2-rTrans-f4-aminocvclohexvl>aminol-6-i4-fl-f3-pvridinvlmethvl))piperidinvlaminol-9- cvclopentvlpurine 10 Préparation of 4-Amino-l-(3-pvridinvlmethvl')piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(3-pvridinvlmethvl)piperidine 4-Carboxamide-l-(3-pyridinylmethyl)piperidine may be prepared from isonipecotamide and 3-picolylchloride hydrochloride essentially as described above in Example 38, Scheme B, step a. 15 Scheme B, step b: 4-Amino-l-f3-pyridinylmethyl')piperidine 4-Amino-l-(3-pyridinylmethyl)piperidine is prepared from 4-carboxamide-l-(3-pyridinylmethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2;

Scheme C, step a: l-f3-PvridinvlmethvP-4-piperidone 20 l-(3-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 3-picolyl chloridehydrochloride essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3-Pvridinylmethvl)-4-piperidone oxime 1- (3-Pyridinylmethyl)-4-piperidone oxime is prepared from l-(3-pyridinylmethyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described a’bove in Example 38, Scheme C, 25 step b.

Scheme C. step c: 4-Amino-l-(3-pvridinvlmethvlïpiperidine 4-Amino-l-(3-pyridinylmethyl)piperidine is prepared from l-(3-pyridinylmethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(,l-f3-pvridinvlmethvn'>piperidinvlamino1-9-cvclopentvlpurine 30 2- Chloro-6-[4-(l-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-pyridinylmethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. 66 011455

Scheme A, step c: 2-rTrans-(4-aminocvclohexvBamino1-6-r4-(l-(3- pvridinvlmethvl))piperidinvlaminol-9-cvclopentvlpurine2-[Trans-(4-aminocyclohexyl)amino]-6-i4-(l-(3-pyridinyimethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-pyridinylmethyl))piperidinylamino]-9- 5 cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 55 2-rrrans-('4-aminocvclohexvBaminol-6-i4-fl-f4-pyridinvlmethvl')'>piperidinvlamino1-9- cyclopentylpurine

Préparation of 4-Amino-l-(4-pvridinvlmethvbpiperidine 10. Method 1

Scheme B. step a: 4-Carboxamide-l-(4-pyridinvlmethvl)piperidine 4-Carboxamide-l-(4-pyridinylmethyl)piperidine may be prepared from isonipecotamide and 4-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme B, step aScheme B, step b: 4-Amino-l-i4-pvridinvlmethvDpiperidine 15 4-Amino-l-(4-pyridinylmethyl)piperidine is prepared from 4-carboxamide-l-(4- pyridinylmethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-(4-PvridinvlmethvB-4-piperidone l-(4-PyridinylmethyI)-4-piperidone is prepared from 4-piperidone and 4-picoIyl chloride 20 hydrochloride essentially as described above in Example 38, Scheme C, step aScheme C, step b: l-(4-PvridinvlmethvD-4-piperidone oxime l-(4-Pyridinylmethyl)-4-piperidone oxime is prepared from l-(4-pyridinylmethyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C,step b. 25 Scheme C, step c: 4-Amino-l-f4-pvridinvImethvl)piperidine 4-Amino-l-(4-pyridinylmethyl)piperidine is prepared from l-(4-pyridinylmethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-r4-('l-(,4-pyridinvlmethvl))piperidinvlamino1-9-cvclopentylpurine 30 2-Chloro-6-[4-( l-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-pyridinylmethyl)piperidine, and triethylamineessentially as described above in Exampie 1, Scheme A, step b.

Scheme A, step c: 2-ITrans-(4-aminocvclohexvBaminol-6-f4-f l-(4- 67 011455 pvridinvlmethvl))piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 5 Example 56 2- ÎTrans-( 4-aminocvcIohexvl,)amino1-6-[4-( 1 -( 3-(2.4- dimethvlisoxazoivI)imethyl)piperidinylamino'l-9-cvclopentvlpurinePréparation of 4-Amino-l-(3-(2.4-dimethvlisoxazolvI)methylpiperidine

Method 1 10 Scheme B. step a: 4-Carboxamide-l-(3-(2.4-dimethvlisoxazolvI)methvl')piperidine4-Carboxamide-l-(3-(2,4-dimethylisoxazolyl)methyl)piperidine may be prepared fromisonipecotamide and 2,4-dimethyl-3-chloromethyl-isoxazole essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(3-(2.4-dimethvlisoxazolvDmethylpiperidine 15 4-Amino-l-(3-(2,4-dimethylisoxazolyl)methylpiperidine is prepared from 4-carboxamide-l-(3-(2,4-dimethylisoxazolyl)methyl)piperidine essentially as described above in Example 38,Scheme B, step b.

Method 2:

Scheme C, step a: l-(3-(2,4-Dimethvlisoxazolyl')methvl)-4-piperidone 20 1 -(3-(2,4-DimethylisoxazolyI)methyl)-4-piperidone is prepared from 4-piperidone and 2,4- dimethyl-3-chloromethyl-isoxazole essentially as described above in Example 38, Scheme C,step a.

Scheme C, step b: l-(3-f2,4-Dimethvlisoxazolvl)methvl')-4-piperidone oxime 1- (3-(2,4-Dimethylisoxazolyl)methyl)-4~piperidone oxime is prepared from 1-(3-(2,4- 25 dimethylisoxazolyl)methyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-(2,4-dimethvlisoxazolvl)methvlpiperidine4-Amino-1-(3-(2,4-dimethyIisoxazolyl)methylpiperidine is prepared from 1-(3-(2,4-dimethylisoxazolyl)methyl)-4-piperidone oxime essentially as described above in Example 38, 30 Scheme C, step c.

Scheme A. step b: 2-Chloro-6-i4-i'l-(3-f2.4-dimethvlisoxazolvl))methvl')piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino}-9-cyclopentylpurine is 68 011455 prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine, and triethylamine essentialiy as described above inExample 1, Schemé A, step b.

Scheme A, step c: 2-ITrans-f4-aminocvclohexvl')aminol-6-[4-('l-f3-f2.4- 5 dirnethviisoxazolvD)methvl,)piperidinvIanunol-9-cvclopentvlpurine 2-[T rans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(3-(2,4- dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3-(2,4-dimethylisoxazôIyl))methyl)piperidinylamino]-9-cyclopentylpurine essentialiyas described in Example 1, Scheme A, step c. 10 Example 57 (R,S)-2-ÎTrans-(4-aminocvclohexvl)aminol-6-F4-( 1 -benzvi-3-methvl~)piperidinvlamino1-9- cvclopentvlpurine

Préparation of (R.SV-4-Amino-l-benzvl-3-methvlpiperidine

Method 1 15 Scheme B. step a: fR.SV-4-Carboxamide-l-benzvl-3-methvlpiperidine (R,S)-4-Carboxamide-l-benzyl-3-methylpiperidine may be prepared from (R,S)-4-carboxamide-3-methylpiperidine and benzyl chloride essentialiy as described above in Example38, Scheme B, step a, substituting (R,S)-4-carboxamide-3-methylpiperidine forisonipecotamide. 20 Scheme B. step b: (R.S~)-4-Amino-l-benzvl-3-methvlpiperidine (R,S)-4-Ammo-l-benzyl-3-methylpiperidine is prepared from (R,S)-4-carboxamide-l-benzyl-3-methyipiperidine essentialiy as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: (R.S)-l-Benzvl-3-methvl-4-piperidone ’· 25 (R,S)-1 -Benzyl-3-methyl-4-piperidone is prepared from (R,S)-3-methyl-4-piperidone and benzyl chloride essentialiy as described above in Example 38, Scheme C, step a, substituting(R,S)-3-methyl-4-piperidone for 4-piperidone.

Scheme C, step b: fR.SVl-Benzvi-3-methv]-4-piperidone oxime (R,S)-l-Benzyl-3-methyl-4-piperidone oxime is prepared from (R,S)-l-benzyl-3-methyl-4- 30 piperidone and hydroxylamine hydrochloride essentialiy as described above in Example 38,

Scheme C, step b.

Scheme C, step c: (R.S)-4-Amino-l-benzvl-3-methylpiperidine (R,S)-4-Amino-l-benzyl-3-methylpiperidine is prepared from (R,S)-l-benzyl-3-methyl-4- 69 - 011455 piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: (R,S)-2-Chloro-6-[4-f l-benzvl-3-methv0piperidinvlaminol-9- cvclopentvlpurine (R,S)-2-Chloro-6-[4-( l-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurine is prepared5 from 2,6-dichloro-9-cyclopentylpurine, (R,S)-4-amino-l-benzyl-3-methylpiperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: ('R,S)-2-rrrans-(4-aminocvclohexvl4amino]-6-i4-(l-benzvl-3- methvl)piperidinvlamino1-9-cvclopentylpurine (R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-benzyl-3-methyl)piperidinylamino]-9-10 cyclopentylpurine is prepared from (R,S)-2-chloro-6-[4-(l-benzyl-3-methyl)piperidinylammo]- 9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 58a fR)-2-FTrans-i4-aminocvclohexvl')aminol-6-r3-fl-benzvl')pvrrolidinvlanùnol-9- cvclopentvlpurine 15 Scheme A, step b: (R~)-2-Chloro-6-r3-(Î-benzvl)pvrrolidinvlamino1-9-cvclopentylpurine (R)-2-Chloro-6-[3-(l-benzyl)pyrrolidinyIamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentyIpurine, (R)-4-amino-l-benzyl-pyrrolidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

Scheme A, step c: ('R)-2-FTrans-f4-aminocvclohexvl)amino1-6-r3-(,l- 20 benzvnpvrrolidinvlaminol-9-cvclopentvlpurine (R) -2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine is prepared from (R)-2-chloro-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 58b 25 (S)-2-rTrans-(4-aminocvclohexvhaminol-6-r3-(l-benzvï)pvrroIidinvlaminol-9- cyclopentylpurine

Scheme A, step b: (S)-2-Chloro-6-i3-f l-benzvl)pvrrolidinylamino1-9-cvclopentyipurine (S) -2-Chloro-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (S)-4-amino-l-benzyl-pyrrolidine, and triethylamine essentially 30 as described above in Example 1, Scheme A, step b.

Scheme A, step c: fS)-2-rTrans-(4-aminocvclohexvbaminol-6-r3-fl- benzvl')pvrrolidinvlaminol-9-cyclopentvlpurine (S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(l-benzyl)pyrrolidinylamino]-9- 70 011455 cyclopentyipurine is prepared from (S)-2-chloro-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 59 2-rTrans-i4-aminocvclohexvl'>aminol-6-i4-('l-butvl)piperidinvlaminol-9-cvclopentvlpurine 5 Préparation of 4-Amino-l-butvlpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-butvlpiperidine 4-Carboxamide-l-butylpiperidirie may be prepared from isonipecotamide and 1-chlorobutaneessentially as described above in Example 38, Scheme B, step a. 10 Scheme B, step b: 4-Amino-l-butvlpiperidine 4-Amino-l-butylpiperidine is prepared from 4-carboxamide-l-butylpiperidine essentially asdescribed above in Exampie 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-Butvl-4-pjperidone 15 1 -Butyl-4-piperidone is prepared from 4-piperidone and 1 -chlorobutane essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-Butvl-4-piperidone oxime 1- Butyl-4-piperidone oxime is prepared from l-butyl-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C, step b. 20 Scheme C, step c: 4-Amino-l-butvlpiperidine 4-Amino-l-butylpiperidine is prepared from l-butyl-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-fl-butvl)piperidinvlaniino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9- 25 cyclopentyipurine, 4-amino-l-butylpiperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step ç: 2-ÎTrans-(4-aminocvclohexvl,)amino1-6-f4-('l-butvl’)piperidinviamino1-9- cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -butyl)piperidinylamino]-9-cyclopentylpurine is 30 prepared from 2-chloro-6-[4-( 1 -butyl)piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 60 2-rTrans-(4-aminocvclohexvl)aminol-6-f4-(l-f2-thiomethoxvethvl)piperidinvlaminol-9- 71 011455 cyclopentvlpurine

Préparation of 4-Amino-l-(2-thiomethoxvethvl~)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-thiomethoxvethvl)piperidine 5 4-Carboxamide-1 -(2-thiomethoxyethyl)piperidine may be prepared from isonipecotamide and l-chloro-2-thiomethoxyethane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-(2-thiomethoxvethvl~)piperidine 4-Amino-l-(2-thiomethoxyethyl)piperidine is prepared from 4-carboxamide-1-(2-thiomethoxyethyl)piperidine essentially as described above in Example 38, Scheme B, step b. 10 Method 2:

Scheme C, step a: l-f2-Thiomethoxvethvl)-4-piperidone 1- (2-Thiomethoxyethyl)-4-piperidone is prepared from 4-piperidone and l-chloro-2-thiomethoxyethane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: 1 -<'2-Thiomethoxvethvn-4-piperidone oxime 15 l-(2-Thiomethoxyethyl)-4-piperidone oxime is prepared from l-(2-thiomethoxyethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-thiomethoxyethvI)piperidine4-Amino-l-(2-thiomethoxyethyl)piperidine is prepared from l-(2-thiomethoxyethyl)-4- 20 piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b; 2-Chloro-6-f4-(l-f2-thiomethoxvethvï)piperidinylamino1-9- cvclopentvlpurine 2- Chloro-6-[4-(l-(2-thiomethoxyethyl)piperidinyiamino]-9-cyclopentylpurine is prepared from2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-thiomethoxyethyl)piperidine, and triethylamine 25 essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)amino1-6-f4-(l-f2- thiomethoxvethvl)piperidinvlaminol-9-cvclopentvIpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-thiomethoxyethyl)piperidinylamino]-9-cyclopentvlpurine is prepared from 2-chloro-6-[4-(l-(2-thiomethoxyethyl)piperidinylamino]-9- 30 cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 61 2-rTrans-(4-aminocvclohexvllaminol-6-f4-(l-f2-phenvlsulfinvl'lethvl)piperidinvlaminol-9·: cyclopentvlpurine 72 011455

Préparation of 4-Amino-l-(2-phenvlsulfinvlethyl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-f2-phenvlsulfinvlethvl)piperidine4-Carboxamide-l-(2-phenylsulûnylethyl)piperidine may be prepared from isonipecotamide and 5 l-chloro-2-phenylsulfmylethane essentially as described above in Exaxnple 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(2-phenvlsulfinvlethvl)piperidine4-Amino-l-(2-phenylsulfmylethyl)piperidine is prepared from4-carboxamide-l-(2-phenylsulfinylethyl)piperidine essentially as described above in Example 38, Scheme B, step b. 10 Method 2:

Scheme C, step a: I-(2-Phenvlsulfinvlethvl)-4-piperidone 1- (2-Phenylsulfinylethyl)-4-piperidone is prepared from 4-piperidone and l-chloro-2-phenylsulfinylethane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-f2-Phenvlsulfmylethvl')-4-piperidone oxime 15 l-(2-Phenylsulfinylethyl)-4-piperidone oxime is prepared from l-(2-phenylsulfinylethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C. step c: 4-Amino-l-f2-phenvlsulfinvlethvl)piperidine 4-Amino-l-(2-phenylsulfinylethyl)piperidine is prepared from l-(2-phenylsulftnylethyl)-4- 20 piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-F4-fl-f2-phenvlsulfinvl)ethyl')piperidinvlaminol-9- cyclopentvlpurine 2- Chloro-6-[4-( 1 -(2-phenylsulfînyl)ethyl)piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-phenylsulfinylethyl)piperidine, and 25 triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl')amino'l-6-r4-n-(2- phenvlsulfinvl')ethvl')piperidinylamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurine is prepared from2-chloro-6-[4-(l-(2-phenylsulfinyl)ethyl)piperidinylamino]- 30 9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 62 2-FTrans-(4-aminocvclohexvl')aminol-6-F4-f l-fS-hvdroxvlpropvDpiperidinvlaminol^ cvclopentvlpurine 73 011455

Préparation of 4-Amino-l-f3-hvdroxvpropvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f3-hvdroxypropvl)piperidine 4-Carboxamide-l-(3-hydroxypropyl)piperidine may be prepared from isonipecotamide and 3- 5 chloro- 1-propanol essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f3-hvdroxvpropyI)piperidine4-Amino-l-(3-hydroxypropyl)piperidine is prepared from 4-carboxamide-l-(3-hydroxypropyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2; 10 Scheme C, step a: 1 -f3-HvdroxvpropyI')~4-piperidone l-(3-Hydroxypropyl)-4-piperidone is prepared from 4-piperidone and 3-chloro-1-propanolessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3-Hvdroxvpropyl)-4-piperidone oxime 1- (3-Hydroxypropyl)-4-piperidone oxime is prepared from l-(3-hydroxypropyl)-4-piperidone 15 and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-hvdroxvpropyIk>iperidine 4-Amino-l-(3-hydroxypropyl)piperidine is prepared from l-(3-hydroxypropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 20 Scheme A, step b: 2-Chloro-6-f4-(l-(3-hvdroxv)propvl)piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(3-hydroxy)propyl)piperidinylaminoJ-9-cyclopentyipurine is prepared from2,6-dichloro-9-cyciopentylpurine, 4-amino-l-(3-hydroxypropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvl)aminol-6-f4-f l-f3- 25 hvdroxv’ipropvOpiperidinvlaminol-g-cyclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 63 30 2-rTrans-('4-aminocvclohexyl')aminol-6-i4-(l-f3-methoxv')propvDpiperidinvlamino1-9- cvclopentylpurine

Préparation of 4-Amino-l-f3-methoxypropvl')piperidine

Method 1 74 011455

Scheme B. step a: 4-Carboxamide-l-(,3-methoxvpropylk>iperidine 4-Carboxamide-l-(3-methoxypropyl)piperidine may be prepared from isonipecotamide and 1-chloro-3-methoxypropane essentiaiiy as described above in Example 38, Scheme B, step a.Scheme B. step b: 4-Amino-l-f3-methoxypropvl)piperidine 5 4-Amino-1 -(3-methoxypropyl)piperidine is prepared from 4-carboxamide-1 -(3- methoxypropyl)piperidine essentiaiiy as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-f3-Methoxvpropyl)-4-piperidone l-(3-Methoxypropyl)-4-piperidone is prepared from 4-piperidone and l-chloro-3- 10 methoxypropane essentiaiiy as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-f3-Methoxvpropvl)-4-piperidone oxime 1- (3-Methoxypropyl)-4-piperidone oxime is prepared from l-(3-methoxypropyl)-4-piperidoneand hydroxylamine hydrochloride essentiaiiy as described above in Example 38, Scheme C,step b. 15 Scheme C. stepc: 4-Amino-l-(,3-methoxvpropvl')piperidine 4-Amino-l-(3-methoxypropyl)piperidine is prepared from l-(3-methoxypropyl)-4-piperidoneoxime essentiaiiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(3-methoxv)propvl')piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 20 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(3-methoxypropyl)piperidine, and triethylamine essentiaiiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-( l-(3- methoxv’)propvl)piperidinvIaminol-9-cvclopentvIpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-methoxy)propyl)piperidinylamino]-9- 25 cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-methoxy)propyl)piperidinylaniino]-9-cyclopentylpurine essentiaiiy as described in Example 1, Scheme A, step c.

Example 64 2-[Trans-f4-aminocvclohexvI)amino1-6-i4-fl-(3-ethoxv)propvi')piperidinvlamino1-9- cvclopentvlpurine 30 Préparation of 4-Amino-l-f3-ethoxypropvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-f3-ethoxvpropvl)piperidine 4-Carboxamide-l-(3-ethoxypropyl)piperidine may be prepared from isonipecotamide and 1- 75 011455 chloro-3-ethoxypropane essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(,3-ethoxvpropvl,)piperidine4-Amino-l-(3-ethoxypropyl)piperidine is prepared from 4-carboxamide-l-(3-ethoxypropyl)piperidine essentially as described above in Example 38, Scheme B, step b. 5 Method 2:

Scheme C, step a: l-(3-EthoxypropvlV-4-piperidone 1- (3-EthoxypropyI)-4-piperidone is prepared from 4-piperidone and l-chloro-3-ethoxypropaheessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3-Ethoxvpropyl)-4-piperidone oxime 10 l-(3-Ethoxypropyl)-4-piperidone oxime is prepared from l-(3-ethoxypropyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C. step c: 4-Amino-l-(3-ethoxvpropyDpiperidine 4-Amino-l-(3-ethoxypropyl)piperidine is prepared from l-(3-ethoxypropyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c. 15 Scheme A, step b: 2-Chloro-6-r4-fl-f3-ethoxv)propvl)piperidinvlaminol-9-cvclopentvlpurine 2- Ghloro-6-[4-(l-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-ethoxypropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c:' 2-rTrans-(4-aminocyclohexvl)amino1-6-r4-fl-f3- 20 ethoxvlpropvlIpiperidinvlaminol-O-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 65 25 2-rTrans-f4-aminocyclohexvl)amino1-6-r4-(l-f3-propoxv')propvl)piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-l-(3-propoxvpropvDpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-('3-propoxvpropvl’)piperidine 30 4-Carboxamide-l-(3-propoxypropyl)piperidine may be prepared from isonipecotamide and 1-chloro-3-propoxypropane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-('3-propoxypropvl')piperidine 4-Amino-l-(3-propoxypropyl)piperidine is prepared from 4-carboxamide-l-(3- 76 U I 14 00 propoxypropyl)piperidine essentialiy as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(3-Propoxvpropvh-4-piperidonel-(3-Propoxypropyl)-4-piperidone is prepared from 4-piperidone and l-chloro-3- 5 propoxypropane essentialiy as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3>PropoxypropvB-4-piperidone oxime 1- (3-Propoxypropyl)-4-piperidone oxime is prepared from l-(3-propoxypropyl)-4-piperidoneand hydroxylamine hydrochloride essentialiy as described above in Example 38, Scheme C,step b. 10 Scheme C, step c: 4-Amino-i-(3-propoxvpropyl)piperidine 4-Amino-1 -(3-propoxypropyl)piperidine is prepared from 1 -(3-propoxypropyl)~4-piperidoneoxime essentialiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(3-propoxv)propvl)piperidinvlamino]-9-cvclopentylpurine 2- Chloro-6-[4-(l-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 15 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-propoxypropyl)piperidme, and triethylamine essentialiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-f4-aminocvclohexvl)aminol-6-i4-n-f3- propoxv)propvDpiperidinvlaminol-9-cvclopentvlporine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-propoxy)propyl)piperidinylamino]-9- 20 cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3-propoxy)propyl)piperidinylaminoî-9-cyclopentyipurine essentialiy as described in Example 1, Scheme A, step c.

Example 66 2-fTrans-(4-aminocvclohexvl)amino1-6-i4-fl-f3-butoxv)propvl’)piperidinvlamino1-9- cyclopentylpurine 25 Préparation of 4-Amino-l-(3-butoxvpropyl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(3-butoxypropvl)piperidine4-Carboxamide-l-(3-butoxypropyl)piperidine may be prepared from isonipecotamide and 1-chloro-3-butoxypropane essentialiy as described above in Example 38, Scheme B, step a. 30 Scheme B, step b: 4-Amino-l-(3-butoxypropvl)piperidine 4-Amino-l-(3-butoxypropyl)piperidine is prepared from 4-carboxamide-l-(3- butoxypropyl)piperidine essentialiy as described above in Example 38, Scheme B, step b.

Method 2: 77 011455

Scheme C. step a: l-f3-Butoxvpropviy-4-Diperidone 1- (3-Butoxypropyl)-4-piperidone is prepared from 4-piperidone and l-chloro-3-butoxypropaneessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f3-ButoxvpropvB-4-piperidone oxime 5 l-(3-Butoxypropyl)-4-piperidone oxime is prepared from l-(3-butoxypropyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-f3-butoxvpropyl)piperidine 4-Amino-l-(3-butoxypropyl)piperidine is prepared from l-(3-butoxypropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 10 Scheme A. step b: 2-Chloro-6-i4-(l-f3-butoxv')propv0piperidinvlamino'l-9-cvclopentvIpurine 2- Chloro-6-[4-(l-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-butoxypropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-f4-aminocvclohexyl,)aminol-6-f4-fl-f3- 15 butoxv)propvl)piperidinvlaminol-9-cvclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-butoxy)propyl)piperidinylaimno]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 67 20 2-rTrans-f4-aminocvclohexvBaminol-6-i4-(l-f3-benzyloxv')propvl)piperidinvlamino1-9-cvclopentvlpurine

Préparation of 4-Amino-1 -(3-benzvloxvpropyl~)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(3-benzvloxvpropvl')piperidine 25 4-Carboxamide-l-(3-benzyloxypropyl)piperidine may be prepared from isonipecotamide and 1-chloro-3-benzyloxypropane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-fS-benzvloxypropvbpiperidine 4-Amino-l-(3-benzyloxypropyl)piperidine is prepared from 4-carboxamide-l-(3-benzyloxypropyl)piperidine essentially as described above in Example 38, Scheme B, step b. 30 Method 2:

Scheme C, step a: l-f3-Benzvloxvpropvl)-4-piperidone l-(3-Benzyloxypropyl)-4-piperidone is prepared from 4-piperidone and l-chloro-3- benzyloxypropane essentially as described above in Example 38, Scheme C, step a. 78 011455

Scheme C, step b: l-(3-Benzvloxvpropyl)-4-piperidone oximel-(3-Benzyloxypropyl)-4-piperidone oxime is prepared from l-(3-benzyloxypropyl)-4-piperidone and hydroxylamine hydrochloride essentjally as described above in Example 38,Scheme C, step b. 5 Scheme C, step c: 4-Amino-l-(3-benzvloxypropvBpiperidine 4-Amino-l-(3-benzyloxypropyl)piperidine is prepared from l-(3-benzyloxypropyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-('l-f3-benzvloxv)propvlipiperidinvlamino'|-9- cvclopentvlpurine 10 2-Chloro-6-[4-( l-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-benzyloxypropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-iTrans-(4-aminocvclohexvbaminol-6-i4-f l-f3- benzvloxv)propvIipiperidinvlaminol-9-cvclopentvlpurine 15 2-(Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-benzyloxy)propyl)piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-benzyloxy)propyl)piperidiriylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 68 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-( 1-(3-(2- 20 phenvlethvleneoxv,)propvhpiperidinvlamino'l-9-cvclopentvlpurine

Préparation of 4-Amino-l-(3-(2-phenvlethvleneoxv)propvPpiperidineMethod 1

Scheme B, step a: 4-Carboxamide-l-(3-(2-phenvlethvleneoxv)propyl)piperidine 4-Carboxamide-l-(3-(2-phenylethyleneoxy)propyl)piperidine may be prepared from 25 isonipecotamide and l-chloro-3-(2-phenylethyleneoxy)propane essentially as described abovein Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(3-(2-phenvIethvleneoxy,)propvl)piperidine4-Amino-l-(3-(2-phenylethyleneoxy)propyl)piperidine is prepared from 4-carboxamide-1-(3-(2-phenylethyleneoxy)propyl)piperidine essentially as described above in Example 38, Scheme B, 30 step b.

Method 2:

Scheme C, step a: l-(3-(2-Phenvlethvleneoxy)-4-piperidone l-(3-(2-Phenylethyleneoxy)-4-piperidone is prepared from 4-piperidone and l-chloro-3-(2- 79 0114 55 phenylethyleneoxy)propane essentiaily as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(3-(2-Phenviethvleneoxv)-4-piperidone oxime 1- (3-(2-Phenylethyleneoxy)-4-piperidone oxime is prepared from l-(3-(2-phenylethyleneoxy)-4-piperidone and hydroxylamine hydrochloride essentiaily as described above in Example 38, 5 Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-(2-phenvlethvleneoxv)propyI)piperidine 4-Amino-l-(3-(2-phenylethyleneoxy)propyl)piperidine is prepared from 1-(3-(2-phenylethyleneoxy)-4-piperidone oxime essentiaily as described above in Example 38, SchemeC, step c. 10 Scheme A. step b: 2-Chloro-6-i4-f l-f3-f2-phenvlethvleneoxv~)propyBpiperidinvlamino'l-9- cyclopentylpurine 2- Chloro-6-[4-( 1 -(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine, and triethylamine essentiaily as described above in 15 Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)amino1-6-i4-( 1-(3-(2- phenyIethyleneoxy>propvl)piperidinvlaminol-9-cyclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(2- phenylethyIeneoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6- 20 [4-( 1 -(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine essentiaily as described in Example 1, Scheme A, step c.

Example 69 2-fTrans-(4-aminocvclohexvnamino1-6-r4-( 1-(3-(3-phenvlpropvleneoxv)propyI')piperidinvlamino1-9-cvclopentvlpurine 25 Préparation of 4-Amino-l-(3-(3-phenvlpropyieneoxv)propvl')piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(3-(3-phenvlpropvleneoxv)propyl,>piperidine 4-Carboxamide-l-(3-(3-phenylpropyleneoxy)propyl)piperidine may be prepared fromisonipecotamide and l-chloro-3-(3-phenylpropyleneoxy)propane essentiaily as described above 30 in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(3-(3-phenvlpropvleneoxv)propyl)piperidine4-Amino-l-(3-(3-phenylpropyleneoxy)propyl)piperidine is prepared from 4-carboxamide-l-(3-(3-phenylpropyleneoxy)propyl)piperidine essentiaily as described above in Example 38, 80 011455

Scheme B, step b.Method 2:

Scheme C. step a: l-(3-(3-Phenvlpropvleneoxv)propvl')-4-piperidonel-(3-(3-Phenyipropyleneoxy)propyl)-4-piperidone is prepared from 4-piperidone and 1-chloro- 5 3-(3-phenylpropyleneoxy)propane essentially as described above in Example 38, Scheme C,step a.

Scheme C, step b: l-(3-(3-Phenvlpropvleneoxv)propvl)-4-piperidone oxime 1- (3-(3-Phenyipropyleneoxy)propyl)-4-piperidone oxime is prepared from 1-(3-(3-phenylpropyleneoxy)propyl)-4-piperidone and hydroxylamine hydrochloride essentially as 10 described above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f3-f3-phenvlnropvleneoxv>)proüvl')pit>eridine 4-Amino-l-(3-(3-phenylpropyleneoxy)propyl)piperidine is prepared from 1-(3-(3-phenylpropyleneoxy)propyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c. 15 Scheme A. step b: 2-Chloro-6-f4-( 1 -(r3-(3-phenvIpropvleneoxv'lpropylk>iperidinvIaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine, and triethylamine essentially as described above in 20 Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl)aminol-6-(4-fl-(3-(3- phenylpropvleneoxv)propvl)piperidinvlaminol-9-cvclopentvlpurine 2-(T rans-(4-aminocyclohexyl)amino]-6- (4-( 1 -(3-(3- phenylpropyleneoxy)propyl)piperidinylamino]-9-cycloperitylpurine is prepared from 2-chloro-25 6-(4-( 1 -(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 70 2-rrrans-(4-atninocvclohexvl)amino]-6-i4-( 1 -(3-(4-phenvlbutvleneoxv)propvl)piperidinvlaminol-9-cvclopentvlpurine 30 Préparation of 4-Amino-1-(3-(4-phenvlbutvleneoxy')propyl,)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(3-(4-phenvlbutvleneoxv,)propvl')piperidine 4-Carboxamide-l-(3-(4-phenylbutyleneoxy)propyl)piperidine may be prepared from 81 011455 isonipecotamide and l-chloro-3-(4-phenylbutyleneoxy)propane essentially as described abovein Example 38. Scheme B, step a.

Scheme B, step b: 4-Amino-l-(3-(4-phenvlbutvleneoxv')propyl)piperidine4-Amino-l-(3-(4-phenylbutyleneoxy)propyl)piperidine is prepared from 4-carboxamide-l-(3- 5 (4-phenylbutyleneoxy)propyI)piperidine essentially as described above in Example 38, SchemeB, step b.

Method 2:

Scheme C. step a: l-(3-f4-Phenvlbutvleneoxv)propyl)-4-piperidone l-(3-(4-Phenylbutyleneoxy)propyl)-4-piperidone is prepared from 4-piperidone and l-chloro-3- 10 (4-phenylbutyleneoxy)propane essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-f3-<'4-Phenvlbutvleneoxvs)propyl~)-4-piperidone oxime 1- (3-(4-PhenyIbutyleneoxy)propyl)-4-piperidone oxime is prepared from 1-(3-(4-phenylbutyleneoxy)propyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b. 15 Scheme C, step c: 4-Amino-l-(3-(4-phenvlbutvleneoxv,)propvl)piperidine ? 4-Amino-l-(3-(4-phenylbutyleneoxy)propyl)piperidine is prepared from 1-(3-(4-phenylbutyleneoxy)propyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(3-(4-phenylbutyleneoxv)propvl')piperidinvlaminol-9- 20 cvclopentylpurine 2- Chloro-6-[4-( 1 -(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. 25 Scheme A. step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-i4-(l-(3-(4- phenvlbutvleneoxv)propvl)piperidinvlamino1-9-cyclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1-(3-(4- phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentyIpurine essentially as 30 described in Example 1, Scheme A, step c.

Example 71 2-rTrans-(4-aminocvclohexvl1amino1-6-r4-(l-(4-hvdroxv')butvl’)piperidinvlaminol-9- cvclopentvlpurine 82 011455

Préparation of 4-Amino-l-(4-hvdroxvbutvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(4-hvdroxvbutvl)piperidine 4-Carboxamide-l-(4-hydroxybutyl)piperidine may be prepared from isonipecotamide and 4- 5 chloro-1 -butanol essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f4-hvdroxvbutyl1piperidine4-Amino-l-(4-hydroxybutyl)piperidine is prepared from 4-carboxamide-l-(4-hydroxybutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 10 Scheme C. step a: l-f4-Hvdroxvbutvl)-4-piperidone l-(4-Hydroxybutyl)-4-piperidone is prepared from 4-piperidone and 4-chloro-l-butanolessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f4-Hvdroxvbutvl1-4-piperidone oxime l-(4-Hydroxybutyl)-4-piperidone oxime is prepared from l-(4-hydroxybutyl)-4-piperidone and 15 hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-I-(4-hvdroxvbutvl~)pipendine 4-Amino-l-(4-hydroxybutyl)piperidine is prepared from l-(4-hydroxybutyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-f4-(l-(4-hvdroxv')butyl')piperidinvlaminol-9-cvclopentvlpurine 20 2-Chloro-6-[4-( 1 -(4-hydroxy)butyl)piperidinylamino]-9-cyclopentyipurine is prepared from 2,6- dichloro-9-cyclopentylpurine, 4-amino-l-(4-hydroxybutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. stepc: 2-rTrans-f4-aminocvclohexvl)aminol-6-i4-fl-(4- hvdroxvlbutvQpiperidinvlaminol-S-cvclopentvlpurine 25 2-[Trans-(4-aminocyclohexyl)amino3-6-[4-( 1 -(4-hydroxy)butyl)piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-hydroxy)butyl)piperidinylaniino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, Step c.

Example 72 2-fTrans-(4-aminocvcIohexvI)amino1-6-r4-('l-f4-methoxy)butvl)piperidinvlamino1-9- 30 cvclopentvlpurine

Préparation of 4-Amino-I-f4-methoxvbutvl')piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-('4-methoxvbutyI)piperidine 83 011455 4-Carboxamide-l-(4-methoxybutyl)piperidine may be prepared from isonipecotamide and 1-chloro-4-methoxybutane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-('4-methoxvbutvl)piperidine 4-Amino-l-(4-methoxybutyl)piperidine is prepared from 4-carboxamide-l-(4- 5 methoxybutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-Methoxvbutvl)-4-piperidone l-(4-Methoxybutyl)-4-piperidone is prepared from 4-piperidone and l-chloro-4-methoxybutaneessentially as described above in Example 38, Scheme C, step a. 10 Scheme C, step b: l-(4-MethoxvbutyI)-4-piperidone oxime 1- (4-Methoxybutyl)-4-piperidone oxime is prepared from l-(4-methoxybutyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-f4-methoxvbutvl)piperidine 4-Amino-l-(4-methoxybutyl)piperidine is prepared from l-(4-methoxybutyl)-4-piperidone 15 oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6~r4-(l-f4-methoxv)butvl')piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(4-methoxy)butyl)piperidinylaniino]-9-cyclopentyipurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-methoxybutyl)piperidine, and triethylamineessentially as described above in Exampie 1, Scheme A, step b. 20 Scheme A, step c: 2-rTrans-('4-ammocvclohexvl’)aminol-6-r4-(l-(4- methoxv)butvl')piperidinvlamino'|-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-methoxy)butyl)piperidinylaniino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 25 Example 73 2-rTrans-(4-aminocvcIohexvl,)amino1-6-F4-fl-f4-ethoxv')butvl')piperidinvlamino1-9- cyclopentylpurine

Préparation of 4-Amino-l-(4-ethoxvbutvDpiperidine

Method 1 30 Scheme B, step a: 4-Carboxamide-l-f4-ethoxvbutvl’)piperidine 4-Carboxamide-l-(4-ethoxybutyI)piperidine may be prepared from isonipecotamide and 1- chloro-4-ethoxybutane essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f4-ethoxvbutvl)piperidine 84 011455 4-Amino-l-(4-ethoxybutyl)piperidine is prepared from 4-carboxamide-l-<4-ethoxybutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-EthoxvbutvlV-4-piperidone 5 l-(4-Ethoxybutyl)-4-piperidone is prepared from 4-piperidone and l-chloro-4-ethoxybutaneessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(4-Ethoxvbutvl)-4-piperidone oxime 1- (4-Ethoxybutyl)-4-piperidone oxime is prepared from l-(4-ethoxybutyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b. 10 Scheme C, step c: 4-Amino-l-(4-ethoxvbutvl)piperidine 4-Amino-l-(4-ethoxybutyl)piperidine is prepared from l-(4-ethoxybutyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-r4-('l-(4-ethoxv)butvl')piperidinvlamino1-9-cvclopentvlnurine 2- Chloro-6-[4-(l-(4-ethoxy)butyl)piperidinyiamino]-9-cyclopentylpurine is prepared from 2,6- 15 dichloro-9-cyclopentylpurine, 4-amino-l-(4-ethoxybutyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvDaminol-6-r4-f 1-Γ4- ethoxv')butvl,)pit>eridinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-ethoxy)butyl)piperidinylamino]-9- 20 cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example l, Scheme A, step c.

Example 74 2-|Trans-f4-anunocvclohexvBaminol-6-r4-fl-(4-propoxv)butvl)piperidinvlaminol-9- cvclopentvlpurine 25 Préparation of 4-Amino-l-(4-propoxvbutvl)piperidineMethod 1

Scheme B. step a: 4-Carboxamide-l-(4-propoxvbutvPpiperidine 4-Carboxamide-l-(4-propoxybutyl)piperidine may be prepared from isonipecotamide and 1-chloro-4-propoxybutane essentially as described above in Example 38, Scheme B, step a. 30 Scheme B, step b: 4-Amino-l-(4-propoxvbutvQpiperidine 4-Amino-l-(4-propoxybutyl)piperidine is prepared from 4-carboxamide-l-(4- propoxybutyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2: 85 011455

Scheme C, step a: l-(4-Propoxvbutvl)-4-piperidone 1- (4-Propoxybutyl)-4-piperidone is prepared from 4-piperidone and l-chloro-4-propoxybutaneessentiaily as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(4-Propoxvbutvl)-4-piperidone oxime 5 l-(4-Propoxybutyl)-4-piperidone oxime is prepared from l-(4-propoxybutyl)-4-piperidone andhydroxylamine hydrochloride essentiaily as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-f4-propoxvbutvPpiperidine 4-Amino-l-(4-propoxybutyl)piperidine is prepared from l-(4-propoxybutyl)-4-piperidoneoxime essentiaily as described above in Example 38, Scheme C, step c. 10 Scheme A. step b: 2-Chloro-6-i4-(l-f4-propoxv)butvl,)piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-propoxybutyl)piperidine, and triethylamineessentiaily as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocyclohexyl')amino1-6-f4-fl-f4- 15 propoxvIbutvlIpiperidinvlaminol-O-cvclopentvlpurine 2-[Trans-(4-anainocyclohexyl)amino]-6-[4-(l-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine essentiaily as described in Example 1, Scheme A, step c.

Example 75 20 2-rTrans-(4-aminocvclohexyl)amino1-6-f4-(l-(4-butoxv)butvl)piperidinvlamino1-9- cvclopentylpurine

Préparation of 4-Amino-l-f4-butoxvbutvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-butoxvbutvDpiperidine 25 4-Carboxamide-1 -(4-butoxybutyl)piperidine may be prepared from isonipecotamide and 1 -chloro-4-butoxybutane essentiaily as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-(4-butoxvbutvl)piperidine 4-Amino-l-(4-butoxybutyl)piperidine is prepared from 4-carboxamide-1-(4-butoxybutyl)piperidine essentiaily as described above in Example 38, Scheme B, step b. 30 Method 2:

Scheme C, step a: l-f4-Butoxvbutvl,>-4-piperidone l-(4-Butoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro^-butoxybutaneessentiaily as described above in Example 38, Scheme C, step a. 86 U I 1^00

Scheme C, step b: l-(4-Butoxvbutvl)-4-piperidone oxime 1- (4-Butoxybutyl)-4-piperidone oxime is prepared from. l-(4-butoxybutyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-Î4-butoxvbutyDpiperidine 5 4-Amino-1 -(4-butoxybutyl)piperidine is prepared from l-(4-butoxybutyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

Scheme A, step b:2-Chloro-6-i4-f l-f4-butoxv)butvl)piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-butoxybutyl)piperidine, and triethylamine 10 essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvl~)aminol-6-F4-f l-(4- butoxv')butyl)pir>eridinvlamino1-9-cvclopentvlpurine2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-biitoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-butoxy)butyl)piperidinylamino]-9- 15 cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 76 2-ITrans-(4-aminocvclohexvl)aminol-6-f4-(l-(4-benzvloxv)butvlhîiperidinvlamino1-9- cyclopentvlpurine

Préparation of 4-Amino-l-M-benzvloxvbutvDpiperidine 20 Method 1

Scheme B, step a: 4-Cafboxamide-l-i4-benzvloxvbutvl)piperidine4-Carboxamide-l-(4-benzyloxybutyl)piperidine may be prepared from isonipecotamide and 1-chloro-4-benzyloxybutane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-(4-benzvloxvbutvl)piperidine 25 4-Amino- l-(4-benzyloxybutyl)piperidine is prepared from 4-carboxamide-l-(4- benzyloxybutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: 1 -f4-Benzvloxybutyl)-4-piperidonel-(4-Benzyloxybutyl)-4-piperidone is prepared from 4-piperidone and l-chloro4- 30 benzyloxybutane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-i4-Benzvloxvbutvb-4-piperidone oxime l-(4-Benzyloxybutyl)-4-piperidone oxime is prepared from l-(4-benzyloxybutyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, 011455 87 step b.

Scheme C, step c: 4-Amino-l-(4-benzvloxvbutyl)piperidine 4-Amino-l-(4-benzyloxybutyI)piperidine is prepared from l-(4-benzyloxybutyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. 5 Scheme A, step b: 2-ChIoro-6-f4-(l-(4-benzvloxv)butvI')piperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-(l-(4-benzyloxy)butyl)piperidinylamino3-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-benzyloxybutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-f4-aminocvclohexvl)aminol-6-i4-f l-f4- 10 benzvloxv)butvl)piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 77 15 2-ITrans-(4-aminocvcIohexvI,)aminol-6-r4-fl-(4-f2-phenvlethvleneoxv)butvl)piperidinvlaminol- 9-cyclopentvlpurine

Préparation of 4-Amino-l-(4-(2-phenvlethyleneoxv)butvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-f2-phenvlethvleneoxv)butvl')piperidine 20 4-Carboxamide-1 -(4-(2-phenylethyleneoxy)butyl)piperidine may be prepared from isonipecotamide and l-chloro-4-(2-phenylethyleneoxy)butane essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(4-(2-phenvlethvleneoxv)butvl)piperidine4-Amino-l-(4-(2-phenylethyleneoxy)butyl)piperidine is prepared from 4-carboxamide-1-(4-(2- 25 phenylethyleneoxy)butyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Method 2:

Scheme C, step a: l-(4-(2-Phenvlethvleneoxv)butvl)-4-piperidone l-(4-(2-Phenylethyleneoxy)butyl)-4-piperidone is prepared from 4-piperidone and l-chloro-4- 30 (2-phenylethyleneoxy)butane essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: 1 -(4-(2-Phenvlethvleneoxv)butvI)-4-piperidone oxime l-(4-(2-Phenylethyleneoxy)butyl)-4-piperidone oxime is prepared from 1-(4-(2-phenylethyleneoxy)butyl)-4-piperidone and hydroxylamine hydrochloride essentially as 88 011455 described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-('4-('2-phenvlethvleneoxv')butvI')piperidine 4-Amino-l-(4-(2-phenylethyleneoxy)butyl)piperidine is prepared from 1-(4-(2-phenylethyleneoxy)butyl)-4-piperidone oxime essentially as described above in Example 38, 5 Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(4-(2-phenvlethvleneoxv)butyl,)piperidinvlaminol-9- cvclopentvlpurine 2-Chloro-6-[4-(l-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(4-(2- 10 phenylethyleneoxy)butyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-FTrans-(4-aminocvclohexvhaminol-6-f4-(l-(4-(2- phenvlethvleneoxv)butvI~)piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-15 9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(4-(2- phenylethyleneoxy)buÎyl)piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 78 2-rTrans-(4-aminocvclohexvBaminol-6-r4-( 1 -(4-(3-20 phenylpropvleneoxv)butvl)pÎperidinvlaminol-9-cvclopentvlpurine

Préparation of 4-Amino-l-f4-f3-phenvlpropvleneoxv)butyl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(4-(3-phenvlpropvleneoxvfoutvDpiperidine 4-Carboxamide-l-(4-(3-phenylpropyleneoxy)butyl)piperidine may be prepared from25 isonipecotamide and l-chloro-(4-(3-phenylpropyleneoxy)butane essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(4-f3-phenylpropvleneoxv)butvl)piperidine4-Amino-l-(4-(3-phenylpropyleneoxy)butyl)piperidine is prepared from 4-carboxamide-l-(4-(3-phenylpropyleneoxy)butyl)piperidine essentially as described above in Example 38, Scheme 30 B, step b.

Method 2:

Scheme C, step a: l-i4-(3-Phenvlpropvleneoxv)butvb-4-piperidone l-(4-(3-Phenylpropyleneoxy)butyl)-4-piperidone is prepared from 4-piperidone and l-chloro-(4- 89 01 1 4 55 (3-phenylpropyleneoxy)butane essentially as described above in Example 38, Scheme Ç, step a.Scheme C. step b: l-f4-(3-PhenvIpropvleneoxv)butvl)-4-piperidone oxime 1- (4-(3-Phenylpropyleneoxy)butyl)-4-piperidone oxime is prepared from 1-(4-(3-phenylpropyleneoxy)butyl)-4-piperidone and hydroxylamine hydrochloride essentially as 5 described above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-(4-(3-phenvlpropvleneoxv)butyl)piperidine 4-Amino-l-(4-(3-phenylpropyleneoxy)butyl)piperidine is prepared from 1-(4-(3-phenylpropyleneoxy)butyl)-4-pipéridone oxime essentially as described above in Example 38,Scheme C, step c. 10 Scheme A, step b: 2-Chloro-6-i4-(l-(4-(3-phenvlpropvleneoxv)butvl')piperidinvlamino1-9- cvclopentylpurine 2- Chloro-6-[4-(l-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineisprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(4-(3-phenylpropylenèoxy)butyl)piperidine, and triethylamine essentially as described above in 15 Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl’)aminol-6-f4-(l-(4-(3- phenylpropvleneoxy')butvl)piperidinvIamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(4-(3- phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6- 20 [4-( 1 -(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 79 2-ÎTrans-(4-aminocvclohexvnamino1-6-f4-( 1-(4-(4-phenvIbutvleneoxv)butvl')piperidinvlamino1-9-cvclopentvipurine 25 Préparation of 4-Amino-l-f4-(4-phenvlbutvleneoxv')butvl’)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-(4-phenvlbutvleneoxv'>butvl')piperidine 4-Carboxamide-l-(4-(4-phenylbutyleneoxy)butyl)piperidine may be prepared fromisonipecotamide and l-chloro-4-(4-phenylbutyleneoxy)butane essentially as described above in 30 Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f4-(4-phenvlbutvleneoxv)butyl')piperidine4-Amino-l-(4-(4-phenylbutyleneoxy)butyl)piperidine is prepared from 4-carboxamide-1-(4-(4-phenylbutyleneoxy)butyl)piperidine essentially as described above in Example 38, Scheme B, 90 011455 step b.Method 2:

Scheme C, step a: l-f4-f4-Phenvlbutvleneoxv)butvl)-4-piperidone l-(4-(4-Phenylbutyleneoxy)butyl)-4-piperidone is prepared from 4-piperidone and l-chloro-4- 5 (4-phenylbutyleneoxy)butane essentially as described above in Exemple 38, Scheme C, step a.Scheme C. step b: l-(4-(4-Phenvlbutvleneoxy,)butvl)-4-piperidone oxime 1- (4-(4-Phenylbutyieneoxy)butyl)-4-piperidone oxime is prepared from 1-(4-(4-phenylbutyleneoxy)butyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b. 10 Scheme C, step c: 4-Amino-l-(4-(4-phenvlbutvleneoxv)butvl,)piperidine 4-Ammo-l-(4-(4-phenylbutyleneoxy)butyl)piperidine is prepared from 1-(4-(4-phenylbutyleneoxy)butyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-ChIoro-6-r4-(l-f4-(4-phenvlbutvleneoxv)butvI)piperidinvlanuno1-9- 15 cvclopentvlpurine 2- Chloro-6-(4-( 1 -(4-(4-phenylbutyleneoxy)butyl)piperidinylaniino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. 20 Scheme A. step c: 2-rTrans-(4-aminocvclohexvnamino1-6-f4-(l-(4-(4- phenvlbutvleneoxv)butvl)piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(4-(4- phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine essentially as 25 described in Example 1, Scheme A, step c.

Example 80 2-ÎTrans-(4-aminocvclohexvl)aminol-6-i4-(l-(5-hvdroxvpentyIÏ)piperidinvIaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-(5-hvdroxypentvl)piperidine 30 Method 1

Scheme B. step a: 4-Carboxamide-l-(5-hvdroxvpentyl,)piperidine 4-Carboxamide-l-(5-hydroxypentyl)piperidine may be prepared from isonipecotamide and 1-chloro-5-hydroxypentane essentially as described above in Example 38, Scheme B, step a. 91 011455

Scheme B, step b: 4-Amino-l-f5-hvdroxvpentvQpiperidine4-Amino-l-(5-hydroxypentyl)piperidine is prepared from 4-carboxamide-1-(5-hydroxypentyl)piperidine essentialiy as described above in Example 38, Scheme B, step b.Method 2: 5 Scheme C, step a: l-f5-HvdroxvpentvI)-4-piperidone l-(5-Hydroxypentyl)-4-piperidone is prepared from 4-piperidone and l-chloro-5-hydroxypentane essentialiy as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-(5-Hvdroxvpentyl)-4-piperidone oxime 1- (5-Hydroxypentyl)-4-piperidone oxime is prepared from l-(5-hydroxypentyl)-4-piperidone 10 and hydroxylamine hydrochloride essentialiy as. described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f5-hvdroxvpentvbpiperidine 4-Amino-l-(5-hydroxypentyl)piperidine is prepared from l-(5-hydroxypentyl)-4-piperidoneoxime essentialiy as described above in Example 38, Scheme C, step c.

Z 15 Scheme A, step b: 2-Chloro-6-r4-(l-(5-hvdroxvpentvl))piperidmvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-anüno-l-(5-hydroxypentyl)piperidine, and triethylamineessentialiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-iTrans-(4-aminocvclohexvnaminol-6-f4-(l-(5- 20 hvdroxvpentvn)pxperidinvlamino1-9-cvclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurine essentialiy as described in Example 1, Scheme A, step c.

Example 81 25 2-ÎTrans-f4-anunocvclohexvl')aminol-6-r4-(l-(5-methoxvpentvl))piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-i5-methoxvpentvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(5-methoxypentvl’)piperidine 30 4-Carboxamide-1 -(5-methoxypentyl)piperidine may be prepared from isonipecotamide and 1 - chloro-5-methoxypentane essentialiy as described above in Example 38, Scheme B, step a

Scheme B. step b: 4-Amino-{'5-methoxypentvDpiperidine 4-Amino-(5-methoxypentyl)piperidine is prepared from 4-carboxamide-1-(5- 011455 92 methoxypentyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-f5-MethoxvpentvO-4-piperidone l-(5-MethoxypentyI)-4-piperidone is prepared from 4-piperidone and l-chloro-5- 5 methoxypentane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-(5-MethoxvpentvlV4-piperidone oxime 1- (5-MethoxypentyI)-4-piperidone oxime is prepared from l-(5-methoxypentyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C,step b. 10 Scheme C. step c: 4-Amino-('5-methoxvpentvl)piperidine 4-Amino-(5-methoxypentyl)piperidine is prepared from l-(5-methoxypentyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(5-methoxvpentvl'))piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-methoxypentyl))piperidinylamino3-9-cyclopentyIpurine is prepared from 15 2,6-dichloro-9-cyclopentylpurine, 4-amino-(5-methoxypentyl)piperidine, and triethylamine essentially as described above in Exampie 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-(4-aminocvclohexvI')aminol-6-f4-f l-(5- methoxvpentyl))piperidinvlamino1-9-cyclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-methoxypentyl))piperidinyIamino]-9- 20 cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 82 2-rrrans-(4-aminocyclohexvPamino'l-6-f4-(l-(5-ethoxvpentvl)')piperidinvlamino1-9- cyclopentylpurine 25 Préparation of 4-Amino-l-i5-ethoxvpentvl)piperidineMethod 1

Scheme B. step a: 4-Carboxamide-l-f5-ethoxypentvlk>iperidine 4-Carboxamide-l-(5-ethoxypentyl)piperidine may be prepared from isonipecotamide and 1-chloro-5-ethoxypentane essentially as described above in Example 38, Scheme B, step a. 30 Scheme B, step b: 4-Amino-l-f5-ethoxvpentvQpiperidine 4-Amino-l-(5-ethoxypentyl)piperidine is prepared from4-carboxamide-l-(5- ethoxypentyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2: 93 011455

Scheme C, step a: l-f5-EthoxvpentvD-4-piperidone l-(5-Ethoxypentyl)-4-piperidone is prepared from 4-piperidone and l-chloro-5-ethoxypentaneessentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f5-Ethoxypentvl)-4-piperidone oxime 1- (5-Ethoxypentyl)-4-piperidone oxime is prepared from l-(5-ethoxypentyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-(5-ethoxypentvl)piperidine 4-Amino-l-(5-ethoxypentyl)piperidine is prepared from l-(5-ethoxypentyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-[4-(l-(5-ethoxypentvl'))piperidinvlamino1-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-ethoxypentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-f4-aminocvclohexvI)amino1-6-f4-f l-(5- ethoxvpentvI))piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 83 2-rTrans-f4-aminocvclohexvl)amino1-6-f4-fl-(,5-propoxvpentvl’ripiperidinvlaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-f5-propoxvpentvl)piperidine

Method 1

Scheme B, step a: 4-Caiboxamide-l-f5-propoxvpentvl)piperidine 4-Carboxamide-l-(5-propoxypentyl)piperidine may be prepared from isonipecotamide and 1-chloro-5-propoxypentane essentially as described above in Example 38, Scheme B, step a.Scheme B. step b: 4-Amino-l-f5-propoxypentvl)piperidine 4-Amino-l-(5-propoxypentyl)piperidine is prepared from 4-carboxamide-l-(5-propoxypentyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-f5-ProPOXvpentvB-4-piperidone l-(5-Propoxypentyl)-4-piperidone is prepared from 4-piperidone and l-chloro-5-propoxypentane essentially as described above in Example 38, Scheme C, step a. 94 011455

Scheme C, step b: l-f5-Propoxvpentyl)-4-piperidone oxime 1- (5-Propoxypentyl)-4-piperidone oxime is prepared from l-(5-propoxypentyl)-4-piperidoneand hydroxylamine hydrochloride essentialiy as described above in Example 38, Scheme C,step b. 5 Scheme C, step c: 4-Amino-l-(5-propoxvpentvbpiperidine 4-Amino-l-(5-propoxypentyI)piperidine is prepared from l-(5-propoxypentyl)-4-piperidoneoxime essentialiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-F4-fl-('5-propoxypentvl),)piperidinylaniinol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-propoxypentyI))piperidinylamino]-9-cyclopentylpurine is prepared from 10 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-propoxypentyl)piperidine, and triethylamine essentialiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl)aminol-6-r4-f l-(5- propoxvpentvl))piperidinvlaininol-9-cvclopentvipurine 2-[Trans-(4-anünocyclohexyl)ainino]-6-[4-( 1 -(5-propoxypentyl))piperidinylamino]-9- 15 cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurine essentialiy as described in Example 1, Scheme A, step c.

Example 84 2-iTrans-f4-aminocvclohexvbamino'l-6-i4-(l-(5-butoxvpentvrÛpiperidinvlamino'l-9- cyclopentylpurine 20 Préparation of 4-Amino-l-(5-butoxypentv0piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f5-butoxvpentvl)piperidine 4-Carboxamide-l-(5-butoxypentyI)piperidine may be prepared from isonipecotamide and 1-chloro-5-butoxypentane essentialiy as described above in Example 38, Scheme B, step a. 25 Scheme B, step b: 4-Amino-l-f5-butoxypentvl)piperidine 4-Amino-l-(5-butoxypentyl)piperidine is prepared from 4-carboxamide-l-(5-butoxypentyl)piperidine essentialiy as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(5-Butoxvpentvl)-4-piperidone 30 l-(5-Butoxypentyl)-4-piperidone is prepared from 4-piperidone and l-chloro-5-butoxypentaneessentialiy as described above in Example 38, Scheme C, step a. 95 011455

Scheme C, step b: l-f5-ButoxvpentvD-4-piperidone oxime 1- (5-Butoxypentyl)-4-piperidone oxime is prepared from l-(5-butoxypentyl)-4-piperidone andhydroxylamine hydrochloride essentialiy as described above in Example 38, Scheme C, step b.Scheme C, step c: 4-Amino-l-(5-butoxvpentvl)piperidine 5 4-Amino-l-(5-butoxypentyl)piperidine is prepared from l-(5-butoxypentyl)-4-piperidone oximeessentialiy as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(,l-f5-butoxvpentvl,))piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-butoxypentyl)piperidine, and triethylamine 10 essentialiy as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-f4-aminocvclohexvI)amino1-6-f4-fl-f5- butoxvpenrvl')')piperidinvlamino'l-9-cvclopentvlpurine 2-[Trans-(4-aininocyclohexyl)amino]-6-[4-(l-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-butoxypentyl))piperidinylamino]-9- 15 cyclopentylpurine essentialiy as described in Example 1, Scheme A, step c.

Example 85 2-rTrans-f4-aminocvclohexvl)aminol-6-r4-(l-f5-benzvloxypentvl')')piperidinvlamino1-9- cyclopentylpurine

Préparation of 4-Amino-l-(5-benzvloxypentvDpiperidine 20 Method 1

Scheme B, step a: 4-Carboxamide-l-(5-benzvloxypentvl)piperidine 4-Carboxamide-l-(5-benzyloxypentyl)piperidine may be prepared from isonipecotamide and 1-chloro-5-benzyloxypentane essentialiy as described above in Example 38, Scheme B, step a.Scheme B. step b: 4-Amino-l-f5-benzvloxvpentvl)piperidine 25 4-Amino-1 -(5-benzyloxypentyl)piperidine is prepared from 4-carboxamide-1 -(5- benzyloxypentyl)piperidine essentialiy as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-(5-BenzvloxvpentvO-4-piperidone l-(5-Benzyloxypentyl)-4-piperidone is prepared from 4-piperidone and l-chioro-5- 30 benzyloxypentane essentialiy as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-f5-Benzvloxvpentv0-4-piperidone oxime l-(5-Benzyloxypentyl)-4-piperidone oxime is prepared from l-(5-benzyloxypentyl)-4- piperidone and hydroxylamine hydrochloride essentialiy as described above in Example 38, 96 011455

Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-benzvloxvpentyl)piperidine 4-Amino-l-(5-benzyioxypentyl)piperidine is prepared from l-(5-benzyloxypentyI)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c. 5 Scheme A, step b: 2-Chloro-6-f4-(l-(5-benzvloxypentvl,)')piperidinvlamino1-9- cvclopentvlpurine 2-Chloro-6-[4-(l-(5-benzyloxypentyl))piperidinylamino3-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-benzyloxypentyl)piperidine, and triethyiamineessentially as described above in Example 1, Scheme A, step b. 10 Scheme A. step c: 2-rTrans-(4-aminocvclohexvbamino1-6-F4-(l-(5- benzvloxvpentvlOpiperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(5-benzyioxypentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-benzyioxypentyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 15 Example 86 2-rrrans-(4-aminocyclohexvllaminol-6-f4-( 1 -( 5-f 2- phenvlethvleneoxv)pentvl,>,)piperidinvlaminol-9-cvclopentvlpurinePréparation of 4-Amino-l-<5-(2-phenvlethvleneoxvk>entvl')piperidine

Method 1 20 Scheme B, step a: 4-Carboxamide-l-(5-(2-phenvlethvleneoxv)pentyl)piperidine4-Caiboxamide-l-(5-(2-phenylethyleneoxy)pentyl)piperidine may be prepared fromisonipecotamide and l-chloro-5-(2-phenylethyleneoxy)pentane essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(5-(2-phenvlethvleneoxv)pentvl)piperidine 25 4-Amino-1 -(5-(2-phenylethyleneoxy)pentyl)piperidine is prepared from 4-carboxaraide-1 -(5-(2- phenylethyleneoxy)pentyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Method 2:

Scheme C. step a: l-(5-(2-Phenvlethvleneoxv')pentyO-4-piperidone 30 I -(5-(2-Phenylethyleneoxy)pentyl)-4-piperidone is prepared from 4-piperidone and 1 -chloro-5-(2-phcnylethyleneoxy)pentane essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-(5-(2-Phenvlethvieneoxv)pentvlV-4-piperidone oxime l-(5-(2-Phenylethyleneoxy)pentyl)-4-piperidone oxime is prepared from 1-(5-(2- 01145b 97 phenylethyleneoxy)pentyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-f2-phenvlethvleneoxv,)pentvl)piperidine 4-Amino-l-(5-(2-phenylethyleneoxy)pentyl)piperidine is prepared from 1-(5-(2- 5 phenylethyleneoxy)pentyI)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-(l-(5-(2-phenvlethvleneoxv)pentvlOpiperidinvlamino1-9- cvclopentvlpurine 2-Chloro-6-[4-( 1 -(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine is 10 prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(5-(2- phenylethyleneoxy)pentyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl')aminol-6-f4-(l-(5-(2- , phenvlethvleneoxv)pentvl))piperidinvlamino'l-9-cvclopentvlpurine 15 2-[Trans-(4-aininocyclohexyl)amino]-6-[4-( 1-(5-(2- .phenylethyleneoxy)pentyI))piperidinyIamino]-9-cyciopentylpurine is prepared from 2-chloro-6-i [4-( 1 -(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 87 20 2-rTrans-(4-aminocyclohexvl)aminol-6-f 4-( 1 -( 5-(3- phenvlpropyleneoxv')pentvl)')piperidinvlaminol-9-cvclopentvlpurine

Préparation of 4-Amino-l-(5-(3-phenvlpropyleneoxv)pentvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(5-(3-phenvIpropvleneoxv')pentvl)piperidine 25 4-Carboxamide-1 -(5-(3-phenylpropyleneoxy)pentyl)piperidine may be prepared from isonipecotamide and l-chloro-5-(3-phenylpropyleneoxy)pentane essentially as described abovein Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f5-f3-phenvlpropyleneoxv')pentvl')piperidine4-Amino-l-(5-(3-phenylpropyleneoxy)pentyl)piperidine is prepared from 4-carboxamide-1-(5- 30 (3-phenylpropyleneoxy)pentyl)piperidine essentially as described above in Example 38, SchemeB, step b.

Method 2:

Scheme C, step a: l-(5-(3-Phenylpropvleneoxv)pentvl1-4-piperidone 98 011455 1- (5-(3-Phenylpropyleneoxy)pentyl)-4-piperidone is prepared from 4-piperidone and 1-chlpro- 5- (3-phenylpropyleneoxy)pentane essentially as described above in Example 38, Scheme C,step a.

Scheme C, step b: l-f5-(3-Phenvlpropvleneoxv)pentvl)-4-piperidone oxime5 1 -(5-(3-Phenylpropyleneoxy)pentyl)-4-piperidone oxime is prepared from 1 -(5-(3- phenylpropy!eneoxy)pentyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-(3-phenvlpropvleneoxv)pentvl)piperidine 4-Amino-l-(5-(3-phenylpropyleneoxy)pentyl)piperidine is prepared from 1-(5-(3-10 phenylpropyleneoxy)pentyl)-4-piperidone oxime essentially as described above in Example 38,

Scheme C, step c.

Scheme A, step b: 2-Chloro-6-F4-f l-(5-(3-phenvlpropyleneoxv')pentvl')')pit>eridinvlamino1-9- cyclopentvlpurine 2- Chloro-6-[4-( 1 -(5-(3-phenylpropyleneoxy)pentyI))piperidinyiamino]-9-cyclopentylpurine is 15 prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-l-(5-(3- phenylpropyleneoxy)pentyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-(4-aniinocvclohexvnaminol-6-f4-f 1-(5-(3- phenvlpropvleneoxv')pentvlOpiperidinvlamino'l-9-cyclopentylpurine 20 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1-(5-(3- phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro- 6- [4-( l-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 88 25 2-rTrans-(4-aminocvclohexvnaminol-6-f4-( 1-(5-(4- phenvlbutvleneoxvlpentvl))piperidinvlaminol-9-cvclopentvlpurine

Préparation of 4-Amino-l-(5-('4-phenvlbutvleneoxv')pentvik)iÎ>eridine

Method 1

Scheme B, step a: 4-Carboxamide-l-(5-(4-phenvlbutvleneoxv')pentvl')piperidine30 4-Carboxamide-1 -(5-(4-phenylbutyleneoxy)pentyl)piperidine may be prepared from isonipecotamide and l-chloro-5-(4-phenylbutyleneoxy)pentane essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(5-(4-phenvlbutvleneoxv)pentvl)piperidine 99 011455 4-Amino-l-(5-(4-phenylbutyleneoxy)pentyl)piperidine is prepared from 4-carboxamide-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Method 2: 5 Scheme C. step a: l-(5-(4-Phenvlbutvleneoxv)pentyl)-4-piperidone l-(5-(4-Phenylbutyleneoxy)pentyl)-4-piperidone is prepared from 4-piperidone and l-chloro-5-(4-phenylbutyleneoxy)pentane essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(5-f4-Phenvlbutvleneoxv>)pentvl'>-4-piperidone oxime 1- (5-(4~Phenylbutyleneoxy)pentylH-piperidone oxime is prepared from 1-(5-(4- 10 phenylbutyleneoxy)pentyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-(4-phenvlbutvleneoxv')pentvl)piperidine 4-Amino-1 -(5-(4-phenylbutyleneoxy)pentyl)piperidine is prepared from 1 -(5-(4-phenylbutyleneoxy)pentyl)-4-piperidone oxime essentially as described above in Example 38, 15 Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(5-(4-phenvlbutyleneoxv')pentvlOpiperidinvlaminol-9- cyclopentylpurine 2- Chloro-6-[4-( 1 -(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(5-(4- 20 phenylbutyleneoxy)pentyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-r4-(l-(5-(4- phenvlbutvleneoxy,)pentvl))piperidinylaininol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-(4- 25 phenyibutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(5-(4-phenylbutyIeneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 89 2-[Trans-(4-aminocvclohexyl)amino1-6-f4-(l-(6-hvdroxv')hexvbpiperidinvlaminol-9- 30 cvclopentylpurine

Préparation of 4-Amino-l-f6-hvdroxvhexvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f6-hvdroxvhexvPpiperidine îoo 0114 55 4-Carboxamide-l-(6-hydroxyhexyl)piperidine may be prepared from isonipecotamide and 6-chloro-l-hexanol essentially as described above in Example 38, Scheme B, step a.

Scheme B, stepb: 4-Amino-l-(6-hvdroxvhexvl)piperidine 4-Amino-l-(6-hydroxyhexyl)piperidine is prepared from 4-carboxamide-l-(6- 5 hydroxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: 1-(6-Hvdroxvhexvl)-4-piperidone l-(6-Hydroxyhexyl)-4-piperidonè is prepared from 4-piperidone and 6-chloro-l-hexanolessentially as described above in Example 38, Scheme C, step a. 10 Scheme C. step b: l-(6-Hvdroxvhexvl)-4-piperidone oxime 1- (6-Hydroxyhexyl)-4-piperidone oxime is prepared from l-(6-hydroxyhexyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.Scheme C. step c: 4-Amino-l-(6-hvdroxvhexvl)piperidine 4-Amino-l-(6-hydroxyhexyl)piperidine is prepared from l-(6-hydroxyhexyl>-4-piperidone 15 oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. stepb: 2-Chloro-6-[4-(l-f6-hvdroxv’)hexvl,)piperidinylaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(6-hydroxy)hexyl)piperidinylamino]-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(6-hydroxyhexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. 20 Scheme A, step c: 2-ITrans-(4-aminocvclohexvDamino1-6-f4-(l-(6- hvdroxvihexvl')piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-( 1 -(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 25 Example 90 2-rTrans-f4-aminocvclohexvI~)aminol-6-f4-fl-(6-methoxv')hexvl)piperidinvlaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-(6-methoxvhexvl)piperidine

Method 1 30 Scheme B, step a: 4-Carboxamide-l-(,6-methoxvhexvl)piperidine 4-Carboxamide-l-(6-methoxyhexyl)piperidine may be prepared from isonipecotamide and 1- chloro-6-methoxyhexane essentially as described above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(6-methoxvhexvl)piperidine 101 011455 4-Amino-l-(6-methoxyhexyl)piperidine is prepared from 4-carboxamide-l-(6-methoxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-f6-Methoxyhexvl)-4-piperidone l-(6-Methoxyhexyi)-4-piperidone is prepared from 4-piperidone and l-chloro-6-methoxyhexane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-(6-Methoxyhexvl)-4-piperidone oxime 1- (6-Methoxyhexyl)-4-piperidone oxime is prepared from l-(6-methoxyhexyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C,step b.

Scheme C, step c: 4-Amino-l-f6-methoxvhexvl~)piperidine 4-Amino-l-(6-methoxyhexyl)piperidine is prepared from l-(6-methoxyhexyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c. ..Scheme A, step b: 2-Chloro-6-r4-(l-f6-methoxv')hexvl)piperidinvlamino1-9-cvclopentylpurine 2- Chloro-6-[4-(l-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(6-methoxyhexyl)piperidine, and triethylamine ^ essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-f4-aminocvclohexvl,)aminol-6-i4-(l-f6- methoxv)hexvl)piperidinvlaminol-9-cvclopentylpurme 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 91 2-rTrans-f4-aminocvclohexyl')aminol-6-i4-f 1 -f 6-ethoxv)hexvl)piperidinylaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-(6-ethoxvhexyl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(6-ethoxvhexvl)piperidine 4-Carboxamide-l-(6-ethoxyhexyl)piperidine may be prepared from isonipecotamide and I-chloro-6-ethoxyhexane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-i6-ethoxvhexvl~)piperidine 4-Amino-l-(6-ethoxyhexyl)piperidine is prepared from4-carboxamide-l-(6-ethoxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b. 102 011455

Method 2:

Scheme C, step a: l-('6-Ethoxv'nexvO-4-piperidone l-(6-Ethoxyhexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-ethoxyhexaneessentially as described above in Example 38, Scheme C, step a. 5 Scheme C. step b: l-f6-EthoxvhexvB-4-piperidone oxime 1- (6-Ethoxyhexyl)-4-piperidone oxime is prepared from l-(6-ethoxyhexyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b?Scheme C, step c: 4-Amino-l-f6-ethoxvhcxvl)pipcridine 4-Amino-l-(6-ethoxyhexyl)piperidine is prepared from l-(6-ethoxyhexyl)-4-piperidone oxime 10 essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(6-ethoxv)hexvl')piperidinvlamino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentyipurine is prepared from 2,6-dichioro-9-cyclopentylpurine, 4-amino-l-(6-ethoxyhexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. 15 Scheme A. step c: 2-rTrans-(4-aminocvclohexvDaminol-6-r4-(l-i6- ethoxv)hexvl)piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 20 Example 92 2-rTrans-(4-aminocvclohexvl)aminol-6-f4-fl-(6-propoxv)hexvl1)piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-l-f6-propoxvhexvl)piperidine

Method 1 25 Scheme B, step a: 4-Caiboxamide-l-(6-propoxvhexvl)pipéridine 4-Carboxamide-l-(6-propoxyhexyl)piperidine may be prepared from isonipecotamide and 1-chloro-6-propoxyhexane essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-(6-propoxvhexvl)piperidine 4-Amino-l-(6-propoxyhexyl)piperidine is prepared from 4-carboxamide-l-(6- 30 propoxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: I-(6-Propoxvhexvr)-4-piperidone l-(6-Propoxyhexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-propoxyhexane 103 011455 essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: 1-f 6-Propoxvhex vB-4-piperidone oxime 1- (6-Propoxyhexyl)-4-piperidone oxime is prepared from l-(6-propoxyhexyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b. 5 Scheme C. step c: 4-Amino-l-('6-propoxvhexvl')piperidine 4-Amino-l-(6-propoxyhexyl)piperidine is prepared from l-(6-propoxyhexyI)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-f6-propoxv)hexvl')piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 10 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(6-propoxyhexyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvDamino]-6-r4-( 1 -f 6- propoxv)hexvDpiperidinvlamino1-9-cvclopentvlpurine,, 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(6-propoxy)hexyl)piperidinylamino]-9- 15 cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. „ Example 93 2-rrrans-f4-aminocvclohexvnaminol-6-[4-(l-f6-butoxv)hexvl)piperidinvlamino1-9- cvclopentvlpurine 20 Préparation of 4-Amino-l-i6-butoxvhexvl)piperidineMethod 1

Scheme B, step a: 4-Carboxamide-l-i6-butoxvhexvPpiperidine 4-Carboxamide-l-(6-butoxyhexyI)piperidine may be prepared from isonipecotamide and 1-chloro-6-butoxyhexane essentially as described above in Example 38, Scheme B, step a. 25 Scheme B. step b: 4-Amino-l-(6-butoxvhexvl')piperidine 4-Amino-l-(6-butoxyhexyl)piperidine is prepared from 4-carboxamide-l-(6-butoxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-f6-Butoxvhexvl)-4-piperidone 30 l-(6-Butoxyhexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-butoxyhexaneessentially as described above in Example 38, Scheme C, step a,

Scheme C, step b: 1 -(6-ButoxyhexvD~4-piperidone oxime l-(6-Butoxyhexyl)-4-piperidone oxime is prepared from l-(6-butoxyhexyl)-4-piperidone and 104 01 1 455 hydroxylamine hydrochloride essentially as described above in Example 38, Scheme Ç, step b.Scheme C. step c: A-Amino-l-fô-butoxvhexvnpiperidine 4-Amino-l-(6-butoxyhexyl)piperidine is prepared from l-(6-butoxyhexyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c. 5 Scheme A, step b: 2-Chloro-6-r4-(l-('6-butoxv)hexvl)piperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-(l-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(6-butoxyhexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-f4-aminocvclohexvI)amino1-6-f4-(l-f6- 10 butoxv~)hexvl')piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-butoxy)hexyl)piperidinylainmo]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 94 15 2-fTrans-f 4-aminocvclohexvi>)amino1-6-i4-( 1 -f 6-benzvloxv)hexvBpiperidinylamino'l-9- cvclopentvlpurine

Préparation of 4-Amino-l-(6-benzvIoxvhexvI)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(6-Benzvloxvhexylk»iperidine 20 4-Carboxamide-1 -(6-Benzyloxyhexyl)piperidine may be prepared from isonipecotamide and 1 -chloro-6-benzyIoxyhexane essentially as described above in Example 38, Scheme B, step a.Scheme B. step b: 4-Amino-l-(6-benzvloxvhexvl)pipcridine 4-Amino-l-(6-benzyloxyhexyl)piperidine is prepared from 4-caiboxamide-1-(6-benzyloxyhexyl)piperidine essentially as described above in Example 38, Scheme B, step b. 25 Method 2:

Scheme C. step a: l-(6-Benzvloxvhexvl)-4-piperidone l-(6-Benzyloxyhexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-benzyloxyhexane essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-(6-Benzyloxvhexvl)-4-piperidone oxime 30 l-(6-Benzyloxyhexyl)-4-piperidone oxime is prepared from l-(6-benzyloxyhexyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C,step b.

Scheme C, step c: 4-Amino-l-(6-benzvloxvhexyl)piperidine 011455 105 4-Amino-l-(6-benzyloxyhexyl)piperidine is prepared from l-(6-benzyloxyhexyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, stepb: 2-Chloro-6-f4-f l-fô-benzvloxvlhexvDpiperidinvlaminol-Ç-cvcIopentvlpurine 5 2-Chloro-6-[4-(l-(6-benzyioxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentyipurine, 4-amino-l-(6-benzyioxyhexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexyl)amino'|-6-i4-(l-(6- benzvloxv')hexvPpiperidinvlaminol-9-cyclopentvlpurine 10 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-benzyloxy)hexyl)piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 95 2-ÎT rans-(4-aminocvclohexvl,)aminol-6-f4-( 1 -( 6-(2- 15 S phenvlethvleneoxv)hexvPpiperidinvIaminol-9-cvcIopentylpurine

Préparation of 4-Amino-l-(6-(2-phenvlethvleneoxv’)hexvDpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(6-(2-phenvlethvleneoxv)hexvl)piperidine 4-Carboxamide-l-(6-(2-phenylethyleneoxy)hexyl)piperidine may be prepared from 20 isonipecotamide and l-chloro-6-(2-phenylethyleneoxy)hexane essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(6-(2-phenvlethvleneoxy')hexvl)piperidine4-Amino-l-(6-(2-phenylethyleneoxy)hexyl)piperidine is prepared from 4-carboxamide-1-(6-(2-phenylethyleneoxy)hexyl)piperidine essentially as described above in Example 38, Scheme B, 25 step b.

Method 2:

Scheme C, step a: l-(6-(2-Phenvlethvleneoxv)hexvl)-4-piperidone l-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-(2-phenylethyleneoxy)hexane essentially as described above in Example 38, Scheme C, step a. 30 Scheme C. step b: l-(6-f2-Phenvlethvleneoxv1hexvl1-4-piperidone oxime l-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidone oxime is prepared from 1-(6-(2-phenylethyleneoxy)hexyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b. 106 011455

Scheme C, step c: 4-Amino-l-('6-f2-phenviethvleneoxv')hexvBpiperidine 4-Amino-l-(6-(2-phenylethyleneoxy)hexyl)piperidine is prepared from 1 -(6-(2-phenylethyleneoxy)hexyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c. 5 Scheme A, step b: 2-Chloro-6-i4-( l-(6-(2-phenvlethvleneoxv'ihexvl>piperidinvlanrtinol-9- cvclopentvlpurine 2-Chloro-6-[4-( 1 -(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentyipurine, 4-amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine, and triethylamine essentially as described above in 10 Example 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-(4-anünocvclohexvl)aminol-6-F4-( 1-(6-(2- phenvlethvleneoxv)hexvlipiperidinviaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-(2- phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6- 15 [4-( 1 -(6-(2-phenylethyleneoxy)hexyl)piperidinylainino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 96 2-ΓΓ rans-( 4-aminocvclohexvbamino1-6-f 4-( 1-(6-(3-phenvlpropvleneoxv)hexvl')piperidinvlamino1-9-cvclopentvtourine 20 Préparation of 4-Amino-l-(6-(3-phenvlpropvleneoxv)hexvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(6-(3-phenylpropvleneoxv)hexvl')piperidine 4-Carboxamide-l-(6-(3-phenylpropyleneoxy)hexyl)piperidine may be prepared fromisonipecotamide and l-chloro-6-(3-phenylpropyleneoxy)hexane essentially as described above 25 in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(6-(3-phenvlpropvleneoxv)hexvl)piperidine4-Amino-l-(6-(3-phenylpropyIeneoxy)hexyI)piperidine is prepared from 4-carboxamide-l-(6-(3-phenylpropyleneoxy)hexyl)piperidine essentially as described above in Example 38, SchemeB, step b. 30 Method 2:

Scheme C. step a: l-(6-(3-Phenvlpropvleneoxvlhexvl-4-piperidone l-(6-(3-Phenylpropyleneoxy)hexyl-4-piperidone is prepared from 4-piperidone and l-chloro-6-(3-phenyipropyleneoxy)hexane essentially as described above in Example 38, Scheme C, step a 011455 107

Scheme C, step b: l-(’6-(3-Phenvlpropvleneoxy,)hexvi-4-piperidone oxime 1- (6-(3-Phenylpropyleneoxy)hexyl-4-piperidone oxime is prepared from 1-(6-(3-phenylpropyleneoxy)hexyl-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f6-(3-phenvlpropyleneoxv')hexvl)piperidine 4-Amino-l-(6-(3-phenylpropyleneoxy)hexyl)piperidine is prepared from 1-(6-(3- phenylpropyleneoxy)hexyl-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-Î4-(l-(6-(3-phenvlpropvIeneoxy)hexvl)piperidinvlamino'l-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(6-(3-phenylpropyleneoxy)hexyl)piperidine, and triethylamine essentially as described above in 'Example 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-(4-aminocvclohexvl,)amino1-6-r4-( 1-(6-(3- , phenvlpropvleneoxvlhexvl)piperidinvlamino1-9-cyclopentylpurine 2-[T rans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(6-(3- phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(6-(3-phenylpropyleneoxy)hexyl)piperidinyIaminol-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 97 2-rTrans-(4-aminocvclohexvI)aminol-6-[4-( 1-(6-(4-phenvibutvleneoxv')hexvl~)piperidinvlamino'l-9-cvciopentvtpurine

Préparation of 4-Amino-l-(6-(4-phenvlbutvleneoxv')hexvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f6-(4-phenvlbutvleneoxy,)hexvl)piperidine 4-Carboxamide-l-(6-(4-phenylbutyleneoxy)hexyl)piperidine may be prepared fromisonipecotamide and l-chloro-6-(4-phenylbutyleneoxy)hexane essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(6-(4-phenvlbutvleneoxv')hexvl’)piperidine4-Amino-l-(6-(4-phenylbutyleneoxy)hexyl)piperidine is prepared from 4-carboxamide-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine essentially as described above in Example 38, Scheme B,step b. 108 011455

Method 2:

Scheme C. step a: l-f6-(4-Phenvlbutvleneoxv)hexvO-4-piperidone l-(6-(4-Phenylbutyleneoxy)hexyl)-4-piperidone is prepared from 4-piperidone and l-chloro-6-(4-phenylbutyleneoxy)hexane essentially as described above in Example 38, Scheme C, step a. 5 Scheme C, step b: l-f6-(4-Phenvlbutvleneoxv)hexvl)-4-piperidone oxïme 1- (6-(4-Phenylbutyleneoxy)hexyl)-4-piperidone oxime is prepared from 1-(6-(4-phenylbutyleneoxy)hexyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f6-('4-phenvlbutvleneoxv)hexvI')piperidine 10 4-Amino-1 -(6-(4-phenylbutyleneoxy)hexyl)piperidine is prepared from 1 -(6-(4- phenylbutyleneoxy)hexyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A. step b: 2-Chloro-6-f4-f l-(6-(4-phenvlbutvleneoxv)hexvl)piperidinvlamino1-9- cvclopentvlpurine 15 2-Chloro-6-[4-( 1 -(6-(4-phenylbutyleneoxy)hexyl)piperidinylammo]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-r4-(l-(6-(4- 20 phenvIbutvleneoxv’)hexvl)piperidinvlamino'l-9-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-(4- phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c. 25

Example 98 2-fTrans-(4-aminocvclohexvI')anùnol-6-f4-(l-(allvl)piperidinvlamino1-9-cvciopentvlpurine

Préparation of 4-Amino-l-(aIlvIk>iperidine

Method 1 30 Scheme B, step a: 4-Carboxamide-l-(allvDpiperidine 4-Carboxamide-l-(allyl)piperidine may be prepared from isonipecotamide and allyl chloride essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(allvl')piperidine 109 011455 4-Amino-l-(aIlyl)piperidine is prepared from 4-carboxamide-l-(allyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: 1 -(allvl)-4-piperidone 5 l-(allyl)-4-piperidone is prepared from 4-piperidone and allyl chloride essentially as describedabove in Example 38, Scheme C, step a.

Scheme C, step b: l-(allvl)-4-piperidone oxime 1- (allyl)-4-piperidone oxime is prepared from l-(allyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C, step b. 10 Scheme C, step c: 4-Amino-l-(allvDpiperidine 4-Amino-l-(allyl)piperidine is prepared from l-(allyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

Scheme A. step b: 2-Οι1ογο-6-Γ4-(1-fallyl)piperidinviamino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(allyl)piperidinylammo]-9-cyclopentylpurine is prepared from 2,6-dichloro-9- 15 cyçlopentylpurine, 4-amino- l-(allyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl)aminol-6-f4-fl-faIlvDpiperidinvlaminol-9- cvclopentvlpurine 2-[Trans-(4-aininocyclohexyi)amino]-6-[4-( 1 -(allyl)piperidinylamino]-9-cyclopentylpurine is 20 prepared from 2-chloro-6-[4-( l-(allyl)piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 99 2-ÎTrans-( 4-aminocvclohexvl)amino1-6-F4-f 1 -f 2-f2-hvdroxvethvleneoxv~)ethvlOpiperidinvlamino1-9-cvclopentvlpurine 25 Préparation of 4-Amino-l-('2-(2-hvdroxvethvleneoxy’)ethvl')piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f2-f2-hvdroxvethvleneoxv')ethvDpiperidine 4-Carboxamide-l-(2-(2-hydroxyethyleneoxy)ethyl)piperidine may be prepared fromisonipecotamide and 2-(2-chloroethoxy)ethanol essentially as described above in Example 38, 30 Scheme B, step a.

Scheme B. step b: 4-Amino-l-('2-(2-hvdroxvethvleneoxv)ethvDpiperidine4-Amino-l-(2-(2-hydroxyethyleneoxy)ethyl)piperidine is prepared from 4-carboxamide-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine essentially as described above in Example 38, Scheme B, 110 011455 step b.

Method 2:

Scheme C, step a: l-(2-f2-Hvdroxvethvleneoxv)ethvn-4-piperidonel-(2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidone is prepared from 4-piperidone and 2-(2- 5 chloroethoxy)ethanol essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(2-f2-Hvdroxvethvleneoxy)ethvl')-4-piperidone oxime 1- (2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidone oxime is prepared from 1-(2-(2-hydroxyethyleneoxy)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b. 10 Scheme C, step c: 4-Amino-l-f2-f2-hvdroxvethvleneoxv)ethvI)piperidine 4-Amino-l-(2-(2-hydroxyethyleneoxy)ethyl)piperidine is prepared from 1-(2-(2-hydroxyethyieneoxy)ethyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-f2-(2-hvdroxvethvleneoxv)ethviy)piperidinvlamino'l-9- 15 cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-(2-hydroxyethyleneoxy)ethyI))piperidmylamino)-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(2-(2-hydroxyethyleneoxy)ethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. 20 Scheme A. step c: 2-FTrans-(4-aminocvclohexvnaminol-6-r4-( 1-(2-(2- hvdroxvethvleneoxv)ethvB)piperidinvIamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)aimno]-6-(4-( 1 -(2-(2- hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine essentially as 25 described in Example 1, Scheme A, step c.

Example 100 2-rTrans-(4-aminocvclohexvl)amino]-6-i4-(l-(2-N,N-dimethylaminoethvIÏ)piperidinvlaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(2-N.N-dimethylaminoethvl')piperidine 30 Method 1

Scheme B, step a: 4-Carboxamide-l-(2-N.N-dimethvlaminoethvl)piperidine 4-Carboxamide-l-(2-N,N-dimethylaminoethyl)piperidine may be prepared from isonipecotamide and 2-N,N-dimethylaminoethyl chloride essentially as described above in 111 011455

Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(2-N.N-dimethylaminoethyl')piperidine4-Amino-l-(2-N,N-dimethylaminoethyl)piperidine is prepared from 4-carboxamide-l-(2-N,N-dimethylaminoethyl)piperidine essentially as described above in Example 38, Scheme B, step b. 5 Method 2:

Scheme C. step a: l-(2-N,N-dimethvIaminoethvD-4-piperidone 1- (2-N,N-dimethylaminoethyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-dimethylaminoethyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-f2-N.N-dimethvlaminoethvl')-4-piperidone oxime 10 l-(2-N,N-dimethylaminoethyl)-4-piperidone oxime is prepared from l-(2-N,N- dimethylaminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f2-N,N-dimethvlaminoethvhpiperidine4-Amino-l-(2-N,N-dimethylaminoethyl)piperidine is prepared from l-{2-N,N- 15 dimethylaminoethyl)-4-piperidone oxime essentially as described above in Example 38,

Scheme C, step c.

Scheme A. step b: 2-Chloro-6-r4-fl-f2-N,N-dimethvlaminoethvB)piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurine is 20 prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-N,N- dimethylaminoethyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexvBaminol-6-i4-(l-(2-N.N- dimethvlaminoethvl))piperidinvlaminol-9-cvclopentvlpurine 25 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dimethylaminoethyl))piperidinyiamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 101 30 2-[Trans-(4-aminocvclohexvl)aminol-6-f4-fl-f3-N,N-dimethvlaminopropvl))piperidinvlaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(3-N.N-dimethvlaminopropvl)piperidine

Method 1 112 011455

Scheme B, step a: 4-Carboxamide-l-(3-N.N-dimethvlaminopropvI')piperidine 4-Carboxamide-l-(3-N,N-dimethylaminopropyl)piperidine may be prepared fromisonipecotamide and 3-N,N-dimethylaminopropyl chloride essentially as described above inExample 38, Scheme B, step a. 5 Scheme B. step b: 4-Amino-I-f3-N.N-dimethvlaminopropvlk>iperidine 4-Amino-l-(3-N,N-dimethylaminopropyl)piperidine is prepared from 4-carhoxamirie-1 -(3-N N-dimethylaminopropyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2: 10 Scheme C, step a: l-(3-N.N-dimethylaminopropyl)-4-piperidone l-(3-N,N-dimethylaminopropyl)-4-piperidone is prepared from 4-piperidone and 3-N,N-dimethylaminopropyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-f3-N,N-dimethylaminopropvll-4-piperidone oxime 1- (3-N,N-dimethylaminopropyl)-4-piperidone oxime is prepared from l-(3-NJ4- 15 dimethylaminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-N.N-dimethvlaminopropvDpiperidine4-Amino-l-(3-N,N-dimethylaminopropyl)piperidine is prepared from l-(3-N,N-dimethylaminopropyl)-4-piperidone oxime essentially as described above in Example 38, 20 Scheme C, step c.

Scheme A. step b: 2-Chloro-6-f4-(l-f3-N.N-dimethvlaminopropvb')piperidinvlamino'l-9- cvclopentvlpurine 2- Chloro-6-[4-< 1 -(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-N,N- 25 dimethylaminopropyl)piperidine, and triethylamine essentially as described above in Example1, Scheme A, step b.

Scheme A. step c: 2-rTrans-f4-aminocyclohexvI)aminol-6-f4-(l-(3-N,N- dimethvlaminopropyl')’)piperidinvlamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dimethylaminopropyl))piperidinylamino] 30 9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-N,N- dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 102 113 - 011455 2-fTrans-f4-aminocvclohexvl)aminol-6-f4-fl-(4-N.N-dimethvlaminobutvn')piperidinvlamino1- 9-cvclopentvlpurine

Préparation of 4-Amino- l-^-N.N-dimethvlaminobutvDpiperidine

Method 1 5 Scheme B, step a: 4-Carboxamide-l-(4-N,N-dimethvlaminobutvl)piperidine4-Carboxamide-l-(4-N ,N-dimethylaminobutyl)piperidine may be prepared fromisonipecotamide and 3-N,N-dimethylaminobutyI chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-(4-N.N-dimethvlaminobutvDpiperidine 10 4-Amino*l-(4-N,N-dimethylaminobutyl)piperidine is prepared from 4-carboxamide-l-(4-N,N-dimethylaminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-N,N-dimethvlaminobutvl)-4-piperidonea l-(4-NJ\-dimethylaminobutyl)-4-piperidone is prepared from 4-piperidone and 3-N,N- 15 -î dimethylaminobutyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(4-N,N-dimethvlaminobutvl)-4-piperidone oxime ς l-(4-N,N-dimethylaminobutyI)-4-piperidone oxime is prepared from l-(4-N,N- dimethylaminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b. 20 Scheme C. step c: 4-Amino-l-f4-N.N-dimethvlaminobutvl)piperidine 4-Amino-l-(4-N,N-dimethylaminobutyl)piperidine is prepared from l-(4-N,N-dimethylaminobutyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-('l-(4-N,N-dimethvIaminobutvO')piperidinvlamino'l-9- 25 cvclopentvlpurine 2-Chloro-6-[4-( 1 -(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-N,N- dimethylaminobutyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b. 30 Scheme A, step c: 2-ÎTrans-(4-aminocvclohexvBamino1-6-i4-(,l-(4-N,N- dimethvlaminobutvI))piperidinvlamino1-9-cvclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dimethylaminobutyl))piperidinylanüno]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-N,N- 011455 114 dimethylanünobutyl))piperidinylamino]-9-cycIopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 103 2-rTrans-(4-aminocvclohexvnaininol-6-i4-fl-('5-N.N-dimethvlaminopentvI')')piperidinvIarnino'l- 5 9-cvclopentvlpurine

Préparation of 4-Amino-l-f5-N.N-dimethvlaminopentvl')piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(5-N,N-dimethvlaminopentvl)piperidine 4-Carboxamide-l-(5-N,N-dimethylaminopentyl)piperidine may be prepared from 10 isonipecotamide and 5-N,N-dimethylaminopentyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f5-N.N-dimethvIaminopentvl~)piperidine4-AminO“l-(5-NJ4-dimethylaminopentyl)piperidine is prepared from 4-carboxamide-l-(5-N,N-dimethylaminopentyl)piperidine essentially as described above in Example 38, Scheme B, step 15 b.

Method 2:

Scheme C. step a: l-f5-N.N-dimethvlaminopentvlM-piperidonel-(5-N,N-dimethylaminopentyI)-4-piperidone is prepared from 4-piperidone and 5-N,N-dimethylaminopentyl chloride essentially as described above in Example 38, Scheme C, step a. 20 Scheme C, step b: l-(5-N.N-dimethvlaminopentvl)-4-piperidone oxime l-(5-N,N-dimethylaminopentyl)-4-piperidone oxime is prepared from l-(5-N,N-dimethylaminopentyl)-4-piperidone and hydroxylamine hydrochlori.de essentially as describedabove in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f5-N,N-dimethvlaminopentvl)piperidine 25 4-Amino-l-(5-N,N-dimethylaminopentyl)piperidine is prepared from l-(5-N,N- dimethylaminopentyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A. step b: 2-Chloro-6-i4-(l-(,5-N,N-dimethvlaminopentvl))piperidinvlaminol-9- cvclopentvlpurine 30 2-Chloro-6-[4-(l-(5-NJQ-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N- dimethylaminopentyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A. step b. 115 011455

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)amino'l-6-f4-f l-(5-N,N- dimethvlaminopentvlï)piperidinvtamino'l-9-cvctopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyciopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 104 2-ÎTrans-(4-aminocvclohexvnaminol-6-i4-f l-f2-N.N-diethylaminoethvl))piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino-l-(2-N,N-diethvlaminoethvbpiperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(2-N.N-diethvlaminoethvl)piperidine 4-Carboxamide-l-(2-N,N-diethylaminoethyl)piperidine may be prepared from isonipecotamideand 2-N,N-diethylaminoethyl chloride essentially as described above in Example 38, Scheme B,step a.

Scheme B, step b: 4-Amino-l-('2-N.N-diethvlaminoethvl)piperidine 4-Amino-l-(2-NJ4-diethylaminoethyl)piperidine is prepared from 4-carboxamide- l-(2-N,N-diethylaminoethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(2-N.N-diethvlaminoethvl)-4-piperidonel-(2-N,N-diethylaminoethyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-diethylaminoethyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(2-N,N-diethviaminoethvl)-4-piperidone oxime 1- (2-N,N-diethylaminoethyl)-4-piperidone oxime is prepared from l-(2-NJST-diethylaminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-N,N-diethvlaminoethvl)piperidine4-Amino-l-(2-N,N-diethylaminoethyl)piperidine is prepared from l-(2-N,N-diethylaminoethyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-('2-N.N-diethvlaminoethvl'>')piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared υιisb 116 from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-NJi-diethylaminoethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-ITrans-f4-aminocvclohexvl)aminol-6-[4-(l-f2-N,N- diethvlaminoethyiy)piperidinvlaminol-9-cvclopentvlpurine 5 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine is prcpared from 2-chloro-6-[4-(l-(2-N,N- diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 105 10 2-rTrans-(4-aminocvclohexyl)amino1-6-i4-(l-(3»N.N-diethvlaminopropvD)piperidinvlammol-9- cvclopentvlpurine

Préparation of 4-Amino-l-(3-N.N-diethvlaminopropvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f3-N.N-diethvlaminopropvbpiperidine 15 4-Carboxamide-1 -(3-N,N-diethylaminopropyl)piperidine may be prepared from isonipecotamide and 3-N,N-diethylaminopropyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f3-N.N-diethylaminopropvl)piperidine4-Amino-b(3-N,N-diethylaminopropyl)piperidine is prepared from 4-carboxamide-l-(3-N,N- 20 diethylaminopropyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(3-N,N-diethvlaminopropyl)-4-piperidonel-(3*N,N-diethylaminopropyl)-4-piperidone is prcpared from 4-piperidone and 3-N,N-diethylaminopropyl chloride essentially as described above in Example 38, Scheme C, step a. 25 Scheme C, step b: l-(3-N,N-diethylaminopropyl)-4-piperidone oxime l-(3*N,N-diethylaminopropyl)-4-piperidone oxime is prepared from l-(3-NJ4-diethylaminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-N.N-diethvlaminopropvl)piperidine 30 4-Amino-l-(3-N,N-diethylaminopropyl)piperidine is prepared from l-(3-N,N- diethylaminopropyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A, step b: 2-^1θΓθ-6-[4-(1-(3-Ν.Ν-άΐ£ών^ηίηορΓθρν1')')ρΐρ€πάΐηνΐΗτηΐηον9- 117 011455 cvclopentvlpurine 2-Chloro-6-[4-( 1 -(3-N,N-diethylaminopropyi))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentyipurine, 4-amino-1 -(3-N,N-diethylaminopropyl)piperidine, and triethylamine essentially as described above in Example 1, 5 Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6'i4-fl-f3-N.N- diethvlaminopropvIOpiperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentyipurine is prepared from 2-chioro-6-[4-(l-(3-NJ4- 10 diethylaminopropyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 106 2-ITrans-f4-aniinocvclohexvl')aminol-6-f4-(l-(4-N.N-diethvlaminobutvI)')piperidinvlamînol-9- cvclopentvlpurine 15 Préparation of 4-Amino-l-(4-N,N-diethvlaminobutvllpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-N.N-diethylammobutvl,)piperidine4-Carboxamide-l-(4-N,N-diethylaminobutyl)piperidine may be prepared from isonipecotamide. and 4-N,N-diethylaminobutyl chloride essentially as described above in Example 38, Scheme B, 20 step a.

Scheme B. step b: 4-Amino-l-f4-N.N-diethvlaminobutvDpiperidine4-Amino-l-(4-N,N-diethylaminobutyl)piperidine is prepared from 4-carboxamide-l-(4-N,N-diethylaminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 25 Scheme C. step a: l-(4-N,N-diethvlaminobutvl')-4-piperidone l-(4-N,N-diethylaminobutyl)-4-piperidone is prepared from 4-piperidone and 4-N,N-diethylaminobutyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: 1 -f4-N.N-diethvlaminobutvl)-4-piperidone oxime l-(4-N,N-diethylaminobutyl)-4-piperidone oxime is prepared from l-(4-N,N- 30 diethylaminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f4-N,N-diethylaminobutvl')piperidine4-Amino-l-(4-N,N-diethylaminobutyl)piperidine is prepared from l-(4-NJ4- 118 01 1 455 diethylaminobutyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A, step b: 2-Chloro-6-i4-f l-(4-N.N-diethvlaminobutvl))piperidinvlamino1-9- cvclopentvlpurine 5 2-Chloro-6-{4-( 1 -(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-N24-diethylanainobutyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvciohexyl)amino1-6-F4-(l-(4-N.N- diethvlaminobtitvl))piperidinvlaminol-9-cvclopentvlpurine 10 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-NJ^-diethyIaminobutyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-NJsT- diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Exampie1, Scheme A, step c.

Example 107 15 2-rTrans-(4-aminocyclohexvl)amino1-6-f4-<l-(5-N.N-diethvlaminopentvnpiperidinvIaminol-9- cyclopentylpurine

Préparation of 4-Amino-l-f5-N.N-diethvlaminopentvlk>iperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-fS-N.N-diethvlaminopentvllpiperidine 20 4-Carboxamide-1 -(5-N»N-diethylaminopentyl)piperidine may be prepared from isonipecotamide and 5-N,N-diethylaminopentyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f5-N.N-diethvlaminopentvl)piperidine4-Amino-l-(5-N,N-diethylaminopentyl)piperidine is prepared from 4-cafboxamide-l-(5-NJQ- 25 diethylaminopentyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(5-N.N-diethvlaminopentvl)-4-piperidonel-(5-N,N-diethylaminopentyl)-4-piperidone is prepared from 4-piperidone and 5-N,N-diethylaminopentyl chloride essentially as described above in Example 38, Scheme C, step a. 30 Scheme C, step b: l-(5-N.N-diethvlaminopentvl)-4-piperidone oxime l-(5-N,N-diethylaminopentyl)-4-piperidone oxime is prepared from 1~(5-N,N-diethylaminopentyiy-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b. 119 011455

Scheme C. step c: 4-Amino-l-f5-N.N-diethvlaminopentyl)piperidine4-Amino-l-(5-N,N-diethylaminopentyl)piperidine is prepared from l-(5-N,N-diethylaminopentyI)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c. 5 Scheme A, step b: 2-Chloro-6-[4-(l-(5-N,N-diethvlaminopentvl)piperidinylamino1-9- cvclopentvlpurine 2-Chloro-6-[4-(l-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyciopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N- diethylaminopentyl)piperidine, and triethylamine essentially as described above in Example 1, 10 Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-r4-(l-f5-N,N- diethvlaminopentvl)piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-(l-(5-N,N-diethylaminopentyI)pipeiidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-N,N- 15 diethylaminopentyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 108 2-rrrans-(4-aminocvclôhexvl)amino1-6-i4-fl-f2-N.N-dipropvlaminoethvl’)')piperidinvlamino1-9- cyclopentylpurine 20 Préparation of 4-Amino-l-(2-N.N-dipropylaminoethvI)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-N,N-dipropylaminoethvl')piperidine 4-Carboxamide-l-(2-N,N-dipropylaminoethyl)piperidine may be prepared fromisonipecotamide and 2-N,N-dipropylaminoethyl chloride essentially as described above in 25 Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-N,N-dipropylaminoethvDpiperidine 4-Amino-l-(2-N,N-dipropylaminoethyl)piperidine is prepared from 4-carboxamide-l-(2-N,N-dipropylaminoethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 30 Scheme C, step a: l-(2-N,N-dipropylaminoethvl)-4-piperidone l-(2-N,N-dipropylaminoethyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-dipropylaminoethyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: 1 -(2-N.N-dipropvlaminoethvl)-4-piperidone oxime 120 011455 1- (2-N,N-dipropylaminoethyl)-4-piperidone oxime is prepared from l-(2-N,N-dipropylaminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-i2-N.N-dipropvlaminoethvl')piperidine 5 4-Amino-l-(2-N,N-dipropylaminoethyl)piperidine is prepared from l-(2-N,N- dipropylaminoethyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-f2-N.N-dipropylaminoethvl,)~)piperidinvlamino1-9- cvclopentvlpurine 10 2-Chloro-6-[4-( 1 -(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-N,N- dipropylaminoethyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A. step c: 2-ÎTrans-('4-aminocvclohexvl')amino1-6-f4-(l-f2-N.N- 15 dipropvlaminoethvDlpiperidinvlaminol^-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-N,N- dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c. 20 Example 109 2-ΓΤ rans-(4-aminocvclohexvl,)aminol-6-r4-( 1 -('3-N.N-dipropvlaminopropvD')piperidinvIaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(3-N.N-dipropvlaminopropvDpiperidine

Method 1 25 Scheme B. step a: 4-Carboxamide-1-f 3-N.N-dipropvlaminopropvI)piperidine 4-Carboxamide-l-(3-N,N-dipropylaminopropyl)piperidine may be prepared fromisonipecotamide and 3-N,N-dipropylaminopropyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f3-N.N-dipropvlaminopropyl)piperidine 30 4-Amino-1 -(3-N,N-dipropylaminopropyl)piperidine is prepared from 4-carboxamide-1 -(3-N.N- dipropylaminopropyl)piperidine essentially as described above in Example 38, Scheme B, stepb.

Method 2: 121 01.1 455

Scheme C, stepa: l-(3-N.N-dipropvlaminopropyl)-4-piperidone l-(3-N,N-dipropylaminopropyl)-4-piperidone is prepared from 4-piperidone and 3-N.N-dipropylaminopropyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: 1 -i3-N.N-dipropvlaminopropvl)-4-piperidone oxime 1- (3-N,N-dipropylaminopropyl)-4-piperidone oxime is prepared from l-(3-N,N- dipropylaminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-N.N-dipropvlaminopropvBpiperidine 4-Amino-l-(3-N,N-dipropylaminopropyl)piperidine is prepared from l-(3-N,N- dipropylaminopropyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A. step b: 2-Chloro-6-f4-(l-f3-N.N-dipropylaminopropvl),)piperidinvlamino1-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-N,N- dipropylaminopropyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-r4-f l-f3-N.N- dipropvlaminopropvblpiperidinvlaminol^-cvclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 110 2-rrrans-f4-aminocvclohexyl')aminol-6-r4-(,l-(4-N,N-dipropvlaminobutvl))piperidinvlamino1- 9-cyclopentylpurine

Préparation of 4-Amino-l-(4-N.N-dipropylaminobutvl')piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f4-N.N-dipropvlaminobutvl)piperidine 4-Carboxamide- l-(4-N,N-dipropylaminobutyl)piperidine may be prepared from isonipecotamide and 4-N,N-dipropylaminobutyl chloride essentially as described above in

Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f4-N.N-dipropvlaminobutvl’)piperidine 122 011455 4-Amino-l-(4-N,N-dipropylaminobutyl)piperidine is prepared from 4-carboxamide-l-(4-N,N-dipropyiaminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C. step a: l-(4-N.N-dipropylaminobutyl)-4-piperidone 5 1 -(4-N ,N -dipropylaminobutyl)-4-piperidone is prepared from 4-piperidone and 4-N,N- dipropylaminobutyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-(4-N,N-dipropvlaminobutyl)-4-piperidone oxime 1- (4-N,N-dipropylaminobutyl)-4-piperidone oxime is prepared from l-(4-N,N-dipropylaminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described 10 above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-(4-N,N-dipropvlaminobutvl')piperidine4-Amino-l-(4-NJ^-dipropylaminobutyl)piperidine is prepared from l-(4-N,N-dipropylaminobutyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c. 15 Scheme A. step b: 2-Chloro-6-f4-(l-(4-N.N-dipropvlaminobutvb)piperidinvlamino1-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-N,N- dipropylaminobutyl)piperidine, and triethylamine essentially as described above in Example 1, 20 Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexyI)aminol-6-i4-(l-f4-N.N- dipropylaminobutvlOpiperidinvlaminoK9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dipropyiaminobutyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-N,N- 25 dipropyIaminobutyl))piperidinylamino]-9-cyclopentylpuiine essentially as described inExaniple l, Scheme A, step c.

Example 111 2-rTrans-f4-aminocyclohexvl)amino1-6-f4-(l-f5-N.N-dipropylaminopentvl')')piperidinvlaminol- 9-cvclopentvlpurine 30 Préparation of 4-Amino-1 -f5-N.N-dipropylaminnopentvI)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-('5-N.N-dipropvlaminopentvl')piperidine 4-Carboxamide-l-(5-N,N-dipropylaminopentyl)piperidine may be prepared from WO 99/43675 123 011455 isonipecotamide and 5-N,N-dipropyiaminopentyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f5-N,N-dipropvlaminnopentvl)piperidine4-Amino-l-(5-N,N-dipropylaminnopentyl)piperidine is prepared from4-carboxamide-l-(5- 5 N,N-dipropylaminopentyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Method 2:

Scheme C, step a: l-(5-N.N-dipropylaminopentvl)-4-piperidonel-(5-N,N-dipropylaminopentyI)-4-piperidone is prepared from 4-piperidone and 5-N,N- 10 dipropylaminopentyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: i-f5-N.N-dipropvlaminopentvl)-4-piperidone oxime 1- (5-N,N-dipropylaminopentyl)-4-piperidone oxime is prepared from l-(5-N,N-dipropylaminopentyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b. 15 Scheme C. step c: 4-Amino-l-f5-N.N-dipropylaminnopentvl')piperidine 4-Amino-l-(5-N,N-dipropylaminnopentyl)piperidine is prepared from l-(5-N,N-dipropylaminopentyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(5-N.N-dipropvlaminopentvlDpiperidinvlaminol-9- 20 cvclopentvlpurine 2- Chloro-6-[4-( 1 -(5-N,N-dipropylaminopentyI))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichIoro-9-cyclopentylpurine, 4-amino-l-(5-N,N- dipropylaminnopentyl)piperidine, and triethylamine essentially as described above in Example1, Scheme A, step b. 25 Scheme A. step c: 2-rrrans-f4-aminocvclohexvl)amino1-6-14-(l-(5-N,N- dipropylaminopentvl),)piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine essentially as described in 30 Example 1, Scheme A, step c.

Example 112 2-rTrans-(4-aminocvclohexvl')aTnino1-6-i4-(l-(,2-N,N-dibutvlaminoethvl'))piperidinvlaminol-9- cvclopentvlpurine 124 011455

Préparation of 4-Amino-l-f2-N,N-dibucvlaminoethvl)piperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-(,2-N.N-dibutvlaminoethvl)piperidine4-Carboxamide-l-(2-N,N-dibutylaminoethyI)piperidine may be prepared from isonipecotamide 5 and 2-NJ\'-dibutylaminoethyl chloride essentially as described above in Example 38, Scheme B,step a.

Scheme B, step b: 4-Amino-l-f2-N,N-dibutvlaminoethvl,)piperidine4-Amino-l-(2-N,N-dibutylaminœthyl)piperidine is prepared from 4-carboxamide-l-(2-N,N-dibutylaminoethyl)piperidine essentially as described above in Example 38, Scheme B, step b. 10 Method 2:

Scheme C. step a: l-(2-N.N-dibutvlaminoethvl')-4-piperidone 1- (2-N,N-dibutylaminoethyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-dibutylaminoethyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-(2-N.N-dibutvlaminoethvl)-4-piperidone oxime 15 l-(2-N,N-dibutylaminoethyl)-4-piperidone oxime is prepared from l-(2-N,N- dibutylaminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-N.N-dibutvlairunoethvBpiperidine4-Amino-l-(2-N,N-dibutylaminoethyl)piperidine is prepared from l-(2-N,N- 20 dibutylaminoethyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A. step b: 2-Chioro-6-i4-(l-(2-N.N-dibutviaminoethvl')')piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared 25 from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-N,N-dibutylaminoethyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-FTrans-f4-aminocvcIohexvbaminol-6-f4-('l-f2-N.N- dibutvlaminoethvb')piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dibutylaminoethyl))piperidinylamino]-9- 30 cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(2-N,N- dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, stepc. 125 011455

Example 113 2-lTrans-(4-aminocvclohexvI)amino1-6-f4-(l-(3-N,N-dibutvlaminopropvl,))piperidinvlamino1- 9-cvclopentvlpurine

Préparation of 4-Amino-1 -f 3-N.N-dibutvlaminopropvl)piperidine 5 Method 1

Scheme B, step a: 4-Carboxamide-l-(3-N,N-dibutvlaminopropyl)piperidine 4-Carboxamide-l-(3-N,N-dibutylaminopropyl)piperidine may be prcpared fromisonipecotamide and 3-N,N-dibutylaminopropyl chloride essentially as described above inExample 38, Scheme B, step a. 10 Scheme B. step b: 4-Amino-l-f3-N.N-dibutvlaminopropylk>iperidine 4-Amino-l-(3-N,N-dibutylaminopropyl)piperidine is prepared from 4-carboxamide-l-(3-N,N-dibutylaminopropyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(,3-N.N-dibutylaminopropvIV-4-piperidone 15 l-(3-N,N-dibutylaminopropyI)-4-piperidone is prepared from 4-piperidone and 3-N,N- dibutylaminopropyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C. step b: l-(3-N.N-dibutvlaminopropyl)-4-piperidone oxime 1 -(3-N,N-dibutylaminopropyl)-4-pipsridone oxime is prepared from 1 -(3-NJSf-dibutylaminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described 20 above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-N,N-dibutvlaminopropvl)piperidine4-Amino-l-(3-N,N-dibutylaminopropyl)piperidine is prepared from l-(3-N,N-dibutylaminopropyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c. 25 Scheme A. step b: 2-Chloro-6-i4-f l-f3-N,N-dibutvlaminopropyl))piperidinvlamino1-9- cvclopentvlpurine 2-Chloro-6-[4-( 1 -(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyciopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-N,N- dibutylaminopropyl)piperidine, and triethylamine essentially as described above in Example 1, 30 Scheme A, step b.

Scheme A. step c: 2-rTrans-f4-aminocvclohexvl)aminol-6-i4-('l-f3-N,N- dibutvlaminopropvl'Bpiperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dibutylaminopropyl))piperidinylamino]- 126 011455 9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3-N,N- dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurine essentially as described in

Example 1, Scheme A, step c.

Example 114 5 2-rTrans-<'4-aminocvclohexvllaminol-6-i4-fl-(4-N,N-dibutvlaminobutvbpiperidinvlaminol-9- cvclopentvlpurine

Préparation of 4-Amino-l-f4-N.N-dibutvlaminobutvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-N,N-dibutvlaminobutvl)piperidine 10 4-Carboxamide-1 -(4-N,N-dibutylaminobutyl)piperidine may be prepared from isonipecotamide and 4-NJ4-dibutylaminobutyl chloride essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-i4-N.N-dibutvlaminobutvDpiperidine4-Amino-l-(4-N,N-dibutylaminobutyl)piperidine is prepared from 4-carboxamide-1-(4-N ,N- 15 dibutylaminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-N,N-dibutvlaminobutvl)-4-piperidonel-(4-N,N-dibutylaminobutyl)-4-piperidone is prepared from 4-piperidone and 4-N J4-dibutylaminobutyl chloride essentially as described above in Example 38, Scheme C, step a. 20 Scheme C, step b: l-(4-N.N-dibutvlaminobutvh-4-piperidone oxime l-(4-N,N-dibutylaminobutyl)-4-piperidone oxime is prepared from l-(4-N,N-dibutylaminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f4-N.N-dibutvlaminobutvl~)piperidine 25 4-Amino-1 -(4-N ,N-dibutylaminobutyl)piperidine is prepared from 1 -(4-N,N- dibutylaminobutyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-(l-(4-N.N-dibutvlaminobutvl)piperidinvlamino1-9- cvclopentylpurine 30 2-Chloro-6-[4-(l-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-N,N-dibutylaminobutyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexyl')aminol-6-f4-(l-(4-N.N- 127 011455 dibutvlaminobutvl)piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dibutylaminobutyl)piperidinylamino3-9-cyclopentylpurine is prepared from 2-chloro-6-(4-(l-(4-N,N- dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 115 2-[Trans-(4-aminocvclohexvbaminol-6-f4-(l-(5-N,N-dibutvlaminopentvl),)piperidinvlaminol-9- cvclopentvlpurine

Préparation of 4-Amino-1-f5-N.N-dibutvlaminopentvQpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(5-N,N-dibutvlaminopentvl)piperidine 4-Carboxamide-l-(5-N,N-dibutylaminopentyl)piperidine may be prepared from isonipecotamide and 5-N,N-dibutylaminopentyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(5-N,N-dibutvlaminopentvl)piperidine 4-Anùno-l-(5-N,N-dibutyiaminopentyl)piperidine is prepared from 4-carboxamide-l-(5-N,N-dibutylaminopentyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(5-N.N-dibutvlaminopentvl)-4-piperidonel-(5-N,N-dibutylaminopentyl)-4-piperidone is prepared from 4-piperidone and 5-N,N-dibutylaminopentyl chloride essentially as described above in Exampie 38, Scheme C, step a.Scheme C, step b: l-(5-N.N-dibutvlaminopentvlY-4-piperidone oxime 1- (5-N,N-dibutyiaminopentyI)-4-piperidone oxime is prepared from l-(5-N,N-dibutylaminopentyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-N.N-dibutvlaminopentvDpiperidine4-Amino-l-(5-NJ4-dibutylaminopentyl)piperidine is prepared from l-(5-N,N-dibutylaminopentyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A. step b: 2-Chloro-6-[4-(l-f5-N,N-dibutvlaminopentvl))piperidinylamino1-9- cyclopentylpurine 2- Chloro-6-[4-( 1 -(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N- 128 011455 dibutylaminopentyl)piperidine, and triethylamine essentially as described above in Example 1,

Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl~)aminol-6-f4-(l-(5-N.N- dibutvlaminopentvl)~)piperidinvlaminol-9-cvclopentvlpurine5 2-[Trans-(4-aniinocyclohexyl)amino]-6-[4-(l-(5-N,N-dibutyiaminopentyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(5-N,N- dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 116 10 2-rTrans-i 4-aminocvclohexvl'iamino1-6-i4-f 1 -(2-N.N-dibenzvlaminoethvlOpiperidinvlaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(2-N,N-dibenzvlaminoethvDpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-1-(2-N .N-dibenzvlaminoethvl)piperidine15 4-Carboxamide-1 -(2-N,N-dibenzylaminoethyl)piperidine may be prepared from isonipecotamide and 2-N,N-dibenzylaminoethyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-N.N-dibenzvlaminoethvl)piperidine4-Amino-l-(2-N,N-dibenzylaminoethyl)piperidine is prepared from 4-carboxamide-1-(2-N,N-20 dibenzylaminoethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme CL step a: l-(2-N.N-dibenzvlaminoethvl)-4-piperidonel-(2-N,N-dibenzylaminoethyI)-4-piperidone is prepared from 4-piperidone and 2-N,N-dibenzylaminoethyl chloride essentially as described above in Example 38, Scheme C, step a. 25 Scheme C, step b: l-(2-N.N-dibenzvIaminoethvl)-4-piperidone oxime l-(2-N,N-dibenzylaminoethyl)-4-piperidone oxime is prepared from l-(2-N,N-dibenzylaminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Exampie 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f2-N.N-dibenzvlaminoethvl)piperidine30 4-Amino-l-(2-N,N-dibenzylaminoethyl)piperidine is prepared from l-(2-N,N- dibenzylaminoethyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A. step b: 2-Chloro-6-f4-(l-(2-N.N-dibenzvlaminoethvl))piperidinvlaminol-9- 129 cvclopentvlpurine 2-Chloro-6-[4-(l-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-N,N- dibenzylaminoethyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A, step c: 2-rrrans-f4-aminocyclohexvl)amino1-6-i4-fl-f2-N,N- dibenzvlaminoethvl))piperidinvlaminol-9-cvclopentylpurine 2-[7rans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dibenzylaniinoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Ex ample 117 2-rrrans-(4-aminocvclohexvI)ainino'l-6-r4-('l-f3-N,N-dibenzvlaminoproPvD)piperidinvlaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(3-N,N-dibenzvlaminopropvBpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-I-f3-N.N-dibenzvlaminopropvlipiperidine 4-Carboxamide-l-(3-N,N-dibenzyiaminopropyl)piperidine may be prepared fromisonipecotamide and 3-N,N-dibenzylaminopropyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f3-N.N-dibenzvlaminopropvQpiperidine4-Amino-l-(3-NJsi-dibenzylaminopropyl)piperidine is prepared from 4-carboxamide-l-(3-N,N-dibenzylaminopropyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(3-N,N-dibenzvlaminopropyl)-4-piperidonel-(3-N,N-dibenzylaminopropyl)-4-piperidone is prepared from 4-piperidone and 3-N.N-dibenzylaminopropyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-f3-N,N-dibenzvlaminopropvl)-4-piperidone oxime l-(3-N,N-dibenzylaminopropyl)-4-piperidone oxime is prepared from l-(3-N,N- dibenzylaminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-N.N-dibenzvlaminopropvl')piperidine 011455 130 4-Amino-l-(3-N,N-dibenzylaminopropyl)piperidine is prepared from l-(3-N,N-dibeixzylaminopropyI)-4-piperidone oxime essentially as described above in Example 38,

Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(i-(3-NJQ-dibenzvlaminopropvl)>piperidinvlaminol-9- 5 cvclopentylpurine 2-Chloro-6-[4-( 1 -(3-N ,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentyipurine, 4-amino-l-(3-N,N- dibenzylaminopropyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b. 10 Scheme A, step c: 2-rTrans-f4-aminocvclohexvI)aminol-6-i4-fl-(3-NJ|J- diben2vlaminopropvl’))piperidinvlaminol-9-cyciopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-N,N-dibenzylaminopropyl))piperidinylaminoî-9-cyclopentylpurine essentially as described in 15 Example 1, Scheme A, step c.

Example 118 2-rTrans-f4-aminocvclohexvl)amino1-6-f4-<'l-(4-N.N-dibenzvlaminobutviy)piperidinvlamino'l- 9-cvclopentvlpurine

Préparation of 4-Amino-l-(4-N.N-dibenzvlaminobutvDpiperidine 20 Method 1

Scheme B. step a: 4-Carboxamide-l-i4-N.N-dibenzvlaminobutvlk>iperidine 4-Carboxamide-l-(4-N,N-dibenzylaminobutyl)piperidine may be prepared fromisonipecotamide and 4-N,N-dibenzylaminobutyl chloride essentially as described above inExample 38, Scheme B, step a. 25 Scheme B. step b: 4-Amino-l-(4-N,N-dibenzvlaminobutvhpiperidine 4-Amino-l-(4-N,N-dibenzylaminobutyI)piperidine is prepared from 4-carboxamide-l-(4-N,N-dibenzylaminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(4-N.N-dibenzvlaminobutvO-4-piperidone 30 l-(4-N,N-dibenzylanùnobutyl)-4-piperidone is prepared from 4-piperidone and 4-N,N- dibenzylaminobutyl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(4-N,N-dibenzvlaminobutvl)-4-piperidone oxime l-(4-N,N-dibenzylaminobutyl)-4-piperidone oxime is prepared from l-(4-N,N- 131 011 4 5 5 dibenzylaminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-i-f4-N.N-dibenzvlaminobutvl~)piperidine4-Amino-l-(4-N,N-dibenzylaminobutyl)piperidine is prepared from l-(4-N,N- 5 dibenzylaminobutyl)-4-piperidone oxime essentially as described above in Example 38, SchemeC, step c.

Scheme A, step b: 2-Chloro-6-r4-(l-f4-N,N-dibenzvlaminobutvl)')piperidinvlaminol-9- cvclopentylpurine 2-Chloro-6-[4-( 1 -(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine is10 prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(4-N,N- dibenzylaminobutyOpiperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl')aminol-6-r4-(î-(,4-N.N- dibenzvIaminobutvn)piperidinvIaminol-9-cvclopentvlpurine15 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(4-N J4-dibenzylaminobutyl))piperidinylamino]- 9-cyciopentylpurine is prepared from 2-chloro-6-[4-(l-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 119 20 2-rTrans-(4-aminocvclohexvl)amino1-6-i4-fl-(5-N.N-dibenzvlaminopentvl))piperidinvlaminol- 9-cvclopentylpurine

Préparation of 4-Amino-l-(’5-N.N-dibenzvlaminopentvlk>iperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f5-N,N-dibenzvIaminopentvl)piperidine25 4-Carboxamide-1-(5-N,N-dibenzylaminopentyl)piperidine may be prepared from isonipecotamide and 5-N,N-dibenzylaminopentyl chloride essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(5-N.N-dibenzvlaminopentvI)piperidine 4-Amino-1 -(5-N,N-dibenzylaminopentyl)piperidine is prepared from 4-carboxamide-1 -(5-N,N- 30 dibenzylaminopentyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(5-N.N-dibenzvlaminopentvl)-4-piperidone 132 011455 l-(5-N,N-dibenzylaminopentyl)-4-piperidone is prepared from 4-piperidone and 5-N,N- dibenzylaminopentyl chloride essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(5-N.N-dibenzvlaminopentvl)-4-piperidone oxime 1- (5-N,N-dibenzylaminopentyl)-4-piperidone oxime is prepared from l-(5-N,N- 5 dibenzylaminopentyl)-4-piperidone and hydroxylamine hydrochioride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(5-N,N-dibenzvlaminopentvBpiperidine4-Amino-l-(5-N,N-dibenzylaminopentyl)piperidine is prepared from l-(5-NJN-dibenzylaminopentyl)-4-piperidone oxime essentially as described above in Example 38, 10 Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(5-N.N-dibenzvlaminopentvl))piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(5-N ,N-dibenzylaminopentyl))piperidinylamino]-9-cyciopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N- 15 dibenzylaminopentyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A. step c: 2-ITrans-f4-aminocvciohexvDamino1-6-Î4-f 1-Î5-N.N- dibenzylaminopentviDpiperidinvlaminol^-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-dibenzylaminopentyl))piperidinylammo]-20 9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(5-N,N- dibenzylaminopentyl))piperidinylaminol-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 120 2-rTrans-(4-aminocvclohexvl~)amino1-6-i4-(l-f2-N.N-di-(2-25 phenylethvlene)aminoethvl)')piperidinvlamino'l-9-cvclopentvlpurine

Préparation of 4-Amino-l-f2-N.N-di-(2-phenvlethvlene'>aminoethvi)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-f2-N.N-di-f2-phenvlethvlene'>aminoethvl)piperidine 4-Carboxamide-l-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine may be prepared from30 isonipecotamide and 2-N,N-di-(2-phenylethyleneamino)ethyl chloride essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-N,N-di-(2-phenvlethvlene')aminoethv0piperidine 4-Amino-l-(2-N,N-di-(2-phenylethylene)aminoethyI)piperidine is prepared from 4- 133 011455 carboxamide-1 -(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(2-N.N-di-f2-phenvlethvlene'laminoethvl)-4-piperidone5 l-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone is prepared from 4-piperidone and 2- N,N-di-(2-phenylethyleneamino)ethyl chloride essentially as described above in Example 38,Scheme C, step a.

Scheme C, step b: l-('2-N,N-di-(,2-phenvlethvlene')aminoethvl'>-4-Diperidone oxime 1- (2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone oxime is prepared from l-(2-N,N-di-10 (2-phenylethylene)aminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f2-N;N-di-f2-phenvlethvlene)aminoethvDpiperidine4-Amino-l-(2-NJ4-di-(2-phenylethylene)aminoethyl)piperidine is prepared from l-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone oxime essentially as described above in Example 15 38, Scheme C, stepc. £

Scheme A, step b: 2-Chloro-6-[4-(l-(2-N,N-di-f2-phenvlethvlenelaminoethvIOpiperidinvlaminol-Ç-cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-N ,N-di-(2-phenylethyIene)aminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-<2-N,N-di-(2- 20 phenylethylene)aminoethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-n,rans-(4-aminocvclohexvl')amino1-6-f4-(l-(2-N,N-di-(2- phenvlethvlene')aminoethvl')')piperidinvlamino1-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(2-25 phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro- 6-[4'(l-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

Example 121 2-rTrans-f4-aminocvclohexv0amino1-6-f4-fl-(3-N.N-di-(2-30 phenvlethvlene’)aminopropvl))piperidinvlaminol-9-cvclopentvlpurine

Préparation of 4-Amino-l -f3-N,N-di-(2-phenvlethvlene')aminopropvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-('3-N.N-di-(2-phenvlethvlene')aminopropvl’)piperidine • 011455 134 4-Carboxamide-l-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine may bc prepared fromisonipecotamide and 3-N,N-di-(2-phenylethyleneamino)propyl chloride essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-('3-N,N-di-f2-phenvlethvlene,)aminopropvBpiperidine 5 4-Amino-l-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine is prepared from 4- carboxamide-l-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: !-(3-NJ4-di-f2-phenvlethvlene)aminopropvlM-proeridone 10 l-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone is prepared from 4-piperidone and 3-N,N-di-(2-phenylethyleneamino)propyl chloride essentially as described above in Example 38,Scheme C, step a.

Scheme C. step b: l-f3-N.N-di-('2-phenvlethvlene)aminopropvl)-4-piperidone oxime 1- (3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone oxime is prepared from l-(3-N,N-di- 15 (2-phenylethylene)aminopropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-f3-N.N-di-('2-phenvlethvlene')aminopropvlk>iperidine4-Amino-l-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine is prepared from l-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone oxime essentially as described above in Example 20 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-r4-fl-f3-N.N-di-(2-phenvlethvlene')aminopropvl))piperidinvlamino1-9-cvclopentvlpurine 2- Chloro-6-[4-( 1 -(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-N,N-di-(2- 25 phenylethylene)aminopropyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocyclohexvDamino'l-6-i4-(,l-f3-N.N-di-(2- phenvlethvlene)aminopropvl>»piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino3-6-[4-(l-(3-N,N-di-(2- 30 phenylethylene)aminopropyI))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro6-[4-( 1 -(3-N JN-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

Example 122 135 011455 2-ITrans-^-aminocyclohexvBaminol-6-r4-(l-f4-N.N-di-('2- phenvlethvlenelaminobutvl))piperidinvlamino1-9-cyclopentvlpurine

Préparation of 4-Amino-1 -f4-N.N-di-f2-phenvlethvlenelaminobutvl~)piperidine

Method 1 5 SchemeB, step a: 4-Carboxamide-l-(4-N,N-di-(2-phenvlethvlene')aminobutvl)piperidine 4-Carboxamide-l-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine may be prepared fromisonipecotamide and 4-N,N-di-(2-phenylethyleneamino)butyl chloride essentially as describedabove in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-<’4-N,N-di-f2-phenvlethvlene)aminobutyl')piperidine 10 4-Amino-l-(4-N,N-di-(2-phenyIethyiene)aminobutyl)piperidine is prepared fiom 4- carboxamide-l-(4-N^N-di-(2-phenylethylene)aminobutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C. step a: l-f4-N.N-di-f2-phenvlethvlene)aminobutvl')-4-piperidone 15 l-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone is prepared from 4-piperidone and 4-N,N-di-(2-phenylethyleneamino)butyl chloride essentially as described above in Example 38,Scheme C, step a.

Scheme C, step b: l-f4-N,N-di-(’2-phenvlethvlene)aminobutvl,)-4-piperidone oxime 1- (4-N,N-di-(2-phenylethylene)aniinobutyl)-4-piperidone oxime is prepared from l-(4-N,N-di- 20 (2-phenylethylene)aminobutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C. step c: 4-Amino-l-(4-N.N-di-f2-phenvlethvlene)aminobutvl)piperidine4-Amino-l-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine is prepared from l-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone oxime essentially as described above in Example 25 38, Scheme C, step c.

Scheme A. step b: 2-Chloro-6-f4-(l-(4-N.N-di-(2-phenvlethvlene')aminobutvlDpiperidinvlamino'l-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-NJ4-di-(2- 30 phenylethylene)aminobutyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-i4-aminocvclohexyl,)aminol-6-i4-(l-(4-N,N-di-(2- phenvlethvleneiaminobutvlDpiperidinvlaminol-Q-cvclopentvlpurine 136 011455 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( l-(4-N ,N-di-(2- phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentyipurine is prepared from 2-chloro-6-[4-(l-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 5 Example 123 2-ÎTrans-(4-aminocvclohexvbamino'l-6-î4-(l-(5-N.N-di-f2-phenvlethvlene')aminopentvl'>'>- piperidinvlaminol-9-cvclQpentvlpurine

Préparation of 4-Amino-1 -(5-N,N-di-f2-phenvlethvlene)aminopentvl')piperidine

Method 1 10 Scheme B. step a: 4-Carboxamide-l-(5-N.N-di-(2-phenvlethyleneiaminopentvnpiperidine 4-Caiboxamide-l-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine may be prepared fromisonipecotamide and 5-N,N-di-(2-phenylethyleneamino)pentyl chloride essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-1-(5-N .N-di-(2-phenvlethvlene')aminopentvl,)piperidine 15 4-Amino-1 -(5-NJ4-di-(2-phenylethylene)aminopentyl)piperidine is prepared from 4- carboxamide-l-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C. step a: l-(5-N.N-di-(2-phenvlethvlene)aminopentvl)-4-piperidone 20 l-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone is prepared from 4-piperidone and 5-N,N-di-(2-phenylethyleneamino)pentyl chloride essentially as described above in Example 38,Scheme C, step a.

Scheme C. step b: l-(5-N.N-di-(2-phenvlethvlene,>aminopentvl,>-4-piperidone oxime 1- (5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone oxime is prepared from l-(5-N,N-di- 25 (2-phenylethylene)aminopentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-('5-N.N-di-f2-phenvlethvIene)aminopentvI')piperidine4-Amino-1-(5-N,N-di-(2-phenylethyiene)aminopentyl)piperidine is prepared from l-(5-N,N-di-(2-phenylethyiene)aminopentyl)-4-piperidone oxime essentially as described above in Example 30 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(5-N.N-di-(2-phenvlethvlene'>aminopentylB- piperidinvlaminol-9-cvclopentvlpurine 2- Chloro-6-[4-(l-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9- 137 0114 55 cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine, and triethylamine essentially as described above inExampie 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-f4-aminocvclohexvl)aminol-6-i4-(l-(5-N.N-di-(2- phenylethvlenelaminopentyl))-piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurine essentially as described inExampie 1, Scheme A, step c.

Example 124 2-FTrans-f4-aminocvclohexvl)aminol-6-i4-('l-('2-N,N-di-(3- phenvIpropvIene,)aminoethvl'))piperidinylamino1-9-cvclopentvlpurine

Préparation of 4-Amino-l-f2-N.N-di-('3-phenvlpropylene')aminoethvI)piperidine

Method 1 *··

Scheme B, step a: 4-Carboxamide-l-(2-N.N-di-f3-phenvlpropvlene')aminoethvI,)piperidine 4-Carboxamide-l-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine may be prepared fromisonipecotamide and 2-N,N-di-(3-phenyIpropyleneamino)ethyl chloride essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-f-(2-N.N-di-(3-phenvlpropylene)aminoethvDpiperidine 4-Amino-l-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine is prepared from 4-carboxamide-l-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C. step a: l-(2-N,N-di-f3-phenvlpropylene')aminoethvl)-4-piperidonel-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-di-(3-phenylpropyleneamino)ethyl chloride essentially as described above in Example 38,Scheme C, step a.

Scheme C, step b: l-f2-N.N-di-f3-phenvlpropvlene')aminoethvl'>-4-piperidone oximel-(2-N,N-di-(3-phenylpropylene)aminoethyI)-4-piperidone oxime is prepared from l-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f2-N.N-di-f3-phenvlpropvlene)aminoethvl')piperidine4-Amino-l-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine is prepared from l-(2-N,N-di- 138 011455 (3-phenylpropyiene)aminoethyl)-4-piperidone oxime essentially as described abovc in Example 38, Scheme C, step c.

Scheme A, stepb: 2-Chloro-6-f4-n-(2-N.N-di-(3- phenvlpropylene^aminoethvlOpiperidinvlaminol-Q-cvclopentvlpurine 5 2-Chloro-6-[4-( 1 -(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. .

Scheme A. step c: 2-fTrans-i4-aminocvclohexyl)amino1-6-f4-(l-f2-N.N-di-(3- 10 phenvlpropvlene')aminoethvl))piperidinylamino1-9-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(3- phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 15 Example 125 2-rrrans-(4-aminocvclohexvDaminol-6-i4-(l-f3-N.N-di-f3- phenvlpropvlene')aminopropvl1l)piperidinvlaminol-9-cvclopentvlpurinePréparation of 4-Amino-1 -f3-N.N-di-f3-phenvtpropvlene)aminopropvhpiperidine

Method 1 20 Scheme B. step a: 4-Carboxamide-l-i3-N.N-di-('3-phenvlpropy]ene)aminopropvl')piperidine 4-Carboxamide-l'(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine may be prepared fromisonipecotamide and 3-N,N-di-(3-phenylpropyleneamino)propyl chloride essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(3-N.N-di-f3-phenvlpropvlene)aminopropvlk>iperidine 25 4-Amino-l-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine is prepared from 4- carboxamide-l-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

Method 2:

Scheme C. step a: l-f3-N.N-di-f3-phenvlpropvlene~)aminopropvlV-4-piperidone 30 l-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone is prepared from 4-piperidone and 3- N,N-di-(3-phenylpropyleneamino)propyl chloride essentially as described above in Example38, Scheme C, step a.

Scheme C. step b: l-(3-N,N-di-(3-phenylpropvlene~)aminopropvO-4-piperidone oxime 139 1- (3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone oxime is prepared front l-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone and hydroxylamine hydrochloride essentiallyas described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-N.N-di-f3-phenvlpropvlene'>aminopropyl')piperidine 5 4-Amino-l-(3-NJ4-di-(3-phenylpropylene)aminopropyl)piperidine is prepared from l-(3-NJQ-di-(3-phenylpropylene)aminopropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(3-N,N-di-(3-phenvl,propvlene')aminopropvl))piperidin vl aminol-9-cvclopentvlpurine 10 2-Chloro-6-[4-(l-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentyipurine, 4-amino-l-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-(4-aminocvclohexvl)amino1-6-F4-(l-(3-N.N-di-(3- 15 phenvlpropvlene')aminopropvl')'ipiperidinvlaminol-9-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(3-N,N-di-(3- phenylpjOpylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 20 Example 126 2-ITrans-(4-aminocvclohexvDamino'l-6-r4-il-(4-N.N-di-(3- phenvlpropvlene^aminobutvDlpiperidinvlaminol-O-cvclopentvlpurinePréparation of 4-Amino-1 -(4-N.N-di-f 3-phenvlpropylene)aminobutvl')piperidine

Method 1 25 Scheme B. step a: 4-Carboxamide-l-(4-N.N-di-('3-phenvlpropvlene')aminobutvl')piperidine 4-Carboxamide-l-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine may be prepared fromisonipecotamide and 4-N,N-di-(3-phenylpropyleneamino)butyl chloride essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f4-N.N-di-f3-phenvlpropvlene)aminobutvl)piperidine 30 4-Amino-1 -(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine is prepared from 4- carboxamide-l-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2: 140 011455

Scheme C, step a: l-(4-N.N-di-i3-phenvlpropvlene')aminobutvl')-4-piperidonel-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone is prepared from 4-piperidone and4-N,N-di-(3-phenylpropyleneamino)butyl chloride essentially as described above in Example38, Scheme C, step a, 5 Scheme C, step b: l-(4-N,N-di-f3-phenvlpropvlene)aminobutvl)-4-piperidone oxime 1- (4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone oxime is prepared from l-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone and hydroxylamine hydrochloride essentiallyas described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-t-(4-NJ4-di-i3-phenylpropvlene)aminobutvl)piperidine 10 4-Amino-l-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine is prepared from l-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone oxime essentially as described above in Example38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-fl-(4-N.N-di-(3-phenvIpropvlene)aminobutvl))piperidinvlamino'l-9-cvclor>entvlpurine 15 2-Chloro-6-[4-( 1 -(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-N,N-di-(3-phenylpropyiene)aminobutyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-n,rans-f4-aminocyclohexvl)amino1-6-f4-( l-(4-N.N-di-f3- 20 phenvlpropvlenelaminobutvDipiperidinvlaminol^-cvcIopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-di-(3- phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c. 25 Example 127 2-ÎTrans-(4-aminocvclohexvhaminol-6-r4-f 1 -( 5-N.N-di-f 3- phenylpropvlenelaminopentvlDpiperidinylaminol-Ç-cvclopentvlpurinePréparation of 4-Amino-1 -f5-N,N-di-(3-phenvlpropvlene)aminopentvl)piperidine

Method 1 30 Scheme B. step a: 4-Carboxamide-l-(5-N,N-di-(3-phenvlpropvlene')aminopentvI)piperidine 4-Carboxamide-l-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine may be prepared from isonipecotamide and 5-N,N-di-(3-phenylpropyleneamino)pentyl chloride essentially as described above in Example 38, Scheme B, step a. 141 011455

Scheme B, step b: 4-Amino-l-(5-N,N-di-(3-phenylpropvlene')aminopentvl,)piperidine 4- Amino-1-(5-N ,N-di-(3-phenylpropylene)aminopentyl)piperidine is prepared from 4-carboxamide-1 -(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b. 5 Method 2:

Scheme C, step a: l-(5-N,N-di-(3-phenvlpropvlene)aminopentvl)-4-piperidone l-(5-N,N-di-(3-phenyipropylene)aminopentyl)-4-piperidone is prepared from 4-piperidone and 5- N,N-di-(3-phenylpropyleneamino)pentyl chloride essentially as described above in Example38, Scheme C, step a. 10 Scheme C. step b: l-(5-N.N-di-(3-phenvlpropvlene,)aminopentvI')-4-piperidone oxime 1- (5-N,N-di-(3-phenyipropylene)aminopentyl)-4-piperidone oxime is prepared from l-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidone and hydroxylamine hydrochloride essentiallyas described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f5-N.N-di-f3-phenvlpropylene1aminopentvl')piperidine 15 4-Amino-1 -(5-N,N-di-(3 -phenylpropylene)aminopentyl)piperidine is prepared from 1 -(5-N,N- di-(3-phenylpropylene)aminopentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-(l-(5-N,N-di-(3-phenylpropylene)aminopentvl'),)piperidinvlamino1-9-cvclopentvlpurine 20 2-Chloro-6-[4-( 1 -(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylaminoj-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexyl)aminol-6-i4-(l-(5-N,N-di-(3- 25 phenvlpropvlenelaminopentvlOpiperidinvlaminol^-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l -(5-N,N-di-(3- phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(5-N,N-di-(3-phenylpropylene)aminopentyI))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 30 Example 128 2-rTrans-(4-aminocvclohexvBamino1-6-i4-fl-(2-N,N-di-f4- phenvlbutvleneiaminoethvlfrpiperidinvlaminol-g-cvclopentvlpurinePréparation of 4-Amino-1 -f2-N,N-di-(4-phenvlbutvlene)aminoethvIlpiperidine 142 011455

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-N.N-di-(4-phenvlbutvlene)aminoethyl')piperidine 4-Carboxamide-l-(2-N?4-di-(4-phenylbutylene)aminoethyl)piperidine may be prepared fromisonipecotamide and 2-N,N-di-(4-phenylbutyleneamino)ethyl chloride essentially as described 5 above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-N.N-di-(4-phenvlbutvlene)aminoethvl)piperidine 4-Amino-l-(2-N,N-di-(4-phenylbutylene)aminoethyI)piperidine is prepared from 4-carboxamide-l-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b. 10 Method 2:

Scheme C, step a: l-(2-N.N-di-f4-phenvlbutvlene')aminoethvI)-4-piperidonel-(2-N,N-di-(4-phenylbutylene)aminœthyl)-4-piperidone is prepared from 4-piperidone and 2-N,N-di-(4-phenylbutyleneamino)ethyl chloride essentially as described above in Example 38,Scheme C, step a. 15 Scheme C. step b: l-(2-N.N-di-(4-phenvlbutvlene')anunoethvl)-4-piperidone oxime 1- (2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone oxime is prepared from l-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-N.N-di-(4-phenvIbutvlene')aminoethvl)piperidine 20 4-Amino-l-(2-N,N-di-(4-phenylbutyIene)aminoethyI)piperidine is prepared from l-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone oxime essentially as described above in Example38, Scheme C, step c.

Scheme A, step b: 2-ChIoro-6-r4-(l-f2-N.N-di-(4-phenvlbutvlene)aminoethvlDpiperidinylamino1-9-cvclopentvlpurine 25 2-Chloro-6-[4-( 1 -(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2,6-dichIoro-9-cyciopentyipurine, 4-amino-l-(2-N,N-di-(4-phenylbutyiene)aminoethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-i4-aminocvclohexvl~)aminol-6-i4-(l-f2-N.N-di-(4- 30 phenvIbutvlene')aminoethvn)piperidinvlamino'l-9-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(4- phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine 143 011455 essentially as described in Example 1, Scheme A, step c.

Example 129 2-rTrans-(4-aminocyclohexyl)amino1-6-r4-il-f3-N.N-di-(4- phenvlbutvlene)aminopropvl))piperidinvlaminol-9-cvclopentvlpurine 5 Préparation of 4-Amino-1 -f S-N.N-di-M-phenvIbutvlenelaminopropvDpiperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-('3-N.N-di-(4-phenvlbutvlene)aminopropvl)piperidine . 4-Carboxamide-l-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine may be prepared fromisonipecotamide and 3-N,N-di-(4-phenylbutyleneamino)propyl chloride essentially as described 10 above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-f3-N,N-di-(4-phenvlbutvlene)aminoproPvl)piperidine 4-Amino- l-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine is prepared from 4-carboxamide-l-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidme essentially as describedabove in Example 38, Scheme B, step b. 15 Method 2:

Scheme C, step a: l-f3-N.N-di-('4-phenvibutvlene')aminopropvl')-4-piperidonel-(3-N,N-di-(4-phenyibutylene)aminopropyl)-4-piperidone is prepared from 4-piperidone and 3-N,N-di-(4-phenylbutyleneamino)propyl chloride essentially as described above in Example38, Scheme C, step a. 20 Scheme C, step b: l-f3-N.N-di-f4-phenvlbutvlene)aminopropvl)-4-piperidone oxime l-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone oxime is prepared from l-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4~piperidone and hydroxylamine hydrochloride essentiallyas described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-f3-N.N-di-f4-phenylbutvlene')aminopropvl)piperidine 25 4-Amino-1 -(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine is prepared from 1 -(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone oxime essentially as described above in Example38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-r4-fl-f3-N.N-di-(4-phenvlbutvlenelaminopropvlDpiperidinvIaminol-Ç-cvclopentvlpurine 30 2-Chloro-6-[4-(l-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. 144 U IΊ 4 b 5

Scheme A, step c: 2-fTrans-(4-aminocvclohexyl)aminol-6-i4-(l-(3-N,N-di-(4- phenvlbutvlene'laminopropvb'ïpiperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-di-(4- phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro- 5 6-[4-( 1 -(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinyiamino]-9-cyciopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 130 2~rTrans-(4-aminocvclohexvbaminol-6-f4-(l-(4-N.N-di-(4- phenvlbutvlene)aminobutvl)')piperidinvlaminol-9-cvclopentylpurine 10 Préparation of 4-Amino-1 -(4-N.N-di-(4-phenvlbutvlene)aminobutvl,)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(4-N.N-di-(4-phenvlbutvlene)aminobutvI)piperidine 4-Carboxamide-l-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine may be prepared fromisonipecotamide and 4-N,N-di-{4-phenylbutyleneamino)butyl chloride essentially as described 15 above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(4-N.N-di-(4-phenvlbutylene)aminobutvPpiperidine 4-Amino- l-(4-N,N-di-(4-phenylbmylene)aminobutyl)piperidine is prepared from 4-carboxamide-l-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b. 20 Method 2:

Scheme C, step a: l-(4-fDi-(4-phenylbutylene)aminobutyl)-4-piperidonel-(4-(Di-(4-phenylbutylene)aminobutyl)-4-piperidone is prepared from 4-piperidone and 4-N,N-di-(4-phenylbutyleneamino)butyl chloride essentially as described above in Example 38,Scheme C, step a. 25 Scheme C, step b: l-(4-fDi-(4-phenylbutylene)aminobutyl)-4-piperidone oxime l-(4-(Di-(4-phenylbutylene)aminobutyl)-4-piperidone oxime is prepared from l-(4-(di-(4-phenylbutylene)aminobutyI)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(4-N,N-di-(4-phenvlbutvlene,)aminobutyl)piperidine 30 4-Amino-1 -(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine is prepared from 1 -(4-(di-(4- phenyIbutylene)aminobutyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-f4-N,N-di-(4- 145 011455 phenylbutvlenelaminobutvnipiperidinylaininol-Q-cvclopentvlpurine2-Chloro-6-[4-( 1 -(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylaniino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyciopentylpurine, 4-amino-l-(4-N,N-di-(4-phenyibutylene)aminobutyl)piperidine, and triethylamine essentially as described above in 5 Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-aminocvclohexyPaminol-6-i4-(l-(4-N.N-di-(4- phenvlbutvlene)aminobutvl'))piperidinylaminol-9-cvclopentylpurine 2-[Trans-(4-aminocyclohexyl)aminoi-6-[4-(l-(4-N,N-di-(4- phenylbutylene)aminobutyl))pipéridinylamino]-9-cyclopentylpurine is prepared from 2-chloro- 10 6-[4-( 1 -(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylaminol-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 131 2-FTrans-f 4-aminocvclohexvl')amino'l-6-r4-( 1 -( 5-N ,N-di-(4-phenvIbutylene)aminopentvP)piperidinvlamino'l-9-cvclopentvlpurine 15 Préparation of 4-Anuno-l-(5-N,N-di-f4-phenvlbutvlene)aminopentvPpiperidine

Methôd 1

Scheme B. step a: 4-Carboxamide-l-f5-N,N-di-(4-phenvlbutvlene,)aminopentvnpiperidine 4-Carboxamide-l-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine may be prepared fromisonipecotamide and 5-N,N-di-(4-phenylbutyleneamino)pentyl chloride essentially as described 20 above in Example 38, Scheme B, step a.

Scheme B. step b: 4-Amino-l-f5-N.N-di-f4-phenvlbutvlene)aminopentvl)piperidine 4-Amino-l-(5-N JsT-di-(4-phenylbutylene)aminopentyl)piperidine is prepared from 4-carboxamide-l-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b. 25 Method 2:

Scheme C, step a: l-(5-N.N-di-(4-phenvlbutvlene)aminopentvl)-4-piperidonel-(5-N,N-di-(4-phenyibutylene)aminopentyl)-4-piperidone is prepared from 4-piperidone and 5-N,N-di-(4-phenylbutyleneamino)pentyl chloride essentially as described above in Example 38,Scheme C, step a. 30 Scheme C. step b: I-f5-N.N-di-(4-phenvlbutvlene')aminopentvl,)-4-piperidone oxime l-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidone oxime is prepared from l-(5-N,N-di- (4-phenylbutylene)aminopentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b. 146

Scheme C, step c: 4-Amino-l-f5-N.N-di-(4-phenvlbutylene)aminopentyl)piperidine4-AminO’l-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine is preparcd from l-(5-N,N-di-(4-phenylbutylene)aminopentyl)~4-piperidone oxime essentially as described above in Example38, Scheme C, step c.

Scheme A, step b: 2-ChIoro-6-r4-(l-(5-N,N-di-(4- phenvlbutvlene)aminopentvl))piperidinvlaminol-9-cvclopentvlpurine 2-ChloiO-6-[4-(l-(5-N,N-di-(4-phenylbutylene)aminopenty!))piperidi!!ylamino}-9-cyclopentyipurine is preparcd from 2,6-dichloro-9-cyclopentylpurine, 4-ammo-l-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-i4-aminocvclohexvl)amino1-6-f4-(l-(5-N.N-di-(4- phenvibutvlene)aminopentvl))piperidinvlaminol-9-cvclopentvlpurine 2'[Trans-(4-aininocyclohexyl)amino]-6-[4-( 1 -(5-N ,N-di-{4- phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine is preparcd from 2-chloro-6-[4-(l-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

Example 132 2-rrrans-i4-aminocvclohexvl')aminol-6-f4-(l-f3-tetrahvdrofuranvl)methvl')piperidinvlaminol-9- cyclopentyipurine

Préparation of 4-Amino-l-(3-tetrahvdrofuranvlmethvBpiperidine

Method 1

Scheme B. step a: 4-Carboxamide-l-f3-tetrahvdrofuranvlmethvDpiperidine4-Caiboxamide-l-(3-tetrahydrofuranylmethyl)piperidine may be preparcd from isonipecotamideand tetrahydrofurfuryl chloride essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-(3-tetrahvdrofuranvlmethvBpiperidine 4-Amino-l-(3-tetrahydrofuranylmethyl)piperidine is preparcd from 4-carboxamide-l-(3-tetrahydrofuranylmethyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Method 2:

Scheme C, step a: l-(3-Tetrahydrofuranvlmethvb-4-piperidonel-(3-Tetrahydrofuranylmethyl)-4-piperidone is prepared from 4-piperidone andtetrahydrofurfuryl chloride essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(3-Tetrahvdrofuranvlmethvl)-4-piperidone oxime 147 011455 1- (3-Tetrahydrofuranylmethyl)-4-piperidone oxime is prepared from l-(3-tetrahydrofuranylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Exampie 38, Scheme C, step b.

Scheme C, step c: 4-Amino- l-(3-tetrahvdrofuranvlmethyl)piperidine 5 4-Amino-l-(3-tetrahydrofuranylmethyl)piperidine is prepared from l-(3- tetrahydrofuranyimethyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-(l-(3-tetrahvdrofuranvl)methvl')piperidinvlamino1-9- cyclopentylpurine 10 2-Chloro-6-[4-( 1 -(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-tetrahydrofuranylmethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-(4-aminocvclohexvl,)aminol-6-f4-f l-(3- 15 tetrahvdrofuranvOmethvPpiperidinvlaminol-g-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(3- tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. 20 Example 133 2-rTrans-(4-aminocvclohexvl)aminol-6-f4-(l-(2-( l-pvnOlidinvbethvl))piperidinvlaminol-9- cyclopentylpurine

Préparation of 4-Amino-1-(2-( l-pvrrolidinvDethvBpiperidine

Method 1 25 Scheme B. step a: 4-Carboxamide-1-(2-( l-pyrrolidinvhethvDpiperidine 4-Carboxamide-1 -(2-( l-pyrrolidinyl)ethyl)piperidine may be prepared from isonipecotamideand l-(2-chloroethyl)pyrrolidine essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-1-(2-( l-pynOlidinvDethvDpiperidine 30 4-Amino-1-(2-( l-pyrrolidinyl)ethyl)piperidine is prepared from 4-carboxamide-1-(2-(1- pyrrolidinyl)ethyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: 1-(2-( l-PvrrolidinvDethvll-4-piperidone 148 U I I 4 b b 1-(2-( l-Pyrroiidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and l-(2- chloroethyl)pyrrolidine essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: 1-(2-( l-Pvrroiidinvhethvl)-4-piperidone oxime 1- (2-( l-Pyrrolidinyi)ethyI)-4-piperidone oxime is prepared from 1-(2-( l-pyrroIidinyl)ethvl>-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C. step c: 4-Amino-l-(2-( l-pvrrolidinyBethvl)piperidine 4-Amino-l-(2-(l-pyrrolidinyl)ethyl)piperidine is prepared from 1-(2-( 1-pyrrolidinyI)ethyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-[4-( 1-(2-( l-pvrrolidinvnethvlfrpiperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1-(2-( l-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentyipurine is preparedfrom 2,6-dichioro-9-cyclopentyipurine, 4-amino-l-(2-(l-pyrrolidinyl)ethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-(l-(2-(1- PVrrolidinvl)ethvl))piperidinvlaminol-9-cvclopentvlpurine 2-[Trans-(4-aininocyclohexyl)amino]-6-[4-(l-(2-(i-pyrroIidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1-(2-(1- pyrroIidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 134 2-rTrans-(4-aminocvclohexvI)aminol-6-f4-(l-(2-( l-piperidinvhethvl))piperidinylamino1-9- cvclopentvlpurine

Préparation of 4-Amino-1 -(2-( 1 -piperidinvllethvDpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-( l-piperidinvl)ethvl)piperidine4-Carboxamide-l-(2-( l-piperidinyl)ethyl)piperidine may be prepared from isonipecotamide andl-(2-chloroethyl)piperidine essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-1 -(2-(l-piperidinvllethvl)piperidine 4-Amino-1-(2-( l-piperidinyl)ethyi)piperidine is prepared from 4-carboxamide-l-(2-(1-piperidinyl)ethyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: I-(2-( l-PiperidinvbethvlM-piperidone 149 011455 1 -(2-( l-Piperidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and l-(2-chloroethyl)piperidine essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: 1-(2-( l-PiperidinvDethvD-4-piperidone oxime 1- (2-( l-Piperidinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-( 1-piperidinyl )ethyl)-4-5 piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,

Scheme C, step b.

Scheme C, step c: 4-Amino-1-(2-( 1-piperidinvDethylïpiperidine 4-Amino-1-(2-( l-piperidinyl)éthyl)piperidine is prepared from 1-(2-( l-piperidinyl)ethyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c. 10 Scheme A, step b: 2-Chloro-6-r4-(l-(2-( l-piperidinyl)ethvl))piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-( l-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-( l-piperidinyl)ethyl)piperidine, andtriethylamine essentially as described above in Exemple 1, Scheme A, step b. 15 Scheme A, step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-r4-( 1-(2-( 1- piperidinyl)ethvl,))piperidinvlaminol-9-cyclopentvlpurine J2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-(l-piperidinyl)ethyl))piperidinylamino]-9-cyclopentyipurine is prepared from 2-chloro-6-[4-( 1 -(2-( l-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 20 Example 135 2-|Trans-(4-aminocvclohexvbamino1-6-i4-(l-(2-(4-morpholinvl')ethvl'))piperidinvlamino1-9- cyclopentyipurine

Préparation of 4-Amino-l-(2-(4-morpholinvl')ethvl')piperidine

Method 1 25 Scheme B, step a: 4-Carboxamide-l-(2-(4-morphoIinyl')ethvl)piperidine 4-Carboxamide-l-(2-(4-morpholinyl)ethyl)piperidine may be prepared from isonipecotamideand l-(2-chloroethyl)morpholine essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-(4-morpholinvl')ethyIlpiperidine30 4-Amino-1 -(2-(4-morpholinyl)ethyl)piperidine is prepared from 4-carboxamide-1 -(2-(4- morpholinyl)e±yl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: l-(2-(4-Morpholinvl)ethvl,>-4-piperidone 150 l-(2-(4-Morpholinyl)ethyl)-4-piperidone is prepared frora 4-piperidone and l-(2- chloroethyl)morpholine essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(2-(4-Morpholinyl)ethvl)-4-piperidone oxime 1- (2-(4-Morpholinyl)ethyI)-4-piperidone oxime is prepared from l-(2-(4-morpholinyl)ethyl)-4- 5 piperidone and hydroxylamine hydrocnloride essentially as described above in Example 38,

Scheme C, step b.

Scheme C, step c: 4-Amino-l-^-(^-morpholinvBethvDpiperidine 4-Amino-l-(2-(4-morpholinyl)ethyl)piperidine is prepared from l-(2-(4-morpholinyl)ethyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c. 10 Scheme A, step b: 2-Chloro-6-r4-fl-i2-f4-morpholinyI)ethvl,))piperidinviamino1-9- cyclopentvlpurine 2- Chloro-6-[4-( l-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-(4-morpholinyl)ethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b. 15 Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-i4-( 1-(2-(4- morpholinvl)ethvlBpiperidinylaminol-9-cyclopentylpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine di is prepared from 2-chloro-6-[4-( 1-(2-(4- morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 20 1, Scheme A, step c.

Example 136 2-rTrans-(4-aminocvclohexvl)amino1-6-r4-(l-(3-(l-piperidinvl)propvl,))piperidinvlaminol-9- cyclopentylpurine

Préparation of 4-Amino-l-(3-( l-piperidinvl)propvl)piperidine 25 Method 1

Scheme B, step a: 4-Carboxamide-1 -(3-(l-piperidinvl)propyl)piperidine 4-Carboxamide-1-(3-( l-piperidinyl)propyl)piperidine may be prepared from isonipecotamide and l-(3-chloropropyl)piperidine essentially as described above in Example 38, Scheme B, step a. 30 Scheme B, step b: 4-Ami no-1-(3-( l-piperidinvbpropvl)piperidine 4-Amino-l-(3-( l-piperidinyl)propyl)piperidine is prepared from4-carboxamide-l-(3-(l-piperidinyl)propyl)piperidine essentially as described above in Example 38, Scheme B, step b.Method 2: 011455 151

Scheme C, step a: 1-(3-( l-Piperidinyl)propvl)-4-piperidone 1- (3-( l-Piperidinyl)propyl)-4-piperidone is prepared from 4-piperidone and l-(3-chloropropyl)piperidine essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: 1-(3-( l-PiperidinvI)propvl)-4-piperidone oxime 5 1 -(3-(l-Piperidinyl)propyl)-4-piperidone oxime is prepared from l-(3-(l-piperidinyl)propyl)-4- piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C, step c: 4-Amino-l-(3-( l-piperidinvl)propyl)piperidine 4-Amino-l -(3-( l-piperidinyl)propyl)piperidine is prepared from 1-(3-( l-piperidinyl)propyl)-4- 10 piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-(l-(3-( l-piperidinvl')propvIripiperidinvlamino'l-9- cvclopentvlpurine 2- Chloro-6-[4-( 1-(3-( l-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3-( l-piperidinyl)propyl)piperidine, and 15 triethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocyclohexyl)aminol-6-i4-( 1-(3-(1- Λ piperidinyl)propyl)')piperidinvlamino'l-9-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(3-( 1 -piperidinyl)propyI))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1-(3-(1- 20 piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example1, Scheme A, step c.

Example 137 (R,S)-2- ΓΤ rans-(4-aminocvclohexvl)aminol-6-i4-( 1 -(3-( 1 -methvl-)piperidinvl')methvb)piperidinvlamino1-9-cvclopentvlpurine 25 Préparation of (R,S~)-4-Amino-1 -(3-( 1 -methvlpiperidinvllmethvPpiperidine

Method 1

Scheme B, step a: (R,S)-4-Carboxamide-1-(3-( l-methvlpiperidinyl)methvl)piperidine (R,S)-4-Carboxamide-1 -(3-( I -methylpiperidinyl)methyl)piperidine may be prepared fromisonipecotamide and (R,S)-3-chloromethyl-l-methylpiperidine essentially as described above in 30 Example 38, Scheme B. step a.

Scheme B, step b: (R,S)-4-Amino-l-(3-( l-methvlpiperidinylimethvl)piperidine (R,S)-4-Amino-l-(3-(l-methylpiperidinyl)methyl)piperidine is prepared from (R,S)-4- carboxamide-1-(3-( l-methylpiperidinyl)methyl)piperidine essentially as described above in 152 UT 1455

Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: (R,S)-1-(3-( l-MethvipiperidinvDmethvlH-piperidone (R,S)-1-(3-( l-Methylpiperidinyi)methyl)-4-piperidone is prepared from 4-piperidone and (R,S)- 5 3-chloromethyl-l-methylpiperidine essentialiy as described above in Example 38, Scheme C,step a.

Scheme C, step b: (R,S)-1-(3-( l-Methvlpiperidinvllmethvb-4-piperidone oxime (R,S)-1 -(3-( l-Methylpiperidinyl)methyl)-4-piperidone oxime is prepared from (R,S)-1 -(3-(1- methylpiperidinyl)methyl)-4-piperidone and hydroxylamine hydrochloride essentialiy as 10 described above in Example 38, Scheme C, step b.

Scheme C, step c: (R.SV-4-Amino-l-(3-( l-methvlpiperidinvl)methvl)piperidine(R,S)-4-Amino-l-(3-( l-methylpiperidinyl)methyl)piperidine is prepared from (R,S)-1 -(3-(1-methylpiperidinyl)methyl)-4-piperidone oxime essentialiy as described above in Example 38,Scheme C, step c. 15 Scheme A, step b: (R.S)-2-Chloro-6-[4-fl-(3-(l-methvl~)piperidinyl')methvl))piperidinvlamino1- 9-cvclopentylpurine (R,S)-2-Chloro-6-[4-( 1-(3-( 1 -methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R,S)-4-amino-l-(3-(1-methylpiperidinyl)methyl)piperidine, and triethylamine essentialiy as described above in 20 Example 1, Scheme A, step b.

Scheme A. step c: (R.S)-2-rTrans-.''4-aminocvclohexvbamino1-6-[4-<'l-(3-(l- methvl)piperidinvl)methvl,))piperidinvlamino1-9-cvclopentvlpurine (R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(1- methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentyipurine is prepared from (R,S)-2- 25 chloro-6-[4-( 1 -(3-(l-methyl)piperidinyl)me±yl))piperidinyiamino]-9-cyclopentylpurine essentialiy as described in Example 1, Scheme A, step c.

Example 138 (R,SV2-[Trans-(4-aminocvciohexvl)amino1-6-i4-(l-(2-(3-(l- methvnpvrrolidinvbethvl~)')piperidinvlamino1-9-cvclopentvlpurine 30 Préparation of (R,S)-4-Amino-l-(2-(3-( l-methvlpyrrolidinvlBethvDpiperidine

Method 1

Scheme B, step a: (R.Sl-4-Carboxamide-l-(2-(3-( 1-Methvlpvrrolidinvl)ethyl)piperidine (R,S)-4-Carboxamide-1-(2-(3-(l-methylpyrrolidinyl)ethyl)piperidine may be prepared from 011455 153 isonipecotamide and (R,S)-3-(2-chloroethyl)-l-methylpyrrolidine essentially as described abovein Example 38, Scheme B, step a.

Scheme B. step b: fR,S')-4-Amino-l-f2-(3-fl-methvlpvrrolidinyl)'>ethvl)piperidine (R,S)-4-Amino-l-(2-(3-( l-methylpyrrolidinyl))ethyl)piperidine is prepared from (R.S)-4-carboxamide-1 -(2-(3-( l-methylpyrrolidinyl)ethyl)piperidine essentially as described above inExample 38, Scheme B, step b.

Method 2:

Scheme C, step a: (R,S)-1-(2-(3-( l-MethvlpvrrolidinvDethvlM-piperidone (R,S)-l-(2-(3-(l-Methylpyrrolidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and(R,S)- 3-(2-chloroethyl)-l-methylpyrroIidine essentially as described above in Example 38,Scheme C, step a.

Scheme C, step b: (R,S)-l-(2-(3-(l-Methvlpyrroiidinvr>ethvl)-4-piperidone oxime (R,S)-l-(2-(3-(l-Methylpyrrolidinyl)ethyl)-4-piperidone oxime is prepared from (R,S)-1-(2-(3-(l-methylpynOlidinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: fR,S)-4-Amino-l-(2-(3-(l-methvlpvrrolidinvlï)ethvl)piperidine (R,S)-4-Amino-l-(2-(3-( l-methylpyrrolidinyl))ethyi)piperidine is prepared from (R,S)-l-(2-(3-( 1-methylpyrrolidinyl)ethyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A. step b: (R.Sl-2-Chloro-6-r4-( I -(2-(3-(1- methvl)pvrrolidinvl)ethvl))piperidinylaminol-9-cvcIopentvlpurine (R,S)-2-Chloro-6-[4-( 1-(2-(3-( 1-methyl)pyrrolidinyl)ethyl))piperidinylaniino]-9- cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R,S)-4-amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Scheme A, stepc: (R,S)-2-fTrans-(4-aminocvclohexvbaminol-6-i4-(l-(2-(3-(1- methyl)pvrroIidinvI)ethvl')’lpiperidinvlarnino1-9-cvclopentvlpurine (R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(2-(3-( 1 - methyl)pyrroiidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is prepared from (R,S)-2- chloro-6-[4-( 1-(2-(3-( 1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 139 2-[Trans-(4-aminocvclohexvBaminol-6-f4-( 1-(2-(1-(4- 011455 154 methvDpiperazinvliethvlbPiperidinvlaminol^-cvclopentvlpurinePréparation of 4-Amino-l-(2-( l-(4-methvlpiperazinylBethvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-(l-(4-methvipiperazinvl))ethyl)piperidine 5 4-Carboxamide-1 -(2-( l-(4-methylpiperazinyl))ethyl)piperidine may be prepared from isonipecotamide and l-(2-chloroethvl)-4-methylpiperazine essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-l-(2-( l-(4-methvIpiperazinyl))ethvl)piperidine 4-Amino-l-(2-( l-(4-methylpiperazinyl))ethyl)piperidine is prepared from 4-carboxamide-1-(2- 10 (1 -(4-methylpiperazinyl))ethyl)piperidine essentially as described above in Example 38,

Scheme B, step b.

Method 2:

Scheme C, step a: 1-(2-( l-(4-Methvlpipera2invl),)ethvl)-4-piperidone1 -(2-( l-(4-Methylpiperazinyl))ethyl)-4-piperidone is prepared from 4-piperidone and l-(2- 15 chloroethyl)-4-methylpiperazine essentially as described above in Example 38, Scheme C, stepa.

Scheme C, step b: 1-(2-( l-(4-Methvlpiperazinyl),)ethvl)-4-piperidone oxime 1- (2-( l-(4-Methylpiperazinyl))ethyl)-4-piperidone oxime is prepared from 1-(2-(1-(4-methylpiperazinyl))ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as 20 described above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(2-( l-(4-methvlpiperazinvI)')ethvl)piperidine4-Amino-l-(2-(l-(4-methylpiperazinyl))ethyl)piperidine is prepared from 1-(2-(1-(4-methylpiperazinyl))ethyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c. 25 Scheme A, step b: 2-Chloro-6-f4-(l-(2-(l-(4-methyl')piperazinvl)ethvI)~)piperidinvlaminol-9- cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-( l-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentyIpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-(1 -(4-methylpiperazinyl))ethyl)piperidine, and triethylamine essentially as described above in 30 Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexvI)aminol-6-F4-(l-(2-(l-(4- methvl~)piperazinvl~)ethvD~)piperidinvlaminol-9-cvclopentvIpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-( 1-(2-(1-(4- 011455 155 methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1 -(2-( 1 -(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

Example 140 5 (R.S)-2-rrrans-(4-aminocvclohexvPaminol-6-r4-(l-f2-phenvl-2- hvdroxvethvl))piperidinvlamino]-9-cvclopentylpurine

Préparation of (R.S>-4-Amino-l-(2-phenvI-2-hvdroxvethyl\piperidine

Method 1

Scheme B, step a: (R,S)-4-Carboxamide-l-('2-phenvl-2-hvdroxvethvl)piperidine 10 (R,S)-4-Carboxamide-l-(2-phenyl-2-hydroxyethyl)piperidine may be prepared from isonipecotamide and (R,S)-l-hydroxy-2-chloroethylbenzene essentially as described above inExample 38, Scheme B, step a.

Scheme B. step b: (R,S)-4-Amino-l-(2-phenvl-2-hvdroxvethvl)piperidine(R,S)-4-Amino-l-(2-phenyl-2-hydroxyethyl)piperidine is prepared from (R,S)-4-carboxamide- 15 l-(2-phenyl-2-hydroxyethyl)piperidine essentially as described above in Example 38, SchemeB, step b.

Method 2:

Scheme C. step a: (R.S’)-l-(2-Phenvl-2-hvdroxvethvP-4-piperidone (R,S)-l-(2-Phenyl-2-hydroxyethyl)-4-piperidone is prepared from 4-piperidone and (R,S)-1- 20 hydroxy-2-chloroethylbenzene essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: (R,S)-l-(2-Phenyl-2-hvdroxvethvP-4-piperidone oxime(R,S)-l-(2-Phenyl-2-hydroxyethyl)-4-piperidone oxime is prepared from (R,S)-l-(2-phenyl-2-hydroxyethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above inExampie 38, Scheme C, step b. 25 Scheme C, step c: (R.S)-4-Amino-l-(2-phenvI-2-hvdroxvethvPpiperidine (R,S)-4-Amino-l-(2-phenyl-2-hydroxyethyl)piperidine is prepared from (R,S)-l-(2-phenyl-2-hydroxyethyl)-4-piperidone oxime essentially as described above in Example 38, Scheme C,step c.

Scheme A, step b: ('R,S)-2-Chloro-6-r4-(l-(2-phenvl-2-hvdroxvethvB')piperidinvlamino'l-9- 30 cvclopentvlpurine (R,S)-2-Chloro-6-[4-(l-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R,S)-4-amino-l-(2-phenyl-2- hydroxyethyl)piperidine, and triethylamine essentially as described above in Example 1, 156

Scheme A, step b.

Scheme A, step c: (R,S)-2-ÎTrans-(,4-aminocvclohexyl)aminol-6-f4-( l-f2-phenvl-2- hvdroxvethvB)piperidinvlaminol-9-cvclopentvlpurine (R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-phenyl-2- hydroxyethyl))piperidinylamino]-9-cyclopentylpurine di is prepared from (R,S)-2-chloro-6-[4-(l-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Example 141 2-FTrans-(4-aminocvclohexvI,)amino1-6-f4-(l-(3.4-methvlenedioxvbenzvll))piperidinvlaminol- 9-cvclopentvlpurine

Préparation of 4-Amino-(3.4-methvlenedioxvbenzvl)piperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-('3,4-methvlenedioxvbenzvBpiperidine 4-Carboxamide-l-(3,4~methylenedioxybenzyl)piperidine may be prepared from isonipecotamide and 5-chloromethyl-l,3-benzodioxole essentially as described above inExample 38, Scheme B, step a.

Scheme B, step b: 4-Amino-(3.4-methvlenedioxybenzvl)piperidine 4-Amino-(3,4-methylenedioxybenzyl)piperidine is prepared from 4-carboxamide-1-(3,4-methylenedioxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Method 2:

Scheme C, step a: l-(3,4-Methvlenedioxv')benzvl-4-piperidone l-(3,4-Methylenedioxy)benzyl-4-piperidone is prepared from 4-piperidone and 5-chloromethyl-1,3-benzodioxole essentially as described above in Example 38, Scheme C, step a.

Scheme C. step b: l-(3,4-Methvlenedioxv)benzyl-4-piperidone oxime l-(3,4-Methylenedioxy)benzyl-4-piperidone oxime is prepared from 1-(3,4- methylenedioxy)benzyl-4-piperidone and hydroxylamine hydrochloride essentially as describedabove in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-f3.4-methvlenedioxybenzvî')piperidine 4-Amino-(3,4-methylenedioxybenzyl)piperidine is prepared from 1-(3,4- methylenedioxy)benzyl-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-f4-fl-f3.4-methvlenedioxvbenzvIl'))piperidinvlamino1-9- 157 011455 cvclopentvlpurine 2-Chloro-6-[4-(l-(3,4-methylenedioxybenzyIl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-(3,4- methyienedioxybenzyl)piperidine, and triethylamine essentially as described above in Example 5 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-(1-f3.4- methvlenedioxvbenzvlDipiperidinvlaminol-O-cvclopentvlpurine 2-[Trans-(4-aminocyclohexyi)amino]-6-[4-(l-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( 1-(3,4- 10 methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

Ex ample 142 2-rrrans-(4-aminocyclohexvl')aminol-6-[4-(l-(2-benzimidazolinvl)methvl)pir>eridinvlaminol-9- cvclopentvlpurine 15 Préparation of 4-Amino-l-(2-benzimidazolinvl')methvlpiperidine

Method 1

Scheme B, step a: 4-Carboxamide-l-(2-benzimidazoIinvl)methvlpiperidine4-Carboxamide-l-(2-benzimidazolinyl)methylpiperidine may be prepared from isonipecotamideand 2-(chloromethyI)benzimidazole essentially as described above in Example 38, Scheme B, 20 step a.

Scheme B, step b: 4-Amino-l-f2-benzimidazolinvl,)methvlpiperidine4-Amino-l-(2-benzimidazoiinyl)methylpiperidine is prepared from 4-carboxamide-l-(2-benzimidazolinyl)methyipiperidine essentially as described above in Example 38, Scheme B,step b. 25 Method 2:

Scheme C, step a: l-f2-Benzimidazolvl)methyl-4-piperidonel-(2-Benzimidazolyl)methyl-4-piperidone is prepared from 4-piperidone and 2-(chloromethyl)benzimidazole essentially as described above in Example 38, Scheme C, step a.Scheme C, step b: l-(2-Benzimidazolvi')methvl-4-piperidone oxime 30 l-(2-Benzimidazolyl)methyl-4-piperidone oxime is prepared from l-(2-benzimidazolyl)methyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38,Scheme C, step b.

Scheme C, step c: 4-Amino-l-('2-benzimidazolinvBmethvlpiperidine 011455 158 4-Amino-l-(2-benzimidazolinyl)methylpiperidine is prepared from l-(2-benzimidazolyl)methyl-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-F4-f l-(2-benzimidazolinvl)methvl)piperidinvlamino1-9- 5 cvclopentylpurine 2-Chioro-6-[4-( 1 -(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-benzimidazolinyl)methylpiperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b. 10 Scheme A, step c: 2-rTrans-(4-aminocvclohexvbaminol-6-f4-(l-(2- benzimidazoIinvl)methvl)piperidinvlamino1-9-cvclopentvlpurine2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2- benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine essentially as described in 15 Example 1, Scheme A, step c.

Example 143 2-fTrans-(4-aminocyclohexvl)amino1-6-f4-( 1-(4-(2-methvl)thiazolinyl)methvl)piperidinylamino1-9-cvclopentvlpurine

Préparation of 4-Amino-l-(4-(2-methvlthiazolinvl')methvl)piperidine 20 Method 1

Scheme B, step a: 4-Carboxamide-l-(4-(2-methylthiazolinvl))methylpiperidine 4-Carboxamide-l-(4-(2-methylthiazolinyl))methylpiperidine may be prepared fromisonipecotamide and 2-methyl-5-(chloromethyl)thiazole essentially as described above inExample 38, Scheme B, step a. 25 Scheme B. step b: 4-Amino-l-(4-(2-methvlthiazolinvl’)methvl')piperidine 4-Amino-l-(4-(2-methylthiazolinyl)methyl)piperidine is prepared from 4-carboxamide-1-(4-(2-methylthiazolinyl))methylpiperidine essentially as described above in Example 38, Scheme B,step b.

Method 2: 30 Scheme C, step a: l-(4-(2-Met'nvlthiazolinvl,)methvl')-4-piperidone 1 -(4-(2-Methylthiazolinyl)methyl)-4-piperidone is prepared from 4-piperidone and 2-methyl-5- (chloromethyl)thiazole essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(4-(2-Methvlthiazolinvl')methvb-4-piperidone oxime 159 011455 1- (4-(2-Methylthiazolinyl)methyl)-4-piperidone oxime is prepared from 1-(4-(2-methylthiazolinyl)methyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

Scheme C, step c: 4-Amino-l-(4-(2-methvIthiazolinvl)methvl)piperidine 5 4-Amino-l-(4-(2-methylthiazolinyl)methyl)piperidine is prepared from 1-(4-(2- methylthia2oiinyl)methyl)-4-piperidone oxime essentially as described above in Example 38,Scheme C, step c.

Scheme A, step b: 2-Chloro-6-i4-f l-(4-(2-methvl)thiazolinvl)methvl')piperidinvlantinol-9- cvclopentvlpiirine 10 2-Chloro-6-[4-( 1 -(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(4-(2-methylthiazolinyl)methyl)piperidine, and triethylamine essentially as described above inExample 1, Scheme A, step b.

Schème A. step c: 2-rTrans-f4-aminocvclohexvPamino'l-6-f4-f 1-(4-(2- 15 methvl)thiazolinvl)methvl)piperidinvlaminol-9-cvclopentvlpurine 2- [Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-(2- methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-( l-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c. 20 Example 144 2-ÎTrans-(,4-aminocvclohexvl)amino1-6-f4-fl-f2-thiophenevI')methvl')piperidinvlamino1-9- cvclopentvlpurine

Préparation of 4-Amino- l-(2-thiophenevlimethvlpiperidine

Method 1 25 Scheme B. step a: 4-Carboxamide-l-f2-thiopheneyl)methvlpiperidine 4-Carboxamide-l-(2-thiopheneyl)methylpiperidine may be prepared from isonipecotamide and2-(chloromethyl)thiophene essentially as described above in Example 38, Scheme B, step a.Scheme B, step b: 4-Amino-l-f2-thiophenevl')methvlpiperidine 4-Amino-l-(2-thiopheneyl)methylpiperidine is prepared from 4-carboxamide-l-(2- 30 thiopheneyl)methylpiperidine essentially as described above in Example 38, Scheme B, step b.Method 2:

Scheme C, step a: 1 -f2-Thiophenevl')methvl-4-piperidonel-(2-Thiopheneyl)methyl-4-piperidone is prepared from 4-piperidone and 2- U il 455 160 (chloromethyl)thiophene essentially as described above in Example 38, Scheme C, step a.

Scheme C, step b: l-(2-Thiophenevl)methvl-4-piperidone oxime 1- (2-Thiopheneyl)methyl-4-piperidone oxime is prepared from l-(2-thiopheneyl)methyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, 5 Scheme C, step b.

Scheme C. step c: 4-Amino-l-(2-thiophenevl)methvlpiperidine 4-Amino-l-(2-thiopheneyl)methylpiperidine is prepared from l-(2-thiopheneyl)methyl-4-piperidone oxime essentially as described above in Example 38, Scheme C, step c.

Scheme A. step b: 2-ChIoro-6-f4-(l-(2-thiophenevl)methvl)piperidinyIamino1-9- 10 cvclopentvlpurine 2- Chloro-6-[4-( 1 -(2-thiopheneyI)methyl)piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-thiopheneyl)methylpiperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-ÎTrans-f4-aminocvclohexvl)aminol-6-i4-(l-f2- 15 thiophenevl)methvl)piperidinylaminol-9-cvcIopentvIpurine 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2-chloro-6-[4-(l-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.

Example 145a 20 Trans-2-ÎTrans-(4-aminocvcIohexyl)amino1-6-r(4-hvdroxv)cvclohexvlaminol-9- cvclopentvlpurined dihvdrochloride

Scheme A, step b: Trans-2-chloro-6-i(4-hvdroxy)cvclohexvlaminol-9-cvclopentvlpurine

Trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, trans-4-(amino)cyclohexanol, and triethylamine essentially as 25 described above in Example 1, Scheme A, step b.

Scheme A, step c: Trans-2-ftrans-(4-aminocvclohexyl)aminol-6-f(4-hvdroxv)cvclohexylaminol- 9-cyclopentylpurine dihvdrochloride

Trans-2-[trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine dihydrochloride is prepared from trans-2-chloro-6-[(4- 30 hydroxy)cyclohexylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. CIMS (NH3)414 (MH*)

Rf (min.) = 3.25 011455 161

Ex ample 145b

Cis-2-rTrans-(4-aminocvclohexvl~)amino1-6-r(,4-hvdroxvlcvclohexvlaminol-9-cvclopentvlpurine dihvdrochloride

Scheme A, step b: Cis-2-chloro-6-l74-hvdroxv')cvclohexvlaminol-9-cvclopentvlpurine 5 Cis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyciopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, cis-4-(amino)cyclohexanol, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

Scheme A, step c: Cis-2-ftrans-(4-aminocvclohexyl)amino1-6-rf4-hvdroxy)cvclohexvlaminol-9- cvclopentvlpurine dihvdrochloride 10 Cis-2-(trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurinedihydrochloride is prepared from cis-2-chioro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine hydrochloride essentially as described in Example 1, Scheme A, step c. CIMS (NH3) 414 (MH*)

Rf (min.) = 3.25 15 Example 146 (R,S)-2-|Trans-i4-aminocvclohexvl)aminol-6-r(l-hvdroxvmethvl)cvclopentvlamino1-9- cyclopentvlpurine dihvdrochloride

Scheme A, step b: (R,S)-2-Chloro-6-f(l-hvdroxvmethvI)cvclopentvlaminol-9-cyclopentvlpurine 20 (R,S)-2-Chloro-6-[( l-hydroxymethyl)cyclopentyIamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R,S)-2-hydroxymethyl-l-aminocyclopentane, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: (R,S)-2-rTrans-(4-aminocvclohexvl)aminol-6-if 1- hydroxvmethvl)cvclopentvlaminol-9-cvclopentylpurine dihvdrochloride 25 (R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[(l-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurine dihydrochloride is prepared from (R,S)-2-chloro-6-[(l-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurine essentially as described in Example 1,Scheme A, step c. CIMS (NH3) 414 (MH*) 30 Rf (min.) = 3.27

Example 147 2-rrrans-<,4-aminocvclohexvl)amino1-6-(2,4-dichlorophenvlhvdrazinoV9-cvclopentvlpurine dihvdrochloride 011455 162

Scheme A, step b: 2-Chloro-6-f2.4-dichlorophenvIhvdrazino)-9-cvclopentvIpurine2-Chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorophenylhydrazine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b. 5 Scheme A. step c: 2-rTrans-<'4-aminocvclohexvi)aminol-6-f2.4-dichlorophenvlhvdra2ino)-9- cvclopentvlpurine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-(2.4-dichlorophenylhydrazino)-9-cyclopentylpurinedihydrochloride is prepared from 2-chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 10 CIMS (ΝΗ3) 475 (MH+)

Rf (min.) = 3.49

Example 147-a 2-FTrans-(4-aminocvclohexvbamino1-6-i4-i I -( 1 -naphthvl)methvllpiperidinvlamino1-9- cvclopentvlpurine trihvdrochloride 15 Scheme B, step a: 4-Carboxamide-l-f 1-naphthvDmethvlpiperidine 4-Carboxamide-l-(l-naphthyl)methylpiperidine may be prepared from isonipecotamide and 1-(chloromethyl)naphthalene (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-fl-naphthyI)methylpiperidine 20 4-Amino-l-(l-naphthyl)methylpiperidine is prepared from4-carboxamide-l-(l- naphthyl)methylpiperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-1 -( 1 -naphthvl)methvnpiperidinvlamino1-9-cvclopentvlpurine 2-Chloro-6-[4-l-(l-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine is prepared from2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(l-naphthyl)methylpiperidine, and triethylamine25 essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocyclohexvl)aminol-6-F4-il-(l-naphthyl)methvnpiperidinvlamino1-9-cvclopentvlpurine trihvdrochloride2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-( 1 -naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-1 -( 1 -30 naphthyl)methyl]piperidinylamino]-9-cyciopentylpurine essentially as described in Example 1,Scheme A, step c. APCI: 539 (NT1)

Rf (min.) = 2.33 011455 163

Ex ample 147-b 2-rTrans-(4-aminocvclohexvl~)aminol-6-i4-il-(2-trifluoromethvIbenzvl'>lpiperidinylamino1-9- cvclopentvlpurine trihvdrochloride

Scheme B, step a: 4-Carboxamide-l-(2-trifluoromethylbenzyl)piperidine 4-Carboxamide-l-(2-trifluoromethylbenzyl)piperidine may be prepared from isonipecotamideand 2-(trifluoromethyl)benzyl bromide (available from Aldrich Chemical Company) essentiallyas described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2-trifluoromethvlbenzvl)piperidine 4-Amino-l-(2-trifluoromethylbenzyl)piperidine is prepared from 4-carboxamide-l-(2-trifluoromethylbenzyl)piperidine essentially as described above in Example 38, Scheme B, stepb.

Scheme A, step b: 2-ChIoro-6-Î4-il-f2-trifluoromethvlbenzyl)lpiperidinvlaminol-9- cyclopentylpurine 2-Chloro-6-[4-[ 1 -(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-trifluoromethylbenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-i4-fl-(2- trifluoromethylbenzvI)lpiperidinvlaminol-9-cvclopentylpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-trifluoromethylbenzyl)]-piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-trifluoromethylbenzyl)3piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. APCI: 557 (M*‘)

Rf (min.) = 2.29

Example 147-c 2-rTrans-(4-aminocvclohexyl')aminol-6-i4-ri-(3,5-dimethoxvbenzvl)lpiperidinvlaminol-9- cyclopentvlpurine trihvdrochloride

Scheme B, step a: 4-Carboxamide-l-(3,5-dimethoxylbenzyI)piperidine 4-Carboxamide-l-(3,5dimethoxybenzyl)piperidine may be prepared from isonipecotamide and3,5-dimethoxybenzyl chloride (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B. step b: 4-amino-l-(3,5-dimethoxvbenzvl)piperidine 011455 164 4-Amino-l-(3,5-dimethoxybenzyl)piperidme is prepared from 4-carboxamide-1-(3,5-dimethoxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-il-(3.5-dimethoxvbenzvlllpiperidinvlaminol-9- cvclopentvlpurine 5 2-Chloro-6-[4-[l-(3,5-dimethoxybenzyl)]piperidinylamino)-9-cyclopentylpurine is preparedfrom 2,6-dic’nloro-9-cyciopentylpurine, 4-amino-l-(3,5-dimethoxybenzyl)-piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvciohexvl)aminol-6-r4-ri-f3,5-dimethoxv- benzyl)lpiperidinvlamino1-9-cvclopentvlpurine trihydrochloride 10 2-[Trans-(4-aminocyclohexyl)aminoî-6-[4-(l-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-(1-(3,5-dimethoxy-benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 549 (M*1) 15 R, (min.) = 2.27

Example 147-d 2-rrrans-(4-aminocvclohexvl)aminol-6-[4-[l-[3,5-bis(trifluoromethvl)benzvlllpiperidinylaminol-9-cvclopentvlpurine trihydrochloride

Scheme B, step a: 4-Carboxamide-1-(3,5-bis-trifluoromethylbenzyl)piperidine 20 4-Carboxamide-1 -(3,5-bis-trifluoromethylbenzyl)piperidine may be prepared from isonipecotamide and bis(3,5-trifluoromethyl)benzyl bromide (available from Aldrich ChemicalCompany) essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-I-('3.5-bis-trifluoromethvlbenzyl)piperidine4-Amino-l-(3,5-bis-trifluoromethylbenzyl)piperidine is prepared from 4-carboxamide-1-(3,5- 25 bis-trifluoromethylbenzyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Scheme A, step b: 2-Chloro-6-i4-i 1 -(3,5-bis-trifluoromethvlbenzvI)1piperidinvlamino1-9- cyclopentvlpurine 2-Chloro-6-[4-[ 1 -(3,5-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine is 30 prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(3,5-bis- trifluoromethylbenzyl)piperidine, and triethylamine essentially as described above in Example 1,Scheme A, step b.

Scheme A, step c: 2-fTrans-i4-aminocvclohexvl)aminol-6-[4-f l-f3,5-bis- 011455 165 (trifluoromethvlbenzvI)lpiperidinvlamino1-9-cyclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-[3,5-bis(trifluoromethyl)benzyl]]- piperidinylamino]-9-cyclopentylpurine tnhydrochlonde is prepared from 2-chloro-6-[4-[l-bis(3,5-trifluoromethyl)benzyl))piperidinylamino]-9-cyclopentylpurme essentially as describedin Example 1, Scheme A, step c. APCI: 625 (M+l)

Rf (min.) = 2.37

Example 147-e 2-ÎTrans-(4-aminocvclohexvl')aminol-6-r4-ri-(2.3-difluorobenzvl)lpiperidinylamino1-9- cvclopentylpurine trihvdrochlorideScheme B, step a: 4-Carboxamide-1-(2,3-difluorobenzyl)piperidine4-Carboxamide-l-(2,3-difluorobenzyl)piperidine may be prepared from isonipecotamide and 2,3-difluorobenzyl bromide (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2.3-difluorobenzvl)piperidine 4-Amino-l-(2,3-difluorobenzyl)piperidine is prepared from 4-carboxamide-1-(2,3-difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-r4-il-(2,3-difluorobenzvl)1piperidinvlaminol-9- cyclopentylpurine 2-Chloro-6-[4-[l-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentyIpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2,3-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rTrans-(4-amtnocvclohexyl)amino1-6-i4-fl-(2.3-difluorobenzvl)l- piperidinvlaminol-9-cvclopentvlpurine trihvdrochlôride 2-[’ïrans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,3-difluoro-benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 525 (NT1)

Rf (min.) = 2.26

Example 147-f 2-rrrans-f4-aminocvclohexvl)amino1-6-f4-ri-(2.5-difluorobenzvl)1piperidinvlaininol-9- cyclopentvlpurine trihydrochloride 166 011455

Scheme B, step a: 4-Carboxamide-1-(2.5-difIuorobenzvl)piperidine 4-Carboxamide-1-(2,5-difluorobenzyl)piperidine may be prepared from isonipecotamide and 2.5- difluorobenzyl bromide (available from Aldrich Chemical Company) essentially as 5 described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2,5-difluorobenzvl)piperidine4-Amino-l-(2,5-difluorobenzyI)piperidine is prepared from 4-carboxamide-1-(2,5-difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-f4-il-(2,5-difluorobenzvl)1piperidinvlaminol-9- 10 cvclopentvlpurine 2-Chloro-6-[4-[l-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2.6- dichloro-9-cyclopentylpurine, 4-amino-l-(2,5-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-r4-fl-(2,5-difluorobenzvl)l- 15 piperidinvlaminol-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)ainino]-6-[4-[l-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,5-difluoro-benzyI)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. 20 APCI: 525 (M*1)

Rf (min.) = 2.26

Example 147-g 2-ÎTrans-(4-aminocvclohexvl)aminol-6-r4-ri-(3,5-difluorobenzvl)lpiperidinvlaminol-9- cvclopentvlpurine trihvdrochloride 25 Scheme B. step a: 4-Carboxamide-l-i3.5-difluorobenzvl)piperidine 4-Carboxamide-l-(3,5-difluorobenzyl)piperidine may be prepared from isonipecotamide and3,5-difluorobenzyI bromide (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B. step b: 4-amino-l-(3.5-difluorobenzvl)piperidine 30 4-Amino-1 -(3,5-difluorobenzyl)piperidine is prepared from 4-carboxamide-1 -(3,5- difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-ri-(3.5-difluorobenzvl)lpiperidinvlaminol-9- cyclopentvipurine 011455 167 2-Chloro-6-[4-[l-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3,5-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-('4-aminocvclohexvI)aminol-6-i4-|'l-f3,5-difluorobenzyrn- piperidinvlaminol -9-cvclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3,5-difluoro-benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 525 (M+1)

Rf (min.) = 2.25

Example 147-h 2-rrrans-(4-aminocvclohexvl)aminol-6-T4-fl-(2.4-difluorobenzyîïlpiperidinvlamino'l-9- cvclopentylpurine trihydrochlorideScheme B, step a: 4-Carboxamide-l-(2.4-difluorobenzvl)piperidine4-Cârboxamide-l-(2,4-difluorobenzyl)piperidine may be prepared from isonipecotamide and 2,4-difluorobenzyl bromide (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2,4-difluorobenzvl)piperidine4-Amino-l-(2,4-difluorobenzyl)piperidine is prepared from 4-carboxamide-1-(2,4-difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-r4-r 1 -(2.4-difluorobenzyl)1piperidinvlaminol-9- cvclopentvlpurine 2-Chloro-6-[4-[l-(2,4-difluorobenzyI)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2,4-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocvclohexvl)aminol-6-f4-fl-(2.4-difIuorobenzvl)l- piperidinvlaminol-9-cvclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,4-difluorobenzyl)]piperidinylamino]-9- cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,4-difluoro- benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. APCI: 525 W) 168 011455

Rf (min.) = 2.25

Example 147-i 2-rTrans-i4-aminocvclohexvl)anüno1-6-(4-fl-(3-methylbenzvl)lpiperidinvlaminol-9- cyclopentvlpurine trihvdrochloride 5 Scheme B, step a: 4-Carboxamide-l-(3-methvlbenzvl)piperidine 4-Carboxamide-l-(3-methylbenzyl)piperidine may be prepared from isonipecotamide and 3-methylbenzyl bromide (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(3-methvlbenzvl)piperidine 10 4-Amino-1 -(3-methylbenzyl)piperidine is prepared from 4-carboxamide-1 -(3- methylbenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-f4-i l-(3-methvlbenz^l)lpiperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-[l-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-methylbenzyl)piperidine, and triethylamine 15 essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-(4-aminocvclohexyl)aminol-6-f4-ri-f3-methvlbenzvl)1- piperidinvlaminol-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-[ 1 -(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3-methylbenzy 1)]- 20 piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.APCI: 503 (M+l)

Rf (min.) = 2.24

Example 147-i 2-rTrans-(4-aminocvclohexvl)amino1-6-i4-fl-(3-fluor9benzvl)lpiperidinvlaminol-9- 25 cvclopentvlpurine trihvdrochloride

Scheme B, step a: 4-Carboxamide- l-(3-fluorobenzvl)piperidine 4-Carboxamide-l-(3-fluorobenzyl)piperidine may be prepared from isonipecotamide and 3-fluorobenzyl bromide (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a. 30 Scheme B, step b: 4-amino-l-(3-fluorobenzvl)piperidine 4-Amino-l-(3-fluorobenzyl)piperidine is prepared from 4-carboxamide-1-(3- fluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Scheme A, step b: 2-Chioro-6-f4-il-(3-fluorobenzyl)1piperidinvlaminol-9-cyclopentylpurine 011455 169 2-Chloro-6-[4-[l-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-fluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-rrrans-(4-aminocvclohexvl)amino1-6-F4-il-(3-fluorobenzvI)l- piperidinvlaminol-9-cyclopentvIpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3-fluorobenzyI)]piperidinyiamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chioro-6-[4-[l-(3-fluorobenzyl)]-piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.APCI: 507 (M+1)

Rf (min.) = 2.25

Example 147-k 2-rrrans-(4-aminocvclohexvl)aminol-6-i4-fl-(2-fluorobenzvl)lpiperidinvlanünol-9- cvclopentylpurine trihydrochlorideScheme B, step a: 4-Carboxamide-l-(2-fluorobenzvl)piperidine 4-Caiboxamide-l-(2-fluorobenzyl)piperidine may be prepared from isonipecotamide and 2-fluorobenzyl bromide (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-f2-fluorobenzyl)piperidine 4-Amino-l-(2-fluorobenzyl)piperidine is prepared from 4-carboxamide-l-(2-fluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.

Scheme A, step b: 2-Chioro-6-r4-ri-(2-fluorobenzvl)1piperidinvlamino1-9-cvcîopentvlpurine 2-Chloro-6-[4-[l-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-fluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-fTrans-(4-aminocvclohexvl)aminol-6-i4-Fl-(2-fluorobenzvl)l- piperidinvlaminol-9-cyclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-[l-(2-fluorobenzyl)]piperidinylamino3-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-fluorobenzyl)]-piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c.APCI: 507 (M+1)

Rf (min.) = 2.22

Example 147-1 170 2-rTrans-('4-aminocvclohexvl)amino'l-6-i4-n-(4-fluorobenzvnipiperidinvlamino1-9- cvclopentvlpurine trihvdrochlorideScheme B. step a: 4-Carboxamide-l-f4-fluorobenzvI)piperidine 4-Carboxamide-l-(4-fluorobenzyl)piperidine may be prepared from isonipecotamide and 4- 5 fluorobenzyl bromide (available from Aldrich Chemical Company) essentiaily as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(4-fluorobenzvI)piperidine4-Amino-l-(4-fluorobenzyl)piperidine is prepared from 4-carboxamide-l-(4-fluorobenzyl)piperidine essentiaily as described above in Example 38, Scheme B, step b. 10 Scheme A, step b: 2-Chloro-6-f4-ri-(4-fluorobenzvl)lpiperidinviamino1-9-cvcIopentvlpurine 2-Chloro-6-[4-[l-(4-fluorobenzyl)]piperidinylamino}-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-fluorobenzyl)piperidine, and triethylamineessentiaily as described above in Example 1, Scheme A, step b

Scheme A, step c: 2-fTrans-(4-aminocvclohexvllaminol-6-f4-il-(4-fluoTobenzyl))- 15 piperidinvlaminol-9-cyclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(4-fluorobenzyl)]-piperidinylamino]-9-cyclopentylpurine essentiaily as described in Example 1, Scheme A, step c.APCI: 507 (M+1) 20 Rf (min.) = 2.23

Example 147-m 2-rTrans-f4-aminocvclohexvI)aminol-6-i4-ri-f3-trifluoromethylbenzvl)lpiperidinvlaminol-9- cyclopentylpurine trihvdrochloride

Scheme B, step a: 4-CarbQxamide-l-(3-trifluoromethvIbenzvl)piperidine 25 4-Caiboxamide-1 -(3-trifluoromethylbenzyl)piperidine may be prepared from isonipecotamideand 3-(trifluoromethyl)benzyl bromide (available from Aldrich Chemical Company) essentiailyas described above in Example 38, Scheme B, step a.

Scheme B, step b: .4-amino-l-i3-trifiuoromethvIbenzyl)piperidine4-Amino-l-(3-trifluoromethylbenzyl)piperidine is prepared from4-carboxamide-l-(3- 30 trifluoromethylbenzyl)piperidine essentiaily as described above in Example 38, Scheme B, stepb.

Scheme A, step b: 2-Chloro-6-[4-[l-(3-trifluoromethvlbenzvl)1piperidinyIamino1-9- cvclopentvlpurine 011455 171 2-Chloro-6-[4-[ l-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-aroino-l-(3-trifluoromethylbenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-iTrans-(4-aminocvclohexvl)aminol-6-f4-Fl-(3- trifluoromethvlbenzvl)lpiperidinvlaminol-9-cvclopentylpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyI)amino]-6-[4-[l-(3-trifluoromethylbenzyl)]-piperidinylamino]-9-cyciopentyïpurine trihydrochloride is prepared from 2-chloro-6-[4-(l-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. APCI: 557 (M+1)

Rf (min.) = 2.31

Example 147-n 2-rTrans-(4-aminocvclohexvl)aminol-6-f4-il-(2-chloro-6-fluorobenzvI)lpiperidinvlaminol-9- cyciopentyïpurine trihvdrochloride

Scheme B. step a: 4-Carboxamide-l-(2-chioro-6-fluorobenzvI)piperidine 4-Carboxamide-l-(2-chloro-6-fluorobenzyl)piperidine may be prepared from isonipecotamideand 2-chloro-6-fluorobenzyl chloride (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2-chloro-6-fluorobenzvl)piperidine 4-Amino-l-(2-chloro-6-fluorobenzyl)piperidine is prepared from 4-carboxamide-l-(2-chloro-6-fluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-f4-il-(2-chloro-6-fluorobenzyl)lpiperidinylamino1-9- cyciopentyïpurine 2-Chloro-6-[4-[ 1 -(2-chloro-6-fluorobénzyI)]piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-chloro-6-fluorobenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocyclohexvl)amino1-6-i4-f'l-{'2-chloro-6- fluorobenzvl)lpiperidinvlaminol-9-cvclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-chloro-6-fluorobenzyl)]-piperidniylamino]-9- cyciopentyïpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-chloro-6- fluorobenzyl)]piperidinylamino]-9-cyciopentylpurine essentially as described in Example 1,

Scheme A, step c. APCI: 541 (M+1) 172 011455

Rf (min.) = 2.22

Example I47-o 2-ΓΤ rans-( 4-aminocvclohexvl)aminol-6-f4-i I -f 3.4-dichlorobenzyl)lpiperidinvIamino1-9- cvclopentvlpurine trihvdrochloride 5 Scheme B, step a: 4-Carboxamide-l-(3,4-dichlorobenzyl)piperidine 4-Carboxamide-1-(3,4-dichlorobenzyl)piperidine may be prepared from isonipecotamide and 3,4-dichlorobenzyl chloride (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(3.4-dichlorobenzvl)piperidine 10 4-Amino-l-(3,4-dichlorobenzyl)piperidine is prepared from 4-carboxamide-1-(3,4- dichlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-14-fl-(3.4-dichlorobenzvl)lpiperidinvlaminol-9- cvclopentylpurine 2-Chloro-6-[4-[l-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 15 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3,4-dichlorobenzyl)piperidine, and tri ethyl amineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocyclohexvl)amino1-6-r4-ri-(3.4-dichlorobenzvl)l- piperidinvlaminol-9-cvclopentylpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)ainino]-6-[4-[l-(3,4-dichlorobenzyl)]piperidinylamino]-9- 20 cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3,4-dichloro- benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 557 (M+l)

Rf (min.) = 2.33 25 Example 147-p 2-rTrans-(4-aminocvclohexvl)amino1-6-r4-ri-(2-naphthvl)methvllpiperidinvlaminol-9- cvclopentvlpurine trihydrochlorideScheme B, step a: 4-Carboxamide-l-(2-naphthyI)methvlpiperidine 4-Carboxamide-l-(2-naphthyl)methylpiperidine may be prepared from isonipecotamide and 2- 30 (chioromethyl)naphthalene (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2-naphthvl)methvlpiperidine C1US5 173 4-Amino-l-(2-naphthyl)methylpiperidine is prepared from4-carboxamide-l-(2-naphthyl)methylpiperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-l-f2-naphthvl)methvnpiperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-l-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine is prepared from 5 2,6-dichloro-9-cyclopentylpurine, 4-amino- l-(2-naphthyl)methylpiperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-i4-ri-(2- naphthvl)methvIlpiperidinylaminol-9-cyclopentvlpurine trihvdrochloride2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-naphthyl)methyl]piperidinylamino]-9- 10 cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-l-(2- naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1,Scheme A, step c. APCI: 539 (M+1)

Rf (min.) = 2.30 15 Example 147-q 2-rrrans-(4-aminocvclohexvl)amino1-6-i4-n-(2-methoxvbenzvl)lpiperidinvlamino1-9- cvclopentvlpurine trihvdrochlorideScheme B, step a: 4-Carboxamide-l-(2-methoxvbenzvl)piperidine 4-Carboxamide-l-(2-methoxybenzyl)piperidine may be prepared from isonipecotamide and 2- 20 methoxybenzyl bromide (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-f2-methoxvbenzvl)piperidine4-Amino-l-(2-methoxybenzyl)piperidine is prepared from 4-carboxamide-l-(2-methoxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b. 25 Schème A, step b: 2-Chloro-6-i4-il-(2-methoxvbenzvl)lpiperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-[l-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-methoxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-i4-Fl-(2-methoxvbenzvl)l- 30 piperidinvlaminol-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-methoxybenzyl)]-piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, Scheme A, step c. 174 APCI: 519 (M+l)R, (min.) = 2.19

Example 147-r 2-ÎTrans-(4-aininocvclohexyl)aminol-6-i4-il-(2.5-dichlorobenzvI)lpiperidinvlaminol-9- 5 cvclopentylpurine trihvdrochloride

Scheme B, step a: 4-Carboxamide-l-(2,5-dichlorobenzvl)piperidine4-Carboxamide-1-(2,5-dichlorobenzyl)piperidine may be prepared from isonipecotamide and 2.5- dichlorobenzyl chloride (available from Lancaster) essentially as described above inExample 38, Scheme B, step a. 10 Scheme B, step b: 4-atnino-l-(2.5-dichlorobenzyl')piperidine 4-Amino-l-(2,5-dichlorobenzyl)piperidine is prepared from 4-carboxamide-1-(2,5-dichlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-i4-ri-(2.5-dichlorobenzyl)lpiperidinvlaminol-9- cvclopentvlpurine 15 2-Chloro-6-[4-[ 1 -(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2.6- dichloro-9-cyclopentylpurine, 4-amino-l-(2,5-dichlorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexvi)aminol-6-i4-il-(2.5-dichlorobenzvl)l- piperidinvlanunol-9-cvclopentvlpurine trihvdrochloride 20 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from2-chloro-6-[4-[l-(2,5-dichloro-benzyl)]piperidinylanüno]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 557 (M+1) 25 (min.) = 2.22

Example 147-s 2-rTrans-(4-anünocvclohexvl)aminol-6-r4-(l-cvclohexvlmethvl)piperidinvlaminol-9- cyclopentylpurine trihvdrochlorideScheme B, step a: 4-Carboxamide-l-cyclohexylmethylpiperidine 30 4-Carboxamide-l-cyclohexylmethylpiperidine may be prepared from isonipecotamide and cyclohexylmethyl bromide (available from Aldrich Chemical Company) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-cvclohexvlmethvlpiperidine 011455 175 4-Amino-1 -cyclohexy lmethy lpiperidine is prepared from 4-carboxamide-1 - cyclohexylmethylpiperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-f4-(l-cvclohexvlmethvl)piperidinvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-(l-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-cyclohexylmethylpiperidine, and triethy lamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l- cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine trihydrochloride 2-(Trans-(4-aminocyclohexyl)amino]-6-[4-(l-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-(l- cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine_essentially as described in Example 1,Scheme A, step c. APCI: 495 (M+1)

Rf (min.) = 2.25

Example 147-t 2-fTrans-f4-aminocvclohexyI)aminol-6-r4-f 1 -(2-chloro-4-fluorobenzvl)1piperidinvlamino1-9- cyclopentylpurine trihydrochloride

Scheme B. step a: 4-Carboxamide-l-f2-chloro-4-fluorobenzvl)piperidine 4-Carboxamide- l-(2-chloro-4-fluorobenzyl)piperidine may be prepared from isonipecotamideand 2-chloro-4-fluorobenzyl chloride (available from Lancaster or Acros) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B. step b: 4-amino-l-f2-chloro-4-fluorobenzvl)piperidine 4-Amino-l-(2-chloro-4-fluorobenzyl)piperidine is prepared from 4-carboxamide-l-(2-chloro-4-fluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-f4-f l-f2-chIoro-4-fluorobenzvl)1piperidinvIaminol-9- cyclopentvlpurine 2-Chloro-6-[4-[ 1 -(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-chloro-4-fluorobenzyI)piperidine, andtriethy lamine essentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-fTrans-(4-aminocvclohexyl)amino]-6-f4-f l-(2-chloro-4- fluorobenzvl)lpiperidinylaminol-9-cyclopentvlpurine trihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-chloro-4-fluorobenzyl)]-piperidinylamino]-9- cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-chloro-4- 011455 176 fluorobenzyl)]piperidinylamino}-9-cyclopentylpurine essentially as described in Example 1,Scheme A, step c. APCI: 541 (M+i)

Ri (min.) = 2.28 5 Example 147-u 2-ÎTrans-(4-aminocyclohexvi )aminol-6-f4-f 1 -(3.4-difluorobenzvl)lpiperidinvlamino1-9- cvclopentylpurine trihvdrochlorideScheme B, step a: 4-Carboxamide-l-(3.4-difluorobenzvl)pirieridine 4-Carboxamide-1-(3,4-difluorobenzyl)piperidine may be prepared from isonipecotamide and 10 3,4-difluorobenzyl bromide (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(3.4-difiuorobenzvPpiperidine4-Amino-l-(3,4-difluorobenzyl)piperidine is prepared from 4-carboxamide-1-(3,4-difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b. 15 Scheme A. step b: 2-ChIoro-6-f4-n-(3,4-difluorobenzvI)1piperidinvIamino'l-9- cvclopentylptirine 2-Chloro-6-[4-[l-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3,4-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. 20 Scheme A, stepc: 2-rTrans-(4-aminocvclohexvI)aminol-6-i4-fl-(3.4-difluorobenzvl)1- piperidinvlaminol-9-cyclopentvlpurine trihvdrochloride 2-ITrans-(4-anûnocyclohexyl)amino]-6-[4-[l-(3,4-difluorobenzyl)]piperiàinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3,4-difluoro-benzyl)]piperidinylatnino]-9-cyclopentylpurine essentially as described in Example 1, Scheme 25 A, step c. APCI: 525 (M+1)

Rf (min.) = 2.29

Example 147-v 2-rTrans-(4-aminocvcIohexvl)aminol-6-i4-fl-(2,6-difluorobenzvl)lpiperidinvlaminol-9- 30 cyclopentylpurine trihvdrochloride 011 455 177

Scheme B, step a: 4-Carboxamide-l-f2.6-difluorobenzvl)piperidine 4-Carboxamide-1-(2,6-difluorobenzyl)piperidine may be prepared from isonipecotamide and 2.6- difluorobenzyI bromide (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-1-(2,6-difluorobenzvl)piperidine 4-Amino-l-(2,6-difluorobenzyl)piperidine is prepared from 4-carboxamide-1-(2,6-difluorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-il-(2,6-difluorobenzvl)lpiperidinylaminol-9- cyclopentylpurine 2-Chloro-6-[4-[l-(2,6-difluorobenzyl)]piperidinylamino]-9-cyciopentylpurine is prepared from 2.6- dichloro-9-cyclopentylpurine, 4-amino-1 -(2,6-difluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rrrans-(4-aminocyclohexyl)amino1-6-i4-il-(2,6-difluorobenzvl)l- piperidinvlamino1-9-cvclopentvlpurine trihydrochloride 2-Prans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,6-difluoro-benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. AFCI: 525 (M+1) R,· (min.) = 2.26

Example 147-w 2-rTrans-(4-aminocyclohexvl)aminol-6-r4-ri-(3.5-dichlorobenzyl)lpiperidinvlamino'}-9- cyclopentylpurine trihydrochlorideScheme B. step a: 4-Carboxamide-l-(3.5-dichIorobenzvl)piperidine4-Carboxamide-1 -(3,5-dichlorobenzyl)piperidine may be prepared from isonipecotamide and 3,5-dichlorobenzyl chloride (available from Trans World Chemicals or Fluorochem Ltd.)essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-f3,5-dichlorobenzvl)piperidine4-Amino-l-(3,5-dichlorobenzyl)piperidine is prepared from 4-carboxamide-1-(3,5-dichlorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-i4-ri-(3,5-dichlorobenzyl)1piperidinvlaminol-9- cyclopentvlpurine 011455 178 2-Chloro-6-[4-[l-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(3,5-dichlorobenzyI)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b. -

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino1-6-i4-il-(3.5-dichlorobenzvl)1- 5 piperidinvlaminol-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(3,5-dichlorobenzyI)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-(l-(3,5-dichloro-benzyI)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. 10 APCI: 557 (M+1)

Rf (min.) = 2.31

Example 147-x 2-rTrans-(4-aminocvclohexvl)aminol-6-F4-il-(2.4-dichlorobenzvI)lpiperidinylaminol-9- cvclopentvlpurine trihvdrochloride 15 Scheme B, step a: 4-Carboxamide-l-(2.4-dichlorobenzvl)piperidine 4-Carboxamide-l-(2,4-dichlorobenzyl)piperidine may be prepared from isonipecotamide and 2,4-dichlorobenzyl chloride (available from Aldrich Chemical Company) essentially asdescribed above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(2.4-dichlorobenzvI)piperidine 20 4-Amino-1 -(2,4-dichlorobenzyl)piperidine is prepared from 4-carboxamide-1 -(2,4- dichiorobenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-F4-fl-(2.4-dichlorobenzvl)lpiperidinvlamino1-9- cyclopentvlpurine 2-Chloro-6-[4-[l-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 25 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(2,4-dichlorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-FTrans-i4-aminocyclohexvl)aminol-6-F4-ri-(2,4-dichlorobenzvl)1- piperidinvIaminol-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,4-dichlorobenzyl)]piperidinylamino]-9- 30 cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,4-dichloro- benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 557 (M+I) 179 °H455

Rf (min.) = 2.31

Example 147-v 2-|Trans-(4-aminocvclohexvl)amino1-6-r4-[l-(3-chloro-4-methvlbenzvl)1piperidinvIaminol-9- cvclopentylpurine trihvdrochloride

Scheme B. step a: 4-Carboxamide-l-(3-chloro-4-methvlbenzvl)piperidine 4-Carboxamide-l-(3-chloro-4-methyIbenzyl)piperidine may be prepared from isonipecotamideand 3-chloro-4-methylbenzyl chloride (available from Pfaltz-Bauer) essentially as describedabove in Example 38, Scheme B, step a.

Scheme B. step b: 4-amino-l-(3-chloro-4-methvlbenzvI)piperidine 4-Amino-l-(3-chloro-4~methylbenzyl)piperidine is prepared from 4-caiboxamide-l-(3-chloro-4-methylbenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A. step b: 2-Chloro-6-i4-f l-(3-chloro-4-methvlbenzvI)lpiperidinvIamino'l-9- cvclopentylpurine 2-Chioro-6-[4-[ 1 -(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(3-chloro-4-methylbenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. stepc: 2-fTrans-(4-aminocvciohexvl')amino1-6-i4-il-(3-chloro-4-methvlbenzvl)l- piperidinvIaminol-9-cvclopentvIpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3-chloro-4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1,Scheme A, step c. APCI: 537 (M+1) R<. (min.) = 2.25

Example 147-z 2-rrrans-(4-aminocvclohexvl)amino)-6-f4-fl-(4-trifluoromethoxybenzvl)lpiperidinvlamino1-9- cvclopentylpurine trihvdrochloride

Scheme B, step a: 4-Carboxamide-l-(4-trifluoromethoxvbenzyI)piperidine4-Carboxamide-l-(4-trifluoromethoxybenzyI)piperidine may be prepared from isonipecotamideand 4-(trifluoromethoxy)benzyl bromide (available from Aldrich Chemical Company)essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-(4-trifluoromethoxvbenzvI)piperidine 180 4-Amino-l-(4-trifluoromethoxybenzyl)piperidine is prepared from 4-carboxamide-1-(4-trifluoromethoxybenzyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Scheme A, step b: 2-Chloro-6-i4-ri-f4-trifluoromethoxybenzvl)lpiperidinvlamino1-9- 5 cvclopentylpurine 2-Chloro-6-[4-[l-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(4-trifluoromethoxybenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b.

Scheme A. step c: 2-ÎTrans-(4-aminocvclohexyI)amino'l-6-f4-n-i4-10 trifIuoromethoxvbenzvl)lpiperidinvlaminol-9-cvclopentylpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(4-trifluoromethoxybenzyI)]-piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[I-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. 15 APCI: 573 (M*‘)

Rf (min.) = 2.23

Example 147-aa 2-rTrans-(4-aminocvclohexvl)amino1-6-f4-fl-(2.4-bis-trifïuoromethvlbenzyl)lpiperidinvlaminol- 9-cyclopentvlpurine trihvdrochloride 20 Scheme B, step a: 4-Carboxamide-l-(2.4-bis-trifIuoromethvlbenzvl)piperidine 4-Carboxamide-1-(2,4-bis-trifluoromethylbenzyl)piperidine may be prepared fromisonipecotamide and bis(2,4-trifluoromethyl)benzyl bromide (available from Aldrich ChemicalCompany) essentially as described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-1 -(^^-bis-trifluoromethvlbenzvhpiperidine25 4-Amino-1 -(2,4-bis-trifluoromethylbenzyl)piperidine is prepared from 4-carboxamide-1 -(2,4- bis-trifluoromethylbenzyl)piperidine essentially as described above in Example 38, Scheme B,step b.

Scheme A, step b: 2-Chloro-6-i4-Fl-(2.4-bis-trifluoromethvlbenzvI)lpiperidinvlaminol-9- cvclopentvlpurine 30 2-Chloro-6-[4-[l-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyciopentylpurine, 4-amino-1-(2,4-bis- trifluoromethylbenzyl)]piperidine, and triethylamine essentially as described above in Example1, Scheme A, step b. 181 011455

Scheme A, step c: 2-rTran$-('4-aminocyclohexvl')amino1-6-i4-il-f2,4-bis- trifluoromethvlbenzvl)lpiperidinvlamino1-9-cvclopentvlpurine trihvdrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,4-bis-trifluoromethylbenzyl)]-piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2,4- 5 bis-trifluoromethylbenzyl)]piperidinyiamino]-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c. APCI: 625 (M*1)

Rf (min.) = 1.44

Example 147-ab 10 2-rTrans-(4-aminocyclohexvl)amino1-6-i4-il-(2-trifluoromethoxvbenzvl)lpiperidinylaminol-9- cvclopentvlpurine trihvdrochloride

Scheme B. step a: 4-Carboxamide-l-(2-trifluoromethoxvbenzvl)piperidine4-Carboxamide-l-(2-trifluoromethoxybenzyl)piperidine may be prepared from isonipecotamideand 2-(trifluoromethoxy)benzyl bromide (available from Fluorochem Ltd.) essentially as 15 described above in Example 38, Scheme B, step a.

Scheme B, step b: 4-amino-l-f2-trifluoromethoxvbenzvl)piperidine4-Amino-1 -(2-trifluoromethoxybenzyI)piperidine is prepared from 4-carboxamide-1 -(2-trifluoromethoxybenzyl)piperidine essentially as described above in Example 38, Scheme B,step b. 20 Scheme A, step b: 2-Chloro-6-[4-ri-(2-trifluoromethoxvbenzvl)lpiperidinvlaminol-9- cvclopentvlpurine 2-Chloro-6-[4-[ 1 -(2-trifluoromethoxybenzyl)Jpiperidinylamino]-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-amino-l-(2-trifluoromethoxybenzyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A, step b. 25 Scheme A. step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-r4-ri-(2- trifluoromethoxvbenzvl)1piperidinvlamino1-9-cyclopentvlpurine trihvdrochloride2-[Trans-(4-aminocyclohexyi)amino]-6-[4-[l-(2-trifluoromethoxybenzyl)]-piperidinylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(2-trifluoromethoxybenzyI)]piperidinylamino]-9-cyclopentylpurine essentially as described in 30 Example 1, Scheme A, step c. APCI: 573 (M*1)

Rf (min.) = 2.26

Exampie 147-ac 011455 182 2-rTrans-(4-aminocyclohexvl)amino1-6-r4-(l-benzvl)piperidinylmethvlamino1-9- cyclopentvlpurine trihydrochlorideN-Benzyl-4-f aminomethyDpiperidine N-Benzyl-4-aminomethylpiperidine is prepared from 4-(aminomethyl)piperidine (available from 5 Aldrich Chemical Company) as described by L. G. Humber [J. Med. Chem., 9,441-443 (1966)]Scheme A, step b: 2-Chloro-6-f4-(l-benzvl)piperidinvlmethvlaminol-9-cvclopentvlpurine 2-Chloro-6-[4-(l-benzyl)piperidinylmethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, N-benzy]-4-aminomethylpiperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b. 10 Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)amino]-6-r4-(l-benzvl)piperidinvlmethylamino]-9-cyclopentvlpurine trihvdrochloride2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-benzyl)piperidinylmethylamino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chioro-6-[4-(l-benzyl)piperidinylmethylamino]-9-cyclopentylpurine essentially as described in Example 1, 15 Scheme A, step c. APCI: 503 (M*1)

Rf (min.) = 2.24

Example 147-ad 2-FTrans-(4-aminocvclohexvl)amino]-6-i4-il-(3-phenoxvbenzvl)lpiperidinvlamino1-9- 20 cyclopentvlpurine trihydrochloride

Scheme B. step a: 4-Carboxamide-l-(3-phenoxvbenzvl)piperidine 4-Carboxamide-l-(3-phenoxybenzyl)piperidine may be prepared from isonipecotamide and 3-phenoxybenzyl chloride (available from Lancaster) essentially as described above in Example38, Scheme B, step a. 25 Scheme B. step b: 4-amino-l-(3-phenoxvbenzvI)piperidine 4-Amino-l-(3-phenoxybenzyl)piperidine is prepared from 4-carboxamide-l-(4-phenoxybenzyl)piperidine essentially as described above in Example 38, Scheme B, step b.Scheme A, step b: 2-Chloro-6-f4-il-(3-phenoxvbenzyl)lpiperidinvlamino]-9-cvclopentylpurine 2-Chloro-6-[4-[l-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurine is prepared from 30 2,6-dichloro-9-cyclopentylpurine, 4-amino-1 -(3-phenoxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

Scheme A, step c: 2-rTrans-(4-aminocvclohexvl)aminol-6-r4-Fl-(3-phenoxvbenzyl)1- piperidinvlaminol-9-cvclopentvlpurine trihvdrochloride 011455 183 2-[Trans-(4-aminocyclohexyl)aminoj-6-[4-[l-(3-phenoxybenzyl)]piperidinylarnino]-9-cyclopentylpurine trihydrochloride is prepared from 2-chloro-6-[4-[l-(3-phenoxy-benzyl)]piperidinylamino]-9-cyclopentylpurine essentially as described in Example 1, SchemeA, step c. APCI: 581 (M+1)

Rf (min.) = 2.35

The term "neoplastic disease State" as used herein refers to an abnormal State or conditioncharacterized by uncontroiled prolifération. Neoplastic disease States include leukemias,carcinomas and adenocarcinomas, sarcomas, melanomas, and mixed types of neoplasms.

Leukemias include, but are not limited to, acute lymphoblastic, chronic lymphocytic,acute myeloblastic and chronic myelocytic leukemias.

Carcinomas and adenocarcinomas include, but are not limited to, those of the cervis,breast, prostate, esophagus, stomach, small intestines, colon, ovary and lungs.

Sarcomas include, but are not. limited to, œsteromas, osteosarcoma, lipoma, lipsarcoma,hemangiomas and hemangiosarcoma.

Melanomas include, but are not limited to, amelanotic and melanotic melanomas.

Mixed types of neoplasms include, but are not limited to, carcinosarcoma, lymphoidtissue type, foiiculiar réticulum, cell sarcoma and Hodgkins Disease.

The terni "therapeutically effective amount"of a compound of the formula (I) refers to anamount which is effective, upon single or multiple dose administration to the patient, incontrolling the growth of the neoplasm or métastasés of the neoplasm or preventing apoptosis. A therapeutically effective amount of a compound of the formula will vary according to the âge,weight, type of neoplasm to be treated, the combination of other antineoplastic agents, and othercriteria well known to those skilled in the art using standard clinical and laboratory tests andprocedures. A therapeutically effective amount of a compound of the formula will varyaccording to the type of cell susceptible to apoptosis, the location of the infarct, as well as theâge, weight and other criteria well known to those skilled in the art.

The term "controlling the growth" of the neoplasm refers to slowing, interrupting,arresting or stopping the growth of the neoplasm or metastates of the neoplasm. The term"controlling the growth" of the neoplasm also refers to killing the neoplasia or metastates of theneoplasia.

An effective amount of a compound of the formula is that amount which is effective, 184 011455 upon single or multiple dose administration to a patient in providing an antineopiastic effect or inpreventing apoptosis. An "antineopiastic effect" refers to the slowing, interrupting, preventing ordestruction of further growth of neoplastic cells.

An effective antineopiastic amount of a compound of the formula can be readily 5 determined by an attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under anaiogous circumstances. In determining theeffective amount, a number of factors are considered by the attending diagnostician, includingbut not limited to, the species of mammal; its size, âge and general health; the spécifie diseaseinvolved; the degree of or involvement or the severity of the disease; the response of the 10 individual patient; the particular compound of the formula administered; the mode ofadministration; the bioavailability characteristics of the préparation administered; the doseregimen selected; the use of concomitant médication; and other relevant circumstances. A further embodiment of the présent invention includes a method for the prophylactictreatment of a patient at risk of developing a neoplastic disease State comprising administering a 15 prophylactically effective antineopiastic amount of a compound of the formula. The term "apatient at risk of developing a neoplastic disease State" refers to a patient who, because of anidentified genetic prédisposition to neoplasms, had or currently hâve neoplasms, exposure ofcarcinogenic agents, diet, âge or has other risk factors associated with the development ofneoplastic disease States. Preferred patients at risk of developing a neoplastic disease State 20 include patients who are positive for oncogenic viruses, are in remission from prior treatment ofneoplasm(s), use tobacco products or hâve previously been exposed to carcinogens such asasbestos, or are positive for various neoplastic genetic markers.

Oncogenic viruses are those viruses associated with cancers. For example, Rous sarcomaof chickens, Shope rabbit papilloma, murine leukemia viruses are animal viruses recognized as 25 having a rôle in development of various cancers. Human papillomavirus is associated withgénital cancer. Molluscum contagiosum virus is associated with molluscum contagiosumtumors. The JC virus, a human papovirus, is associated with disorders of reticulendothelialSystem such as leukemia and lymphoma. Human retroviruses such as human T-celllymphotropic viruses (HTLV) types 1 and 2 are associated with some human leukemias and 30 lymphomas. Human immunodeficiency viruses (HIV) types 1 and 2 are the causes of AIDS.Epstein-Barr virus has been associated with various malignancies, including nasopharyngealcarcinoma, African Burkitt’s lymphoma and lymphomas in immunosuppressed organ transplantrécipients. 011455 185

Genetic markers such as mutations, rearrangments and the like in BRCA 1, bcl-1/PRADl,cyclin D1/CCND1, p!6, cdk4, especially an Arg24Cys mutation, plô^4*. Genetic markers areassociated with prédispositions to various neopiasms. For example, alterations in the BRCA 1gene are associated with a higher risk for breast and ovarian cancer. Other genetic markersinclude alterations in the MMSCl gene, which interracts with the MMCA1 brain and prostatecancer gene, in the CtlP gene, which is linked to the BRACA1 gene in breast and ovarian cancer,binds to the BRCA1 gene and is linked to the E1A oncogene pathway, and in the MKK3 gene,which is a cell cycle control gene that acts as a tumor supressor in lung cancer by activatingapoptosis. Patients at risk of developing a neoplastic disease State also include patients whooverexpress various cell cycle proteins, including cdk4, cyclins B1 and E. Patients at risk ofdeveloping a neoplastic disease State include those with elevated levels of tumor markers.

Known tumor markers include prostate spécifie antigen (PSA) and plasma insulin-like growthfactor-1 (IGF-1), which are markers for prostate cancer. Nuclear matrix proteins (NMPs) areassociated with the presence of cancer, particularly bladder and colon cancers.

An effective amount of a compound of the formula is expected to vary from about 25nonograms per kilogram of body weight per day (ng/kg/day) to about 500 mg/kg/day. Preferredeffective amounts of a compound of the formula is from about 1 pg/kg/day to about 500pg/kg/day. A more preferred amount of a compound of the formula is from about 1 pg/kg/day toabout 50 pg/kg/day. A compound of the formula may be administered in any form or mode which makes thecompound bioavailable in effective amounts. Compounds of the formula may be administeredby oral or parental routes. Compounds of the formula may be administered orally,subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, ocularly andthe like. Oral administration is preferred. One skilled in the art of preparing pharmacueticalformulations may readily détermine appropriate forms of a compound of the formula bydetermining particular characteristics of the compound, the disease to be treated, the stage of thedisease, response of other patients and other relevant circumstances. A compound of the formula may be combined with carriers, excipients or othercompounds to préparé compositions of a compound of the formula. A composition of theformula comprise a compound of the formula in admixture or otherwise in association with oneor more inert carriers. Compositions of the formula are useful, for example, as convenient meansof making bulk shipments, or for storing, a compound of the formula. An inert carrier is amaterial which does not dégradé or otherwise covalently react with a compound of the formula. 186 011455

An inert carrier may be a solid, semi-solid or liquid material. Preferred carriers are water,aqueous buffers, organic solvents and pharmaceutically acceptable carriers or excipients.

Preferred aqueous buffers provide a buffering range at which a compound of the formula doesnot dégradé. Preferred buffering ranges are about pH 4 to about pH 9. Preferred organic solvents 5 are acetonitrile, ethyl acetate, hexane. A pharmaceutical composition of a compound of the formula comprises a compound ofthe formula in admixture or otherwise in association with one or more pharmaceuticallyacceptable carrier or excipient. A pharmaceutically acceptable carrier or excipient may be asolid, semi-solid or liquid material which can serve as a vehicle or medium for the compound of 10 the formula. Suitable pharmaceutically acceptable carriers or excipients are well-known to thoseskilled in the art. A pharmaceutical composition of a compound of the formula may be adapted for theroute of administration. A preferred pharmaceutical composition of a compound of the formula isa tablet, troche, capsule, élixir, syrup, wafer, chewing gum, suppository, solution or suspension if 15 the route of administration is oral, parental or topical. A preferred oral pharmaceutical composition of a compound of the formula comprises acompound of the formula with an inert diluent or with an edible carrier. Preferred forms of oralpharmaceutical compositions of a compound of the formula are tablets, troches, capsules, élixirs,syrups, wafers, chewing gum, solutions or suspensions. 20 Preferred pharmaceutical compositions of a compound of the formula contain frorn about 4% to about 80% of the compound. Preferred pharmaceutical compositions contain an amount ofthe compound of the formula from about 50 qg to about 500 gg; more preferred pharmaceuticalcomposition contain an amount of the compound of the formula from about 1 gg to about 200P-g· 25 A compound of the formula may be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients.

The following abbreviations are used herein: mg, milligram; pg, microgram; qg,nanogram; TEA, triethlyamine; mmol, millimole: mL, milliliter; C, Celsius; hr, hour, TLC, thinlayer chromotography; CH2CL,, methylene chloride; MeOH, methanol; EtOH, éthanol; N, 30 Normal; HCl, hydrogen chloride; TFA, trifluoroacetic acid, DIEA, diisopropylethylamine; RTPCR, reverse transcription polymerase chain reaction; HEPES, 4-(2-hydoxyethyl0-l-piperazineethanesulfonic acid); MgCl2, Magnésium chloride; EGTA, ethylene glycol-bis(P- aminoethylether)-N,N,N’,N’-tetraacetic acid; EDTA, ethylenediaminetetraacetic acid; DTT, 187 ο 11 4;5 $ dithiothreitol; MOI, multiplicity of infection; NaF, Sodium flouride; BSA, bovine sérumalbumin; p.o., oral(ly) i.v., intravenous(ly); s.c., subcutaneous(ly). EXAMPLE 148

Cyclin-dependent kinase 4 Assay

The ICJ0 values for cdk-4 inhibition were by the following method:

Substrate:

Glutathione S-transferase - retinoblastoma fusion protein (GST-Rb) (Kaelin, W. G., Jr., et al..,

Cell 64: 521-532, 1991) was obtained from Dr. William Kaelin. GST-Rb was prepared bytransformation of E. coli with the plasmid pGEX-Rb (379-928). The transformed bacteria weregrown ovemight to saturation, then diluted in YT broth and incubated at 37°C for 2 h. Theprotein was induced by incubation with 0.1 mM isopropylthioglycoside for 3 h. Followingsédimentation by centrifugation, the cells were lysed by sonication in STE buffer (0.1 mM NaCl,10 mM Tris, pH 8.0, 1 mM EDTA) containing 10 % sarkosyl. Particulate matter was removed bycentrifugation and the lysate was incubated with glutathione-Sepharose at 4°C. The beads werewashed with kinase buffer and then quantitation of Coomassie blue-stained proteins separated bySDS-PAGE was performed using a protein standard of known concentration.

Expression of CDK4/Cvclin DI in Insect Cells:

Human cyclin-dependent kinase 4 (cdk4) was cloned by RT PCR using degenerateprimers based on thè published amino acid sequence (Matsushime, H, et al., Cell. 7 T. 323-334,1992). The cDNA for human cyclin DI was cloned by RT PCR using genomic DNA from MCF-7 cells. The sequence was consistent with the published sequence (Xiong, Y., et al„ Cell. 65:691-699, 1991.). Both the cDNAs for cdk4 and cyclin DI were cloned into pFastBac (LifeTechnologies) and recombinant Bacmid DNA containing the cDNAs was produced by site-specific transposition using the Bac-to-Bac Baculovirus expression System purchased from LifeTechnologies (catalog # 10359-016). Bacmid DNA was used to transfect Sf9 insect cells toproduce recombinant virus. Following plaque purification of the virus, the viral préparationswere amplified until high titer stocks were acheived. Optimum coexpression of the recombinantproteins was determined to be acheived with an MOI of 0.1 for both cdk4 and cyclin DI at 72 hpost infection.

Lysâtes were prepared by lysis of Sf9 cells coinfected with cdk4 and cyclin DI in 50mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.1 mM phenylmethylsulfonyl fluoride, 5p.g/ml aprotinin, and 5 pg/ml Ieupeptin using a PARR bomb under 500 p.s.i nitrogen pressure for5 min at 4°C. Insoluble material was sedimented at 10,000 x g for 20 min at 4°C. Giycerol was 188 011455 added to the supematant to 10 % and stored at -80°C in aliquots.

Kinase Assav:

Pre-wet Millipore Multiscreen 96-weII filter plates (0.65 pm Durapore filters) with 200 μΐkinase buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM EGTA). GST-Rb (0.5 pg) bound 5 to glutathione-Sepharose beads is added in 50 μΐ per well and the solution removed by application of vacuum. The assay contains 50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM EDTA, 1 mM DTT, 1 mM EGTA, 10 mM β-glycerophosphate, 0.1 mM sodium orthovanadate, O.lmMNaF, 0.25 % BSA, 10 μΜ ATP and 0.25 pCi of [γ33Ρ]-ΑΤΡ. Add 0.1 pg cdk4/cyclin DI (insectcell lysate) to initiate assay. Incubate 30 min at 37°C. Terminate reaction by filtration on 10 Millipore Vacuum Manifold. Wash four times with TNEN (20 mM Tris, pH 8.0,100 mM Na Cl,lmM EDTA, 0.5 % nonidet P-40). After drying the plates at room température, the filter plateswere placed in adapter plates (Packard) and 40 pl of Microscint-O® (Packard) was added to eachwell. Top Seal A film was used to cover the plates before counting in a Top Count ScintillationCounter. 15 The results are provided in Table 1. EXAMPLE 149 cdk-2 Inhibition Studies

The IC50 values for CDK-2 inhibition were determined by the following method:Cvclin-Dependent Kinase 2 Assav

20 Substrate: GST-Rb as described above for cdk4/cvclin DI

Expression of CDK2/Cvclin E in Insect Cells:

Recombinant baculoviruses for human cdk2 and cyclin E were obtained from Dr. David

Morgan at UC, Berkeley (Desai, D. et al. Molec. Biol. Cell, 3:571-582, 1992). Optimumcoexpression in insect cells was obtained at MOI’s of 0.1 and 1.0 for cdk2 and cyclin E, 25 respectively, at 72 h post infection.

Kinase Assay:

Assay conditions for cdk2/cyclin E were identical to those for cdk4/cyclin DI includingthe substrate. The concentration of recombinant cdk2/cyclin E in the assay was 0.1 pg per 100 plassay. Incubation was for 30 min at 30°C. 30 The results are provided in Table 1.

Example 150

Cdkl/Cvclin H Assav Protocol 189 01 1455

Substrate: Peptide substrate H?N-RRR(YSPTSPSVCQOH based on seouence of CTD of RNA

polvmerase IL

Expression of CDK7/Cvclin H in insect cells:

Human cdk7 was cloned by reverse transcription PCR. The sequence was consistent with thatreported by Tassan, J. P., et al., J. Cell Biol. 127: 467-478,1994 and Darbon, J. M. et al.Oncogene. 9: 3127-3138, 1994. The cDNA for cyclin H was also cloned by reverse transcriptionPCR and the sequence was consistent with that reported by Fisher &amp; Morgan, Cell, 78:713-724,1994.Recombinant Bacmid DNA and viral stocks were prepared as described above for cdk4 andcyclin Dl. Optimum coexpression was achieved at MOI’s of 1 and 2 for cdk7 and cyclin H,respectively at 48 h post infection.

Kinase Assav:

The assay measures the phosphorylation of a peptide substrate (based on the C-terminal domainof RNA polymerase Π) by cyclin-dependent kinase 7 which is activated by cyclin H. [yæP]-phosphate is transferred from ίγ®Ρ]-ΑΤΡ to the peptide substrate by the enzyme. The assay isrun in 96-well V-bottom plates, then following termination the réaction is transfemed to 96-wellMillipore Multiscreen phosphocellulose fïlter plates. The peptide is retained on thephosphocellulose membrane after washing with a phosphoric acid solution.

Method:

Enzyme assay is run in 96-well V-bottom plates in a total volume of 100 μΐ.

Assay contains 15 μΜ ATP, 0.5 μθ [γ*3Ρ]-ΑΤΡ, 50 mM Hepes, pH 7.5,10 mM MgCl2,1 mMEDTA, 1 mM DTT, 10 mM β-glycerophosphate, 0.1 mM sodium orthovanadate, 0.1 mM NaF,10 μΜ peptide substrate. To initiate the assay, 0.125 ng cdk7 and cyclin H (insect cell lysate) isadded. Incubation is for 5 min at 24°C. Réaction is terminated by addition of 40 μΐ cold 300 mMphosphoric acid to each sample. Contents of V-bottom wells were then transferred to a Millipore96-well phosphocellulose filter plate. After sitting for 15 min at room température vacuum wasapplied to the filter plate and the wells were washed 4 x with 100 μΐ of cold 75 mM phosphoricacid. After removal of the underdrain assembly, filters were dried completely, placed inMultiscreen microplate adapters, and 40 μΐ of Micro-Scint O added to each well. Plates werecovered with Top-Seal A film and counted for 1.5 min using a Packard Top Count ScintillationCounter.

The results are provided in Table 1

Example 151 190 011455 CDKl/cvclin B f33P1 SP A Assav Protocol

Substrate:

The assay uses a biotinylated substrate peptide (biotin-PKTPKKAKKL) derived from the in vitrop34ed!:2 phosphorylation site of histone Hl. 5 Expression of Cdkl/Cvciin B1 in insect cells:

Human cdkl was cloned by reverse transcription PCR. The sequence was consistent with thatreported by Lee, M. G. and Nurse, P. Nature. 327:31-33,1987. The cDNA for cyclin H was alsocloned by RT PCR and the sequence was consistent with that reported by Pines, J. and Hunter, T., Cell. 58: 833-846, 1989. Recombinant Bacmid DNA and viral stocks were prepared as 10 described above for cdk4 and cyclin D1. Optimum coexpression was achieved at an MOI of 0.1for both cdkl and cyclin B1 at 48 h post infection.

Kinase Assay: p34cdc2 SP A [33P] kinase enzyme assay kit was purchased from Amersham LifeScience (catalog # RPNQ0170) and the protocol was performed as a 96-well format assay assuggested by the manufacturer. Each assay contained 50 mM Tris HCl, pH 8.0,10 mM MgCl2, 15 0.1 mM Na3VO4 (sodium orthovanadate), 0.5 uM ATP, 0.2 gCi 33P-ATP, 2 μΜ DTT and 0.75 uMbiotinylated peptide and 3 gg cdkl/cyclin B insect cell lysate in a total assay volume of 100 gl.Incubation was for 30 min at 30°C. The reaction was terminated by addition of 200 uL of stopbuffer (50 uM ATP, 5 mM EDTA, 0.1%(v/v) Triton X-100 in phosphate bufferedsaline)ystreptavidin-coated SPA beads (2.5 mg/ml). The plate was left at room température 20 ovemight then covered with a Packard TopSeal and counted on a Packard TopCount. The IC50value was determined by fitting the data into a sigmodial curve using GraphPad Prism software!

Example 152In Vitro Tumor Inhibition

In Vitro Prolifération Assay: 25 The prolifération of tumor cells was measured using a sulforhodamine B assay as described inSkehan, P., et al., J. Natl. Cancer Inst. 82: 1107-1112, 1990. Tumor cells were harvested withtrypsin-EDTA, cells that excluded trypan blue were counted, added to 96-well plates andincubated ovemight at 37°C. Drug was added to the wells following dilution in culture medium.Three days later, the medium was removed and replenished with medium containing fresh drug 30 and incubated an additional 4 days.The cells were then fïxed with 0.1 ml 10 % trichloroaceticacid for 60 min at 4°C. The plates were rinsed five times with tap water, air-dried and stained for30 min with 0.4 % sulforhodamine B in 1% acetic acid and air-dried. Bound dye wassolubilized with 0.1 ml 10 mM Tris (pH 10.5) for 5 min and the absorbance measured at 490 nm 011 455 191 using a Titertek Multiscan MCC/340 plate reader.

Altematively, the CyQUANT cell prolifération assay was used to quantitate cell prolifération.

CvOUANT Cell Prolifération Assav:

Altematively, the CyQUANT cell prolifération assay was used-to quantify tumor cellprolifération. Tumor cells were harvested with trypsin-EDTA, cells that excluded trypan bluewere counted, added to 96-well plates and incubated overnight at 37°C. Drug was added to thewells following dilution in culture medium. Three days later the medium was removed and theplates frozen at -80 °C for at least 30 minutes. After thawing the plates, 200 /zL of CyQUANT-GR in Cell Lysis Buffer (Molecular Probes # C-7026) was added to each well and incubated 3-5minutes at room température. Fluorescence of CyQUANT-GR was measured on a MolecularDevices Fmax fluorescence microplate reader (excitation 485 nm, émission 530 nm).

Cell Lines: MCF7 is a human breast adenocarcinoma, hormone-dependent (HTB 22); MDA-MB-231 is a human breast adenocarcinoma, hormone-independent (HTB 26); HT-29 is a human colon adenocarcinoma, moderately well-differentiated grade Π (HTB 38);HCT-15 is a human colon adenocarcinoma (CCL 225); A549 is a human non-small cell lung carcinoma (CCL 185); PC-3 is a human prostate adenocarcinoma, hormone-independent (CRL 1435); andDU 145 is a human prostate carcinoma, hormone-independent (HTB 81).

Ail of the cell lines were obtained from American Type Tissue Collection, with the ATCCaccession number in parentheticals. MCF-7, MDA-MB-435 and and MDA-MB-231 cells were grown in improved minimumessential medium (Biofluids) without phénol red, supplemented with 5 % fêtai bovine sérum,0.01 mg/ml gentamicin and 3 mM L-glutamine. Ail of the other cell lines were grown in RPMI1640 medium (Life Technologies) supplemented with 5 % fêtai bovine sérum, 0.01 mg/mlgentamicin and 3 mM L-glutamine.

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O en CM 0.33* 0.34* 0.60* 0.65* 0.50* 0.49* 0.61* 0.62* • · O» Vlr- Γ-Ο O • « — CM CM* 0.23* 0.27* 0.31· 0.48* « · w* 00en © © 0.46* 0.53* m n• ·en ** o o 0.67 0.60 CM enxr 1.1 2.1 20 t~~ r- μ o— m w-j 5j- o o © ô © o \e r- v> Vl tS Xf©’ © ©' O> 00 V» —O Vl v> Ooooo — N t'· V) CS \ô© © © 0.50 0.45 P X d Z I* P ) Cd1Ï~M* î Q d xw x" c-O-s Q rfy d x, X* « » c Q î i-G^ QiP d Z X* Exemple 147-ac Exemple 31 Exemple 147-c Example 147-r Example 147-f Example46 205 011455 6.4 9.1 6.5* 13* » · νί rn « > en 0.59* 0.60* ! 4.8 6.4 • O\ r-’ 3.1* 3.8* « * 0.69* 0.69* 6.1 7.7 « «n rY • ♦ en en « » cs »n 1 0.74* 0.64* O\ * * Ό OO VÎ TT * · \Q —wS en # « CS en CS — 0.33* 0.39* 13* » » en en « « CS O 0.43* 0.45* 1 >20 >20 I cs en « \© r* r- « * 2 s- ♦ » en esr* Όo o ♦ » » (S CS S" CS ♦ · O 00 CS — 0.84* 0.91* es -s* 4.8* * CS en ♦ » 2 2 0.62* 0.70* 5.6 11 «S Όes es 4.5 20 wn r*es’ 0.480 0.497 <s Ώ BO s o -S il O S 0.25 0.90 Y^ Y XZ Ap-O l Lr X r Yf SX £ Yô'Y;]..... Ç-Cr ;T oo rs — CL c CO X □J Example 20 Example 36 Example 19 Example 147-ab 206 üll455 0.33* 0.35* « * 00 0\ ♦ # ♦ r*· \o oci ci ri 0.69* 0.58* 0.28* 0.36* ! 0.35» 0.46* 6.4* 8.2* 1 ♦ ♦ # r> oo ri ri ci -1 0.66* 0.66* 0.33* 0.44* i 0.40* 0.45* « · ΓΊ <O\O ♦ · ♦ (*i r* in 0.34* 0.36* 0.34* 0.42* 0.16* 0.29* « es r*‘ » » rn rj 0.23* 0.25* 0.18* 0.30* 0.32* 0.35* 5.4* 4.7* ♦ * ♦ r» rn 0.38* 0.52* 0.38* 0.46* 1 1 « « —* 00 ο d 13* 7.7* * * · es oo <nri — ci 0.44* 0.34* 0.43* 0.44* 0.47* 0.55* 14* 11* ♦ · · ’f N cri ri es 0.69* 0.94* 0.50* 0.57* 0.34* 0.35* • · *© \d « » * O O Ori rî ri 0.47* 0.42* 0.37* 0.35* TT 00 d d 5.2 64 o\ r~ «ri 0.51 0.67 0.690(n-= 1) o O 5 D © S r> «noo m cd d d 0.72 1.0 0- T) S'rQ -U} d Z, X* SB / f î V as i i"Cy H d af U. O Q H cf Z i- Example 147-y Example 6 Example 37 Example 147-d Example 147-z 207 011455 0.51* 0.46* « * Ό — TT \© O O • * TT TT « » en ττs© r* O O » « en oo Ό r-© o ♦ « oo \qen "sT « · Γ-. O « ♦ PS PS Os oo© © ♦ ♦ P^ Os PS PS ♦ » s© PS’T <n O O « ♦ PS o TT ’T© o ♦ « —; >©tt en • ♦ en oo ΜΊ O Ô • « 00 PS’T s© © © • > © Os’T es’ ♦ ♦ -* Mlr* wno o * » «n —« S© S© © © ♦ ♦ oo en PS PS • « SO V>os r*o o « » os in Os Os© © » « OO Os«PÎ TT ♦ « Os *-oo r-o o • » tt en\© © o » ♦ wn ps en 1.4 ΓΠ V© — tt «nes TT PS o •M 0Q /-η 5? es s-*· — oos ** o OJ <N Os © o — D ** c X© \© —; PS G -G zc J Qfr° J X, x" Q -‘Ά X* s X ï *=< <5 x. X Example 18 Exaniple 45 Example 147-b o en 4> Cl C a X ω Exemple 147-aa 208 18 >20 o O Λ Θ0 00·* *a «A 13 >20 O m r** 14 >20 Ov Os Ό SO „ <=> S2 rt Λ n m Ο Ό 51 >20 m oo«A «A 157 >20 13 >20 m *am <*> 46 >100 \q o TT ** 36 >1000 19.4 27.1 0.31 <A r%q-0 ZX X X 0 zx * X zx H 1 v( zx ? O Z Exantple 4 Exaniple 24 107.446 roscovitinc Oloinoucine 209 011455 80Ό 11 X c* «« ο II ο x 00 ο II ο X 00 ο D © X r* ο ο »η ’Τ π s Γ" — Os π ο CS — c ν> Os ο B © e <= « Os Os B _ ο CS —· e r» -s· r- ο Os n ο e ο O\ CS *“ζ U ο O o X δ-/Λ Y 0-0 / \ ΛΥ ° \ ζ as /.......( I / \ / \ X r**/ θ' —'(. < Ζ-U / 1 \ / νν }} ο X r i _-, sn ο -ο c*> ’ϊΖ J) ‘5. O. ο 5 > 3 eo X 7Γ" ta

Claims (184)

1. 210 CLAIMS What is claimed is:

   1. A compound of the formula

   wherein R is selected from the group consisting of R2, R2NH-, or R3R4N-R5- whereinR2 is selected from the group consisting of C9-C12 alkyl, R6 R6 I I —(C)X—OM and —(<jî)n—T R6 R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)ra-phenyl, wherein m is an integer 0-8; x is an integer 1-8; n isan integer 0-8; Z is selected from the group consisting of phenyl, heterocycle, cycloalkyl, andnaphthanlene; and M is selected from the group consisting of hydrogen, C,-C4 alkyl, —(' and —(C)n*—z wherein each R6' is independently selected from the group consisting ofhydrogen, C3-C8 cycloalkyl, Ct-C4 alkyl, and (CH2)m,-phenyl,wherein m’is an integer 0-8; n’ is an integer 0-8; x’ is an integer1-8; Q is hydrogen or C,-C4 alkyl; and Z’ is selected from thegroup consisting of phenyl, heterocycle, cycloalkyl, andnapthalene; and 10 211 wherein each C9-C12 alkyl or Z is optionally substituted with 1 to 3 substituents, which may be the same or different, and which are selected from the group consisting of D, E, 10 01 1455 R 6" Ç°)b I l —(Ç)x--S-R,fV

   n-r6

   OM* and —(Ç)na Z" R6 II wherein each D is independently selected from the group consisting of trifluoromethyl, trifluoromethoxy, and Ci-C4 alkoxy; eachE is independently selected from the group consisting of Hal, OH, and CrC8 alkyl; b is aninteger 0-2; Z” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, andnaphthalene; each R6” is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, Ci-C4 alkyl, and (CH2)m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8;x” is an integer 1-8; and M’is selected from the group consisting of hydrogen, CrC4 alkyl, Rfi” Γ —(<ρχ“-ΟΟ'FV and —(<y)n--Z" FV wherein each R6’” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8;n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogenor C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, andnapthalene, 15 wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or 212 U I 14 00 R6"" wherein each R6”” is independently selected from thegroup consisting of hydrogen, C3-Cg cycloalkyl, C,-C4alkyl, and (CH2)m....-phenyl, wherein m”” is an integer 0-8;x”” is an integer 1-8; Q” is hydrogen or CrC4 alkyl; eachD’is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; eachE’ is independently selected from the group consisting ofHal, OH, and C,-C8 alkyl; R3 and R4 are selected from the group consisting of hydrogen, C,-C4alkyl and (CH2)y-phenyl, wherein y is an integer 0-8, with the provisothat R3 and R4 not both be hydrogen; R5 is Cj-Cg alkylene; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof,with the proviso that when R2 is the group R6 I -(^)n-2 R6 wherein n is 1 or greater; RI is isopropyl or cyclopentyl; R6 is hydrogen, Cj-C4 alkyl, or(CH2)m-phenyl; and Z is phenyl, heterocycle, or cycloalkyl, that Z is substituted with 1 to 3substituents, which may be the same or different, and which are selected from the groupconsisting of D, —(Çlx^-N-Rg" —(^)χ—OM' and —(ç)n«—2« 20 R6" (°)b I * —(Ç)x“~· S-FÇ Re" R ' •V Re- Re" Re" 213 011455 wherein D, b, R6”, x”, η”, M’, and Z” are as previously defined.
2. 2. A compound according to claim 1 which is

   wherein R is R2, wherein R2 is C9-CI2 alkyl, which may be optionally substituted with 1 to3 substituents, which may be the same or different, and which areselected from the group consisting of D, E, Rs„ (O)b—(<jî)x—s—R6" —(Ç)x“—N—R'' r6“ ?e” —(C)x“—OM* and —(Cjn4*—2" r6" r6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and Cj-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; x” is an integer 1-8; n” is an integer 0-8; Z” is selected from the group consistingof phenyl, heterocycle, cycloalkyl, and naphthalene; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, 214 FL“ 1 —(<pn=—Z"' V fl” Γ —(^)x^OQ'V and wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, CrC4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted withthe groups D’, E’ or R6“‘ R6- wherein each R6”” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 10 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer 1-8; Q” is hydrogen or CrC4 alkyl; eachD’is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and CrC4 alkoxy; eachE’ is independently selected from the group consisting ofHal, OH, and C,-C8 alkyl; 15 RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
3. 3. A compound according to claim 2 wherein R2 is CH-C12 alkyl. 4 A compound according to claim 3 wherein R2 is C12 alkyl. 215 01 1455
4. 5. A compound according to claim 4 which is 2-[trans-(4-aminocyclohexyl)amino]-6-(dodecylamino)-9-cyclopentylpurine dihydrochloride.
5. 6. A compound according to claim 1 which is

   R1 wherein R is R2, wherein R2 is R6 -(C)x-OM R6 10 wherein each R6 is independently selected from the groupconsisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and(CH2)m-phenyl, wherein m is an integer 0-8; x is an integer 1-8;and M is selected from the group consisting of hydrogen, C,-C4alkyl, —(Ç)x--OQRe' and —(Ç)n—ZFV 15 wherein each R6' is independently selected from the groupconsisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and(CH2)m,-phenyl, wherein m’is an integer 0-8; n’ is aninteger 0-8; x’ is an integer 1-8; Q is hydrogen or C,-C4alkyl; and Z’ is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and napthalene; and 216 01 1 455 RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
6. 7. A compound according to claim 6 wherein M is hydrogen.
7. 8. A compound according to claim 6 wherein M is C,-C4 alkyl.
8. 9. A compound according to claim 8 which is 2-[trans-(4-aminocyclohexyl)amino]6-(2-methoxyethylamino)-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-(3-methoxypropylamino)-9-cyclopentylpurine dihydrochloride; or2-[trans-(4-aminocyclohexyl)amino]-6-(4-methoxybutylamino)-9-cyclopentylpurinedihydrochloride
9. 10. A compound according to claim 6 wherein M is the group wherein R6', x’, and Q are as defined in claim 6.
10. 11. A compound according to claim 10 wherein Q is hydrogen.
11. 12. A compound according to claim 11 which is 2-[trans-(4-aminocyclohexyl)- amino]-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine dihydrochloride.
12. 13. A compound according to claim 10 wherein Q is C,-C4 alkyl.
13. 14. A compound according to claim 13 which is 2-[trans-(4-aminocyclohexyl)- amino]-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurine dihydrochloride 217 011455
14. 15. A compound according to claim 6 wherein M is the group R' I -(<f)n!-Z' R6’ wherein R6', n’, and Z’ are as defined in claim 6.
15. 16. A compound according to claim 1 wherein R is R2, wherein R2 is R6 I -((jî)n-z R6 wherein each R6 is independently selected from the group consisting ofhydrogen, C3-C8 cycloalkyl, Ct-C4 alkyl, and (CH2)m-phenyl, wherein m is aninteger 0-8; n is an integer 0-8; and Z is naphthalene, wherein Z may be optionally substituted with 1 to 3 substituents, which may bethe same or different, and which are selected from the group consisting of D, E, r6" I6 (O,b R" 1 —(Ç)x“—-S—R6b —(Ç)x' R5" 1 R6" R” 1 î6 —(<?)x“— OM' and —(Ç)n*— 1 R6" Re" wherein each D is independently selected from the group consisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; eachE is independently selected from the group consisting of Hal, OH, and C,-C8 alkyl; b is aninteger 0-2; each R6” is independently selected from the group consisting of hydrogen, C3-C8 i5 cycloalkyl, C,-C4 alkyl, and (CH2)m.-phenyl, wherein m” is an integer 0-8; x” is an integer 1-8;n” is an integer 0-8; Z” is selected from the group consisting of phenyl, heterocycle, cycloalkyl,and naphthalene; and M’is selected from the group consisting of hydrogen, C,-C4 alkyl, FL" Γ —φη- FV

    and -Z" wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, Ct-C4 alkyl, and (CH2)m--phenyl, wherein m’” is an integer 0-8; n’” is aninteger 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected fromthe group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with thegroups D’, E’ or fie” wherein each R6”” is independently selected from the group consistingof hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..,-phenyl, whereinm”” is an integer 0-8; x”” is an integer 1-8; Q” is hydrogen or C,-C4alkyl; each D’is independently selected from the group consisting of 10 trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independently selected from the group consisting of Hal, OH, and Ci-C8alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
16. 17. A compound according to claim 16 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[(l-napthyl)methylamino]-9-cyclopentylpurine dihydrochloride. 219 011455
17. 18. A compound according to claim 1 wherein R is R2, wherein R2 is Z,wherein Z is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents,which may be the same or different, and which are selected fromthe group consisting of D, E, 10 *6“ (O)b ! •(^)x“—S—Re" R6" r i6 -(Ç)X“- N—Rg“ fV ?6" -(C)x“— OM' and —(C)n“—Z" Re" r6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C1-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; each R6“ is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; x” is an integer 1-8; n” is an integer 0-8; Z” is selected from the group consistingof phenyl, heterocycle, cycloalkyl, and naphthalene; and M’is selected from the groupconsisting of hydrogen, CrC4 alkyl,

    FL"’ r and — (^)n- Re'’ -Z" wherein each R6’” is independently selected from the15 group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; 220 n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted withthe groups D’, E’ or 011455 —(C)x“- OQ" wherein each R6”” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m....-phenyl, wherein m”” is an integer 0-8; 10 x”” is an integer 1-8; Q” is hydrogen or C,-C4 alkyl; each D’is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; eachE’ is independently selected from the group consisting ofHal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
18. 19. A compound according to claim 18 which is 2-[trans-(4-aminocyclohexyl)amino]-6-(phenylamino)-9-cyclopentylpurine dihydrochloride.
19. 20. A compound according to claim 18 wherein Z is substituted with the group D. 221 0114 SS
20. 21. A compound according to claim 20 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurinedihydrochloride.
21. 22. A compound according to claim 18 wherein Z is substituted with the group E. 5
22. 23. A compound according to claim 22 wherein E is Hal.
23. 24. A compound according to claim 23 which is 2-[trans-(4-aminocyclohexyl)amino]-6-(3-fluorophenylamino)-9-cyclopentylpurine dihydrochloride.
24. 25. A compound according to claim 22 wherein E is C,-C8 alkyl.
25. 26. A compound according to claim 25 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine dihydrochloride.
26. 27. A compound according to claim 1 wherein R is R2, R2 is R6 I —(C)n-7. R6 wherein each R6 is independently hydrogen or C3-C8 cycloalkyl, with the proviso that at least one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, 15 222 011455

    —(C)x“—N—R '6 R, '6 R, R, '6 (C)x“-OM' and —(Ç)n"—Z R, wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and CrC4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-C8 alkyl; b is an integer 0-2; each R6“ is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m,-phenyl, wherein m” isan integer 0-8; x” is an integer 1-8; n” is an integer 0-8; Z” is selected from the group consistingof phenyl, heterocycle, cycloalkyl, and naphthalene; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl,

    10 wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected fromthe group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

    223 011455 wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, Q-C* alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or Ci-C4 alkyl or phenyl ; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and CrCg alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
27. 28. A compound according to claim 27 which is (+/-)-2-[trans-(4-aminocyclohexyl)amino]-6-[(a-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurinedihydrochloride.
28. 29. A compound according to claim 1, wherein R is R2,R2 is R6 R6 wherein each R6 is independently selected from the group consisting of hydrogen, ί\-04alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 1-8; and Z isphenyl, wherein Z is substituted with 1 to 3 substituents, which may be the same or different,and which are selected from the group consisting of 011455 221¼ Re" l6 (O)b ! R6" 1 D, —(Ç)x“—S—R6“ —(C)x‘ 1 r6" > Rs“ ?6" —(Ox'-OM' and —(Ç)n11—2" R6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and CrC4 alkoxy; b is an integer 0-2; Z” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6” isindependently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2) m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is aninteger 1-8; and M’is selected from the group consisting of hydrogen, C\-C4 alkyl, FL“ ? —(ρχ^-οσV 10 wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n”’ is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

    OQ" wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer 0- 22S 011455 8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and CrC4 alkoxy; and each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
29. 30. A compound according to claim 29 wherein Z is substituted with the group D.
30. 31. A compound according to claim 30 wherein D is trifluoromethyl.
31. 32. A compound according to claim 31 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurine dihydrochloride or2-[trans-(4-aminocyclohexyl)amino]-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurinedihydrochloride.
32. 33. A compound according to claim 30 wherein D is C,-C4 alkoxy.
33. 34. A compound according to claim 33 which is 2-[trans-(4-aminocyclohexyl)amino]-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurinedihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride; 210 011455 2-[trans-(4-aminocyclohexyl)amino]-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride; 5 2-[trans-(4-aminocyclohexyl)amino]-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride; or 2-[trans-(4-aminocyclohexyl)amino]-6-(4-methoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride.
34. 35. A compound according to claim 1, wherein R is R2, R2 isR6 I (ÿ)n-1 R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C810 cycloalkyl, C,-C4 alkyl, and (CH2)n-phenyl; n is an integer 0-8; and Z is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents, whichmay be the same or different, and which are selected from the groupconsisting of D, E, ,,, (O)b î‘" î6" —(Ç)X—S-R6" —(C)x“—N—Re" Rs" ' k" R" Γ î’· —(C)x“—OM' and —(Ç)n--Z" 1 R.” 0 1 r6" 15 wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E isindependently selected from the group consisting of Hal, OH, and C^Csalkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” isindependently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from thegroup consisting of hydrogen, C,-C4 alkyl, 20 227 17 à 5 s

    r -(^)nïï—2·» fV wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cgcycloalkyl, CrC4 alkyl, and (CH2)m. ..-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted withthe groups D’, E’ or R"’’ I —(Ç)x“—OQ“ R MM6 wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is aninteger 0-8; Q” is hydrogen or C,-C4 alkyl; each D’is independently selected from thegroup consisting of trifluoromethyl, trifluoromethoxy, and CrC4 alkoxy; each E’ isindependently selected from the group consisting of Hal, OH, and Cj-Cg alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
35. 36. A compound according to claim 35 wherein Z is substituted with the group E
36. 37. A compound according to claim 36 wherein E is Hal.
37. 38. A compound according to claim 37 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[(3-iodobenzyl)amino]-9-(2-cyclopentenyl)purine hydrochloride. 22S 01145 δ
38. 39. A compound according to claim 1,wherein R is R2, wherein R2 is Z wherein Z is heterocycle,wherein Z may be optionally substituted with 1 to 3substituents, which may be the same or different, and which are selected fromthe group consisting of D, E, R.. (O)b |6 R " Rfi” I6 1 —(Ç)X“—s—R6" _(Ç)x—n-r6" l r6- r6" R" 1 ?6 —(C)x“—OM’ and —(C)ns-Z" 1 Re" V wherein each D is independently selected ffom the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, and ? —(^)n—Z"V wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, Cj-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, 011455 ΧΆ wherein the groups M’ and Z” may be optionally substituted with the groups D’,E’ or Rs“" I —(C)x“^OQ" I R6"“ wherein each R6”” is independently selected from the group consisting ofhydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m....-phenyl, wherein m”” is an integer 0-8;x”” is an integer 0-8; Q” is hydrogen or C,-C4 alkyl; each D’is independently selected from thegroup consisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ isindependently selected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
39. 40. A compound according to claim 39 wherein Z is piperidine.
40. 41. A compound according to claim 40 wherein Z is substituted with the group D.
41. 42. A compound according to claim 40 wherein Z is substituted with the group E.
42. 43. A compound according to claim 42 wherein E is C,-C8 alkyl.
43. 44. A compound according to claim 43 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-propyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-butyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(allyl)piperidinylamino]-9-cyclopentylpurine. 230 01 1455
44. 45. A compound according to claim 40 wherein Z is substituted with the group FV f* -KK-s-iv wherein R6", x”, and b are defîned as in claim 39.
45. 46. A compound according to claim 45 wherein b is 0.
46. 47. A compound according to claim 46 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(2-thiomethoxyethyl)piperidinylamino]-9-cyclopentylpurine.
47. 48. A compound according to claim 45 wherein b is 1.
48. 49. A compound according to claim 48 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(2-phenylsulfmyl)ethyl)piperidinylamino]-9-cyclopentylpurine
49. 50. A compound according to claim 40 wherein Z is substituted with the group I6" ?6" —(Ç)X—N-R6" Re" wherein R6" and x” are defîned as in claim 39.
50. 51. A compound according to claim 50 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N- 231 011455 dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- 5 aminocyclohexyl)amino]-6-[4-(l-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l -(3-N,N- 10 dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l -(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dibutylaniinoethyl))piperidinylamino]-9- 15 cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(5-N,N- &amp; dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(3- phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- 011455 232 aminocyclohexyl)amino]-6-[4-( 1 -(3-N,N-di-(3- phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-di-(3- phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-di-(3- phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine
51. 52. A compound according to claim 40 wherein Z is substituted with the group —(C)x“—OM* wherein R6", x” and M’ are defined as in claim 39.
52. 53. A compound according to claim 52 wherein M’is hydrogen.
53. 54. A compound according to claim 53 wherein x” is 2.
54. 55. A compound according to claim 54 which is (R,S)-2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurine. 233 01 1 4
55. 56. A compound according to claim 53 wherein x” is 3.
56. 57. A compound according to claim 56 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine.
57. 58. A compound according to claim 53 wherein x” is 4.
58. 59. A compound according to claim 58 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurine.
59. 60. A compound according to claim 53 wherein x” is 5.
60. 61. A compound according to claim 60 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurine.
61. 62. A compound according to claim 53 wherein x” is 6.
62. 63. A compound according to claim 62 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurine.
63. 64. A compound according to claim 52 wherein M’is CrC4 alkyl.
64. 65. A compound according to claim 64 wherein x” is 1.
65. 67. A compound according to claim 64 wherein x” is 2.
66. 68. A compound according to claim 65 wherein x” is 3. ZJH- w ' ' -r U Ο
67. 69. A compound according to claim 68 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3- propoxy)propyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine.
68. 70. A compound according to claim 65 wherein x” is 4.
69. 71. A compound according to claim 70 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4- propoxy)butyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurine.
70. 72. A compound according to claim 65 wherein x” is 5.
71. 73. A compound according to claim 72 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-ethoxypentyl))piperidinylamino]-9'cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(5- propoxypentyl))piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurine.
72. 74. A compound according to claim 65 wherein x” is 6.
73. 75. A compound according to claim 74 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6- propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine; or2-[trans-(4-aminocyclohexyl)amino]- 6-[4-(l-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine. 235 0114 5 ΟΊ
74. 76. A compound according to claim 52 wherein M’is a group of the formula

    Re' wherein R6’”, x’” and Q’ are as defmed in claim 39.
75. 77. A compound according to claim 76 wherein Q’ is hydrogen.
76. 78. A compound according to claim 77 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine.
77. 79. A compound according to claim 76 wherein Q’ is C,-C4 alkyl.
78. 80. A compound according to claim 52 wherein M’is a group of the formula

    wherein R6’”, n’” and Z’” are defined as in claim 39. 81 82 A compound according to claim 80 wherein Z’” is phenyl. A compound according to claim 81 wherein x” is 2. 10 83 A compound according to claim 82 which is 2-[trans-(4- 011455 236 aminocyclohexyl)amino]-6-[4-(l-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurine.
79. 84. A compound according to claim 81 wherein x” is 3.
80. 85. A compound according to claim 84 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(2- phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine.
81. 86. A compound according to claim 81 wherein x” is 4.
82. 87. A compound according to claim 86 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine;2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-(3- phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9- cyclopentylpurine.
83. 88. A compound according to claim 81 wherein x” is 5.
84. 89. A compound according to claim 88 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurine;2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-(2- phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9- cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(5-(4- phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine. 231 011455
85. 90. A compound according to claim 81 wherein x” is 6.
86. 91. A compound according to claim 90 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurine;2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]- 9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(6-(3- phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9- cyclopentylpurine.
87. 92. A compound according to claim 40 wherein Z is substituted with the group Re” I -(Ç)nJ-Z" R6" 10 wherein R6”, n” and Z” are defined as in claim 39.
88. 93. A compound according to claim 92 wherein Z” is phenyl.
89. 94. A compound according to claim 93 wherein η” = 1.
90. 95. A compound according to claim 94 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-benzyl)piperidinylamino]-9-cyclopentylpurine 5 trihydrochloride; (R,S)-2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-benzyl-3- methyl)piperidinylamino]-9-cyclopentylpurine or (+/-)-2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(a-methylbenzyl))piperidinylamino]-9-cyclopentylpurine.
91. 96. A compound according to claim 93 wherein n” = 2. u I l 45b 23S
92. 97. A compound according to claim 96 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurinetrihydrochloride.
93. 98. A compound according to claim 63 wherein Z” is substituted with the group D’. 5 99. A compound according to claim 98 wherein D’is C,-C4 alkoxy.
94. 100. A compound according to claim 99 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3- methoxybenzyl))piperidinylamino]-9-cyclopentylpurine.2-[Trans-(4- 10 . , . aminocyclohexyl)amino]-6-[4-[l-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride
95. 101. A compound according to claim 98 wherein D’is trifluoromethyl.
96. 102. A compound according to claim 101 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurine. ; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-[3,5-bis(trifluoromethyl)benzyl]]piperidinylamino]-9-cyclopentylpurine trihydrochloride;2-[Trans- 20 (4-aminocyclohexyl)amino]-6-[4-[ 1 -(3-trifluoromethylbenzyl)]piperidinylamino]-9- cyclopentylpurine trihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride;
97. 103. A compound according to claim 93 wherein Z” is substituted with the group E’.
98. 104. A compound according to claim 103 wherein E’ is C,-C8 alkyl. 25 23<\
99. 105. A compound according to claim 104 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine or2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine.;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3- 5 methylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride;
100. 106. A compound according to claim 103 wherein E’ is Hal.
101. 107. A compound according to claim 106 which is 2-[trans-(4- I aminocyclohexyl)amino]-6-[4-(l-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2- chlorobenzyl))piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine.;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)ammo]-6-[4-[l-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1-(3,4- 240 difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[ 1 -(3,4- difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride; 2-[Trans-(4- aminocyclohexyl)amino]-6-[4-[l-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(3-chloro-4- methylbenzyl)]piperidinylamino]-9-cyclopentylpurine trihydrochloride
102. 108. A compound according to claim 92 wherein Z” is heterocycle.
103. 109. A compound according to claim 108 wherein Z” is 1,3-benzodioxolyl.
104. 110. A compound according to claim 109 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3,4-methylenedioxybenzyl))piperidinylamino]-9-cyclopentylpurine.
105. 111. A compound according to claim 108 wherein Z” is pyridinyl.
106. 112. A compound according to claim 111 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine;2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine; or 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4- pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine.
107. 113. A compound according to claim 108 wherein Z” is isoxazolyl.
108. 114. A compound according to claim 113 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurine.
109. 115. A compound according to claim 108 wherein Z” is tetrahydrofuranyl. 25
110. 116. A compound according to claim 115 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9- 011455 24« cyclopentylpurine.
111. 117. A compound according to claim 108 wherein Z” is pyrrolidinyl.
112. 118. A compound according to claim 117 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-(l-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine or (R,S)-2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(2-(3 -( 1 -methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine.
113. 119. A compound according to claim 108 wherein Z” is piperidinyl.
114. 120. A compound according to claim 119 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-(l-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine; 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(3-(l-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine; or (R,S)-2-[trans-(4-aminocyclohexyl)amino]-6-[4-( 1 -(3-(1 -methyl)piperidinyl)methyl))piperidinylamino] -9-cyclopentylpurine.
115. 121. A compound according to claim 108 wherein Z” is morpholinyl.
116. 122. A compound according to claim 121 which is 2-[trans-(4-aminocyclohexyl)-amino]-6-[4-(l-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine.
117. 123. A compound according to claim 108 wherein Z” is piperazinyl.
118. 124. A compound according to claim 123 which is 2-[trans-(4-aminocyclohexyl)- amino]-6-[4-( 1 -(2-( 1 -(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine.
119. 125. A compound according to claim 108 wherein Z” is benzimidazolinyl.
120. 126. A compound according to claim 125 which is 2-[trans-(4- aminocyclohexyl)amino]-6-[4-(l-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine. » \J 242
121. 127. A compound according to claim 108 wherein Z” is thiazolinyl.
122. 128. A compound according to claim 127 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine. 5
123. 129. A compound according to claim 108 wherein Z” is thiopheneyl.
124. 130. A compound according to claim 129 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine.
125. 131. A compound according to claim 92 wherein Z” is cycloalkyl. 10
126. 132. A compound according to claim 131 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[4-(l-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurine; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(l-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine trihydrochloride
127. 133. A compound according to claim 39 wherein Z is pyrrolidine. 15
128. 134. A compound according to claim 133 wherein Z is substituted with the group FL" I6 —(^)n=-Z» V wherein R6", n” and Z” are as defïned in claim 39.
129. 135. A compound according to claim 134 wherein Z” phenyl.
130. 136. A compound according to claim 135 which is (R)-2-[trans-(4- 243 011455 aminocyclohexyl)amino]-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine or (S)-2-[trans-(4-aminocyclohexyl)amino]-6-[3-(l-benzyl)pyrrolidinylamino]-9-cyclopentylpurine.
131. 137. A compound according to claim 1 .wherein R is R2, R2 is R6 I (<pn- R6 wherein each R6 is independently hydrogen or C3-C8 cycloalkyl, with the proviso that atleast one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is heterocycle, wherein Z may be optionally substituted with 1 to 3 substituents, which may bethe same or different, and which are selected from the group consisting of D, E, R „ (O)b 1 * R Y* I6 1 —(Ç)x“—S-R6" —(Ç)x“—N—R6" Y’ Y R" 1 î6 —(C)x^OM' and —(Ç)na—Z" 1 Y Y wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and Q-C,, alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, Cj-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the group consisting of hydrogen, C,-C4 alkyl, 24K

     wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or Cj-C^ alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ andthe groups D’, E’ or Z” may be optionally substituted with

     wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m-..-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and Cj-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and Cj-Cg alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
132. 138. A compound according to claim 1, wherein R is R2, R2 is R6

     wherein each R6 is independently selected from the group consisting of hydrogen, C\-C4 15 245 011455 alkyl, and (CH2)n.-phenyl, wherein n’ is an integer 0-8; n is an integer 1-8; and Z is heterocycle, wherein Z is substituted with 1 to 3 substituents, which may be the same or different,and which are selected from the group consisting of (O)b (Ç)x°—S—R6" R, r6'· ? .(Qx*—n_R6« r6- Rc ?e- —(C)x^OM' and —(Ç)n“—2" R6“ r6- fV wherein each D is independently selected from the group consisting of trifluoromethyl,5 trifluoromethoxy, and Cj-C4 alkoxy; b is an integer 0-2; Z” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independentlyselected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2) m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’isselected from the group consisting 10 of hydrogen, CrC4 alkyl, R.’" Γ and —(Ç)n'~Z"' ϊγ wherein each R6’” is independently selected from the group consisting of hydrogen, C3- C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or 15 W 24é> —(0)χ““-00' wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m...-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
133. 139. A compound according to claim 138 wherein Z is substituted with the group D.
134. 140. A compound according to claim 139 wherein D is CrC4 alkoxy. 10
135. 141. A compound according to claim 140 which is 2-[trans-(4-aminocyclohexyl)amino]-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurinedihydrochloride
136. 142. A compound according to claim 1,wherein is R2, R2 is R6 R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)n-phenyl; n is an integer 0-8; and Z is heterocycle, 15 011455 24Ί wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, Fe" (O)b r6u -(Ç)x“—S~ R6"R6" —(Ç)x“~N—R6" ?6" -(C)x“—OM' and —(Ç)n-—Z" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m.,-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, F —(ipx^OQ'Re" FL" Γ and —((pn'-ï—Z" FV wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, 15 wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or R““ I —(<p)x“—OQ" 248 w 0 j wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, Cj-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alky or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independently 5 selected from the group consisting of Hal, OH, and C)-C8 alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
137. 143. A compound according to claim 1, wherein R is R2,R2 is Z,wherein Z is cycloalkyl, 0 wherein Z may be optionally substituted with 1 to 3 substituents, which may bethe same or different, and which are selected from the group consisting of D, E, n. (O)b 1 * ?6 16 —(Ç)x—S—R6" —(Ç)X—N-R6“ 1 R "n6 r6" R" 1 r6 —(C)x“— OM' and —(Ç)n4—Z" 1 r6" r6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Ct-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m,-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the group 011455 2W3 consisting of hydrogen, C,-C4 alkyl, —(Qx--OQ' and —(<^)n—Z" IV >V wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, Ci-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or Ο,-Ο4 alkyl; and Z’” is selected from the group $ consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     R —(C)x^-OQ" UN 6 wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C[-C4 alkyl or phenyl ; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
138. 144. A compound according to claim 143 wherein Z is substituted with the group E.
139. 145. A compound according to claim 144 wherein E is OH.
140. 146. A compound according to claim 145 which is tran-2-[trans-(4-aminocyclohexyl)- amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine dihydrochloride or cis-2-[trans- 250 01145S (4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine dihydrochloride.
141. 147. A compound according to claim 143 wherein Z is substituted with the group r6“ I6 —(Ç)x*—OM'Re" wherein R6", x”, and M’ are as defined in claim 143.
142. 148. A compound according to claim 147 wherein M’is hydrogen.
143. 149. A compound according to claim 148 which is (R,S)-2-[trans-(4-aminocyclohexyl)amino]-6-[(l-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurinedihydrochloride.
144. 150. A compound according to claim 1, wherein R is R2,RS is R6 I —(Ç)n-2 R6 wherein each R6 is independently hydrogen or C3-Cg cycloalkyl, with the proviso that atleast one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is cycloalkyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be the same or different, and which are selected ffom the group consisting of D, E, 251 (O)b I -(Ç)x“—S—R6nR6" R " Re“ I6 |6 -(C)x“—N—R6" 011455 Re- Re" -(C)x“-OM‘ and —(Ç)n*—Z" R6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and CrC8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, FV“ ? —(px^OQ'IV V Γ and —(Ç)n^—2" V wherein each R6’” is independently selected from the10 group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m,..-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, 15 wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or 252

     011455 wherein each R6”” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4alkyl, and (CH2)m ...-phenyl, wherein m”” is an integer 0-8;x”” is an integer 0-8; Q” is hydrogen or C,-C4 alkyl orphenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4alkoxy; each E’ is independently selected from the groupconsisting of Hal, OH, and C,-C8 alkyl; and 10 RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
145. 151. A compound according to claim 1, wherein R is R2,R2 is R6 (Ç)n-Z R6 wherein each R6 is independently selected from the group consisting of hydrogen, C,-C.alkyl, and (CH2)n.-phenyl, wherein n’ is an integer 0-8; n is an integer 1-8; and Z is cycloalkyl, wherein Z is substituted with 1 to 3 substituents, which may be the same or different,and which are selected from the group consisting of V P)bi *

     15 011455 253 wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; b is an integer 0-2; Z” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independentlyselected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’isselected from the group consisting of hydrogen, C3-C4 alkyl,

     (Ç)n—Z01 wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and Cj-C,, alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl and isopropyl,and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
146. 152. A compound according to claim 151 wherein Z is substituted with the group 011455 25«+ —(C)x“—OM' wherein R6", χ”, and Μ’ are as defined in claim 146.
147. 153. A compound according to claim 152 wherein M’is hydrogen.
148. 154. A compound according to claim 153 which is 2-[trans-(4-aminocyclohexyl)-amino]-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurine dihydrochloride.
149. 155. A compound according to claim 1,wherein R is R2,R2 is R6 I -(γ)η-Z R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)„-phenyl; n is an integer 0-8; and Z is cycloalkyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, r6" I6 (O)b T R « R " i* T —(Ç)x“— S-Re" —(C)x*— N—R6" 1 r6·' > R6- R6" 1 r6" I —(Ç)x“- —OM* and —(C)n^—Z" r6b R6" 10 011455 255 wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, FU* r —(^)x“-OQ'FV FU' I6 and —(C)n-—z"' Re” wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     OQ" r6 H wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 1-8; x”” is an integer0-8; Q” is hydrogen or CrC4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and CrC8 alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
150. 156. A compound according to claim 1, wherein R is R2 NH-, whereinR2 is C9-C,2 alkyl, which may be optionally substituted with 1 to 3 substituents, which may be the same or different, and which are selected from the group consisting of D, E, R6" (O)b ιβ I —(^)x“— S-Rfi” —(Ç)x—N-R R6" R6- r6" *6" ’(C)x“—-OM' and —(C)n-—Z" r6° r6" 011455 wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C!-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C^Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C]-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, FL- Rb“ r r —(<px“—OQ' and —(<jî)n=—Z" FV Re" wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, CrC4 alkyl,and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8;Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl,heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or —(C)x“—OQ” 251 wherein each R6”” is independently selected from the group consisting of hydrogen, C3- C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer 0-8; Q” is hydrogen or C,-C4 alkyl; each D’is independently selected from the group consisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independently selected from 5 the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof. 011455
151. 157. A compound according to claim 1, wherein R is R2NH-, wherein R2 isR6 I -(Cjï)x—OM R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; x is an integer 1-8; andM is selected from the group consisting of hydrogen, C,-C4 alkyl, Re* l6 Re' and —(^)n'—Z Re’ wherein each R6' is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m.-phenyl, wherein m’is an integer 0-8; n’ is an integer 0-8; x’ is an integer 1-8; Q is hydrogen or C,-C4 alkyl; and Z’ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl and isopropyl,and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof. 25® 011455
152. 158. A compound according to claim 1, wherein R is R2NH-, wherein R2 is

     wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, Q-C4 alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 0-8; andZ is naphthalene, wherein Z may be optionally substituted with 1 to 3 substituents, which may be the same ordifferent, and which are selected from the group consisting of D, E,

     '6 R, —(Ο)χ^-ΟΜ' and —(Ç)n*—Z" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C3-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, and

     V 011455 2S=1 wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, 10 wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ orFt,“" I —(Ç)x“—OQ" R6" wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C3-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and CrC4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-Cg alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
153. 159. A compound according to claim 1, wherein R is R2NH-, wherein R2 is Z,wherein Z is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, Rg" I6 (O)b T R" 1 —(C)X—s-r6u —(Ç)x-- 1 Re" » Ra" Rg" 1 Re —(Ç)x^- OM* and —(Ç)n“—Z 1 R6° r6" 260 01145b wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and CrC8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, CrC4 alkyl, —(Qx“-OQ and —(Ç)n—Z" wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, 15 wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or R " I —(Ç)x“~OQBR6" wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C[-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyland isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
154. 160. A compound according to claim 159 wherein Z is substituted with the group E. 20
155. 161. A compound according to claim 160 wherein E is Hal. 10 011455 261
156. 162. A compound according to claim 161 which is 2-[trans-(4-aminocyclohexyl)-amino]-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino] -6-(2-chlorophenylhydrazino)-9-cyclopentylpurine dihydrochloride; 2-[trans-(4-aminocyclohexyl)amino]-6-[-2-fluorophenylhydrazino]-9-cyclopentylpurinedihydrochloride; or 2-[trans-(4-aminocyclohexyl)amino]-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine dihydrochloride
157. 163. A compound according to claim 1, wherein R is R2NH-, wherein R2 isR6 I -(pn-z R6 wherein each R6 is independently hydrogen or C3-C8 cycloalkyl, with the proviso that atleast one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R," (.0)b I ♦ -(Ç)X“—S—R6" R6" r6'· R6" R6h —(C)x“— OM' and —(Ç)na—Z" Rs“ R6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, 15 262 Γ I —(C)x“—OQ' and — (<^)η—Ζ“ V V wherein each R6’” is independently selected ffom the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or CrC4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     R N 6 OQ" wherein each R6”” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)ra ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C[-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
158. 164. A compound according to claim 1, wherein R is R2NH-, wherein R2 is R6 I -(^)n-2 R6 wherein each R6 is independently selected from the group consisting of hydrogen, C,-C4alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 1-8; and Z is phenyl, wherein Z is substituted with 1 to 3 substituents, which may be the same or different,and which are selected from the group consisting of 263 01145b Γ D, —(C)x-— S— R6° ? -(Ç): r6u FjV N-Re" FÇ FÇ —(C)x“—OM1 and—(ÇJrf1—2” FV wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6”is independently selected from thegroup consisting of hydrogen, C3-Cg cycloalkyl, CrC4 alkyl, and (CH2) m..-pheny, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, —(C)x^-OQ' and —(Ç)n—Z” Re” V wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or FL'“ I —(C)x“—OQ" I r6"’ wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-Cg alkyl; and 26 Η- 0Π455 RI is selected from the group consisting of cyclopentyl and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
159. 165. A compound according to claim l,wherein R is R2NH-, wherein R2 is R6 I —(<jî)n-z R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C,-C4 alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 0-8; andZ is phenyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R6" —(Ç)x“ R6" (O)b R? 1 I6 S-Rs” —(Ç)x' ) 1 Re" -(C)x11—OM‘ and —(C)n*—Z” I R.· R6" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, 15 26¾ 011455

     15

     ;)x“—OQ' and —I —Z"' wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and Cj-C8 alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
160. 166. A compound according to claim 1,wherein R is R2NH-, wherein R2 is Z wherein Z is heterocycle, optionally substituted with 1 to 3 substituents, whichmay be the same or different, and which are selected from the group consisting of D, E, —(Ç)x—S—Re"

     —(C)x^OM' and —(C)n«—Z" 26b wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, r F —(C)x—OQ' and —(^)n—Z" wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cgcycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or N· —(C)x“~OQ" I r6- wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, Q-C^ alkyl, and (CH2)m ....-phenyl, whereinm”” is an integer 0-8; x”” is an integer 0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’isindependently selected from the group consisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independently selected from the group consisting of Hal, OH, and C,-C8alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, 20 and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
161. 167. A compound according to claim 1, wherein R is R2NH-, wherein R2 is 26^ 01Ί 455 R6 I -(Ç)n-2 R6 wherein each R6 is independently hydrogen or C3-C8 cycloalkyl, with the proviso that atleast one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is heterocycle, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R" Iw 6 * * * an —(Ç)X^R6" (O)b t -s-R6" 9 R" I6 —(C)x' r6* R" I R." 1 —(Ç)x“- OM‘ and (Ç)n^— 1 R6" R6" R " I -N-Re· 10 wherein each D is independently selected from the group consisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consisting of Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, Ct-C4 alkyl, •V 'V' and —(Ç)n—2"' wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0- 8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, 268 R, ‘6 011455 wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C,-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
162. 168. A compound according to claim 1, wherein R is R2NH-, wherein R2 is R6 R6 wherein each R6 is independently selected from the group consisting of hydrogen, C,-C4alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 1-8; and Z is heterocycle, wherein Z is substituted with 1 to 3 substituents, which may be the same or different,and which are selected from the group consisting of

     D, — (Ç)x— S-R6" 2Μ 011455 wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C[-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6”is independently selected from thegroup consisting of hydrogen, C3-Cg cycloalkyl, Cj-C4 alkyl, and (CH2)m..-pheny, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, CrC4 alkyl,

     wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C[-C4 alkyl, and (CH2)m..-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or CrC4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or Cj-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and Cj-Cg alkyl; and RI is selected from the group consisting of cyclopentyl, and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof. 20 270 011455 a
163. 169. A compound according to claim 1, wherein R is R2NH-, wherein R2 is R6 -«jî)n-z R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, CrC4 alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 0-8; andZ is heterocycle, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R(O)bI * —(ψ)χ-—S—R6'

     —(C)x^-OM' and —(Ç)ns—Z" wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and CrC4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, 271 01145b FL" Γ -(<ρχ""-οα Rs" FL" r and — (<pnï v -z- wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or —(C)x“-OQnR/" wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integerO-8; Q” is hydrogen or C,-C4 alky or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
164. 170. A compound according to claim 1, wherein R is R2NH-, wherein R2 is Z, wherein Z is cycloalkyl, 272. wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R" I6 —(Ç)X-r6" (O)b —s-r6·· 1 H " R " 1' 1 —(Ç)x—N-R6"Ré’ R" 1 R6" 1 —(Ç)X- —OM’ and - —(Ç)n^-Z" 1 r6- Rs“ wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and Q-C, alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, CrC4 alkyl, and (CH2)m..-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, C,-C4 alkyl, F f —(C)x^-OQ' and —(<y)n=—Z" V v wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or Cj-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or un OQ"

     6 273 011455 wherein each R6”” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or Cj-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and CrC4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-Cg alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
165. 171. A compound according to claiml, wherein R is R2NH-, wherein R2 is R6

     R6 wherein each R6 is independently hydrogen or C3-C8 cycloalkyl, with the proviso that atleast one of R6 is C3-C8 cycloalkyl; n is an integer 1-8; and Z is cycloalkyl, wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, R·· (O)b 1 ' R " R " 1 1 θ -(Ç)xæ- S—R6" —(Ç)X—N-R6" V V f6 î6" (CJx^-OM1 and 1 —(Ç)n8—Z” R6O V U I I H J J 27H- wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from the 5 group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m.-phenyl, wherein m” isan integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, CrC4 alkyl,

     wherein each R6’” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 10 0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the group consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or

     wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, CrC4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer 0-8; Q” is hydrogen or Cj-C,, alky or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and Cj-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and CrC8 alkyl; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl andisopropyl, 20 and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
166. 172. A compound according to claim 1,wherein R is R2NH-, wherein R2 is 011455 275 Λ « R6 I -(<jî)n-ζ R6 wherein each R6 is independently selected from the group consisting of hydrogen, C[-C4alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 1-8; and Z is cycloalkyl, wherein Z is substituted with 1 to 3 substituents, which may be the same or different, and whichare selected from the group consisting of D, — (O)bI (Ç)x“—S—R6" D « R l‘ I6 -(C)x·1—N-R6" «6* —(C)x*1—OM' and —(CJn5—Z" R6· R= wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and Cj-Cg alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthalene; each R6”is independently selected from thegroup consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m..-pheny, wherein m” is 10 an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the groupconsisting of hydrogen, Cj-C4 alkyl, r i —(C)x“—OQ' and —(Ç)n'°—Z"' V wherein each R6’” is independently selected from the group consisting of hydrogen, C3- Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer 0-8; x’” is an integer 1-8; Q’ is hydrogen or CrC4 alkyl; and Z’” is selected from the group 15 consisting of phenyl, heterocycle, cycloalkyl, and napthalene, wherein the groups M’ and Z” may be optionally substituted with the groups D’, E’ or 27G

     —( R6- wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m ....-phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or C^-C^ alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is selected from the group consisting of cyclopentyl and isopropyl,and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
167. 173. A compound according to claim 1, wherein R is R2NH-, wherein R2 isR6 I -(^)n-Z R6 wherein each R6 is independently selected from the group consisting of hydrogen, C3-C8cycloalkyl, C(-C4 alkyl, and (CH2)m-phenyl, wherein m is an integer 0-8; n is an integer 0-8; andZ is cycloalkyl wherein Z may be optionally substituted with 1 to 3 substituents, which may be thesame or different, and which are selected from the group consisting of D, E, -((px‘ FV (O)b T -s-R6" R6" R6" —((ρ)χ^-ΟΜ' and —(<jî)n*—Z” wherein each D is independently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C,-C4 alkoxy; each E is independently selected from the group consistingof Hal, OH, and C,-C8 alkyl; b is an integer 0-2; Z” is selected from the group consisting ofphenyl, 15 011455 271 heterocycle, cycloalkyl, and naphthalene; each R6” is independently selected from the group ♦ consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m--phenyl, wherein m” is an integer 0-8; n” is an integer 0-8; x” is an integer 1-8; and M’is selected from the group consisting of hydrogen, Ci-C4 alkyl,

     FL” Γ Z" V wherein each R6’” is independently selected from the group consisting of hydrogen, C3-Cg cycloalkyl, C,-C4 alkyl, and (CH2)m...-phenyl, wherein m’” is an integer 0-8; n’” is an integer0-8; x’” is an integer 1-8; Q’ is hydrogen or C,-C4 alkyl; and Z’” is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and napthalene,

     wherein the groups M’ and Z” may be optionally substituted with the groupe D’, E’ or P M« R6-· wherein each R6”” is independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C,-C4 alkyl, and (CH2)m--phenyl, wherein m”” is an integer 0-8; x”” is an integer0-8; Q” is hydrogen or Cj-C4 alkyl or phenyl; each D’is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C,-C4 alkoxy; each E’ is independentlyselected from the group consisting of Hal, OH, and C,-C8 alkyl; and RI is cyclopentenyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
168. 174. A compound according to claim 1, wherein R is R3R4N-R5- wherein R3 and R4 are selected from the group consisting of hydrogen, C,-C4 alkyl and (CH2)n- phenyl, wherein n is an integer 0-8, with the proviso that R3 and R4 not both be hydrogen; 011455 27½ R5 is C,-C8 alkylene; and RI is selected from the group consisting of cyclopentyl, cyclopentenyl and isopropyl, and the pharmaceutically acceptable salts, optical isomers, and hydrates thereof.
169. 175. A compound according to claim 174 which is 2-[trans-(4-aminocyclohexyl)-amino]-6-[(2-N,N-diethylamino)ethylamino]-9-cyclopentylpurine trihydrochloride; 2-[trans-(4- 5 aminocyclohexyl)amino]-6-[(3-N,N-diethylamino)propylamino]-9-cyclopentylpurine trihydrochloride; or ]2-[trans-(4-aminocyclohexyl)amino]-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine trihydrochloride.
170. 176. A compound according to claim 1 for use in a method of making a médicamentfor use in a method of treating a hyperproliferative disorder in a patient.
171. 177, The compound according to claim 176, wherein the hyperproliferative disorder is a neoplastic disease State.
172. 178. The compound according to claim 177, wherein the neoplastic disease State isselected from leukemia, carcinoma, adenocarcinoma, sarcoma, melanoma or a mixed type ofneoplasm.
173. 179. The compound according to claim 178, wherein the leukemia is selected from acute lympholastic leukemia, chronic leukemia, acute myeloblastic leukemia and chronicmylocytic leukemia.
174. 180. The compound according to claim 178, wherein the carcinoma is selected fromthose of the cervis, breast, prostate, esophagus, stomach, small intestines, colon, ovary and 20 lungs.
175. 181. The compound according to claim 178, wherein the adenocarcinoma is selectedfrom those of the cervis, breast, prostate, esophagus, stomach, small intestines, colon, ovary andlungs. 213 01 1 455 * 182. The compound according to claim 178, wherein the sarcoma is selected from oesteroma, osteosarcoma, lipoma, lipsarcoma, hemangiomas and hemangiosarcoma.
176. 183. The compound according to claim 178, wherein the melanoma is selected fromamelanotic melanoma and melanotic melanoma.
177. 184. The compound according to claim 178, wherein the mixed type of neoplasm isselected from carcinosarcoma, lymphoid tissue type, folicullar réticulum, cell sarcoma andHodgkins Disease.
178. 185. A compound according to claim 1 for use in a method of making a médicamentfor use in a method of protecting neuronal cells from apoptosis. 1θ 186. A compound according to claim 1 for use in a method of making a médicament for use in a method of protecting neuronal cells from damage induced by antineoplastic agents. /
179. 187. A composition comprising an assayable amount of a compound of claim 1 inadmixture or otherwise in association with an inert carrier.
180. 188. A pharmaceutical composition comprising an effective cdk-2 inhibiting amountof a compound of claim 1 in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.
181. 189. The compound according to claim 1, wherein Z is a heterocycle substituted with -QiRA-Z”
182. 190. The compoud according to claim 189, wherein wherein Z” is naphthalene.
183. 191. The compound according to claim 190, wherein wherein n” is 1. 20 U I I H □ J 280
184. 192. The compound according to claim 190, wherein the compound is; 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurinetrihydrochloride;2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[l-(l-naphthyl)methyl]-piperidinylamino]-9-cyclopentylpurine trihydrochloride.